Method of improving breast health management

Abstract

Disclosed herein are methods of treating breast cancer in a subject. Preferably, these methods include presenting a plurality of mammograms from one or more breasts of a subject over a time period, performing an algorithm-based analysis of the mammograms, the algorithm predicting a risk of interval or occult mammographic cancers, and administering an estrogen receptor modulating pharmaceutical to the subject based on a breast cancer risk score generated from the algorithm-based analysis.

Description

METHOD OF IMPROVING BREAST HEALTH MANAGEMENTCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims benefit of priority under 35 U.S.C. § 119(e) of U.S. Provisional Patent Application No. 63 / 716.061 filed on November 4, 2024. The disclosure of the prior application is considered part of and is herein incorporated by reference in the disclosure of this application in its entirety.BACKGROUND

[0002] Mammography screening techniques are useful in reducing mortality from breast cancer patients. However, breast cancer is still the most common cause of cancer death in women.

[0003] Effective diagnostic and treatment methods for breast cancers, particularly interval and occult cancers, have yet to be developed. There is currently no automated tool that measures density of the processed images that accounts for alignment and breast compression as part of interval and occult cancer diagnoses.

[0004] A method is needed to process and interpret processed images, including precisely measuring and scoring data, to monitor treatment response and density change over time for patients to produce a risk score and subsequently provide the necessary' treatment based on the risk score.SUMMARY

[0005] Described herein are methods and systems that facilitate efficient diagnostic reviews of mammography images, regardless of the images’ provenance. The methods and systems described herein allow radiologists and other medical personnel to quickly compare and detect differences between mammograms, for instance mammographic density7, and report their findings within clinically acceptable time frames. The methods and systems described herein provide an improvement for measuring the density change over time since density change has proven to be a reliable and strong proxy for therapy response. The methods and systems described herein provide improved methods for processing breast images for diagnosing, predicting, and monitoring the status or outcome of a breast disorder such as breast cancer, and increase the ability' to detect a breast disorder that is otherwise difficult to detect due to mammographic breast density (MBD) masking.

[0006] In one aspect, the present disclosure provides a method of reducing a risk of a breast cancer in a subject in need thereof, the method comprising: presenting a mammogram from one or more breasts of the subject in need thereof; and-1-KTS Docket No. 1 16771-1 29908 (817 WO 1 )subsequently administering a therapeutically effective amount of an estrogen receptor-modulating pharmaceutical to the subject in need thereof, thereby reducing a risk of a breast cancer in the subject in need thereof.

[0007] In another aspect, the present disclosure provides a method of treating an occult breast cancer in a subject in need thereof, the method comprising: presenting a mammogram from one or more breasts of the subject in need thereof; subsequently administering a therapeutically effective amount of an estrogen receptor-modulating pharmaceutical to the subject in need thereof, thereby treating the occult breast cancer in the subject in need thereof.

[0008] In one aspect, the present disclosure provides a method of treating a breast cancer in a subject in need thereof, the method comprising: presenting a mammogram from one or more breasts of the subject in need thereof; performing an algorithm-based analysis of the mammogram, the algorithm-based analysis producing a breast cancer risk score; determining that the subject in need thereof has a higher breast cancer risk score than a baseline or reference breast cancer risk score; and administering a therapeutically effective amount of an estrogen receptor-modulating pharmaceutical to the subject in need thereof, wherein the breast cancer is treated.

[0009] In one aspect, the present disclosure provides a method of reducing breast density in a subject in need thereof, the method comprising: presenting a mammogram from one or more breasts of the subject in need thereof; subsequently performing an analysis of the mammogram, the analysis determining that a breast density score is higher than a baseline or reference score; and administering a therapeutically effective amount of an estrogen receptor-modulating pharmaceutical to the subject in need thereof.

[0010] In some aspects, the techniques described herein relate to a method of treating breast cancer in a subj ect in need thereof, including: presenting a mammogram from one or more breasts of a subject; performing an algorithm-based analysis of the mammogram, the algorithm-based analysis producing a breast cancer risk score; determining that the subject has a higher breast cancer risk score than a baseline or reference breast cancer risk score; and administering an effective amount of an estrogen receptor-modulating pharmaceutical to the subject, wherein the breast cancer is treated.-2-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0011] In some aspects, the estrogen receptor-modulating pharmaceutical includes (Z)-endoxifen. In some aspects, the subject is concurrently or previously treated with a density -reducing pharmaceutical. In some aspects, the breast cancer is an occult cancer. In some aspects, the mammogram includes a plurality of mammograms. In some aspects, the plurality’ of mammograms includes a first mammogram and a second mammogram. In some aspects, the cancer is an interval cancer. In some aspects, the first and second mammograms are separated by a time interval, wherein the algorithm-based analysis includes analyzing the mammogram to identify a cancer.

[0012] In some aspects, the algorithm-based analysis determines the breast cancer risk score based on an age at screening, cancer incidence rate of a breast region and / or type occurring in a specified population in a given year as a baseline for age risk, a learning model assessment of a breast densify and asymmetry’ of breast densify, and a learning model detection of textures, patterns, and radiomic shapes. In some aspects, the textures, patterns, and radiomic shapes includes masses and calcifications and / or asymmetries of mammographic features.

[0013] In some aspects, the method further includes plotting a risk model resulting from the breast cancer risk score. In some aspects, the algorithm-based analysis includes generating a risk model from a digital breast tomosynthesis. In some aspects, the risk model displays a risk of breast cancer higher than a baseline or reference level. In some aspects, the subject is concurrently or previously treated with a densify reducing pharmaceutical.

[0014] In some aspects, the plurality of mammograms is separated by a time interval of about 2 years. In some aspects, the algorithm-based analysis includes analyzing the first and second mammogram to identify a cancer, and wherein the second mammogram presents a densify reduction when compared to the first mammogram as a baseline.

[0015] In some aspects, treating the cancer includes shrinking a size of a tumor, reducing a level of breast densify, or a combination thereof.

[0016] In some aspects, the techniques described herein relate to a method of reducing breast densify in a subject in need thereof, including; presenting a mammogram from one or more breasts of the subject; performing an analysis of the mammogram, the analysis determining that a breast densify score is higher than a baseline or reference score; and administering an effective amount of an estrogen receptor-modulating pharmaceutical to the subject. In some aspects, the breast densify score is reduced by about 5% to 90%.

[0017] In some aspects, the (Z)-endoxifen is formulated as a suspension, a tablet, a capsule, a caplet, a liquid, or a gel. In some aspects, the (Z)-endoxifen is formulated as an enteric formulation. In some aspects, the (Z)-endoxifen is formulated as an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, or a delayed-release capsule. In some-3-KTS Docket No. 1 16771-1529908 (817 WO 1 )aspects, the (Z)-endoxifen includes hydroxypropyl methyl cellulose. In some aspects, the (Z)- endoxifen is administered orally.

[0018] In some aspects, the (Z)-endoxifen is administered at an amount of 0.01 mg to 350 mg. In some aspects, the effective amount of (Z)-endoxifen includes 0.5 to 10 mg. In some aspects, the effective amount of (Z)-endoxifen includes 0.5 mg. 1 mg. 1.5 mg, 2 mg, 2.5 mg. 3 mg. 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg. In some aspects, the effective amount of (Z)-endoxifen includes from about 0.01 mg to 200 mg, about 0. 1 mg to 100 mg, about 0. 1 mg to 50 mg, about 0. 1 mg to 20 mg, or about 1 mg to 20 mg of the (Z)-endoxifen. In some aspects, the (Z)-endoxifen is administered at a dosage of 0.05 to 0.5 mg / kg, 0.5 to 1 mg / kg, 1 to 1.5 mg / kg, 1.5 to 2 mg / kg, 2 to 5 mg / kg, 5 to 10 mg / kg, or 10 to 20 mg / kg. In some aspects, the (Z)-endoxifen is administered at a dosage of 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, or 2.0 mg / kg. In some aspects, the effective amount of (Z)- endoxifen is administered daily for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, or greater.

[0019] In some aspects, the techniques described herein relate to a method, wherein the subject is not diagnosed with a breast cancer after about 1 to 5 or more years of treatment.BRIEF DESCRIPTION OF FIGURES

[0020] The features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present disclosure will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the disclosure are utilized, and the accompanying drawings (also “Figure” and “FIG.” herein), of w hich:

[0021] FIG. 1 is a flow chart that illustrates the steps of an exemplary method for the treatment of an interval mammographic cancer;

[0022] FIG. 2 is a graph showing mean tumor volume of MCF7AC1 tumors treated with tamoxifen, letrozole, and (Z)-endoxifen at 25 mg / kg or 75 mg / kg;

[0023] FIG. 3 is a graph showing mean tumor volume of MCF7LR tumors treated with a combination of androstenedione with several treatment compounds including letrozole, exemestane, a combination of exemestane and everolimus, endoxifen, and fulvestrant; and

[0024] FIG. 4 is a set of graphs showing ESRI transcriptional activity for cells treated with (Z)- endoxifen. Cells tested included wild-type cells, L536Q, Y537S, Y537C, Y537N, and D539G.-4-KTS Docket No. 1 16771-1529908 (817 WO 1 )DETAILED DESCRIPTION

[0025] There is a need to prevent breast cancers that occur between two or more screening mammograms. Fifty percent of women in the world have dense breast tissue. Elevated density is a significant independent, modifiable risk factor for developing breast cancer. Elevated breast density lowers detection capability of mammograms, as dense breast tissue appears white on a mammogram, similar to how cancerous tumors appear. This similarity in appearance can obscure the presence of tumors, making it more difficult to detect breast cancer. This masking of tumors leads to a higher likelihood of false negatives, or occult cancers, where cancer is present but not detected. Consequently, this reduces the sensitivity of mammograms and increases the risk of interval cancers, which are cancers that develop between regular screening mammograms. Notification of breast density to patients upon mammographic screening generates high clinical awareness; however, treatment to reduce breast density for patients with high breast density needs to be developed.

[0026] The present disclosure provides methods of treatment for high breast density as well as methods of detecting and treating interval and occult breast cancers. Administration of effective doses of (Z)-endoxifen both reduces breast density while treating cancer that has already identified, preventing pre-cancerous tissue from developing cancer, and treating occult or interval cancers identified during routine mammographic screening.

[0027] The methods of mammographic screening described herein detect occult or interval cancers at a higher rate than other methods of screening.

[0028] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of skill in the art to which this invention belongs. As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated below:

[0029] As used herein and in the claims, the terms ‘‘comprising,” “containing,” “having”, and “including” are inclusive, open-ended and do not exclude additional unrecited elements, compositional components or method steps. Accordingly, the terms “comprising” and “including” encompass the more restrictive terms “consisting of’ and “consisting essentially of’.

[0030] As used herein and in the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to “an agent” includes a plurality of such agents, and reference to “the cell” includes reference to one or more cells (or to a plurality' of cells) and equivalents thereof know n to those skilled in the art, and so forth. When ranges are used herein for physical properties, such as molecular weight, or-5-KTS Docket No. 1 16771-1529908 (817 WO 1 )chemical properties, such as chemical formulas, all combinations and sub-combinations of ranges and specific embodiments therein are intended to be included.

[0031] The term “about” when referring to a number or a numerical range means that the number or numerical range referred to is an approximation within experimental variability (or within statistical experimental error), and thus the number or numerical range, in some instances, will vary up to 10% of the stated number or numerical range. For example, an XRPD peak (e.g., about 5.00° 2-Theta, about 10.00° 2-Theta, about 15.00° 2-Theta) can vary within a range of ±0.1 °2- Theta, ±0.2° 2-Theta, ±0.3 °2-Theta, ±0.4° 2-Theta, or ±0.5° 2-Theta. In some embodiments of XRPD peaks, about means ± 0.5 ° 2-Theta. For example, a temperature (e.g., about 80.0 °C, about 100.0 °C, about 120.0 °C) associated with a feature in a TGA pattern or a DCS thermogram can vary within a range of ±1.0 °C, ±2.0 °C, ±3.0 °C, ±4.0 °C, or ±5.0 °C.

[0032] The term “substantially as shown in” or “substantially the same” when referring, for example, to an XRPD pattern. DSC thermogram, or TGA thermogram, resembles the reference spectrum to a great degree in both the peak locations and peak intensity but is not necessarily identical to those depicted herein, but that falls within the limits of experimental error or deviations when considered by one of ordinary skill in the art. The relative intensities of XRPD peaks can vary, depending upon the particle size, the sample preparation technique, the sample mounting procedure and the particular instrument employed. Moreover, instrument variation and other factors can affect the 2-Theta (20) values. Accordingly, when a specified 2-Theta angle is provided, it is to be understood that the specified two theta angle can vary by the specified value ± 0.5° 2-Theta, such as ± 0.4° 2-Theta, ± 0.3° 2-Theta, ± 0.2° 2-Theta, or ± 0.1° 2-Theta. As used herein, “major peak” can refer to an XRPD peak with a relative intensity greater than 30%, such as greater than 35%. Alternatively, or in addition thereto, “major peak” can refer to an XRPD peak which is among the ten most intense XRPD peaks within an XRPD pattern. Relative intensity7is calculated as a ratio of the peak intensity7of the peak of interest versus the peak intensity of the largest peak in the XRPD pattern.

[0033] It is specifically understood that any numerical value cited herein includes all values from the lower value to the upper value, i.e., all possible combination of numerical values between the lowest value and the highest value enumerated are to be considered to be expressly stated in this application and the endpoint of all ranges are included within the range and independently combinable. For example, if a concentration range or beneficial range is stated as 1% to 50%, it is intended that values such as 2% to 40%, 10% to 30%, or 1% to 3% etc., are expressly enumerated in this specification. It is also to be understood that if a concentration or dose is stated as a specific value such as 1 mg or 10 mg, it is intended that it is intended to include 10% variation.-6-KTS Docket No. 1 16771-1529908 (817 WO 1 )As another example, a stated concentration of 20% is intended to include values ±10%. Yet another example, if a ratio of 1 : 10 to 10: 1 is stated, then it is intended that ratios such as 1 :9 to 9: 1, from 1:8 to 8: 1, from 1 :7 to 7:1, from 1:6 to 6: 1, from 1 :5 to 5: 1, from 1:4 to 4: 1, from 1:3 to 3: 1, from 1 :2 to 2: 1, from 1 : 1 to 2: 1 or from 2:5 to 3:5 etc. are specifically intended. There are only some examples of what is specifically intended. Unless specified otherwise, the values of the constituents or components of the compositions are expressed in weight percent of each ingredient in the component.

[0034] All methods described herein can be performed in a suitable order unless otherwise indicated or otherwise clearly contradicted by context. The use of any and all examples, or exemplary language (e.g., '‘such as” and “the like”) is intended merely to illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as any indicating any non-claimed element as essential to practice of the invention as used herein.

[0035] All methods described herein can be performed in a suitable order unless otherwise indicated or otherwise clearly contradicted by context. The use of any and all examples, or exemplary7language (e.g., “such as” and “the like”) is intended merely to illustrate the invention and does not pose a limitation on the scope of the invention unless otherwise claimed. No language in the specification should be construed as any indicating any non-claimed element as essential to practice of the invention as used herein.

[0036] The term “modulate” or “modulating” or “modulation” refers to an increase or decrease in the amount, quality7, or effect of a particular activity, function or molecule. By way of illustration and not limitation, agonists, partial agonists, inverse agonists, antagonists, and allosteric modulators of a G protein-coupled receptor are modulators of the G protein-coupled receptor.

[0037] The term “selective inhibition” or “selectively inhibit” as referred to a biologically active agent refers to the agent's ability to preferentially reduce the target signaling activity as compared to off-target signaling activity, via direct or interact interaction with the target.

[0038] The term “acceptable” with respect to a formulation, composition or ingredient, as used herein, means having no persistent detrimental effect on the general health of the subject being treated.

[0039] The phrase “pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity7, irritation, allergic response, or other problem or complication, commensurate-7-KTS Docket No. 1 16771-1529908 (817 WO 1 )with a reasonable benefit / risk ratio. In some embodiments, the phrase “pharmaceutically acceptable” refers to a material, such as a carrier or diluent, which does not abrogate the biological activity or properties of the compound, and is relatively nontoxic, i.e., the material is administered to an individual without causing undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.

[0040] The phrase “pharmaceutically acceptable excipient” or “pharmaceutically acceptable carrier” as used herein means a pharmaceutically acceptable material, composition or vehicle, such as a liquid or solid filler, diluent, excipient, solvent or encapsulating material. Each carrier must be “acceptable” in the sense of being compatible with the other ingredients of the formulation and not injurious to the patient. Some examples of materials which can serve as pharmaceutically acceptable carriers include: (1) sugars, such as lactose, glucose and sucrose; (2) starches, such as com starch and potato starch; (3) cellulose, and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose and cellulose acetate; (4) powdered tragacanth; (5) malt; (6) gelatin; (7) talc; (8) excipients, such as cocoa butter and suppository waxes; (9) oils, such as peanut oil, cottonseed oil, safflower oil, sesame oil, olive oil, com oil and soybean oil; (10) glycols, such as propylene glycol; (11) polyols, such as glycerin, sorbitol, mannitol and polyethylene glycol; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering agents, such as magnesium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl alcohol; (20) phosphate buffer solutions; and (21) other non-toxic compatible substances employed in pharmaceutical formulations.

[0041] In some embodiments, the composition described herein is a “pharmaceutical composition” including a combination of at least one active agent (e.g., at least one active pharmaceutical compound or ingredient, API) with a carrier, inert or active (e.g., a phospholipid), making the compositions suitable for diagnostic or therapeutic uses in vitro, in vivo, or ex vivo.

[0042] The term “salt” refers to salts derived from a variety of organic and inorganic counter ions well known in the art, such as organic and inorganic counter ions derived from inorganic or organic acids and bases. The term “pharmaceutically acceptable salt” refers to a form of a therapeutically active agent that consists of a cationic form of the therapeutically active agent in combination with a suitable anion, or in alternative embodiments, an anionic form of the therapeutically active agent in combination with a suitable cation that is physiologically tolerated in a subject (e.g., a mammal, and / or m vivo, ex vivo, in vitro cells, tissues, or organs). Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from -8-KTS Docket No. 1 16771-1529908 (817 WO 1 )which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p- toluenesulfonic acid, salicylic acid, and the like. Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum, and the like. Organic bases from which salts can be derived include, for example, primary', secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like, specifically such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, and ethanolamine. In some embodiments, the pharmaceutically acceptable base addition salt is chosen from ammonium, potassium, sodium, calcium, and magnesium salts. Typically, pharmaceutical salts are more soluble and more rapidly soluble in stomach and intestinal juices than non-ionic species and so are useful in solid dosage forms. Furthermore, because their solubility7often is a function of pH, selective dissolution in one or another part of the digestive tract is possible and this cap ability' can be manipulated as one aspect of delayed and sustained release behaviors. Also, because the salt forming molecule can be in equilibrium with a neutral form, passage through biological membranes can be adjusted.

[0043] For the purposes of this application, the salts of the compounds of the present disclosure are pharmaceutically acceptable for therapeutic uses. However, salts of acids and bases that are non-pharmaceutically acceptable are also useful; for example, in the preparation or purification of a pharmaceutically acceptable compound.

[0044] Examples of anion salts of endoxifen include arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate), pantothenate, phosphate / diphosphate, polygalacuronate. salicylate, stearate, sulfate, tannate, Teoclate, and triethiodide. Examples of cation salts of (Z)-endoxifen selected from the group consisting of benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc, and the like. In some embodiments, the present disclosure provides that embodiments include salts made with acids that are not pharmaceutically acceptable.-9-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0045] In certain embodiments, the term “prevent’’ or “preventing” as related to a disease or disorder may refer to a compound that, in a statistical sample, reduces the occurrence of the disorder or condition in the treated sample relative to an untreated control sample, or delays the onset or reduces the severity of one or more symptoms of the disorder or condition relative to the untreated control sample.

[0046] The term “subject” or “patient” encompasses mammals. Examples of mammals include, but are not limited to, any member of the Mammalian class: humans, non-human primates such as chimpanzees, and other apes and monkey species; farm animals such as cattle, horses, sheep, goats, swine; domestic animals such as rabbits, dogs, and cats; laboratory animals including rodents, such as rats, mice and guinea pigs, and the like. In one aspect, the mammal is a human.

[0047] The term “effective amount” or “therapeutically effective amount” refers to that amount of a compound or salt described herein that is sufficient to effect the intended application including but not limited to disease treatment, prevention or reduction, as defined below. The therapeutically effective amount may vary depending upon the intended application (in vitro or in vivo), or the subject and disease condition being treated, e.g., the weight and age of the subject, the severity of the disease condition, the manner of administration and the like, which can readily be determined by one of ordinary skill in the art. The term can also apply to a dose that can induce a particular response in target cells, e.g.. reduction of proliferation or down regulation of activity of a target protein. The specific dose can vary depending on the particular compounds chosen, the dosing regimen to be followed, whether it is administered in combination with other compounds, timing of administration, the tissue to which it is administered, and the physical delivery system in which it is carried.

[0048] The terms “treat,” “treating” or “treatment,” as used herein, may include alleviating, preventing, abating, or ameliorating a disease or condition symptoms, preventing additional symptoms, ameliorating or preventing the underlying causes of symptoms, inhibiting the disease or condition, e g., arresting the development of the disease or condition, relieving the disease or condition, causing regression of the disease or condition, relieving a condition caused by’ the disease or condition, preventing the disease or condition, or stopping the symptoms of the disease or condition either prophylactically and / or therapeutically. In some embodiments, the terms “treat,” “treating” or “treatment,” may refers to an approach for obtaining beneficial or desired results with respect to a disease, disorder, or medical condition including, but not limited to, a therapeutic benefit and / or a prophylactic benefit. A therapeutic benefit may include the eradication, prevention, or amelioration of the underlying disorder being treated. Also, a therapeutic benefit may be achieved with the eradication or amelioration of one or more of the-10-KTS Docket No. 1 16771-1529908 (817 WO 1 )physiological symptoms associated with the underlying disorder, such as observing an improvement in the subject, notwithstanding that the subject may still be afflicted with the underlying disorder. In certain embodiments, for prophylactic benefit, the compositions are administered to a subject at risk of developing a particular disease, or to a subject reporting one or more of the physiological symptoms of a disease, even though a diagnosis of this disease may not have been made. Treating can include, for example, reducing, delaying, preventing, or alleviating the severity of one or more symptoms of the disease or condition, or it can include reducing the frequency with which symptoms of a disease, defect, disorder, or adverse condition, and the like, are experienced by a patient. Treating can be used herein to refer to a method that results in some level of treatment, prevention, or amelioration of the disease or condition, and can contemplate a range of results directed to that end, including but not restricted to prevention of the condition entirely.

[0049] A ‘“therapeutic effect", as that term is used herein, encompasses a therapeutic benefit and / or a prophylactic benefit. A prophylactic benefit includes preventing, delaying, or eliminating the appearance of a disease or condition, preventing, delaying, or eliminating the onset of symptoms of a disease or condition, slowing, halting, preventing, or reversing the progression of a disease or condition, or any combination thereof.

[0050] As used herein, the terms “active pharmaceutical ingredient” (API), “active ingredient”, “API,” “‘drug,” “active,” “actives” or “therapeutic agent” are used interchangeably to refer to the pharmaceutically active compound(s) in a pharmaceutical composition. This is in contrast to other ingredients in the compositions, such as excipients, which are substantially or completely pharmaceutically inert. A suitable API in accordance with the present disclosure is one where there are or likely are subject compliance issues for treating a certain disease, condition, or disorder. The therapeutic agent as used herein includes the active compounds and their salts, prodrugs, and metabolites. As used herein the term “drug” means a compound intended for use in diagnosis, cure, mitigation, treatment, and / or prevention of disease in man or other animals.

[0051] As used herein, the terms “dose form” or “dosage form” refers to physically discrete unit suitable for unitary dosages for a subject, each unit containing a predetermined quantity of active material calculated to produce the desired therapeutic effect. In some embodiments, the dosage form comprises one or more suitable pharmaceutical excipients. Pharmaceutical compositions may be prepared in a variety of dosage forms suitable for a variety of routes and methods of administration. By way of example only, a pharmaceutical composition may be prepared in a liquid dosage form selected from emulsions, microemulsions, nanoemulsions, solutions, suspensions, syrups, and elixirs; an injectable dosage form; a solid dosage form selected from-11-KTS Docket No. 1 16771-1529908 (817 WO 1 )capsules, tablets, pills, powders, and granules; and a dosage form for topical and / or transdermal administration selected from ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants, and patches.

[0052] As used herein, the terms “unit dose” or “unit dosage” refers to is discrete amount of a pharmaceutical composition comprising a predetermined amount of an active ingredient calculated to produce the desired therapeutic effect. In some embodiments, the unit dose comprises one or more suitable pharmaceutically acceptable excipients. A unit dose a single dose that is capable of being administered to a subject and which can be readily handled and packaged. A “unit dose” is a dose of any therapeutic or active agent administered in one dose / at one time / single route / single point of contact, i.e., one administration event. As used herein, “split dose” refers to (1) dosing regimens in which one or more active agents are administered to a patient at least twice daily; (2) once daily administration of a pharmaceutical composition containing one or more active agent in which a portion of the active agent is formulated for immediate release and a portion of the active agent is formulated for delayed or pulsatile release; and (3) once daily administration of a pharmaceutical composition containing an active agent formulated for controlled or sustained release.

[0053] As used herein, the phrase "a subject in need thereof refers to a subject that suffers from a disease or disorder, has previously suffered from a disease or disorder, experiences a disease or disorder, has previously experienced a disease or disorder, or is at risk of developing a disease or disorder.

[0054] As used herein, "preventive therapy" refers to a therapy that is administered to healthy individuals at increased risk of breast cancer in order to decrease the risk of being diagnosed with breast cancer.

[0055] As used herein, "adjuvant therapy" refers to a therapy that follows a primary therapy of breast cancer and that is administered to patients to decrease the risk of relapsing. Adjuvant systemic therapy in case of breast cancer usually begins soon after primary therapy to delay recurrence, prolong survival or cure a subject.

[0056] As used herein, "neo-adjuvant therapy" refers to a therapy that precedes surgery for breast cancer and is administered to patients in order to decrease the tumor burden.

[0057] As used herein, "breast density masking" refers to a tumor being hidden on a mammogram and not being detected due to the similar appearances of both mammographically dense regions and the tumor, thus, decreasing the sensitivity of mammography.-12-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0058] As used herein, “breast disorder’’ refers to any breast disease, condition or disorder that is accompanied by a change in breast density. For avoidance of doubt, for the purpose of this invention breast disorder includes breast density masking and breast cancer.

[0059] As used herein, “breast cancer” means any malignant tumor of breast cells. Breast cancer may be at any stage of breast cancer, including stages of a pre-cancer, an early-stage cancer, a non-metastatic cancer, a pre-metastatic cancer, a locally advanced cancer, and a metastatic cancer. Breast cancer can be invasive breast cancer or in situ breast cancer. There are several types of breast cancer. Exemplary' breast cancers include, but are not limited to, ductal carcinoma in situ (DCIS), lobular carcinoma in situ (LCIS). invasive (or infiltrating) lobular carcinoma (ILC), invasive (or infiltrating) ductal carcinoma (IDC), microinvasive breast carcinoma (MIC), inflammatory breast cancer, ER-positive (ER+) breast cancer, ER-negative (ER-) breast cancer, HER2+ breast cancer, triple negative breast cancer (TNBC), adenoid cystic (adenocystic) carcinoma, low-grade adenosquamatous carcinoma, medullary carcinoma, mucinous (or colloid) carcinoma, papillary carcinoma, tubular carcinoma, metaplastic carcinoma, or micropapillary carcinoma. A single breast cancer tumor can be a combination of these types or be a mixture of invasive and in situ cancer.

[0060] As used herein, “interval cancer”, refers to a breast cancer or a cancer that is diagnosed in a subject in need thereof after a negative mammogram and before / during a subsequent mammogram. The breast cancer diagnosis may occur due to clinical symptoms arising between screenings or by imaging performed for other reasons during the interval between the negative mammogram and the subsequent mammogram. In some embodiments, the negative mammogram is one or more negative mammograms. In some embodiments, the subsequent mammogram is one or more subsequent mammograms.

[0061] As used herein, “occult cancer” refers to a breast cancer or a cancer that was present at the time of a mammogram of a subject in need thereof, but w as not detected or identified at that time. Upon a subsequent review of the mammogram, signs or features of the breast cancer or the cancer that were previously not recognized become recognized, thereby leading to the subject in need thereof being diagnosed with the breast cancer or the cancer. In some embodiments, the subsequent review is conducted by a panel of radiologists. In some embodiments, the subsequent review is a retrospective analysis after diagnosis of the breast cancer or the cancer as determined by a subsequent mammogram or by one or more clinical symptoms. Occult cancers are distinguished from a cancer that newly develops after the initial screening. In some embodiments, for a method of the present disclosure, the method identifies a breast cancer or a cancer that would otherwise be missed in routine screening, such as a mammogram. In some embodiments, for a -13-KTS Docket No. 1 16771-1529908 (817 WO 1 )method of the present disclosure, the method treats a breast cancer or a cancer that would otherw ise be missed in routine screening, such as a mammogram.

[0062] As used herein, the term “tamoxifen” refers to 2-[4-(l,2-diphenyl-l-butenyl)phenoxy]- N,N-dimethylethanamine, which has two isomeric forms: (Z)-tamoxifen ((Z)-2-[4-(l,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylethanamine) and (E)-tamoxifen ((E)-2-[4-(l,2-diphenyl-l- butenyl)phenoxy]-N,N-dimethylethanamine). Unless otherwise specified, “tamoxifen” refers to a mixture of (E)-tamoxifen and (Z)-tamoxifen. Furthermore, unless otherwise specified, “tamoxifen” refers to the free base (i.e., not a salt) of tamoxifen. Therefore, “tamoxifen” and “tamoxifen free base” are equivalent terms.

[0063] As used herein, the terms “4-hydroxy tamoxifen”, “afimoxifene”, and “4-OHT” used interchangeably refer to 4-l-[4-[2-(dimethylamino)ethoxy]phenyl]-2-phenylbut-l-enyl]phenol, and constitutes an active metabolite of tamoxifen. 4-OHT has two isomeric forms: (Z)-4-OHT and (E)-4-OHT. Unless specified, “4-OHT” refers to a mixture of (E)-4-OHT and (Z)-4-OHT. Furthermore, unless otherwise specified, “4-OHT” refers to the free base (i.e., not a salt) of tamoxifen. Therefore, “4-OHT” and “4-OHT free base” are equivalent terms.

[0064] As used herein, the term “endoxifen” refers to 4-(l-(4-(2-(methylamino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol) (also known as 4-hydroxy -N-desmethyl-tamoxifen or desmethylhydroxytamoxifen). Endoxifen has two isomeric forms: (E)-endoxifen ( (E)-4-(l-(4-(2- (methylamino)ethoxy)phenyl)-2-phenylbut-l-en-l-yl)phenol ) and (Z)-endoxifen ( (Z)-4-(l-(4- (2-(methylamino)ethoxy)phenyl)-2-phenylbut- 1 -en- 1 -yl)phenol). Unless otherwise specified, “endoxifen”, also referred to as “(Z / E)-endoxifen” is a mixture of (Z)-endoxifen and (E)- endoxifen with a Z:E ratio of 1 : 1. By way of example only:“(95:5) endoxifen”, “endoxifen (95:5)”, “endoxifen (Z:E = 95:5)”, “(Z:E = 95:5)”, “endoxifen (Z / E = 95:5)”, and “(Z / E = 95:5)”, are all equivalent terms to denote the endoxifen mixture has aZ:E ratio of 95:5;“(95>5) endoxifen”, “endoxifen (95>5)”, “endoxifen (Z:E = 95>5)”, “(Z:E = 95>5)”, “endoxifen (Z / E = 95>5)”_ and “(Z / E = 95>5)”, are all equivalent terms to denote the endoxifen mixture has a Z:E ratio greater than 95:5;“(95>5) endoxifen”, “endoxifen (95>5)”, “endoxifen (Z:E = 95>5)”, “(Z:E = 95>5)”, “endoxifen (Z / E = 95>5)”, and “(Z / E = 95>5)”, are all equivalent terms to denote the endoxifen mixture has a Z:E ratio greater than or equal to 95:5;“(95<5) endoxifen”, “endoxifen (95<5)”, “endoxifen (Z:E = 95<5)”, “(Z:E = 95<5)”, “endoxifen (Z<E = 95:5)”, and “(Z / E = 95<5)”, are all equivalent terms to denote the endoxifen mixture has a Z:E ratio less than 95:5; and-14-KTS Docket No. 1 16771-1529908 (817 WO 1 )“(95<5) endoxifen”, ‘‘endoxifen (95<5)”, ‘‘endoxifen (Z:E = 95<5)”, ‘‘(Z:E = 95<5)”, “endoxifen (Z<E = 95:5)”, and “(Z / E = 95<5)”, are all equivalent terms to denote the endoxifen mixture has a Z:E ratio less than or equal to 95:5.

[0065] As used herein, unless otherwise specified, “endoxifen” refers to the free base (i.e., not a salt) of endoxifen. Therefore, “endoxifen”, “endoxifen free base”. “(ZZE)-endoxifen”. and “(Z / E)- endoxifen free base” are all equivalent terms. By way of example only:((Z / E)-endoxifen).

[0066] As used herein, the term “(Z)-endoxifen” is isomeric pure (100% of one alkene isomer)(Z)-endoxifen. (Z)-endoxifen is represented by the structure

[0067] As used herein, the term "(E)-endoxifen" is isomeric pure (100% of one alkene isomer)(E)-endoxifen. (E)-endoxifen is represented by the structure

[0068] As used throughout the present disclosure, the wiggly line (' <-) attached to the tetrasubstituted alkene bond of endoxifen or thewritten adjacent to the tetrasubstituted alkene bond of endoxifen denotes a mixture of (E)-endoxifen and (Z)-endoxifen:KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0069] Furthermore, salts of endoxifen, (Z)-endoxifen, and / or (E)-endoxifen are disclosed herein.By way of example only, below are representations of salts of (Z)-endoxifen: the following structures are equivalent representations of (Z)-endoxifen citrate (as referred to asrepresentations of (Z)-endoxifen hydrochloride (also referred to as (Z)-endoxifen hydrochloride):embodiments, the salt is a pharmaceutically acceptable salt.

[0070] The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described.

[0071] Any aspect or embodiment described herein can be combined with any other aspect or embodiment as disclosed herein.KTS Docket No. 1 16771-1529908 (817 WO 1 )Cancer

[0072] DCIS is the most common non-invasive breast cancer. It involves the cells lining the breast ducts. In DCIS, the cells have not spread beyond the walls of the duct into the surrounding breast tissue. About 1 in 5 new breast cancer cases will be DCIS. LCIS is a pre-cancerous neoplasia. It may be indicative of a predisposition for invasive cancer. LCIS only accounts for about 15% of the in situ (ductal or lobular) breast cancers.

[0073] IDC is the most invasive breast cancer. As the name applies, it is a carcinoma that begins in the breast ducts and then invades the surrounding fatty tissue. About 8 to 10 invasive breast cancers are infiltrating ductal carcinomas. IDC is often treated by surgery to excise the cancerous tissue, and by radiation therapy. In addition, chemotherapy combined with endocrine therapy (e.g tamoxifen) and / or immunotherapy (e.g., tratuzumab) is often used to treat IDC.

[0074] ILC is a cancer that develops in the lobules of the breast and has invaded the surrounding tissue. About 1 in 10 invasive breast cancers is an ILC. ILC is treated by surgery to excise the cancerous tissue, and by radiation therapy. In addition, chemotherapy combined with endocrine therapy (e.g tamoxifen) and / or immunotherapy (e.g., tratuzumab) is often used to treat ILC.

[0075] Inflammatory breast cancer accounts for about 1% to 3% of all breast cancers. In inflammatory breast cancer, cancer cells block lymph vessels in the skin resulting in the breast turning red and feeling warm. The affected breast may become larger or firmer, tender, or itchy. Inflammatory breast cancer is treated with chemotherapy, immunotherapy, radiation therapy and in some cases, surgery.

[0076] ER+ breast cancer is characterized by the presence of estrogen receptors (ER) on the surface of the cancerous cells. Growth of ER+ cancer cells is associated with the availability of estrogen (hormone-dependent or hormone sensitive breast cancer). Approximately 80% of all breast cancers are ER+ breast cancers. Treatment options for ER+ breast cancer include endocrine agents such as tamoxifen that block the ER, or aromatase inhibitors that reduce production of estrogen.

[0077] The present disclosure relates to methods and systems for managing breast health, particularly in relation to breast cancer detection and treatment. In some aspects, the disclosure provides a method that involves presenting a series of mammograms from one or more breasts of a subject. This method may facilitate the tracking of changes in breast tissue over time, which can be instrumental in early detection and treatment of breast cancer.

[0078] In some aspects, the method may involve performing an algorithm-based analysis of the mammograms. The algorithm may predict a risk of interval or occult mammographic cancer, providing a valuable tool for assessing the likelihood of breast cancer development in a subject.-17-KTS Docket No. 1 16771-1529908 (817 WO 1 )This predictive capability may enhance the effectiveness of breast cancer screening and potentially lead to earlier intervention and improved patient outcomes.

[0079] In some aspects, the method may further involve administering an estrogen receptor modulating pharmaceutical to the subject based on a breast cancer risk score generated from the algorithm-based analysis. This pharmaceutical intervention may be tailored to the individual's risk profde, potentially improving the efficacy of treatment and reducing the risk of adverse side effects.

[0080] In addition to the method, the present disclosure also encompasses a system for implementing the method. This system may include modules for presenting mammograms, performing the algorithm-based analysis, and administering the estrogen receptor modulating pharmaceutical. The integration of these modules into a single system may streamline the process of breast health management, making it more efficient and user-friendly for both healthcare providers and patients.

[0081] The methods and systems described in the present disclosure may provide a comprehensive approach to breast health management. By combining mammographic analysis with predictive algorithms and targeted pharmaceutical intervention, these methods and systems offer a powerful tool for early detection and treatment of breast cancer.

[0082] In an aspect, the method of managing breast health involves presenting a plurality of mammograms from one or more breasts of a subject wherein a specified time interval occurs between mammograms. This time period may be greater than a year, allowing for a comprehensive view of changes in breast tissue over an extended period. The mammograms may be presented in a chronological order, providing a visual timeline of breast tissue changes. This can be particularly useful in tracking the progression or regression of any abnormalities detected in the breast tissue.

[0083] In some cases, the time period for presenting the mammograms may be about 1, 2, or 3 years. This duration may provide a balance between the frequency of mammogram screenings and the ability to detect meaningful changes in breast tissue. However, the specific duration may be adjusted based on various factors, such as the subject's risk profile, age, family history of breast cancer, and other relevant considerations.

[0084] In other aspects, the method may involve presenting mammograms from multiple breasts of a subject. For instance, if the subject has two breasts, mammograms from both breasts may be presented over the specified time period. This may allow for a comparative analysis between the breasts, potentially aiding in the detection of asymmetrical changes that could be indicative of a breast disorder.-18-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0085] In yet other aspects, the method may involve presenting a series of mammograms from a single breast of a subject. This may be particularly relevant in cases where the subject has had a mastectomy on one breast, or where the focus of the analysis is on a specific breast due to previously detected abnormalities or other reasons.

[0086] In all cases, the presentation of mammograms over a time period greater than a year may provide a valuable tool for tracking changes in breast tissue, potentially aiding in the early detection and treatment of breast disorders such as breast cancer.

[0087] In some aspects, the method involves performing an algorithm-based analysis of the mammograms. This algorithm-based analysis may be designed to predict a risk of an interval mammographic cancer. The algorithm may analyze a series of mammograms, which may include a first and second mammogram from the same breast of a subject. The analysis may involve comparing the first and second mammogram to identify any changes that may indicate the presence of a cancer. For instance, the second mammogram may present a density reduction when compared to the first mammogram as a baseline. This change in density may be indicative of a potential cancerous growth, and may thus contribute to the prediction of a risk of an interval mammographic cancer.

[0088] In some cases, the algorithm determines the breast cancer risk score based on various factors. These factors may include the age of the subject at the time of screening, the cancer incidence rate of a breast region and / or type occurring in a specified population in a given year as a baseline for age risk, a learning model assessment of a breast densify' and asymmetry of breast density, and a learning model detection of textures, patterns, and radiomic shapes. The algorithm may be trained to recognize specific textures, patterns, and radiomic shapes that are associated with different t pes of breast cancer. By analyzing these features in the mammograms, the algorithm may be able to predict the risk of an interval mammographic cancer with a high degree of accuracy.

[0089] In some cases, the algorithm uses an image-derived artificial intelligence (Al) risk model. In an example, the risk model determines a screening mammogram-based future breast cancer risk estimate based on age (e.g., at the time of screening). The Al risk model may include factoring incidence data from population-based cancer registries and mortality tables as a baseline for age risk. The Al risk model may further assess breast density and asymmetry of breast density. The Al risk model may further detect textures, patterns, and radiomic shapes. For example, the Al risk model may detect masses and calcifications as well as asymmetries of these mammographic features.-19-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0090] In other aspects, the algorithm-based analysis may involve the use of machine learning techniques. The algorithm may be trained on a large dataset of mammograms, allowing it to leam the complex patterns and features that are associated with different types of breast cancer. The algorithm may then apply this learned knowledge to new mammograms, enabling it to predict the risk of an interval mammographic cancer based on the features present in the mammograms.

[0091] In yet other aspects, the algorithm-based analysis may be performed in real-time or near real-time. This may allow for immediate feedback to the healthcare provider, potentially enabling prompt intervention if a high risk of an interval mammographic cancer is detected. The real-time or near real-time analysis may also facilitate the tracking of changes in breast tissue over time, providing a dynamic view of the subject's breast health.

[0092] In all cases, the algorithm-based analysis of the mammograms may provide a powerful tool for predicting the risk of an interval mammographic cancer, potentially aiding in the early detection and treatment of this potentially life-threatening condition.

[0093] In some aspects, the method may involve administering an estrogen receptor modulating pharmaceutical to the subject based on a breast cancer risk score generated from the algorithmbased analysis. This pharmaceutical intervention may be tailored to the individual's risk profile, potentially improving the efficacy of treatment and reducing the risk of adverse side effects. The estrogen receptor modulating pharmaceutical may comprise (Z)-endoxifen. a potent derivative of tamoxifen that has been shown to have anti-estrogenic effects in breast cancer cells. However, other estrogen receptor modulating pharmaceuticals may also be used, depending on the specific characteristics of the subject and the type of breast cancer being treated.

[0094] In some cases, the subject may be concurrently or previously treated with a density reducing pharmaceutical. This pharmaceutical may be used to reduce the density of the breast tissue, potentially making it easier to detect any abnormalities in the mammograms. The use of a density reducing pharmaceutical may be particularly beneficial in cases where the subject has high breast density, which can make it more difficult to detect breast cancer using mammography. The density reducing pharmaceutical may be administered in conjunction with the estrogen receptor modulating pharmaceutical, in amounts effective for providing a synergistic effect in the treatment of breast cancer.

[0095] In other aspects, the estrogen receptor modulating pharmaceutical may be administered in a dosage that is determined based on the breast cancer risk score generated from the algorithmbased analysis. The dosage may be adjusted to optimize the therapeutic effect of the pharmaceutical while minimizing any potential side effects. The specific dosage may vary-20-KTS Docket No. 1 16771-1529908 (817 WO 1 )depending on various factors, such as the subject's weight, age, overall health status, and the specific type of estrogen receptor modulating pharmaceutical being used.

[0096] In yet other aspects, the administration of the estrogen receptor modulating pharmaceutical may be monitored over time to assess the effectiveness of the treatment. This may involve regular follow-up appointments with the subject, as well as additional mammograms or other diagnostic tests as deemed appropriate by the healthcare provider. The results of these follow-up assessments may be used to adjust the treatment regimen as needed, potentially improving the overall outcome for the subject.

[0097] In all cases, the administration of an estrogen receptor modulating pharmaceutical based on a breast cancer risk score generated from the algorithm-based analysis may provide a targeted approach to the treatment of breast cancer, potentially improving the prognosis for the subject and reducing the risk of recurrence.

[0098] In an example, FIG. 1 depicts a flowchart of a method for breast cancer treatment. The method steps include presenting a plurality of mammograms from one or more breasts of a subject 101; performing an algorithm-based analysis of the mammograms to predict the risk of an interval mammographic cancer 102; and administering an estrogen receptor modulating pharmaceutical based on the breast cancer risk score generated from the algorithm-based analysis 103.

[0099] In another aspect, the algorithm-based analysis may be configured to predict a risk of an occult mammographic cancer. An occult mammographic cancer refers to a cancer diagnosis that occurs between intervals of standard mammograms, such as a 2-year interval. In some cases, patients may have been treated with a density reducing pharmaceutical and demonstrate a density reduction in a mammogram that identifies the cancer compared to the baseline mammogram. In some instances, a panel of radiologists, such as two out of three radiologists, may agree that the lesion was visible on the baseline mammograms in retrospect.

[0100] The prediction of an occult mammographic cancer may involve similar steps as the prediction of an interval mammographic cancer, including the analysis of a series of mammograms, the assessment of breast density and asymmetry, and the detection of textures, patterns, and radiomic shapes. However, the algorithm may be specifically trained to recognize features and patterns that are indicative of an occult mammographic cancer, which may differ from those associated with an interval mammographic cancer.

[0101] In some cases, the algorithm may use machine learning techniques to learn from a large dataset of mammograms, including mammograms from patients who have been diagnosed with an occult mammographic cancer. This training may enable the algorithm to accurately predict the risk of an occult mammographic cancer based on the features present in the mammograms.-21-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0102] In other cases, the algorithm may incorporate additional factors into the prediction of an occult mammographic cancer, such as the subject's age, family history of breast cancer, and other relevant considerations. The algorithm may also take into account the subject's treatment history, including any previous or concurrent treatment with a density reducing pharmaceutical.

[0103] In all cases, the prediction of an occult mammographic cancer may provide valuable information for the management of breast health, potentially aiding in the early detection and treatment of this type of cancer.

[0104] In some aspects, the algorithm-based analysis may include a panel of three radiologists. This panel may review the mammograms and contribute to the analysis process. For instance, the panel may review the mammograms to identify any lesions or abnormalities that may be indicative of a breast disorder. The inclusion of a radiologist panel may provide an additional layer of expertise and scrutiny, potentially enhancing the accuracy and reliability of the algorithm-based analysis.

[0105] In some cases, the agreement of at least two out of the three radiologists on the panel may be a criterion for determining the visibility of a lesion on the first mammogram. This criterion may provide a consensus-based approach to the identification of lesions, potentially reducing the likelihood of false positives or negatives. The agreement of the radiologists may be based on their independent assessments of the mammograms, and may be facilitated by the use of standardized criteria or guidelines for the identification of lesions.

[0106] In other aspects, the radiologist panel may also contribute to the interpretation of the algorithm-based analysis. For instance, the radiologists may review the results of the algorithmbased analysis, including the predicted risk of an interval or occult mammographic cancer, and provide their expert opinions on the findings. This may include, for example, providing insights on the clinical relevance of the findings, suggesting additional diagnostic tests or procedures, or recommending treatment options based on the predicted risk of breast cancer. The inclusion of a radiologist panel in the algorithm-based analysis may provide a valuable human element to the process, potentially enhancing the accuracy, reliability, and clinical relevance of the analysis.

[0107] In some aspects, the radiologist panel may be involved in the training and validation of the algorithm. The radiologists may provide expert annotations on a training dataset of mammograms, which may be used to train the algorithm to recognize features and patterns associated with different types of breast cancer. The radiologists may also participate in the validation of the algorithm, by reviewing the algorithm's predictions on a validation dataset of mammograms and providing feedback on its performance.-22-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0108] In some aspects, the method may involve a treatment regimen that includes an effective amount of low dose tamoxifen. Tamoxifen is a well-known estrogen receptor modulating pharmaceutical that has been widely used in the treatment of breast cancer. In the context of the present disclosure, tamoxifen may be administered in a low dose, which may be sufficient to exert a therapeutic effect while potentially reducing the risk of adverse side effects. The specific dosage of tamoxifen may be determined based on various factors, such as the subject's weight, age, overall health status, and the specific type of breast cancer being treated.

[0109] About 40-50% of patients discontinue adjuvant endocrine therapy. Around 60% of patients do not benefit from second-line fulvestrant monotherapy, and close to 50% of patients do not respond to first-line aromatase inhibitors and CDK4 / 6 treatment. Endocrine therapy remains the mainstay treatment for patients, but there are numerous unmet needs that still exist for new treatment options. Treatment with (Z)-endoxifen improves efficacy, reduces resistance to anticancer treatment, induces apoptosis, and improves adherence to treatment. There is a strong need for new endocrine therapies in breast cancer.

[0110] (Z)-endoxifen is a highly improved estrogen receptor modulator. Tamoxifen has 20+ metabolites, some of which cause negative effects. (Z)-endoxifen is the most active metabolite of tamoxifen and provides clinical benefit to patients including safety, tolerability and efficacy. It has more potent antiestrogenic activity compared to other agents, and is safer than other treatments. Effects are limited to on-target activity and off-tissue effects are limited. Pharmacokinetic properties allow for higher blood concentrations of the drug and increase the ER-dependent and ER-independent mechanisms of action. (Z)-endoxifen is useful for combination treatment therapies.Table 1 describes benefits of (Z)-endoxifen.Table 2 describes improvements of (Z)-endoxifen over other treatments.-23-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0111] Improved efficacy of (Z)-endoxifen is due in part to its multiple mechanisms of action. It is a powerful ER antagonist, with 100-fold higher potency compared to other SERMs, and shows superior antitumor efficacy in preclinical and clinical studies. The potency is due in part to binding of the molecule to protein kinase C beta 1 (PKC[31), an oncogenic protein. (Z)-endoxifen downregulates the AKT pathway (the PI3K / AKT / mT0R pathway) and induces apoptosis in breast cancer cells. In addition to other inhibitory activities, (Z)-endoxifen has the ability to inhibit clinically relevant ESRI mutants, which is an acquired resistance mechanism to aromatase inhibitors. Other aromatase inhibitors have negative effects known as “on target off tissue7’ effects which reduce efficacy. (Z)-endoxifen can avoid these negative effects of other treatments and can increase adherence to therapy. The multiple effects of (Z)-endoxifen give it the potential to be a preferred endocrine combination treatment.

[0112] Compared to tamoxifen. (Z)-endoxifen is 100-fold more potent in anti-estrogen activity. Preclinical studies revealed superior antitumor activity compared to tamoxifen and aromatase inhibitors in both endocrine-sensitive (MCF7AC1) and endocrine-resistant (MCFLR) ERa+ breast cancer models. As shown in FIG. 2, (Z)-endoxifen has increased activity in reducing mean tumor volume compared to treatment with letrozole or tamoxifen as measured in MCF7AC 1 cells. At both 25 and 75 mg / kg, (Z)-endoxifen decreased mean tumor volume compared to tamoxifen (at 500 pg / day) and letrozole (at lOpg / day) in letrozole-sensitive MCF7 aromatase expressing model (MCF7AC1).

[0113] In letrozole-resistant MCF7 models (MCF7LR), (Z)-endoxifen showed less increase in mean tumor volume than exemestane and a combination of exemestane and everolimus. Androstenedione was injected to test the efficacy of aromatase inhibitors (see FIG. 3).-24-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0114] Preclinical data supports that (Z)-endoxifen does not induce bone loss and does not affect uterine wet weight in ovariectomized animals. (Z)-endoxifen was well tolerated at doses up to 360 mg / day for up to 5 years, with relatively few adverse events reported. In addition, premenopausal subjects with Grade 1 or 2 ER+ / HER2- breast cancer are being treated in the neoadjuvant setting in at least one clinical trial, with doses ranging from 20 to 80 mg / day. (Z)-endoxifen has been generally well-tolerated, with the majority of adverse events being mild or moderate in severity.

[0115] Mutations in the ligand binding domain (LBD) are a common mechanism of acquired resistance to aromatase inhibitors, affecting approximately 30-40% of patients. Additionally, ESRI mutations contribute to resistance against other endocrine therapies, such as fulvestrant. Notably, (Z)-endoxifen is effective against around 68% of all ESRI mutations at clinically relevant doses. Wild type receptors are transcriptionally activated by E2 and inhibited by (Z)- endoxifen. Mutant ESRI receptors are constitutively active but still inhibited by (Z)-endoxifen at clinically relevant doses (represented by purple boxes) (FIG. 4).

[0116] (Z)-endoxifen functions to treat and prevent interval cancers and is apowerful neoadjuvant treatment to improve breast conservation rate for breast cancer patients. The apoptosis induced by (Z)-endoxifen is part of a treatment that has improved efficacious endocrine therapy, with increased safety and tolerability over other treatments. Not only is (Z)-endoxifen used in the prevention of breast cancer in addition to neoadjuvant and adjuvant treatment methods, but (Z)-endoxifen treats relapse and refractory breast cancer in addition to metastatic cancer, in part through induction of apoptosis. In some embodiments, (Z)-endoxifen is used to treat any stage ER+ cancer, with the added advantage of reducing interval cancer.

[0117] In some aspects, the low dose tamoxifen may be in various specific amounts per unit dose, such as ranging from 0.5 mg to 10 mg. In some aspects, the low dose tamoxifen is between 0.5 mg to 2 mg, 2 mg to 6 mg, or 6 mg to 10 mg. The actual dosage may vary depending on the age of the subject, the severity of symptoms, concomitant drug treatments, and other factors that affect clinical outcomes. For instance, the low dose tamoxifen may be 0.5 mg, 1 mg, 1.5 mg. 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg. 4.5 mg, 5 mg, 5.5 mg, 6 mg. 6.5 mg, 7 mg, 7.5 mg, 8 mg. 9 mg. 9.5 mg, or 10 mg per unit dose. The specific amount of low dose tamoxifen may be selected based on the subject's individual characteristics and the specific type of breast cancer being treated. One of ordinary skill recognizes that the methods described herein are not limited to a specific dosage to be effective at treating or preventing cancers.

[0118] In some aspects, the low dose tamoxifen may be administered once a day, twice a day, or at other suitable intervals, depending on the specific treatment regimen.-25-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0119] In other aspects, the low dose tamoxifen may be administered in combination with other pharmaceuticals, such as a density reducing pharmaceutical. This combination therapy may provide a synergistic effect, potentially enhancing the efficacy of the treatment and improving the overall outcome for the subject. The specific combination of pharmaceuticals may be selected based on the subject's individual characteristics and the specific type of breast cancer being treated.

[0120] In yet other aspects, the administration of low dose tamoxifen may be monitored over time to assess the effectiveness of the treatment. This may involve regular follow-up appointments with the subject, as well as additional mammograms or other diagnostic tests as deemed appropriate by the healthcare provider. The results of these follow-up assessments may be used to adjust the treatment regimen as needed, potentially improving the overall outcome for the subject.

[0121] In all cases, the administration of low dose tamoxifen as part of a treatment regimen may provide a targeted approach to the treatment of breast cancer, potentially improving the prognosis for the subject and reducing the risk of recurrence.Compounds for Treating / Preventing Cancer(Z) -Endoxifen, a Potent Selective Estrogen Receptor Modulator

[0122] Endoxifen is an active metabolite of tamoxifen that is broken down in the liver into active compounds, or metabolites. One of the active tamoxifen metabolites is endoxifen, also referred to as 4-hydroxy-N-desmethyltamoxifen. Endoxifen, particularly the active isomer (Z)-endoxifen, is a selective estrogen receptor modulator (SERM) that functions as a competitive partial agonist of estrogen receptor in a tissue-specific manner. (Z)-endoxifen has robust antitumor and antiestrogenic activity compared to tamoxifen therapy and aromatase inhibitor therapy. (Z)-endoxifen is beneficial in treating cancers in patients that are resistant to other hormone therapies, such as tamoxifen, aromatase inhibitors, or fulvestrant, in part because endoxifen functions independently of metabolic enzymes such as CYP2D6.

[0123] In some embodiments, the compositions described herein include endoxifen, which may comprise (Z)-endoxifen, (E)-endoxifen, or a combination thereof. In some embodiments, the composition includes endoxifen which is represented by the compound of Formula (I):-26-KTS Docket No. 1 1 771-1529908 (817 WO 1 )Formula (I), or a pharmaceutically acceptable salt thereof.

[0124] In another aspect, the present disclosure provides a compound of Formula (I-Z):or a pharmaceutically acceptable salt thereof.

[0125] In another aspect, the present disclosure provides a compound of Formula (I-E):or a pharmaceutically acceptable salt thereof.

[0126] In some embodiments, for a compound of Formula (I), Formula (I) is represented by Formula (I-Z). In some embodiments. Formula (I) is represented by Formula (I-E).

[0127] In some embodiments, at least 90% by weight of the compound of Formula (I) in the composition is (Z)-endoxifen. In some embodiments, the endoxifen is in a cry stal I i ne form which is Form I. In some aspects, Form I is characterized by an x-ray powder diffraction (XRPD) pattern which includes major peaks at 16.8 ± 0.3°, 17.1 ± 0.3° and 21.8 ± 0.3° two theta. In some embodiments, the XRPD pattern of Form I further includes at least one peak selected from 16.0 ± 0.3°, 18.8 ± 0.3° and 26.5 ± 0.3° two theta. In some embodiments, the x-ray powder diffraction pattern further includes at least one peak selected from 12.3 ± 0.3°, 28.0 ±0.3°, and 29.0 ± 0.3° two theta. In further aspects, the x-ray powder diffraction pattern further includes peaks at 12.3 ± 0.3°, 16.0 ± 0.3°, 18.8 ± 0.3°, 26.5 ± 0.3°, 28.0 ± 0.3°, and 29.0 ± 0.3° two theta. In some aspects, greater than 90%, 95%, 99%, or any value contained within a range formed by any two of the preceding values, by weight of the compound of Formula (I) in the composition is crystalline Form I. In some aspects, the composition includes 0.01 mg to 200 mg of crystalline Form I, such as about 1 mg, 2 mg. 4 mg, 6 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, or any value contained within a range formed by any tw o of the preceding values of crystalline Form I.-27-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0128] In some embodiments, the composition comprises the (E)-isomer and the (Z)-isomer of the compound of Formula (I) in an E / Z ratio between 0.9 and 1.3, such as about 1.1. In some embodiments, the endoxifen is in a cry stalline form which is Form II. In some aspects, Form II is characterized by an x-ray powder diffraction pattern including major peaks at 7.0 ± 0.3°, 11.9 ± 0.3°, 14.0 ± 0.3° and 18.4 ± 0.3° two theta, and optionally further including a peak at 22.0 ± 0.3° two theta. In some embodiments, the x-ray powder diffraction pattern further includes at least one peak selected from 6.6 ± 0.3°, 13.3 ± 0.3° and 20.0 ± 0.3° two theta. In various aspects, the x-ray powder diffraction pattern further including peaks at 6.6 ± 0.3°, 13.3 ± 0.3°, 20.0 ± 0.3° and 22.0 ± 0.3° two theta. In some aspects, greater than 90%, 95%, 99%, or any value contained within a range formed by any two of the preceding values, by weight of the compound of Formula (I) in the composition is crystalline Form II. In some aspects, the composition includes 0.01 mg to 200 mg of cry stalline Form II, such as about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, or any value contained within a range formed by any two of the preceding values, of crystalline Form II.

[0129] In some embodiments, the composition comprises the (E)-isomer and the (Z)-isomer of the compound of Formula (I) in an E / Z ratio between 0.9 and 1.3, such as about 1.1. In some aspects, the ratio of (E)-isomer to (Z)-isomer is between 1:99 to 99: 1. In some aspects, the ratio of (E)-isomer to (Z)-isomer is about 1 : 1. In some aspects, the ratio of (E)-isomer to (Z)-isomer is between 1: 1 to 1 :10, 1 : 10-1:20, 1 :20-1:30, 1 :30-1 :40, 1 :40-1:50, 1 :50-1:60, 1 :60-1 :70, 1:70-1:80, 1 :80-1:90, or 1:90-1:99. In some aspects, the ratio of (Z)-isomer to (E)-isomer is between 1: 1 to 1 : 10, 1: 10-1:20, 1 :20-1:30, 1:30-1:40, 1 :40-1:50, 1:50-1 :60, 1 :60-1 :70, 1 :70-1:80, 1:80-1:90, or 1 :90-1 :99.

[0130] In some embodiments, the endoxifen is in a crystalline form which is Form III. In some aspects, crystalline Form III is characterized by an x-ray powder diffraction pattern including major peaks at 11.9 ± 0.3°, 13.9 ± 0.3°, 17.1 ± 0.3° and 17.7 ± 0.3° two theta, and optionally further including a peak at 25.3 ± 0.3° two theta. In some embodiments, the x-ray powder diffraction pattern further includes at least one peak selected from 18.2 ± 0.3°, 22.5 ± 0.3° and 26.8 ± 0.3° two theta. In some aspects, the x-ray powder diffraction pattern further includes peaks at 18.2 ± 0.3°, 22.5 ± 0.3°, 25.3 ± 0.3° and 26.8 ± 0.3° two theta. Greater than 90%, 95%, 99%, or any value contained within a range formed by any two of the preceding values, by weight of the compound of Formula (I) in the composition is crystalline Form III. In some aspects, the composition includes 0.01 mg to 200 mg of crystalline Form III, such as about 1 mg, 2 mg, 4 mg, 6 mg, 10 mg, 20 mg, 50 mg, 100 mg, 200 mg, or any value contained within a range formed by any two of the preceding values, of cry stalline Form III.-28-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0131] A “pharmaceutically acceptable salt’’ is any salt (e.g., obtained by reaction with an acid or a base) of a compound of the present disclosure that is physiologically tolerated in a subject (e.g., a mammal, and / or in vivo, ex-vivo, in vitro cells, tissues, or organs). In some embodiments, a “salt” of a compound of the present disclosure is derived from inorganic or organic acids and bases. In some aspects, a “salt” of a compound described herein is derived from inorganic or organic acids and bases. Suitable counter-anions include, arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate. hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (embonate), pantothenate, phosphate / di phosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, teoclate, fatty7acid anions, and triethiodide. Suitable counter-cations include benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some embodiments, a (Z)-endoxifen salt includes arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate. isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (embonate), pantothenate, phosphate / di phosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, or a zinc salt.

[0132] In some embodiments, the compositions comprises (Z)-endoxifen or a (Z)-endoxifen salt or polymorph are administered to the subject at a dose of 0.01 mg to 200.0 mg of (Z)-endoxifen per unit dose. In other embodiments, the oral compositions including (Z)-endoxifen or a (Z)- endoxifen salt or polymorph are administered to the subject at a dose of 1 mg to 200.0 mg of (Z)- endoxifen. In some embodiments, the oral compositions including (Z)-endoxifen or a (Z)- endoxifen salt or polymorph are administered to the subject at a dose of 0.01 mg, 0.05 mg, 0.1 mg, 0.25 mg, 0.5 mg, 0.75 mg, 1.0 mg, 1.5 mg, 2.0 mg, 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg or 200 mg of (Z)-endoxifen per unit dose. In certain embodiments, the oral compositions include at least 90% (Z)-endoxifen (wt / wt) of (Z)-endoxifen and are administered at a dose of 1 mg, 2.0 mg, 4.0 mg 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50, 100 mg or 200 mg of (Z)-endoxifen per unit dose. In some embodiments, the compositions include (Z)-endoxifen gluconate and are administered at a dose ranging from 0.01 to 20 mg of (Z)-endoxifen per unit -29-KTS Docket No. 1 16771-1529908 (817 WO 1 )dose. In some embodiments, a composition including (Z)-endoxifen D-gluconate is administered at 0.5 mg, 1 mg, 2 mg 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg, and 200 mg of (Z)-endoxifen per unit dose. In some embodiments, a composition including 1 mg of (Z)- endoxifen D-gluconate is administered. In other embodiments, a composition including 1 mg of (Z)-endoxifen L-gluconate is administered. In yet other embodiments, a composition including 2 mg of (Z)-endoxifen D-gluconate and (E)-endoxifen D-gluconate is administered. In certain embodiments, an oral composition including at least 90% of a polymorph of endoxifen (wt / wt) is administered at a dose of 1 mg, 2 mg, 4.0 mg, 6 mg, 8 mg, 10 mg, 20 mg, 40 mg, 50 mg, 100 mg or 200 mg per unit dose. In some embodiments, a composition including a polymorphic form of (Z)-endoxifen is administered at a dose ranging from 0.01 mg to 20 mg per unit dose.

[0133] In some embodiments, for a compound or salt of Formula (I), Formula (I-Z), or Formula (I-E), the salt is selected from the acetate, arecoline, benzathine, benzoic, besylate, benzosulfonate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, formate, fumarate, glucolate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, maleate, mandelate, meglumine, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, methanesulfonate, mucate. napsylate, nitric, nitrate, oxalate, pamaoate (Embonate). pantothenate, perchloric, phosphate, diphosphate, piperazine, procaine, polygalacuronate, p-toluenesulfonate, salicylate, stearate, succinate, sulfate, sulfonate, sulfuric, tannate, tartarate, teoclate, triethiodide, trifluoroacetate, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc, or any combination thereof. In some embodiments, the salt is selected from the group consisting of arecoline, besylate, bicarbonate, bitartarate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate, isethionate, malate, mandelate, mesylate, methylbromide, methylbromide, methylnitrate, methylsulfate, mucate, napsylate, nitrate, pamaoate (Embonate). pantothenate, phosphate / di phosphate, polygalacuronate, salicylate, stearate, sulfate, tannate, Teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some embodiments, the salt is D-gluconate. L-gluconate. or a combination thereof. In some embodiments, the salt is hydrochloride. In some embodiments, the salt is citrate. In some embodiments, the salt is (Z)-endoxifen D-gluconate, (Z)-endoxifen L-gluconate, or a combination thereof. In some embodiments, the salt is selected from (Z)-endoxifen hydrochloride and (Z)--30-KTS Docket No. 1 16771-1529908 (817 WO 1 )endoxifen citrate. In some embodiments, the salt is (Z)-endoxifen D-gluconate. In some embodiments, the salt is (Z)-endoxifen L-gluconate. In some embodiments, the salt is (Z)- endoxifen hydrochloride. In some embodiments, the salt is (Z)-endoxifen citrate. In some embodiments, the salt is (E)-endoxifen D-gluconate. (E)-endoxifen L-gluconate, or a combination thereof. In some embodiments, the salt is (E)-endoxifen D-gluconate. In some embodiments, the salt is (E)-endoxifen L-gluconate. In some embodiments, the salt is (E)-endoxifen hydrochloride. In some embodiments, the salt is (E)-endoxifen citrate. In some embodiments, the salt is endoxifen D-gluconate. In some embodiments, the salt is endoxifen L-gluconate. In some embodiments, the salt is endoxifen hydrochloride. In some embodiments, the salt is endoxifen citrate.

[0134] In some embodiments, the compound or salt of Formula (I) is (Z)-endoxifen, (E)- endoxifen, (Z)-endoxifen hydrochloride, (E)-endoxifen hydrochloride, (Z)-endoxifen citrate, (E)- endoxifen citrate, or any combination thereof. In some embodiments, the compound of Formula (I) is (Z)-endoxifen, (E)-endoxifen, (Z)-endoxifen hydrochloride, (E)-endoxifen hydrochloride, (Z)-endoxifen citrate, (E)-endoxifen citrate, or a combination thereof. In some embodiments, the compound of Formula (I) is (Z)-endoxifen, (E)-endoxifen, or a combination thereof. In some embodiments, the compound of Formula (I) is (Z)-endoxifen, (E)-endoxifen, (Z)-endoxifen hydrochloride, (E)-endoxifen hydrochloride, or any combinations thereof. In some embodiments, the compound of Formula (I) is (Z)-endoxifen. (E)-endoxifen, (Z)-end oxifen citrate, (E)- endoxifen citrate, or any combinations thereof. In some embodiments, the compound of Formula (I) is (Z)-endoxifen hydrochloride, (E)-endoxifen hydrochloride, or a combination thereof. In some embodiments, the compound or salt of Formula (I) is (Z)-endoxifen citrate. In some embodiments, the compound or salt of Formula (I) is (E)-endoxifen citrate. In some embodiments, the compound or salt of Formula (I) is (Z)-endoxifen hydrochloride. In some embodiments, the compound or salt of Formula (I) is (E)-endoxifen hydrochloride. In some embodiments, the compound or salt of Formula (I) is (Z)-endoxifen. In some embodiments, the compound or salt of Formula (I) is (E)-endoxifen.

[0135] In some embodiments, the compound or salt of Formula (I-Z) is (Z)-endoxifen, (Z)- endoxifen hydrochloride or (Z)-endoxifen citrate. In some embodiments, the compound of Formula (I-Z) is (Z)-endoxifen. In some embodiments, the compound of Formula (I-Z) is (Z)- endoxifen hydrochloride or (Z)-endoxifen citrate. In some embodiments, the compound of Formula (I-Z) is (Z)-endoxifen hydrochloride. In some embodiments, the compound of Formula (I-Z) is (Z)-endoxifen citrate. In some embodiments, the compound or salt of Formula (I-Z) is (Z)- endoxifen citrate. In some embodiments, the compound or salt of Formula (I-Z) is (Z)-endoxifen hydrochloride. In some embodiments, the compound or salt of Formula (I-Z) is (Z)-endoxifen.-31-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0136] In some embodiments, the compound or salt of Formula (I-E) is (E)-endoxifen, (E)- endoxifen hydrochloride, (E)-endoxifen hydrochloride or (E)-endoxifen citrate. In some embodiments, the compound of Formula (I-E) is (E)-endoxifen. In some embodiments, the compound of Formula (I-E) is (E)-endoxifen hydrochloride or (E)-endoxifen citrate. In some embodiments, the compound of Formula (I-E) is (E)-endoxifen hydrochloride. In some embodiments, the compound of Formula (I-E) is (E)-endoxifen citrate. In some embodiments, the compound or salt of Formula (I-E) is (E)-endoxifen citrate. In some embodiments, the compound or salt of Formula (I-E) is (E)-endoxifen hydrochloride. In some embodiments, the compound or salt of Formula (I-E) is (E)-endoxifen.

[0137] In some embodiments, for a compound or salt of Formula (I), Formula (I-Z), or Formula (I-E), the compound or salt of Formula (I), Formula (I-Z), or Formula (I-E) is a crystalline form, a solvate form, a polymorph form, or an amorphous form. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the compound or salt is a crystalline form. In some embodiments, the compound or salt is a solvate form. In some embodiments, the compound or salt is a polymorph form. In some embodiments, the compound or salt is an amorphous form. In some embodiments, the cry stalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the cry stalline form is hydrated. In some embodiments, the crystalline form is anhydrous. In some embodiments, the crystalline form is an anhydrate. In some embodiments, the polymorph form is solvated. In some embodiments, the polymorph form is unsolvated. In some embodiments, the polymorph form is hydrated. In some embodiments, the polymorph form is anhydrous. In some embodiments, the polymorph form is an anhydrate. In some embodiments, the solvate form comprises a pharmaceutically acceptable solvent. In some embodiments, the solvate form is an ethanol solvate form. In some embodiments, the solvate form is a methanol solvate form. In some embodiments, the solvate form is an isopropanol solvate form. In some embodiments, the solvate form is a hydrate.

[0138] In some embodiments, endoxifen or salt thereof is a crystalline form, a solvate form, a polymorph form, or an amorphous form. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the crystalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the cry stalline form is hydrated. In some embodiments, the cry stalline form is anhydrous. In some embodiments, the crystalline form is an anhydrate. In some embodiments, the polymorph form is solvated. In some embodiments, the polymorph form is unsolvated. In some embodiments, the polymorph form is hydrated. In some embodiments, the polymorph form is anhydrous. In some embodiments, the polymorph form is an anhydrate. In some embodiments, the solvate form comprises a pharmaceutically acceptable -32-KTS Docket No. 1 16771-1529908 (817 WO 1 )solvent. In some embodiments, the solvate form is an ethanol solvate form. In some embodiments, the solvate form is a methanol solvate form. In some embodiments, the solvate form is an isopropanol solvate form. In some embodiments, the solvate form is a hydrate.

[0139] In some embodiments, (Z)-endoxifen or salt thereof is a crystalline form, a solvate form, a polymorph form, or an amorphous form. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the crystalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the cry stalline form is hydrated. In some embodiments, the cry stalline form is anhydrous. In some embodiments, the crystalline form is an anhydrate. In some embodiments, the polymorph form is solvated. In some embodiments, the polymorph form is unsolvated. In some embodiments, the polymorph form is hydrated. In some embodiments, the polymorph form is anhydrous. In some embodiments, the polymorph form is an anhydrate. In some embodiments, (Z)-endoxifen or a salt thereof exists as one or more polymorphs. In some embodiments, the solvate form comprises a pharmaceutically acceptable solvent. In some embodiments, the solvate form is an ethanol solvate form. In some embodiments, the solvate form is a methanol solvate form. In some embodiments, the solvate form is an isopropanol solvate form. In some embodiments, the solvate form is a hydrate.

[0140] In some embodiments, (E)-endoxifen or salt thereof is a cry stalline form, a solvate form, a polymorph form, or an amorphous form. In some embodiments, the salt is a pharmaceutically acceptable salt. In some embodiments, the crystalline form is a solvated. In some embodiments, the crystalline form is unsolvated. In some embodiments, the cry stalline form is hydrated. In some embodiments, the cry stalline form is anhydrous. In some embodiments, the crystalline form is an anhydrate. In some embodiments, the polymorph form is solvated. In some embodiments, the polymorph form is unsolvated. In some embodiments, the polymorph form is hydrated. In some embodiments, the polymorph form is anhydrous. In some embodiments, the polymorph form is an anhydrate. In some embodiments, (E)-endoxifen or a salt thereof exists as one or more polymorphs. In some embodiments, endoxifen is a solvated form. In some embodiments, the solvated form comprises a pharmaceutically acceptable solvent. In some embodiments, the solvated form is an ethanol solvate form. In some embodiments, the solvated form is a methanol solvate form. In some embodiments, the solvated form is an isopropanol solvate form. In some embodiments, the solvated form is a hydrate

[0141] In some embodiments, for a compound or salt of Formula (I) or Formula (I-Z), the compound is crystalline Form I of (Z)-endoxifen. In some embodiments, cry stalline Form I is characterized by an x-ray powder diffraction (XRPD) pattern which includes major peaks at 16.8 ± 0.3° 2-Theta, 17.1 ± 0.3° 2-Theta and 21.8 ± 0.3° 2-Theta. In some embodiments, the XRPD -33-KTS Docket No. 1 16771-1529908 (817 WO 1 )pattern of crystalline Form I further includes at least one peak selected from 16.0 ± 0.3° 2-Theta, 18.8 ± 0.3° 2-Theta, and 26.5 ± 0.3° 2-Theta. In some embodiments, the XRPD pattern of crystalline Form I further includes at least one peak selected from 12.3 ± 0.3° 2-Theta, 28.0 ±0.3° 2-Theta, and 29.0 ± 0.3° 2-Theta. In some embodiments, the XRPD pattern of crystalline Form I further includes peaks at 12.3 ± 0.3° 2-Theta, 16.0 ± 0.3° 2-Theta, 18.8 ± 0.3°, 26.5 ± 0.3° 2- Theta, 28.0 ± 0.3° 2-Theta, and 29.0 ± 0.3° 2-Theta.Further Forms

[0142] Chemical entities having carbon-carbon double bonds or carbon-nitrogen double bonds may exist in Z- or E- form (or cis- or trans- form). Furthermore, some chemical entities may exist in various tautomeric forms. Unless otherwise specified, compounds described herein are intended to include all Z-, E- and tautomeric forms as well.

[0143] “Isomers'’ are different compounds that have the same molecular formula. “Stereoisomers’” are isomers that differ only in the way the atoms are arranged in space. “Enantiomers” are a pair of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a “racemic” mixture. The term “(±)” is used to designate a racemic mixture where appropriate. “Diastereoisomers” or “diastereomers” are stereoisomers that have at least two asymmetric atoms, but are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral carbon can be specified by either R or S. Resolved compounds whose absolute configuration is unknown can be designated (+) or (-) depending on the direction (dextro- or levorotatory) in which they rotate plane polarized light at the wavelength of the sodium D line. Optically active (R)- and (S)-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. The optical activity of a compound can be analyzed via any suitable method, including but not limited to chiral chromatography and polarimetry’, and the degree of predominance of one stereoisomer over the other isomer can be determined.

[0144] When stereochemistry is not specified, molecules with stereocenters described herein include isomers, such as enantiomers and diastereomers, mixtures of enantiomers, including racemates, mixtures of diastereomers, and other mixtures thereof, to the extent they can be made by one of ordinary skill in the art by routine experimentation. In certain embodiments, the single enantiomers or diastereomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates or mixtures of diastereomers. Resolution of the racemates or mixtures of diastereomers, if possible, can be accomplished, for example, by -34-KTS Docket No. 1 16771-1529908 (817 WO 1 )conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example, a chiral high-pressure liquid chromatography (HPLC) column. Furthermore, a mixture of two enantiomers enriched in one of the two can be purified to provide further optically enriched form of the major enantiomer by recrystallization and / or trituration.

[0145] Methods of producing substantially pure enantiomers are known to those of skill in the art. For example, a single stereoisomer, e.g., an enantiomer, substantially free of its stereoisomer may be obtained by resolution of the racemic mixture using a method such as formation of diastereomers using optically active resolving agents (Stereochemistry of Carbon Compounds, (1962) by E. L. Eliel, NicGraw Hill; Lochmuller (1975) J. Chromatogr., 113(3):283-302). Racemic mixtures of chiral compounds can be separated and isolated by any suitable method, including, but not limited to: (1) formation of ionic, diastereomeric salts with chiral compounds and separation by fractional crystallization or other methods. (2) formation of diastereomeric compounds with chiral derivatizing reagents, separation of the diastereomers, and conversion to the pure stereoisomers, and (3) separation of the substantially pure or enriched stereoisomers directly under chiral conditions. Another approach for separation of the enantiomers is to use a Diacel chiral column and elution using an organic mobile phase such as done by Chiral Technologies (www.chiraltech.com) on a fee for service basis.

[0146] A “tautomer’’ refers to a molecule wherein a proton shift from one atom of a molecule to another atom of the same molecule is possible. The compounds presented herein, in certain embodiments, exist as tautomers. In circumstances where tautomerization is possible, a chemical equilibrium of the tautomers will exist. The exact ratio of the tautomers depends on several factors, including physical state, temperature, solvent, and pH. Some examples of tautomeric equilibrium include:KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0147] The compounds disclosed herein, in some embodiments, are used in different enriched isotopic forms, e g., enriched in the content of2H,3H,nC,13C and / or14C. Such deuterated forms can be made by the procedure described in U.S. Patent Nos. 5,846,514 and 6,334,997. As described in U.S. Patent Nos. 5,846,514 and 6.334,997, deuteration can improve the metabolic stability and or efficacy, thus increasing the duration of action of drugs.

[0148] Unless otherwise stated, compounds described herein are intended to include compounds which differ only in the presence of one or more isotopically enriched atoms. For example, compounds having the present structures except for the replacement of a hydrogen by a deuterium or tritium, or the replacement of a carbon by13C- or14C-enriched carbon are within the scope of the present disclosure.

[0149] The compounds of the present disclosure optionally contain unnatural proportions of atomic isotopes at one or more atoms that constitute such compounds. For example, the compounds may be labeled with isotopes, such as for example, deuterium (2H), tritium (3H), iodine-125 (125I) or carbon-14 (14C). Isotopic substitution with2H.nC,13C,14C.15C,12N,13N.15N,16N,16O,17O,14F,15F,16F,17F,18F,33S,34S,35S,36S,35C1,37C1,79Br,81Br, and125I are all contemplated. All isotopic variations of the compounds of the present invention, whether radioactive or not, are encompassed within the scope of the present invention.

[0150] The methods of synthesis for deuteri um-containing compounds are known in the art and include, by way of non-limiting example only, the following synthetic methods

[0151] Deuterium substituted compounds are synthesized using various methods such as described in: Dean, Dennis C.; Editor. Recent Advances in the Synthesis and Applications of Radiolabeled Compounds for Drug Discovery’ and Development. [In: Curr., Pharm. Des., 2000; 6(10)] 2000, 110 pp; George W.; Varma, Raj ender S. The Synthesis of Radiolabeled Compounds -36-KTS Docket No. 1 16771-1529908 (817 WO 1 )via Organometallic Intermediates, Tetrahedron, 1989, 45(21), 6601-21; and Evans, E. Anthony. Synthesis of radiolabeled compounds, J. Radioanal. Chem., 1981, 64(1-2), 9-32

[0152] Deuterated starting materials are readily available and are subjected to the synthetic methods described herein to provide for the synthesis of deuterium-containing compounds. Large numbers of deuterium-containing reagents and building blocks are available commercially from chemical vendors, such as Aldrich Chemical Co.

[0153] The compounds, compositions, and methods described herein include amorphous forms as well as cry stalline forms, including crystalline polymorph forms where applicable. The compounds described herein may be in the form of a pharmaceutically acceptable salt, salt, free base, or free acid. As well, in some embodiments, active metabolites of these compounds having the same type of activity are included in the scope of the present disclosure. In addition, the compounds described herein can exist in an unsolvate form as well as a solvate form. In some embodiments, the solvate form comprises a pharmaceutically acceptable solvent such as water, ethanol, and the like. In some embodiments, the unsolvate form is referred to as an anhydrous form or anhydrate form. In some embodiments, the solvate form comprises water and is referred to as a hydrate form. In some embodiments, the solvate form is referred to as a pseudopolymorph. In some embodiments, the hydrate form is referred to as a pseudopolymorph. Both unsolvate and solvate forms of the compounds presented herein are also considered to be disclosed herein.

[0154] The term “form” refers to a solid-state form of a particular compound (e g., the free base, the free acid, a salt or a pharmaceutically acceptable salt). The term “form” includes crystalline polymorphs, hydrates and solvates (pseudopolymorphs), amorphous forms, and mixtures thereof, unless a particular crystalline, polymorph, pseudopolymorph, or amorphous form is expressly referred to. The term “polymorph” refers to a crystalline form of a given chemical species that differs from another cry stalline form of that same molecular formula solely in cry stal packing and / or molecular conformation within the lattice and, unless otherwise specified, excludes hydrates and solvates. If more than one polymorph, hydrate, or solvate exists, they will be designated for clarity (e.g., Form I, Form II; monohydrate, dihydrate; ethanol solvate, methanol solvate).

[0155] Synthetic chemistry7transformations and methodologies useful in synthesizing the compounds described herein are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd. Ed. (1991); L. Fieser and M. Fieser, Fieser and Fieser 's Reagents for Organic Synthesis (1994); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis (1995).-37-KTS Docket No. 1 16771-1529908 (817 WO 1 )Pharmaceutical Compositions / F ormulations

[0156] Provided herein, in certain embodiments, are compositions comprising a therapeutically effective amount of a compound or pharmaceutically acceptable salt of Formula (I), Formula (I- Z), Formula (I-E). or any combinations thereof. In some embodiments, the compositions are pharmaceutical compositions.

[0157] Pharmaceutical compositions may be formulated using one or more physiologically acceptable carriers including excipients and auxiliaries which facilitate processing of the pharmaceutical agent into preparations which are used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. A summary of pharmaceutical compositions is found, for example, in Remington: The Science and Practice of Pharmacy, Nineteenth Ed. (Easton, Pa., Mack Publishing Company, 1995); Hoover, John E., Remington’s Pharmaceutical Sciences, Mack Publishing Co., Easton, Pennsylvania 1975; Liberman, H.A. and Lachman, L., Eds., Pharmaceutical Dosage Forms, Marcel Decker, New York, N.Y., 1980; and Pharmaceutical Dosage Forms and Drug Delivery Systems, Seventh Ed. (Lippincott Williams & Wilkins, 1999).

[0158] The compounds and pharmaceutically acceptable salts thereof, compositions, and methods of the present disclosure may be utilized to treat a subject in need thereof. In certain embodiments, the subject is a mammal such as a human, or a non-human mammal. When administered to an mammal, such as a human, the composition or the pharmaceutical agent, is preferably administered as a pharmaceutical composition comprising, for example, a pharmaceutical agent and a pharmaceutically acceptable carrier or excipient. Pharmaceutically acceptable carriers are well known in the art and include, for example, aqueous solutions such as water or physiologically buffered saline or other solvents or vehicles such as glycols, glycerol, oils such as olive oil, or injectable organic esters. The excipients can be chosen, for example, to effect delayed release of an agent or to selectively target one or more cells, tissues or organs. The pharmaceutical composition can be in dosage unit form such as tablet, capsule, granule, lyophile for reconstitution, powder, solution, syrup, suppository, injection or the like.

[0159] A pharmaceutically acceptable excipient can contain physiologically acceptable agents that act, for example, to stabilize, increase solubility or to increase the absorption of a compound such as a pharmaceutical agent. Such physiologically acceptable agents include, for example, carbohydrates, such as glucose, sucrose or dextrans, antioxidants, such as ascorbic acid or glutathione, chelating agents, low molecular weight proteins or other stabilizers or excipients. The choice of a pharmaceutically acceptable excipient, including a physiologically acceptable agent, depends, for example, on the route of administration of the composition.-38-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0160] An '‘effective amount” or '‘therapeutically effective” amount refers to an amount of the one or more pharmaceutical agents administered to a subject, either as a single dose or as part of a series of doses, which is effective to produce a desired therapeutic effect benefit and / or a prophylactic benefit.

[0161] Subjects may generally be monitored for therapeutic effectiveness using assays and methods suitable for the condition being treated, which assays will be familiar to those having ordinary skill in the art and are described herein. Pharmacokinetics of a pharmaceutical agent, or one or more metabolites thereof, that is administered to a subject may be monitored by determining the level of the pharmaceutical agent or metabolite in a biological fluid, for example, in the blood, blood fraction, e.g., serum, and / or in the urine, and / or other biological sample or biological tissue from the subject. Any method practiced in the art and described herein to detect the agent may be used to measure the level of the pharmaceutical agent or metabolite during a treatment course.

[0162] The dose of a pharmaceutical agent described herein for treating a disease or disorder may depend upon the subject’s condition, that is, stage of the disease, severity of symptoms caused by the disease, general health status, as well as age, gender, and weight, and other factors apparent to a person skilled in the medical art. In addition to the factors described herein and above related to use of pharmaceutical agent for treating a disease or disorder, suitable duration and frequency of administration of the pharmaceutical agent may also be determined or adjusted by such factors as the condition of the patient, the type and severity’ of the patient’s disease, the particular form of the active ingredient, and the method of administration.

[0163] Pharmaceutical acceptable excipients are well known in the pharmaceutical art and described, for example, in Rowe et al., Handbook of Pharmaceutical Excipients: A Comprehensive Guide to Uses, Properties, and Safety, 5th Ed., 2006, and in Remington: The Science and Practice of Pharmacy (Gennaro, 21st Ed. Mack Pub. Co., Easton, PA (2005)). Exemplary pharmaceutically acceptable excipients include sterile saline and phosphate buffered saline at physiological pH. Preservatives, stabilizers, dyes, buffers, and the like may be provided in the pharmaceutical composition. In addition, antioxidants and suspending agents may also be used. In general, the ty pe of excipient is selected based on the mode of administration, as well as the chemical composition of the active ingredient(s).

[0164] For oral formulations, at least one of the pharmaceutical agents described herein can be used alone or in combination with appropriate additives to make tablets, powders, granules or capsules, and if desired, with diluents, buffering agents, moistening agents, preservatives, coloring agents, and flavoring agents. The pharmaceutical agents may be formulated with a buffering agent -39-KTS Docket No. 1 16771-1529908 (817 WO 1 )to provide for protection of the compound from low pH of the gastric environment and / or an enteric coating. A pharmaceutical agent included in a pharmaceutical composition may be formulated for oral delivery' with a flavoring agent, e.g., in a liquid, solid or semi-solid formulation and / or with an enteric coating.

[0165] Preservatives can be used to prevent the growth of fungi and other microorganisms. Suitable preservatives include, but are not limited to, benzoic acid, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium benzoate, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, thimerosal, and any combinations thereof.

[0166] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen, (E)-endoxifen, or a combination thereof. In some embodiments, the pharmaceutical composition comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 80%, at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 80% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 90%, (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 95% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition is a therapeutic composition.

[0167] In some embodiments, an endoxifen pharmaceutical composition comprises (Z)- endoxifen, (E)-endoxifen. or a combination thereof. In some embodiments, the endoxifen pharmaceutical composition comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition at least 80%, at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition at least 90%, at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition at least 95% or at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the -40-KTS Docket No. 1 16771-1529908 (817 WO 1 )pharmaceutical composition at least 80% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition at least 90%, (Z)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition at least 95% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition at least 99% (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0168] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%. less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, or less than 9% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%. less than 2%, less than 3%. less than 4%, less than 5%, less than 6%. less than 7%, or less than 8% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, or less than 7% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, or less than 6% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, or less than 5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 1% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 2% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 3% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 4% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises less than 0.5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is -41-KTS Docket No. 1 16771-1529908 (817 WO 1 )formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0169] In some embodiments, an endoxifen pharmaceutical composition comprises (Z)- endoxifen, (E)-endoxifen, or a combination thereof. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1%. less than 2%, less than 3%. less than 4%, less than 5%, less than 6%, less than 7%, less than 8%, less than 9%, or less than 10% (E)- endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%. less than 8%, or less than 9% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, less than 6%, less than 7%, or less than 8% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%. less than 6%, or less than 7% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, less than 5%, or less than 6% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1%, less than 2%, less than 3%, less than 4%, or less than 5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 1% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 2% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 3% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 4% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 5% (E)-endoxifen by weight of total endoxifen. In some embodiments, the endoxifen pharmaceutical composition comprises less than 0.5% (E)- endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0170] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a -42-KTS Docket No. 1 16771-1529908 (817 WO 1 )Z:E ratio that is at least 50:50, at least 60:40, at least 64:36, at least 70:30, at least 80:30, at least 82: 18, at least 85: 15, at least 90:10, at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99: 1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 85: 15, at least 90: 10. at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2. at least 99: 1. or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 90: 10, at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99: 1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 90: 10. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 94:6. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 95:5. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 96:4, at least 97:3, at least 98:2, at least 99: 1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 97:3, at least 98:2, at least 99: 1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 95:5. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 96:4. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 97:3. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 98:2. at least 99: 1. In some embodiments, the pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ:E ratio that is 100:0. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0171] In some embodiments, an endoxifen pharmaceutical composition comprises (Z)-endoxifen or a pharmaceutically acceptable salt thereof and (E)-endoxifen or a pharmaceutically acceptable salt thereof in a Z:E ratio that is at least 50:50, at least 60:40, at least 64:36, at least 70:30, at least 80:30, at least 82: 18, at least 85: 15, at least 90: 10, at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99: 1, or at least 100:0. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 85: 15, at least 90: 10, at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99: 1, or at least 100:0. In some embodiments, the pharmaceutical composition comprises-43-KTS Docket No. 1 16771-1529908 (817 WO 1 )(Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 90: 10, at least 94:6, at least 95:5, at least 96:4, at least 97:3, at least 98:2, at least 99: 1, or at least 100:0. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 90: 10. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 94:6. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 95:5. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 96:4, at least 97:3, at least 98:2, at least 99: 1, or at least 100:0. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in aZ:E ratio that is at least 97:3, at least 98:2, at least 99: 1, or at least 100:0. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 95:5. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)- endoxifen in a Z:E ratio that is at least 96:4. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is at least 97:3. In some embodiments, the endoxifen pharmaceutical composition comprises (Z)-endoxifen and (E)- endoxifen in a Z:E ratio that is at least 98:2, at least 99: 1. In some embodiments, the endoxifen composition comprises (Z)-endoxifen and (E)-endoxifen in a Z:E ratio that is 100:0. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0172] In certain aspects, the present disclosure further provides pharmaceutical compositions comprising the crystalline forms, solvate forms, polymorph forms, or amorphous forms described herein. A cry stalline form, a solvate form, a polymorph form, or an amorphous form of a compound or salt disclosed herein may provide the advantage of bioavailability and stability, suitable for use as an active ingredient in a pharmaceutical composition. Variations in the crystal structure of a pharmaceutical drug substance or active ingredient may affect the dissolution rate (which may affect bioavailability7, etc.), manufacturability7(such as ease of handling, ability7to consistently prepare doses of known strength) and stability (such as thermal stability, shelf life, etc.) of a pharmaceutical drug product or active ingredient.

[0173] In some embodiments, for a compound or pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some-44-KTS Docket No. 1 16771-1529908 (817 WO 1 )embodiments, the pharmaceutical composition may comprise one or more crystalline forms of a compound or salt of Formula (I), Formula (I-Z), or Formula (I-E). A crystalline form may be distinguished by its x-ray powder diffraction pattern. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 99%, or greater than or equal to 99.5% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, or greater than or equal to 99% of a single crystalline form of the compound. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0174] In some embodiments, for endoxifen, a pharmaceutical composition is provided comprising endoxifen or a pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition may comprise one or more crystalline forms of endoxifen or a pharmaceutically acceptable salt thereof. A cry stall ine form may be distinguished by its x-ray powder diffraction pattern. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single crystalline form of endoxifen. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96% of a single crystalline form of endoxifen. In some embodiments, the pharmaceutical composition comprises greater than or equal to 98% of a single crystalline form of endoxifen. In some embodiments, the pharmaceutical composition comprises greater than or equal to 99% of a single crystalline form of endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.-45-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0175] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition may comprise one or more polymorphic forms of a compound or salt of Formula (I), Formula (I-Z). or Formula (I-E). A polymorphic form may be distinguished by its x-ray powder diffraction pattern. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 99%, or greater than or equal to 99.5% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, or greater than or equal to 99% of a single polymorphic form of the compound. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0176] In some embodiments, for endoxifen or a pharmaceutically acceptable salt thereof, a pharmaceutical composition is provided comprising endoxifen or the pharmaceutically acceptable salt thereof. In some embodiments, the pharmaceutical composition may comprise one or more polymorphic forms of endoxifen or salt thereof. A polymorphic form may be distinguished by its x-ray powder diffraction pattern. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96%, greater than or equal to 97%, greater than or equal to 98%, greater than or equal to 99%, or greater than or equal to 99.5% of a single polymorphic form of endoxifen. In some embodiments, the pharmaceutical composition comprises greater than or equal to 96% of a single polymorphic form of endoxifen. In some embodiments, the pharmaceutical composition comprises greater than or equal to 98% of a single polymorphic form of endoxifen. In some embodiments, the pharmaceutical composition comprises greater than or equal to 99% of a single polymorphic form of endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the-46-KTS Docket No. 1 16771-1529908 (817 WO 1 )pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0177] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z). or Formula (I-E). In some embodiments, the pharmaceutical composition comprises crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 95% or at least 99% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 80%, at least 90%, at least 95% or at least 99% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 90%, at least 95% or at least 99% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 95% or at least 99% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 80% crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 90%. crystalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 95% crystalline Form I of (Z)- endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition comprises at least 99% cry stalline Form I of (Z)-endoxifen by weight of total endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0178] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (I-E). In some embodiments, the pharmaceutical composition comprises from 0.01 mg to 200 mg of crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 1 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 2 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 3 mg crystalline Form I of (Z)-endoxifen . In some embodiments, the pharmaceutical composition comprises about 4 mg crystalline Form I of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 6 mg -47-KTS Docket No. 1 16771-1529908 (817 WO 1 )crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 10 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 20 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 30 mg crystalline Form I of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 40 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 50 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 100 mg cry stalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 200 mg crystalline Form I of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises from 10 mg to 50 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 20 mg to 40 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 100 mg to 200 mg crystalline Form I of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises from 40 mg to 80 mg crystalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 60 mg to 80 mg cry stalline Form I of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0179] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z). or Formula (I-E). In some embodiments, the pharmaceutical composition comprises from 0.01 mg to 200 mg of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 1 mg (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 2 mg of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 3 mg (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 4 mg of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 6 mg of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 10 mg of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 20 mg of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 30 mg of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 40 mg of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 50 mg of (Z)- endoxifen. In some embodiments, the pharmaceutical composition comprises about 60 mg of (Z)--48-KTS Docket No. 1 16771-1529908 (817 WO 1 )endoxifen. In some embodiments, the pharmaceutical composition comprises about 100 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises about 200 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 10 mg to 50 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 20 mg to 40 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 100 mg to 200 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 40 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition comprises from 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0180] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition comprises from 10% to 100% of (Z)-endoxifen D- gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 100% of (Z)-endoxifen L-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 80% of (Z)-endoxifen D-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 80% of (Z)-endoxifen L-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 30% to 60% of (Z)-endoxifen D-gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 30% to 60% of (Z)-endoxifen L- gluconate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 100% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 80% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 60% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 40% of (Z)- endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 20% of (Z)-endoxifen citrate on a wt / wt-49-KTS Docket No. 1 16771-1529908 (817 WO 1 )basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 30% of (Z)-endoxifen citrate on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 100% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen citrate in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 80% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 60% of (Z)- endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 20% to 40% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 20% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition comprises from 10% to 30% of (Z)-endoxifen hydrochloride on a wt / wt basis of total endoxifen in the composition. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0181] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is an oral formulation. In some embodiments, the pharmaceutical composition comprises a tablet, a caplet, or a capsule. In some embodiments, the tablet is coated with one or more of an enteric coating agent, a control release agent or a film forming agent. The enteric coating agent, the control release agent and / or the film forming agent control or delay disintegration and absorption of the compositions including (Z)-endoxifen or salts thereof and elagolix or salts thereof in the gastrointestinal tract and thereby provide a sustained action over a longer period of time. In some embodiments, the caplet is coated with one or more of an enteric coating agent, a control release agent or a film forming agent. In some embodiments, the capsule is coated with one or more of an enteric coating agent, a control release agent or a film forming. In some embodiments, the tablet is an enteric coated tablet. In some embodiments, the tablet is an enteric tablet. In some embodiments, the caplet is an enteric coated caplet. In some embodiments, the caplet is an enteric caplet. In some embodiments, the capsule is an enteric capsule. In some embodiments, the capsule is an enteric coated capsule. The enteric tablets, enteric-50-KTS Docket No. 1 16771-1529908 (817 WO 1 )caplets, or enteric capsules of the present disclosure are prepared by techniques known in the art. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0182] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition comprises at least one pharmaceutical acceptable excipient and at least one pharmaceutical acceptable carrier. In some embodiments, the pharmaceutical composition comprises at least one pharmaceutical acceptable excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutical acceptable excipient and a pharmaceutical acceptable carrier. In some embodiments, the pharmaceutical composition comprises a pharmaceutical acceptable excipient. In some embodiments, the pharmaceutical composition comprises a pharmaceutical acceptable carrier. In some embodiments, the pharmaceutical acceptable excipients are selected from pharmaceutical acceptable disintegrants, pharmaceutical acceptable fillers, pharmaceutical acceptable lubricants, and pharmaceutical acceptable binders. In some embodiments, the pharmaceutical composition further comprises an enteric coating, an enteric capsule, an enteric caplet, an enteric tablet, or any combinations thereof. In some embodiments, the pharmaceutical composition further comprises an enteric coating, an enteric capsule, an enteric caplet, an enteric tablet, or a combination thereof. In some embodiments, the pharmaceutical composition further comprises an enteric capsule. In some embodiments, the pharmaceutical composition further comprises an enteric caplet. In some embodiments, the pharmaceutical composition further comprises an enteric tablet. In some embodiments, the pharmaceutical composition further comprises an enteric coating, a capsule, a caplet, or a tablet, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises an enteric coating, a capsule, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises an enteric coating, a caplet, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises an enteric coating, a tablet, or any combination thereof. In some embodiments, the pharmaceutical composition further comprises a capsule, a caplet, or a tablet. In some embodiments, the pharmaceutical composition further comprises a capsule. In some embodiments, the pharmaceutical composition further comprises a caplet. In some embodiments, the pharmaceutical composition further comprises a tablet. In some embodiments, the -51-KTS Docket No. 1 16771-1529908 (817 WO 1 )pharmaceutical composition further comprises a tablet-in-tablet, a tablet-in-capsules, a beads-in- capsule, or a spheres-in capsule. In some embodiments, the pharmaceutical composition further comprises a tablet-in-tablet. In some embodiments, the pharmaceutical composition further comprises a tablet-in-capsule. In some embodiments, the pharmaceutical composition further comprises a beads-in-capsule. In some embodiments, the pharmaceutical composition further comprises a spheres-in capsule. In some embodiments, the tablet is an enteric tablet. In some embodiments, the caplet is an enteric caplet. In some embodiments, the capsule is an enteric capsule. In some embodiments, the tablet is an enteric coated tablet. In some embodiments, the caplet is an enteric coated caplet. In some embodiments, the capsule is an enteric coated capsule. In some embodiments, the tablet is a delay ed-release tablet. In some embodiments, the caplet is a delayed-release caplet. In some embodiments, the capsule is a delayed-release capsule. In some embodiments, the tablet is an enteric coated delayed-release tablet. In some embodiments, the caplet is an enteric coated delayed-release caplet. In some embodiments, the capsule is an enteric coated delayed-release capsule. In some embodiments, the tablet of the tablet-in-capsule is a delayed-release tablet. In some embodiments, the capsule of the tablet-in-capsule is a delayed- release capsule. In some embodiments, one of the tablets of the tablet-in-tablet is a delayed-release tablet. In some embodiments, both of the tablets of the tablet-in-tablet are a delayed-release tablet. In some embodiments, the capsule of the beads-in-capsule is a delayed-release capsule. In some embodiments, the capsule of the spheres-in-capsule is a delayed-release capsule. In some embodiments, the tablet of the tablet-in-capsule is an enteric coated tablet. In some embodiments, the capsule of the tablet-in-capsule is an enteric coated capsule. In some embodiments, one of the tablets of the tablet-in-tablet is an enteric coated tablet. In some embodiments, both of the tablets of the tablet-in-tablet are an enteric coated tablet. In some embodiments, the capsule of the beads- in-capsule is an enteric coated capsule. In some embodiments, the capsule of the spheres-in- capsule is an enteric coated capsule. In some embodiments, the tablet of the tablet-in-capsule is an enteric tablet. In some embodiments, the capsule of the tablet-in-capsule is an enteric capsule. In some embodiments, one of the tablets of the tablet-in-tablet is an enteric tablet. In some embodiments, both of the tablets of the tablet-in-tablet are an enteric tablet. In some embodiments, the capsule of the beads-in-capsule is an enteric capsule. In some embodiments, the capsule of the spheres-in-capsule is an enteric capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated caplet. In some embodiments, the pharmaceutical composition further comprises an enteric coated tablet. In some embodiments, the pharmaceutical composition further comprises an enteric coated delayed release capsule, an enteric coated delayed -52-KTS Docket No. 1 16771-1529908 (817 WO 1 )release tablet, an enteric coated delayed release tablet-in-tablet, an enteric coated delayed release tablet-in-capsule, an enteric coated delayed release beads-in-capsule, or an enteric coated delayed release spheres-in capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated capsule, an enteric coated tablet, an enteric coated tablet-in-tablet, an enteric coated tablet-in-capsule, an enteric coated beads-in-capsule, or an enteric coated spheres- in capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated tablet. In some embodiments, the pharmaceutical composition further comprises an enteric coated tablet-in-tablet. In some embodiments, the pharmaceutical composition further comprises an enteric coated tablet-in-capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated beads-in-capsule. In some embodiments, the pharmaceutical composition further comprises an enteric coated spheres-in capsule. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated for oral administration in a subject in need thereof.

[0183] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), the enteric tablet is a hard tablet comprising the compound or the pharmaceutically acceptable salt of Formula (I) Formula (I-Z), or Formula (I-E), or a pharmaceutical composition thereof. In some embodiments, the pharmaceutical composition is formulated as an enteric tablet. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0184] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), the enteric capsule is a capsule comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E), or a pharmaceutical composition thereof. In some embodiments, the pharmaceutical composition is formulated as an enteric capsule. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.-53-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0185] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), the enteric coated tablet is a hard tablet comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), Formula (I-E), or a pharmaceutical composition thereof. In some embodiments, the pharmaceutical composition is formulated as an enteric coated tablet. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0186] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), the enteric coated capsule is a capsule comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E), or a pharmaceutical composition thereof. In some embodiments, the pharmaceutical composition is formulated as an enteric coated capsule. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0187] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z). a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition is formulated as an enteric tablet. In some embodiments, the pharmaceutical composition is formulated as an enteric capsule. In some embodiments, the pharmaceutical composition is formulated as an enteric coated tablet. In some embodiments, the pharmaceutical composition is formulated as an enteric coated capsule. In some embodiments, the pharmaceutical composition is formulated as a capsule. In some embodiments, the pharmaceutical composition is formulated as a tablet. In some embodiments, the pharmaceutical composition is formulated as a delayed-release capsule. In some embodiments, the pharmaceutical composition is formulated as a delayed-release tablet. In some embodiments, the enteric capsule or the enteric tablet is further coated with an enteric coating. In some embodiments, the pharmaceutical composition is formulated for oral administration.

[0188] In some embodiments, for a pharmaceutical composition disclosed herein, the enteric capsule is selected from a non-animal-based capsule, such as a hypromellose capsule (for example, commercially available self-gelling Vcaps, VCaps Plus, VCaps enteric, other enteric capsules made using Xcellodose, ENCODE colonic delivery technology, and EnTrinsicTM drug delivery' technology from Capsugel). Other technologies known in the art and available -54-KTS Docket No. 1 16771-1529908 (817 WO 1 )commercially (for example, Qualicaps, USA, Nutrascience, USA, etc.) can also be utilized for formulating enteric forms of oral solid dosage forms. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen or pharmaceutical composition thereof or elagolix or pharmaceutical composition thereof is filled neat into the capsule. In such API-in- capsule oral dosage forms, the active ingredient, (Z)-endoxifen or elagolix or pharmaceutical compositions thereof are free flowing powders or micronized powders. In some embodiments, the dosage form is a capsule. In some embodiments, the dosage form is an enteric capsule. In some embodiments, the dosage form is an enteric coated capsule. In some embodiments, the capsule is a seamless capsule. In some embodiments, the capsule is a banded capsule. In some embodiments, the capsule is an enteric, seamless capsule. In some embodiments, the capsule is an enteric, banded capsule. In some embodiments, the capsule is an enteric coated, seamless capsule. In some embodiments, the capsule is an enteric coated, banded capsule

[0189] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical compositions (preparations) comprises a control release agent. Examples of control release agent suitable for use include, without limitation, pH-dependent polymers, acidinsoluble polymers, methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, sodium alginate, zein, waxes, including synthetic waxes, microcrystalline waxes, paraffin wax, carnauba wax, and beeswax; polyethoxylated castor oil derivatives, hydrogenated oils, glyceryl mono-, di-tribenates, glyceryl monostearate, glyceryl distearate, long chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol, and any combinations thereof. In some embodiments, a time delay material such as glyceryl monostearate or glyceryl distearate may be used. In some embodiments, the controlled release reagent is a digestible waxy substance such as hard paraffin wax. In some embodiments, the control release agent is selected from methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate trimellitate, glyceryl rnono- , di-tribenates, glyceryl monostearate, glyceryl distearate, long chain alcohols, such as stearyl alcohol, cetyl alcohol, and polyethylene glycol, and any combinations thereof. In some embodiments, the control release agent is selected from methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl-55-KTS Docket No. 1 16771-1529908 (817 WO 1 )cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, cellulose acetate, and any combinations thereof. In some embodiments, the control release agent is selected from methyl acrylate-methacrylic acid copolymers, cellulose acetate phthalate (CAP), cellulose acetate succinate, hydroxypropyl methyl cellulose phthalate, hydroxypropyl methyl cellulose acetate succinate (hypromellose acetate succinate), polyvinyl acetate phthalate (PVAP), methyl methacrylate-methacrylic acid copolymers, shellac, and cellulose acetate.

[0190] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition comprises is a sustained release agent. Sustained release agent present in a sustained release composition of the present disclosure may be any sustained release agent known in the art to slow the release of a hydrophobic drug such as (Z)- endoxifen or a salt thereof. In some embodiments, the pharmaceutical composition is a sustained release pharmaceutical composition. In some embodiments, the sustained release agent is selected from cellulosic ethers, gums, acry lic resins such as polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, methyl methylacrylate, polyvinyl pyrrolidine, protein-derived compounds, and any combinations thereof. In some embodiments, the sustained release agent is selected from cellulosic ethers, gums, acrylic resins such as polymers and copolymers of acrylic acid, methacrylic acid, methyl acrylate, methyl methylacrylate, polyvinyl pyrrolidine, and any combinations thereof. Examples of cellulosic ethers include hydroxyalkyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses (HPMC or Hypromellose, for example Nos. 2208, 2906, 2910), hydroxypropyl methylcellulose phthalate (HPMCP or Hypromellose phthalate), carboxyalkyl celluloses, and carboxymethyl celluloses. In some embodiments, the sustained release agent is selected from hydroxyalkyl celluloses, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses (HPMC or Hypromellose, for example Nos. 2208, 2906, 2910), hydroxypropyl methylcellulose phthalate (HPMCP or Hypromellose phthalate), carboxy alkyd celluloses, and carboxymethyl celluloses. In some embodiments, the sustained release agent is selected from hydroxyalkyl celluloses, hydroxy ethyl celluloses, hydroxypropyl celluloses, and hydroxypropyl methylcelluloses (HPMC or Hypromellose, for example Nos. 2208, 2906, 2910). In some embodiments, the sustained release agent is selected from HPMC. In some embodiments, the sustained release agent is a pH sustained release agent. Examples of pH sustained release agents include, but are not limited to, -56-KTS Docket No. 1 16771-1529908 (817 WO 1 )acid insoluble polymers which become increasingly soluble and permeable above pH 5.0 but remaining impermeable below pH 5.0. Such controlled release polymers target upper small intestines and / or colon. Non-limiting examples of acid-insoluble polymers include cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid-methylacrylic acid copolymers, including those available commercially from EVONIK® or ROHM* (e.g., EUDRAGIT® sustained release polymers EUDRAGIT® RL (high permeability), EUDRAGIT® RS (low permeability) and EUDRAGIT® NM 30D (low permeability)), and any combinations thereof. In some embodiments, the pH sustained release agent is selected from cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, and acrylic acid-methylacrylic acid copolymers such as EUDRAGIT® sustained release polymers EUDRAGIT® RL, EUDRAGIT® RS, and EUDRAGIT® NM 30D. In some embodiments, the acid-insoluble polymers are selected from cellulose acetate phthalate, cellulose acetate butyrate, hydroxypropyl methyl cellulose phthalate, algenic acid salts such as sodium or potassium alginate, shellac, pectin, acrylic acid- methylacrylic acid copolymers (commercially available under the tradename EUDRAGIT* L and EUDRAGIT® S from Rohm America Inc., Piscataway, NJ as a powder or a 30% aqueous dispersion; or under the tradename EASTACRYL®. from Eastman Chemical Co., Kingsport. TN, as a 30% dispersion). In some embodiments, the acid-insoluble polymers are selected from EUDRAGIT® L100-55, EUDRAGIT® L30D-55, EUDRAGIT® L100, EUDRAGIT® L100 12,5, EUDRAGIT® S100, EUDRAGIT® S125, EUDRAGIT® FS 30D, EUDRAGIT® E100, EUDRAGIT® E 12,5, and EUDRAGIT* PO. In some embodiments, the acid-insoluble polymers are selected from EUDRAGIT® LI 00-55, EUDRAGIT® RS, EUDRAGIT® RL, EUDRAGIT® NE, EUDRAGIT® NM 30D, EUDRAGIT® S, EUDRAGIT® L and any combinations thereof. In some embodiments, the acid-insoluble polymers is selected from EUDRAGIT® S, EUDRAGIT® L, and a combination thereof. In some embodiments, the pH sustained release agent is selected from EUDRAGIT® LI 00-55. EUDRAGIT® RS, EUDRAGIT* RL. EUDRAGIT® NE. and EUDRAGIT® NM, and any combinations thereof. In some embodiments, the pH sustained release agent is selected from EUDRAGIT® LI 00-55, EUDRAGIT* RS, EUDRAGIT® RL, EUDRAGIT® NE, and EUDRAGIT® NM, and any combination thereof. In some embodiments, the pH sustained release agent is EUDRAGIT® L30D 55. One of skill in the art will recognize that at least some acid insoluble polymers listed herein will also be biodegradable.

[0191] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the-57-KTS Docket No. 1 16771-1529908 (817 WO 1 )pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition further comprises a delay or delay ed-release agent. Examples of delay or delay ed-release agents glycery l monostearate, glycery l distearate, and acidinsoluble polymers, for example polymethacrylate pH-sensitive polymer-based coatings, are used, (e.g.. as coating material, i.e., enteric coating agents, for enteric coating of capsules, caplets, and tablets). Commercial sources for delayed-release oral dosage forms are available, for example DRCaps made of hypromellose (HPMC) from Capsugel, USA. Such delayed-release oral dosage forms are acid-resistant and resist acidity as seen in stomach for at least 30 min, such as for at least 1 hour, for at least 1.5 hour, or for at least 2 hours. Such delayed release oral dosage forms release at least 40%, at least 50%, at least 60%, at least 70%, at least 80% or at least 90% of the (Z)-endoxifen or salts thereof or elagolix or salts thereof in the intestines (small intestines, large intestine / colon etc.).

[0192] Commercially available delayed release capsules such as those available from Capsugel (e.g., VCAPS® Plus enteric capsules), can be used to prepared delayed release capsules and are encompassed in the present disclosure. In some embodiments, the enteric delayed release capsules can be non-animal-based capsules, such as a Hypromellose capsule (for example, commercially available self-gelling VCAPS®, VCAPS® Plus, VCAPS® Enteric, other enteric capsules made using XCELLODOSE®, DRCAPS®, Encap Colonic Delivery’ (ENCODE), and ENTRINSICTM drug delivery’ technology’ from CAPSUGEL®). Other technologies known in the art and available commercially (for example, QUALICAPS®, USA, NutraScience, USA, etc.) for the formulating enteric forms of oral solid dosage forms can also be utilized. In some embodiments, the pharmaceutical compositions of the present disclosure may be encapsulated in a DRCAPS® enteric-resistant delayed release capsule. In some embodiments, the pharmaceutical compositions of the present disclosure may' be encapsulated in a EurdaCap® capsule. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen free base or salts thereof is filled neat into the capsule. In such API-in-capsule oral dosage forms, the active ingredient, (Z)-endoxifen or salts thereof can be free flowing powders or micronized powders. When the dosage form is a capsule, in at least one embodiment, the capsule can be a seamless capsule or a banded capsule.

[0193] In some embodiments, the enteric capsule is a non-animal based capsule, such as a hypromellose capsule (for example, commercially available self-gelling Vcaps. VCaps Plus, VCaps enteric, other enteric capsules made using Xcellodose, ENCODE colonic delivery technology’, and EnTrinsicTM drug delivery’ technology from Capsugel). Other technologies known in the art and available commercially (for example, Qualicaps, USA, Nutrascience, USA, -58-KTS Docket No. 1 16771-1529908 (817 WO 1 )etc.) for the formulating enteric forms of oral solid dosage forms are also be utilized. In at least one embodiment, the capsule is an API-in-capsule, meaning that the (Z)-endoxifen free base or salts thereof is filled neat into the capsule.

[0194] In some embodiments, for a pharmaceutical composition disclosed herein, an oral dosage form can be of any shape suitable for oral administration, such as spherical (0.05 - 5 mL), oval (0.05 - 7 mL), ellipsoidal, pear (0.3 - 5 mL), cylindrical, cubic, regular and / or irregular shaped. An oral dosage form may be of any size suitable for oral administration, for example, size 0, size 2, and the like.

[0195] In some embodiments, for a pharmaceutical composition disclosed herein, an entericresistant delayed release pharmaceutical composition may comprise an enteric coated delayed release capsule comprising from about from 65% to 95% hydroxypropyl methylcellulose by weight and from 3% to 10% gellan gum by weight, relative to total unfilled capsule weight, endoxifen or a pharmaceutical composition thereof comprising from 10% to 30% (Z)-endoxifen by weight, from 1% to 5% croscarmellose sodium by weight, from 60% to 95% microcrystalline cellulose by weight, and from 0.5% to 3% magnesium stearate by weight, relative to total fill weight of the composition. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising from 10 mg to 80 mg (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 10 mg of (Z)- endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 20 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 30 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 40 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 50 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 60 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 70 mg of (Z)-endoxifen per capsule. In some embodiments, the enteric-resistant delayed release pharmaceutical composition may be formulated in a dosage form comprising about 80 mg of (Z)-endoxifen per capsule.-59-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0196] For time delay or delayed-release pharmaceutical preparations of oral dosage forms, glyceryl monostearate, glyceryl distearate, and acid-insoluble polymers, for example polymethacrylate pH-sensitive polymer-based coatings, are used, (e.g., as coating material, i.e., enteric coating agents, for enteric coating of capsules, caplets, and tablets). Commercial sources for delayed-release oral dosage forms are available, for example DRCaps made of hypromellose (HPMC) from Capsugel, USA. Such delayed-release oral dosage forms are acid-resistant and resist acidity as seen in stomach for at least 30 min, such as for at least 1 hour, for at least 1.5 hour, or for at least 2 hours.

[0197] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition further comprises one or more excipients from 1% to 99%, 5% to 95%, from 5% to 90%, from 10% to 80%, from 15% to 70%, from 20% to 60%, from 30% to 95%, from 50% to 90%, from 60% to 90%, from 60% to 80%, or from 70% to 80% by weight of the total composition. In some embodiments, the composition comprises one or more excipients from 50% to 60%, from 60% to 70%, from 70% to 80%, or from 80% to 90% by weight of the total composition. In some embodiments, the composition comprises one or more excipients from 5% to 10%. from 10% to 20%, from 20% to 30%, or from 30% to 40% by weight of the total composition. In some embodiments, the composition comprises one or more excipients from 70% to 80%, or from 80% to 90% by weight of the total composition. In some embodiments, the composition comprises one or more excipient from 40% to 60% or from 60% to 80% by weight of the total composition. In some embodiments, the excipients are selected from bulking agents, binders, fillers, disintegrating agents, lubricants, glidants, control release agents, enteric coatings, film-forming agents, plasticizers, colorants, sweeteners, flavoring agents, or any combination thereof.

[0198] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a binder. Binders suitable for use in the pharmaceutical compositions provided herein include, but are not limited to, sucrose, starches such as com starch, potato starch, or starches such as starch paste, pregelatinized starch, and starch 1500, PEG 6000, methocel, WALOCEL® HM, LUVITEC®, caparolactam, AVICEL®, SMCC, UNI-PURE®, gelatin, natural and synthetic gums such as acacia, sodium alginate, alginic acid, other alginates, tragacanth, guar gum, cellulose and its derivatives (e.g., ethyl cellulose, cellulose acetate, carboxymethyl cellulose calcium, sodium carboxymethyl cellulose), polyvinyl pyrrolidone, methyl cellulose, polyvinyl pyrrolidone, hydroxypropyl methyl cellulose, (e.g., Nos.-60-KTS Docket No. 1 16771-1529908 (817 WO 1 )2208, 2906, 2910), microcrystalline cellulose, and mixtures thereof. Suitable forms of microcrystalline cellulose include, but are not limited to, the materials sold as AVICEL® PH 101, AVICEL® PH 103 AVICEL® RC 581, AVICEL® PH 105 (available from FMC Corporation, American Viscose Division, Avicel Sales, Marcus Hook, Pa.), and mixtures thereof. In some embodiments, pharmaceutical composition further comprises a mixture of microcrystalline cellulose and sodium carboxymethyl cellulose. Suitable anhydrous or low moisture excipients or additives include AVICEL® PH 103 and Starch 1500 LM.

[0199] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a fdler. In some embodiments, the filler is selected from microcrystalline cellulose, talc, calcium carbonate (e.g., granules or powder), sugars such as dextrose, sucrose, lactose, a salt such as calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, starches, powdered cellulose, cellulosic bases such as methyl cellulose, carboxymethyl cellulose dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatimzed starch, and any combinations thereof.

[0200] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z). or Formula (I-E). In some embodiments, the pharmaceutical composition comprises one or more fillers from 1% to 99%, 5% to 95%, from 5% to 90%, from 10% to 80%, from 15% to 70%, from 20% to 60%, from 30% to 95%, from 50% to 90%, from 60% to 90%, from 60% to 80%, or from 70% to 80% by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 50% to 60%, from 60% to 70%, from 70% to 80%. or from 80% to 90% by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 5% to 10%, from 10% to 20%, from 20% to 30%, or from 30% to 40% by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 70% to 80%. or from 80% to 90% by weight of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 40% to 60% or from 60% to 80% by weight of the total composition. In some embodiments, the pharmaceutical composition comprises one or more fillers from 5% to 10% or from 10% to 20% by weight of the total pharmaceutical composition. In some embodiments, the fillers are selected from dextrose, sucrose, lactose, calcium carbonate, calcium phosphate, sodium carbonate, sodium phosphate, starches, powdered cellulose, cellulosic bases such as methyl cellulose, carboxymethyl cellulose dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and any-61-KTS Docket No. 1 16771-1529908 (817 WO 1 )combination thereof. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0201] In some embodiments, for a pharmaceutical composition disclosed herein, one or more of a binder or a filler is present from 10% to 99% wt / wt of the pharmaceutical composition or the dosage form. In some embodiments, the pharmaceutical composition comprises binders and / or fillers from 15% to 99%, from 20% to 60%, from 25% to 55%, from 30% to 50%, from 35% to 60%. from 50% to 99% wt / wt of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises binders and / or fillers from 15% to 30% wt / wt of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises binders and / or fillers from 5% to 10% wt / wt of the total pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises binders and / or fillers from 30% to 60% wt / wt of the total pharmaceutical composition.

[0202] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a disintegrant. Disintegrants are used in the pharmaceutical composition to provide tablets that disintegrate when exposed to an aqueous environment. In some embodiments, disintegrants are selected from starches, modified starches, sodium starch glycolate, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, alginates, guar gum, xanthan gum, and resins. Tablets that contain too much disintegrant may disintegrate in storage, while those that contain too little may not disintegrate at a desired rate or under the desired conditions. Thus, a sufficient amount of disintegrant that is neither too much nor too little to detrimentally alter the release of the active ingredients should be used to form solid oral dosage forms. In some embodiments, the disintegrant is deep in the oral solid dosage form to delay disintegration. The amount of disintegrant used varies based upon the type of formulation, and is readily discernible to those of ordinary’ skill in the art.

[0203] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition comprises a disintegrant from 0. 1% to 10%, from 1.0% to 10%, from 1.5% to 10%, from 2.0% to 10%, from 2.5% to 10%, from 2.6% to 10%, from 2.8% to 10%, or from 2.9% to 10% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the formulation comprises a disintegrant from 0.1% to 8.0%, -62-KTS Docket No. 1 16771-1529908 (817 WO 1 )from 1.0% to 8.0%, from 1.5% to 8.0%, from 2.0% to 8.0%, from 2.5% to 8.0%, from 2.6% to 8.0%, from 2.8% to 8.0%, from 2.9% to 8.0% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 0.1% to 1.0% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 1% to 8% by weight of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 2% to 8% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 2% to 4% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 1% to 4% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 4% to 8% by weight, of the total fill weight of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 0.5% to 15% wt / wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 1% to 3% wt / wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 1% to 5% wt / wt of the pharmaceutical composition. In some embodiments, the pharmaceutical composition comprises a disintegrant from 5% to 10% wt / wt of the pharmaceutical composition. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is selected from starches, modified starches, sodium starch glycolate, microcrystalline cellulose, croscarmellose sodium, crospovidone. sodium starch glycolate. alginates, guar gum, and xanthan gum, and any combination thereof. In some embodiments, the disintegrant is selected from sodium starch glycolate, microcrystalline cellulose, croscarmellose sodium, crospovidone, sodium starch glycolate, and any combinations thereof. In some embodiments, the disintegrant is selected from sodium starch glycolate, microcrystalline cellulose, croscarmellose sodium, and any combination thereof. In some embodiments, the disintegrant is croscarmellose sodium. In some embodiments, the disintegrant is selected from agar, alginic acid, calcium carbonate, microcrystalline cellulose, croscarmellose sodium, crospovidone, polacrilin potassium, sodium starch glycolate, potato or tapioca starch, pre-gelatinized starch, other starches, clays, other algins, other celluloses, gums, and any combinations thereof.

[0204] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a lubricant. Lubricant that are used in the pharmaceutical compositions provided herein include, but are not limited to, calcium stearate,-63-KTS Docket No. 1 16771-1529908 (817 WO 1 )magnesium stearate, mineral oil, light mineral oil, glycerin, sorbitol, mannitol, polyethylene glycol, other glycols, stearic acid, sodium lauryl sulfate, talc, hydrogenated vegetable oil (e.g., peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil, and soybean oil), zinc stearate, magnesium stearate or potassium stearate, ethyl oleate, ethyl laureate, agar, and mixtures thereof. Additional lubricants include, for example, a SYLOID silica gel (AEROSIL 200, manufactured by W.R. Grace Co. of Baltimore, Md.), a coagulated aerosol of synthetic silica (marketed by Degussa Co. of Plano, Tex.), CABOSIL (a pyrogenic silicon dioxide product sold by Cabot Co. of Boston, Mass.), silicon dioxide, Q7-9120 (Dow Coming), and any combination thereof. If used at all, lubricants are typically used in an amount of less than 1% wt / wt of the formulation, composition, or dosage forms into which they are incorporated. In some embodiments, the lubricant is from 0. 1 % to 1 % of the pharmaceutical composition or dosage form. In some embodiments, the lubricant is from 0.5% to 2% of the pharmaceutical composition or dosage form. In some embodiments, the lubricant is from 1% to 3% of the pharmaceutical composition or dosage form. In some embodiments, the lubricant is magnesium stearate. In some embodiments, the lubricant is selected from zinc stearate, magnesium stearate, potassium stearate, and any combination thereof.

[0205] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition may further comprise a plasticizer. Plasticizers may be added to control the softness or pliability of oral dosage forms such as shell of a capsule, caplet, or a tablet and thus, may improve the mechanical properties of the pH-sensitive materials of the capsules or coatings on the oral dosage forms. Suitable plasticizers, include, without limitation, petroleum oils (for e.g., a paraffinic process oil. a naphthenic process oil. and an aromatic process oil), squalene, squalane, plant oils, (e.g., olive oil, camelia oil, castor oil, tall oil, and a peanut oil), silicon oils, dibasic acid esters, (e.g., dibutyl phthalate, and dioctyl phthalate), liquid rubbers (e.g., polybutene and aliquid isoprene rubber), liquid fatty acid esters (e.g., isopropyl myristate ISM), hexyl laurate, diethyl sebacate, and diisopropyl sebacate, triethyl citrate, triacetin, diethylene glycol, polyethylene glycols, polypropylene glycol, phthalates, sorbitol, glycol salicylate, crotaminton, and glycerin or mixtures thereof. The amount of plasticizer may vary depending upon the chemical composition of the pharmaceutical preparation. In some embodiments, plasticizer is sorbitol, dimethyl isosorbide, or a glycerol. In some embodiments, the plasticizer is 1% to 10%, such as 3% to 5% (wt / wt), of the pharmaceutical composition.

[0206] Examples of glidants include, but are not limited to, colloidal silicone dioxide, cellulose, calcium phosphate, di or tri-basic and the like. As an example, sweeteners or sweetening agents include sucrose, saccharin, dextrose, maltose, sugar substitutes, aspartame, xylitol, mannitol, -64-KTS Docket No. 1 16771-1529908 (817 WO 1 )cyclamate, sucralose, maltitol, sorbitol, acesulfame K, and the like. Examples of flavoring agents include peppermint, methyl salicylate, peppermint, spearmint, methyl salicylate, raspberry, red berry, strawberry, pineapple, orange, cherry and the like.

[0207] Rapid achievement of steady-state plasma levels of (Z)-endoxifen is also highly desirable. In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition provides a plasma level of (Z)-endoxifen in a subject administered the composition or formulation. In some embodiments, the (Z)-endoxifen is a crystalline form of (Z)-endoxifen, a polymorph of (Z)-endoxifen, a solvate of (Z)-endoxifen, or is amorphous (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is a cry stalline form of (Z)- endoxifen or a polymorph of (Z)-endoxifen. In various aspects, steady state plasma levels are achieved from day 7 to day 21. In some aspects, the steady state plasma levels are achieved by day 7 upon daily administration of a composition disclosed herein.

[0208] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z). or Formula (I-E). Area under Curve AUC(0-24hr) ("AUC24hf’) describes the total exposure of the subject in need thereof to a drug from time of dosing (0 hr) over a 24-hour period. The pharmaceutical composition achieves mean (AUC24hr) of 150 hr*ng / mL to 600 hr*ng / mE of (Z)-endoxifen on Day 1 of initial (first) dose of the pharmaceutical composition including 1 mg to 4 mg of (Z)-endoxifen. In some embodiments, the compositions achieves mean AUC24hr of 400 hr*ng / mL to 2500 hr*ng / mL of (Z)-endoxifen on Day 21 of initial (first) dose of compositions including 1 mg to 4 mg of (Z)- endoxifen.

[0209] AUCo-inf is a time-averaged concentration of drug circulating in the body fluid analyzed (normally plasma, blood or serum), describes the total exposure of the subject to a drug. The present disclosure provides that the exposure of a subject to endoxifen (AUCO-inf) isdose proportional. In some embodiments, AUCo-inf ranges from 200 hr*ng / mL to 10000 hr*ng / mL. In other embodiments, the AUCo-inf ranges from 300 hr*ng / mL to 8000 hr*ng / mL. In certain embodiments, the AUCo-inf ranges from 400 hr*ng / mL to 6000 hr*ng / mL over the dosing range of 1 mg to 4 mg of (Z)-endoxifen.

[0210] Dissolution of a formulated pharmaceutical composition disclosed herein is tested by the dissolution tests according to the current methods of USP 711. In some embodiments, the formulated pharmaceutical composition is protected from the acidic environment of the stomach-65-KTS Docket No. 1 16771-1529908 (817 WO 1 )and do not dissolve for at least 2 hours, at least 3 hours, at least 4 hours, at least 5 hours, 6 hours, at least 7 hours or at least 8 hours. In some embodiments, the formulated pharmaceutical composition do not release endoxifen for at least 6 hours. In some embodiments, the formulated pharmaceutical composition do not release endoxifen or a salt thereof for at least 2 hours. In some embodiments, the formulated pharmaceutical composition releases less than 10% of (Z)- endoxifen in the stomach after 2 hours after administration. In some embodiments, the formulated pharmaceutical composition releases less than 40% of (Z)-endoxifen in the stomach after 4 hours after administration. In some embodiments, the formulated pharmaceutical composition releases less than 50% of (Z)-endoxifen in the stomach after 6 hours after administration.

[0211] In some embodiments, for a formulated pharmaceutical composition disclosed herein, the formulated pharmaceutical composition provides that circulating (Z)-endoxifen released from the formulated pharmaceutical composition is cleared faster than tamoxifen. In some embodiments,, terminal elimination half-life of tamoxifen is 5-7 days, and peak concentration time of tamoxifen is approximately 5 hours post-dose. (Z)-endoxifen released from a formulated pharmaceutical composition disclosed herein provides a terminal elimination half-life ranging from 30 to 60 hours. This is significantly lower than tamoxifen. In some embodiments, the mean half-life ranges from 40 to 53 hours. The mean ratio of AUC24hr (Day 2I) / AUCo-inf (Day 1) typically ranges from 0.7 to 1.2 for compositions including 1 mg to 4 mg (Z)-endoxifen, or a salt thereof. Thus, accumulation of (Z)-endoxifen released from a composition disclosed herein does not significantly vary over continued treatment.

[0212] In some embodiments, for a formulated pharmaceutical composition disclosed herein, the formulated pharmaceutical releases at least 10% of endoxifen in the small intestine after 4 hours after administration. In some embodiments, the formulated pharmaceutical composition releases at least 30% of endoxifen after 6 hours after administration. In some embodiments, the formulated pharmaceutical composition releases at least 40% of endoxifen after 7 hours after administration. In some embodiments, the formulated pharmaceutical composition releases at least 50% of endoxifen after 8 hours after administration. In some embodiments, the formulated pharmaceutical composition releases at least 20% of endoxifen in the colon after 4 hours after administration. In some embodiments, the formulated pharmaceutical composition releases at least 40% of endoxifen in the colon after 6 hours after administration. In some embodiments, the formulated pharmaceutical composition releases at least 80% of endoxifen in the colon after 8 hours after administration.

[0213] Rapid absorption and bioavailability of the active agent are highly desirable. In an aspect, the present disclosure provides that the pharmaceutical compositions are formulated for certain -66-KTS Docket No. 1 16771-1529908 (817 WO 1 )pharmacokinetic (PK) properties. In some aspects, (Z)-endoxifen is released predominantly in the intestines (upper GI and colon) and is protected from the acidic environment in the stomach for at least 6 hours. Enteric coating of the capsule prevents the release of (Z)-endoxifen in the stomach for at least 6 hours as tested by a method of USP 711. In one aspect, rapid achievement of maximal and steady state plasma levels of (Z)-endoxifen is a particular aspect of the present disclosure. The present disclosure provides pharmaceutical compositions that achieve a maximal plasma level of (Z)-endoxifen ranging from 2 to 30 hours, from 3 to 20 hours, from 2 to 10 hours, or from 4 to 8 hours after administration of the compositions. Accordingly, in some embodiments, time to maximal (peak) plasma level of (Z)-endoxifen ranges from 2 to 10 hours after administration of the composition. In some embodiments, the time to maximal plasma level of (Z)-endoxifen ranges from 4 to 8 hours after administration of a composition disclosed herein. In some embodiments, the time to maximal plasma level of (Z)-endoxifen ranges from 6 to 8 hours after administration of a pharmaceutical composition disclosed herein.

[0214] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation. In some aspects, the pharmaceutical compositions intended for oral use are prepared in solid or fluid unit dosage forms. In at least some embodiments, the pharmaceutical compositions are formulated for oral delivery as tablets, caplets, capsules, pills, powders, troches, elixirs, suspensions, syrups, wafers, chewing gums, dragees, lozenges, and the like.

[0215] Examples of glidants include, but are not limited to, colloidal silicone dioxide, cellulose, calcium phosphate, di or tri-basic and the like.

[0216] As an example of sweeteners or sweetening agents include sucrose, saccharin, dextrose, maltose, sugar substitutes, aspartame, xylitol, mannitol, cyclamate, sucralose, maltitol, sorbitol, acesulfame K and the like.

[0217] Examples of flavoring agents include peppermint, methyl salicylate, peppermint, spearmint, methyl salicylate, raspberry, red berry, strawberry, pineapple, orange, cherry and the like.

[0218] One of skill in the art will further recognize that pharmaceutical compositions disclosed herein may include one or more of the excipients known in the art and disclosed herein in any combination appropriate for a desired formulation or preparation. Additional excipients may generally be found in Remington's The Science and Practice of Pharmacy, Meade Publishing Co., United States Pharmacopeia / National Formulary. One of skill in the art will be able to select-67-KTS Docket No. 1 16771-1529908 (817 WO 1 )suitable excipients necessary for the preparation of the formulations and appropriate dosage forms compatible with the route of administration based on his or her skill and knowledge in the art and the disclosures made herein. In all cases, the ultimate dosage form should be sterile and stable under the conditions of manufacture and storage.

[0219] In some embodiments, for a pharmaceutical composition disclosed herein, the pharmaceutical composition comprises a water activity (Aw) from 0.5 to 0.9. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.5 to 0.8. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.5 to 0.75. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.4 to 0.6. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.2 to 0.4. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.25 to 0.5. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.1 to 0.25. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.05 to 0.1. In some embodiments, the pharmaceutical composition comprises a water activity (Aw) from 0.1 to 0.25. When the water activity (Aw) is less than 0.75, testing Total Aerobic Plate Count (TAC) and USP indicator organism is ty pically not necessary'. The publication, “Microbial Bioburden on Oral Solid Dosage Form,” by Jose E. Martinez, Pharmaceutical Technology, February 2002, pages 58 to 70, is hereby incorporated byreference in its entirety. In some embodiments, pharmaceutical composition is formulated as a solid dosage. In some embodiments, the solid dosage is an oral solid dosage. In some embodiments, the solid dosage is a tablet or a capsule. In some embodiments, the solid dosage is a tablet.

[0220] In some embodiments, for a pharmaceutical composition disclosed herein, the solid dosage form is a solid oral dosage form. In some embodiments, the solid oral dosage is selected from a tablet, a caplet, a capsule, and any combination thereof. In some embodiments, the capsule is a hard capsule or a soft capsule. In other embodiments, the capsule is a gelatin capsule, gelatin-free capsule, a “cap-in-cap” capsule, an alginate capsule, a hydroxypropylmethyl cellulose (HPMC) capsule, a polyvinyl alcohol (PVA) capsule, a hypromellose capsule, or a starch capsule.

[0221] Dosage to be administered to a subject will be usually in a unit dosage form.

[0222] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z). a pharmaceutical composition is provided comprising the compound or the pharmaceutically acceptable salt of Formula (I), Formula (I-Z), or Formula (I-E). In some embodiments, the pharmaceutical composition is administered at a dose of 0.01 mg to 10.0 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose -68-KTS Docket No. 1 16771-1529908 (817 WO 1 )of 0.1 mg to 10.0 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 1 mg to 10 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 1 mg to 5 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 5 mg to 10 mg of (Z)- endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 10 mg to 20 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 20 mg to 40 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 40 mg to 60 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 80 mg to 100 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 120 mg to 140 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of 140 mg to 200 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose selected from 5 mg to 10 mg, 10 mg to 20 mg, 20 mg to 40 mg, and 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose selected from 10 mg to 20 mg, 20 mg to 40 mg, and 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose selected from 20 mg to 40 mg and 60 mg to 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose selected from 20 mg to 40 mg, 60 mg to 80 mg, 80 mg to 100 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose about 20 mg of (Z)- endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose about 30 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 40 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 50 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 60 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 70 mg of (Z)- endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 80 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 90 mg of (Z)-endoxifen per unit dose to a subject in need thereof. In some embodiments, the pharmaceutical composition is administered at a dose of about 10 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 20 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 70 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical-69-KTS Docket No. 1 16771-1529908 (817 WO 1 )composition is administered at a dose of about 25 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 30 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 35 mg of (Z)-endoxifen per unit dose to a subject in need thereof. In some embodiments, the pharmaceutical composition is administered at a dose of about 45 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 55 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 65 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is administered at a dose of about 75 mg of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the (Z)-endoxifen is a pharmaceutically acceptable salt of (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is (Z)-endoxifen citrate. In some embodiments, the (Z)-endoxifen is (Z)-endoxifen hydrochloride. In some embodiments, the (Z)-endoxifen is a cry stal 1 i ne form of (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is a polymorph form of (Z)-endoxifen. In some embodiments, the (Z)-endoxifen is a solvate form of (Z)-endoxifen. In some embodiments, the pharmaceutical composition is orally administered. In some embodiments, the pharmaceutical composition is administered once every71, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days. In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the pharmaceutical composition is administered once every 1, 2. or 3 days. In some embodiments, the pharmaceutical composition is administered once every 5, 6, 7, or 8 days. In some embodiments, the pharmaceutical composition is administered once every 2 days. In some embodiments, the pharmaceutical composition is administered once every' 3 days. In some embodiments, the pharmaceutical composition is administered twice every 1. 2, 3, 4. 5,6, 7, 8, 9, or 10 days. In some embodiments, the pharmaceutical composition is administered twice daily. In some embodiments, the pharmaceutical composition is administered twice every 1, 2, or 3 days. In some embodiments, the pharmaceutical composition is administered twice every' 5, 6,7, or 8 days. In some embodiments, the pharmaceutical composition is administered twice every’ 2 days. In some embodiments, the pharmaceutical composition is administered twice every 3 days. In some embodiments, the pharmaceutical composition is administered once daily. In some embodiments, the pharmaceutical composition is an oral pharmaceutical composition. In some embodiments, the pharmaceutical composition is formulated for oral administration. In some embodiments, the pharmaceutical composition is formulated as an oral pharmaceutical formulation.

[0223] In some embodiments, for a compound or a pharmaceutically acceptable salt of Formula (I) or Formula (I-Z), the endoxifen is administered as an enteric table, enteric caplet, or enteric-70-KTS Docket No. 1 16771-1529908 (817 WO 1 )capsule. In some aspects, the enteric tablets, enteric caplets, and enteric capsules may be uncoated. In some embodiments, the (Z)-endoxifen is administered as an enteric table, enteric caplet, or enteric capsule. In some aspects, the enteric tablets, enteric caplets, and enteric capsules may be uncoated. Hard uncoated capsules with enteric capability using intrinsically enteric capsule technology (for example, EnTrmsic Drug Delivery available from Capsugel) are suitable for the purpose of the present disclosure.Generation of a Risk Score for Treatment

[0224] In some aspects, the algorithm-based analysis may include generating a risk score resulting from the breast cancer risk estimate determining step. This risk score may provide a quantitative measure of the subject's risk of developing an interval or occult mammographic cancer, based on the features detected in the mammograms and other relevant factors. The risk score may be generated using various statistical or machine learning techniques, and may be calibrated to reflect the prevalence and incidence rates of breast cancer in a specified population. The risk score may be used to guide the administration of an estrogen receptor modulating pharmaceutical, with higher risk scores potentially warranting more aggressive or intensive treatment regimens.

[0225] The algorithm described herein was developed through a rigorous training process using a dataset of mammograms from the KARMA cohort, which includes detailed mammographic images from approximately 70,000 women who have been followed over several years. Among these women, 3,000 to 4,000 have developed breast cancer. The algorithm is trained to compare mammograms of women who developed breast cancer with those who did not, extracting critical features such as mammographic density and microcalcifications. This enables the algorithm to identify breast cancer and assess the risk of breast cancer with high accuracy.

[0226] The training process of the algorithm involves several key steps: data preprocessing, feature extraction, model training, and validation. During data preprocessing, the mammogram images are normalized, and the breast tissue is segmented to focus on the relevant areas. Feature extraction is performed using advanced image processing techniques to identify key characteristics associated with breast cancer risk. The model is then trained using supervised learning techniques, where the algorithm learns to distinguish between mammograms of women with and without breast cancer based on the extracted features. Validation is conducted using a separate set of mammograms to ensure the accuracy and reliability of the algorithm. The algorithm demonstrates high sensitivity and specificity in identifying patterns associated with increased breast cancer risk. Patients identified as high risk can then be preemptively treated, including (Z)--71-KTS Docket No. 1 16771-1529908 (817 WO 1 )endoxifen, to prevent breast cancer, reduce breast density compared to a baseline level of breast density, or reduce a breast cancer risk compared to a pre-determined high score level of risk.

[0227] In some aspects, the method may further involve plotting a risk model resulting from the breast cancer risk estimate determining step. This risk model may provide a visual representation of the subject's risk of developing breast cancer over time, based on the risk score and other relevant factors. The risk model may be plotted on a graph or chart, with the x-axis representing time and the y-axis representing the risk score. The risk model may be updated over time as new mammograms are analyzed and as the subject's risk factors change. The risk model provides a valuable tool for tracking the subject's breast health over time, and aids in the early detection and treatment of breast cancer.

[0228] In other aspects, the algorithm-based analysis may include generating a risk model from a digital breast tomosynthesis. Digital breast tomosynthesis is a type of 3D mammography that captures multiple images of the breast from different angles, providing a more detailed and comprehensive view of the breast tissue. The algorithm may analyze these images to detect features and patterns associated with breast cancer, and may generate a risk model based on this analysis. The risk model may provide a 3D representation of the subject's risk of developing breast cancer, potentially enhancing the accuracy and precision of the risk prediction. The use of digital breast tomosynthesis in the algorithm-based analysis may provide a more nuanced and detailed assessment of the subject's breast health, potentially aiding in the early detection and treatment of breast cancer.

[0229] In some aspects, a system for managing breast health may be provided. This system may include various modules designed to facilitate the method of breast health management as described above. For instance, the system may include a mammogram presentation module. This module may be configured to present a plurality of mammograms from one or more breasts of a subject over a time period greater than a year. In some cases, the mammogram presentation module may be configured to present the mammograms in chronological order, providing a visual timeline of changes in breast tissue over time.

[0230] The system may also include an algorithm-based analysis module. This module may be configured to perform an analysis of the mammograms, predicting a risk of a mammographic cancer, such as an interval or occult mammographic cancer. In some cases, the algorithm-based analysis module may be further configured to compare the chronological order of the mammograms to detect changes in breast density over time. This could provide valuable information about the progression or regression of any abnormalities detected in the breast tissue.-72-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0231] In some aspects, the algorithm-based analysis module may be further configured to generate a risk score based on the detected changes in breast density, the age of the subject, and the incidence rate of breast cancer in a specified population. This risk score may provide a quantitative measure of the subject's risk of developing breast cancer, potentially aiding in the early detection and treatment of this condition.

[0232] The system may further include a pharmaceutical administration module. This module may be configured to administer an estrogen receptor modulating pharmaceutical to the subject based on the breast cancer risk score generated from the algorithm-based analysis. In some cases, the pharmaceutical administration module may be further configured to adjust the dosage of the estrogen receptor modulating pharmaceutical based on the detected changes in breast density. This could allow for a personalized treatment regimen that is tailored to the individual's risk profile and specific breast tissue characteristics.

[0233] In some aspects, the pharmaceutical administration module may be further configured to administer the estrogen receptor modulating pharmaceutical to the subject based on the risk score. This could provide a targeted approach to the treatment of breast cancer, potentially improving the prognosis for the subject and reducing the risk of recurrence.

[0234] In summary, the system for managing breast health may integrate various modules to facilitate the presentation of mammograms, the algorithm-based analysis of the mammograms, and the administration of an estrogen receptor modulating pharmaceutical based on a breast cancer risk score. This integrated approach may streamline the process of breast health management, potentially improving the efficiency and effectiveness of breast cancer detection and treatment.Methods of Treatment, Prevention, and Uses

[0235] In one aspect, the present disclosure provides a method of reducing a risk of a breast cancer in a subject in need thereof, the method comprising: presenting a mammogram from one or more breasts of the subject in need thereof; and subsequently administering a therapeutically effective amount of an estrogen receptor-modulating pharmaceutical to the subject in need thereof, thereby reducing a risk of a breast cancer in the subject in need thereof.

[0236] In another aspect, the present disclosure provides a method of treating an occult breast cancer in a subject in need thereof, the method comprising: presenting a mammogram from one or more breasts of the subject in need thereof;-73-KTS Docket No. 1 16771-1529908 (817 WO 1 )subsequently administering a therapeutically effective amount of an estrogen receptor-modulating pharmaceutical to the subject in need thereof, thereby treating the occult breast cancer in the subject in need thereof.

[0237] In one aspect, the present disclosure provides a method of treating a breast cancer in a subject in need thereof, the method comprising: presenting a mammogram from one or more breasts of the subject in need thereof; performing an algorithm-based analysis of the mammogram, the algorithm-based analysis producing a breast cancer risk score; determining that the subject in need thereof has a higher breast cancer risk score than a baseline or reference breast cancer risk score; and administering a therapeutically effective amount of an estrogen receptor-modulating pharmaceutical to the subject in need thereof, wherein the breast cancer is treated.

[0238] In one aspect, the present disclosure provides a method of reducing breast density in a subject in need thereof, the method comprising: presenting a mammogram from one or more breasts of the subject in need thereof; subsequently performing an analysis of the mammogram, the analysis determining that a breast density score is higher than a baseline or reference score; and administering a therapeutically effective amount of an estrogen receptor-modulating pharmaceutical to the subject in need thereof.

[0239] In some embodiments, for a method of the present disclosure, the breast cancer is an interval breast cancer or an occult breast cancer. In some embodiments, the breast cancer is an interval breast cancer. In some embodiments, the breast cancer is an occult breast cancer.

[0240] In some embodiments, for a method of the present disclosure, the method prevents an interval breast cancer or reduces the risk of an interval breast cancer in the subject in need thereof. In some embodiments, the method prevents an interval breast cancer in the subject in need thereof. In some embodiments, the method reduces the risk of an interval breast cancer in the subject in need thereof.

[0241] In some embodiments, for a method of the present disclosure, the method further comprises presenting a further mammogram on the one or more breasts of the subject in need thereof following administering the therapeutically effective amount of the estrogen receptormodulating pharmaceutical to the subject. In some embodiments, the method further comprises presenting a subsequent further mammogram on the one or more breasts of the subject in need-74-KTS Docket No. 1 16771-1529908 (817 WO 1 )thereof following administering the effective amount of the estrogen receptor-modulating pharmaceutical to the subj ect.

[0242] In some embodiments, for a method of the present disclosure, the method further comprises performing an analysis of the mammogram, the analysis determining that a breast density score is higher than a baseline or reference score. In some embodiments, the method further comprises performing an analysis of the mammogram. In some embodiments, the method further comprises performing an analysis of the further mammogram. In some embodiments, the method further comprises performing an analysis of the subsequent mammogram. In some embodiments, the analysis determines that a breast density score is higher than a baseline or reference score. In some embodiments, the analysis determines that a breast density score is higher than a baseline score. In some embodiments, the analysis determines that a breast density score is higher than a reference score. In some embodiments, the analysis determines that a breast density score is higher in the subject in need thereof than prior to the administering. In some embodiments, the analysis determines that a breast density score is lower in the subject in need thereof than prior to the administering. In some embodiments, the breast density score is from about 10% to 20% higher. In some embodiments, the breast density score is from about 10% to 30% higher. In some embodiments, the breast density score is from about 10% to 40% higher. In some embodiments, the breast density score is from about 20% to 50% higher. In some embodiments, the breast density score is from about 30% to 50% higher. In some embodiments, the breast density score is from about 50% to 80% higher. In some embodiments, the breast density score is from about 50% to 100% higher. In some embodiments, the breast density score is from about 10% to 20% lower. In some embodiments, the breast density score is from about 10% to 30% lower. In some embodiments, the breast density score is from about 10% to 40% lower. In some embodiments, the breast density' score is from about 20% to 50% lower. In some embodiments, the breast density score is from about 30% to 50% lower. In some embodiments, the breast density score is from about 50% to 80% lower. In some embodiments, the breast density score is from about 50% to 100% lower.

[0243] In some embodiments, for a method of the present disclosure, the estrogen receptor- modulating pharmaceutical comprises a compound of Formula (I):KTS Docket No. 1 16771-1529908 (817 WO 1 )some embodiments, the estrogen receptor-modulating pharmaceutical comprises a compound ofFormula (I):Formula (I), wherein: the compound or pharmaceutically acceptable salt of Formula (I) is endoxifen; and the endoxifen is greater than 95% (Z)-endoxifen. In some embodiments, the estrogen receptor-modulating pharmaceutical is (Z)-endoxifen.

[0244] In some embodiments, for a method of the present disclosure or for a compound or pharmaceutically acceptable salt of Formula (I), the endoxifen is greater than 90% (Z)-endoxifen. In some embodiments, the endoxifen is greater than 95%, greater than 96%, greater than 97%, greater than 98%, greater than 99%, or greater than 99.5% (Z)-endoxifen. In some embodiments, the endoxifen is greater than 95% (Z)-endoxifen. In some embodiments, the endoxifen is greater than 98% (Z)-endoxifen. In some embodiments, the endoxifen is in a free base form. In some embodiments, the endoxifen is in a pharmaceutically acceptable salt form. In some embodiments the endoxifen is a pharmaceutically acceptable salt. In some embodiments, endoxifen is a free base form. In some embodiments, the endoxifen is greater than 90% (Z)-endoxifen. In some embodiments, the endoxifen is greater than 91% (Z)-endoxifen. In some embodiments, the endoxifen is greater than 92% (Z)-endoxifen. In some embodiments, the endoxifen is greater than 93% (Z)-end oxifen. In some embodiments, the endoxifen is greater than 94% (Z)-endoxifen. In some embodiments, the endoxifen is greater than 95% (Z)-endoxifen. In some embodiments, the endoxifen is greater than 96% (Z)-endoxifen. In some embodiments, the endoxifen is greater than 97% (Z)-endoxifen. In some embodiments, the endoxifen is greater than 98% (Z)-endoxifen. In some embodiments, the endoxifen is greater than 99% (Z)-endoxifen. In some embodiments, the pharmaceutically acceptable salt of the (Z)-endoxifen is selected from the group consisting of an: arecoline, besylate, bicarbonate, bitartrate, butylbromide, citrate, camysylate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate, hydrabamine, hydrobromide, hydrochloride, hydroxynapthanoate. isethionate, malate, mandelate, mesylate, methylbromide, methylnitrate, methyl sulfate, mucate, napsylate, nitrate, pamoate (embonate), pantothenate, phosphate / diphosphate, polygalacturonate, salicylate, stearate, sulfate, tannate, teoclate, triethiodide, benzathine, clemizole, chloroprocaine, choline, diethylamine, diethanolamine, ethylenediamine, meglumine, piperazine, procaine, aluminum, barium, bismuth, lithium, magnesium, potassium, and zinc. In some embodiments, the pharmaceutically acceptable salt of-76-KTS Docket No. 1 16771-1529908 (817 WO 1 )the (Z)-endoxifen is selected from citrate, gluconate, and hydrochloride. In some embodiments, the pharmaceutically acceptable salt of the (Z)-endoxifen is (Z)-endoxifen gluconate. In some embodiments, the pharmaceutically acceptable salt of the (Z)-endoxifen is (Z)-endoxifen citrate. In some embodiments, the pharmaceutically acceptable salt of the (Z)-endoxifen is (Z)-endoxifen hydrochloride.

[0245] In some embodiments, for a method of the present disclosure, the therapeutically effective amount of (Z)-endoxifen is from about 0.01 to 360 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 1 to 180 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 10 to 80 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 0.01 mg to 200 mg, from 0.1 mg to 100 mg, from 0.1 mg to 50 mg, from 0.1 mg to 20 mg, from 1 mg to 20 mg, from 20 mg to 50 mg, from 50 mg to 100 mg, from 100 mg to 200 mg, or from 200 mg to 360 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 1 mg to about 180 mg, about 10 mg to about 80 mg, about 10 mg to about 40 mg, about 40 mg to about 80 mg, or about 10 mg to about 60 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 10 mg to about 80 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 10 mg to about 60 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 10 mg to about 40 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 10 mg to about 20 mg. In some embodiments, the therapeutically effective amount of (Z)- endoxifen is from about 40 mg to about 80 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 0.5 mg to about 10 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 0. 1 mg to about 5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 1 mg to about 5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 5 mg to about 10 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 0. 1 mg to about 2 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is from about 0.01 mg to 200 mg, about 0.1 mg to 100 mg, about 0.1 mg to 50 mg, about 0. 1 mg to 20 mg, or about 1 mg to 20 mg.

[0246] In some embodiments, for a method of the present disclosure, the therapeutically effective amount of (Z)-endoxifen is 0.5 mg, 1 mg. 1.5 mg, 2 mg, 2.5 mg. 3 mg, 3.5 mg, 4 mg. 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 0.5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 1 mg. In some -77-KTS Docket No. 1 16771-1529908 (817 WO 1 )embodiments, the therapeutically effective amount of (Z)-endoxifen is 1.5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 2 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 2.5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 3 mg. In some embodiments, the therapeutically effective amount of (Z)-end oxifen is 3.5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 4 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 4.5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 5.5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 6 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 6.5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 7 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 7.5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 8 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 8.5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 9 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 9.5 mg. In some embodiments, the therapeutically effective amount of (Z)-endoxifen is 10 mg.

[0247] In some embodiments, for a method of the present disclosure, the (Z)-endoxifen is administered at a unit dose from about 0.05 to 0.5 mg / kg, 0.5 to 1 mg / kg, 1 to 1.5 mg / kg, 1.5 to 2 mg / kg, 2 to 5 mg / kg, 5 to 10 mg / kg, or 10 to 20 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose from about 0.05 to 0.5 mg / kg, about 0.5 to 1 mg / kg, about 1 to 1.5 mg / kg, about 1.5 to 2 mg / kg, about 2 to 5 mg / kg, or about 5 to 10 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose from about 0.05 mg / kg to about 1 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose from about 0.5 mg / kg to about 2 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose from about 1 mg / kg to about 4 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose from about 1 mg / kg to about 8 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose from about 2 mg / kg to about 6 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose from about 0.05 to about 0.5 mg / kg. In some embodiments, the (Z)- endoxifen is administered at a unit dose from about 0.5 to about 1 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose from about 1 to about 1.5 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose from about 1.5 to about 2 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose from about 2 to about 5-78-KTS Docket No. 1 16771-1529908 (817 WO 1 )mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose from about 5 to about 10 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose of about 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, or 2.0 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose is selected from 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg. 1.5 mg / kg. and 2.0 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose of about 0.05 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose of about 0. 1 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose of about 0.5 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose of about 1 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose of about 1.5 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose of about 2.0 mg / kg. In some embodiments, the (Z)-endoxifen is administered at a unit dose of about 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, or 2.0 mg / kg.

[0248] In some embodiments, for a method of the present disclosure, the (Z)-endoxifen is administered once a day, twice a day, three times a day, four times a day, every other day, once evei ' three days, or once every four days. In some embodiments, the (Z)-endoxifen is administered once a day. In some embodiments, the (Z)-endoxifen is administered twice a day. In some embodiments, the (Z)-endoxifen is administered three times a day. In some embodiments, the (Z)-endoxifen is administered four times a days. In some embodiments, the (Z)-endoxifen is administered every other day. In some embodiments, the (Z)-endoxifen is administered once every three days. In some embodiments, the (Z)-endoxifen is administered once every four days. In some embodiments, the (Z)-endoxifen is administered for at least 1 month to 5 years. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 3 months. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 6 months. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 9 months. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 12 months. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 15 months. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 18 months. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 21 months. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 24 months. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 36 months. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 48 months. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 60 months. In some embodiments, (Z)-endoxifen is administered daily for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6-79-KTS Docket No. 1 1 771-1529908 (817 WO 1 )months, or greater. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 1 month. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 2 months. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 1 week. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 2 weeks. In some embodiments, the (Z)-endoxifen is administered for less than or equal to 3 weeks. In some embodiments, the (Z)-endoxifen is administered orally.

[0249] In some embodiments, for a method of the present disclosure, a dosage form comprises a unit dose. In some embodiments, the unit dose comprises a compound or pharmaceutically acceptable salt of Formula (I) or Formula (I-Z). In some embodiments, the unit dose comprises (Z)-endoxifen. In some embodiments, the dosage form is selected from a solid dosage form. In some embodiments, the solid dosage form is formulated as an enteric formulation or as a delayed release formulation. In some embodiments, the solid dosage form is selected from a tablet, a caplet, a capsule, an enteric tablet, an enteric caplet, an enteric capsule, a delay ed-release tablet, a delayed-release caplet, and a delayed-release capsule. In some embodiments, the solid dosage form is selected from a tablet, a caplet, and a capsule. In some embodiments, the solid dosage form is selected from an enteric tablet, an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, and a delayed-release capsule. In some embodiments, the solid dosage form is selected from an enteric tablet, an enteric caplet, and an enteric capsule. In some embodiments, the solid dosage form is selected from a delayed-release tablet, a delayed-release caplet, and a delayed-release capsule. In some embodiments, the solid dosage form is selected from a tablet, an enteric tablet, and a delayed-release tablet. In some embodiments, the solid dosage form is selected from a capsule, an enteric capsule, and a delayed-release capsule. In some embodiments, the solid dosage form is selected from an enteric tablet and a delayed-release tablet. In some embodiments, the solid dosage form is selected from an enteric capsule and a delayed- release capsule.

[0250] In some embodiments, for a method of the present disclosure, a compound or pharmaceutically acceptable salt of Formula (I) is administered in a dosage form. In some embodiments, the dosage form is administered orally. In some embodiments, the dosage form is formulated as an enteric formulation. In some embodiments, the dosage form is formulated as an enteric formulation or as a delayed release formulation. In some embodiments, the dosage form is formulated as a delayed release formulation. In some embodiments, the dosage form is a solid dosage form. In some embodiments, the dosage form is a solid dosage form is selected from a caplet, a capsule, and a tablet. In some embodiments, the dosage form is formulated as an enteric tablet, an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, or a -80-KTS Docket No. 1 16771-1529908 (817 WO 1 )delayed-release capsule. In some embodiments, the dosage form is formulated as an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, or a delayed-release capsule. In some embodiments, the dosage form is formulated as an enteric tablet, an enteric caplet, or an enteric capsule. In some embodiments, the dosage form comprises hydroxypropyl methyl cellulose. In some embodiments, the dosage form is formulated as a delayed release composition. In some embodiments, the dosage form is formulated as a delayed-release caplet, or a delayed- release capsule. In some embodiments, the dosage form is formulated as an enteric capsule or a delayed-release capsule. In some embodiments, the dosage form is formulated as an enteric tablet or a delayed-release tablet.

[0251] In some embodiments, for a method of the present disclosure, a compound or pharmaceutically acceptable salt of Formula (I) is administered in a dosage form. In some embodiments, the dosage form comprises a therapeutically effective amount from 0.01 to 360 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from 0.01 to 360 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from 1 to 180 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from 10 to 80 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from 0.01 mg to 200 mg, from 0. 1 mg to 100 mg, from 0. 1 mg to 50 mg, from 0. 1 mg to 20 mg, from 1 mg to 20 mg, from 20 mg to 50 mg, from 50 mg to 100 mg, from 100 mg to 200 mg, or from 200 mg to 360 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from about 1 mg to about 180 mg, about 10 mg to about 80 mg. about 10 mg to about 40 mg, about 40 mg to about 80 mg, or about 10 mg to about 60 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from 0.1 mg to 20 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from 0. 1 mg to 10 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from 0.1 mg to 5 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from 1 mg to 5 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from 2 mg to 8 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from 1 mg to 4 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from about 10 mg to about 80 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from about 10 mg to about 80 mg of the (Z)- endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount-81-KTS Docket No. 1 16771-1529908 (817 WO 1 )from about 1 mg to about 80 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from about 40 mg to about 80 mg of the (Z)- endoxifen. In some embodiments, the dosage form comprises a therapeutically effective amount from about 10 mg to about 60 mg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a unit dose of 0.05 mg / kg. 0.1 mg / kg. 0.5 mg / kg. 1 mg / kg. 1.5 mg / kg, or 2.0 mg / kg unit dose of the (Z)-endoxifen. In some embodiments, the dosage form comprises a unit dose from about 0. 1 mg / kg to about a 1 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a unit dose from about 0.1 mg / kg to about 1.5 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a unit dose from about 0. 1 mg / kg to about 2.0 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a unit dose from about 0.5 mg / kg to about 2.0 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form comprises a unit dose from about 0.05 mg / kg to about 1 mg / kg of the (Z)-endoxifen.

[0252] In some embodiments, for a method of the present disclosure, a compound or pharmaceutically acceptable salt of Formula (I) is administered in a dosage form. In some embodiments, the dosage form is administered at a unit dose of about 0.05 to 0.5 mg / kg, about 0.5 to 1 mg / kg, about 1 to 1.5 mg / kg, about 1.5 to 2 mg / kg, about 2 to 5 mg / kg, or about 5 to 10 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of about 0.05 to about 0.5 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of about 0.5 to about 1 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of about 1 to about 1.5 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of about 1.5 to about 2 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of about 2 to about 5 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of about 5 to about 10 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, or 2.0 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose selected from 0.05 mg / kg. 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1.5 mg / kg, and 2.0 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of 0.05 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of 0. 1 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of 0.5 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of 1 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of 1.5 mg / kg of the (Z)-endoxifen. In some embodiments, the dosage form is administered at a unit dose of 2.0 mg / kg of the (Z)-endoxifen.-82-KTS Docket No. 1 16771-1529908 (817 WO 1 )In some embodiments, the dosage form is administered once a day, twice a day, three times a day, four times a day, every other day, once every three days, or once every four days. In some embodiments, the dosage form is administered once a day. In some embodiments, the dosage form is administered twice a day. In some embodiments, the dosage form is administered three times a day. In some embodiments, the dosage form is administered four times a days. In some embodiments, the dosage form is administered every other day. In some embodiments, the dosage form is administered once every three days. In some embodiments, the dosage form is administered once every four days. In some embodiments, the dosage form is administered for at least 1 month to 5 years. In some embodiments, the dosage form is administered for less than or equal to 3 months. In some embodiments, the dosage form is administered for less than or equal to 6 months. In some embodiments, the dosage form is administered for less than or equal to 9 months. In some embodiments, the dosage form is administered for less than or equal to 12 months. In some embodiments, the dosage form is administered for less than or equal to 15 months. In some embodiments, the dosage form is administered for less than or equal to 18 months. In some embodiments, the dosage form is administered for less than or equal to 21 months. In some embodiments, the dosage form is administered for less than or equal to 24 months. In some embodiments, the dosage form is administered for less than or equal to 36 months. In some embodiments, the dosage form is administered for less than or equal to 48 months. In some embodiments, the dosage form is administered for less than or equal to 60 months. In some embodiments, the dosage form is administered for less than or equal to 2 months. In some embodiments, the dosage form is administered for less than or equal to 1 month. In some embodiments, the dosage form is administered for less than or equal to 3 weeks. In some embodiments, the dosage form is administered for less than or equal to 2 weeks. In some embodiments, the dosage form is administered for less than or equal to 1 week.

[0253] In some embodiments, for a method of the present disclosure, the (Z)-endoxifen is formulated as a suspension, a tablet, a capsule, a caplet, a liquid, or a gel. In some embodiments, the (Z)-endoxifen is formulated as a tablet, a capsule, or a caplet. In some embodiments, the (Z)- endoxifen is formulated as an enteric formulation. In some embodiments, the (Z)-endoxifen is formulated as a delayed-release formulation. In some embodiments, the (Z)-endoxifen is formulated as an enteric formulation or as a delayed-release formulation. In some embodiments, the (Z)-endoxifen is formulated as an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, or a delayed-release capsule. In some embodiments, the (Z)-endoxifen is formulated as an enteric tablet, an enteric capsule, an enteric caplet, a delayed-release tablet, a delayed-release capsule, or a delayed-release caplet. In some embodiments, the (Z)-endoxifen is -83-KTS Docket No. 1 16771-1529908 (817 WO 1 )formulated as an enteric tablet, an enteric capsule, or an enteric caplet. In some embodiments, the (Z)-endoxifen is formulated as a delayed-release tablet, a delayed-release capsule, or a delayed- release caplet. In some embodiments, the (Z)-endoxifen is formulated as an enteric tablet, an enteric capsule, a delayed-release tablet, or a delayed-release capsule. In some embodiments, the (Z)-endoxifen is formulated as an enteric tablet, an enteric capsule, a delayed-release tablet, or a delayed-release capsule. In some embodiments, the (Z)-endoxifen is formulated as an enteric tablet or a delayed-release tablet. In some embodiments, the (Z)-endoxifen is formulated as an enteric capsule or a delayed-release capsule. In some embodiments, the (Z)-endoxifen is formulated as an enteric tablet. In some embodiments, the (Z)-endoxifen is formulated as an enteric capsule. In some embodiments, the (Z)-endoxifen is formulated as a delayed-release tablet. In some embodiments, the (Z)-endoxifen is formulated as a delayed-release capsule. In some embodiments, the (Z)-endoxifen formulation comprises hydroxypropyl methyl cellulose. In some embodiments, the (Z)-endoxifen formulation comprises from about 10 wt% to about 80 wt% hydroxypropyl methyl cellulose. In some embodiments, the (Z)-endoxifen formulation comprises from about 10 wt% to about 70 wt% hydroxypropyl methyl cellulose. In some embodiments, the (Z)-endoxifen formulation further comprises from about 10 wt% to about 90 wt% microcry stal 1 i ne cellulose. In some embodiments, the (Z)-endoxifen formulation further comprises less than 5 wt% magnesium stearate.

[0254] In some embodiments, for a method of the present disclosure, the (Z)-endoxifen is formulated as a suspension, a tablet, a capsule, a caplet, a liquid, or a gel. In some embodiments, the (Z)-endoxifen is formulated as a tablet, a capsule, or a caplet. In some embodiments, the (Z)- endoxifen is formulated as an oral enteric formulation. In some embodiments, the (Z)-endoxifen is formulated as an oral delayed-release formulation. In some embodiments, the (Z)-endoxifen is formulated as an oral enteric formulation or as an oral delayed-release formulation. In some embodiments, the (Z)-endoxifen is formulated as an enteric caplet, an enteric capsule, a delayed- release tablet, a delayed-release caplet, or a delayed-release capsule. In some embodiments, the (Z)-endoxifen is formulated as an enteric tablet, an enteric capsule, an enteric caplet, a delayed- release tablet, a delayed-release capsule, or a delayed-release caplet. In some embodiments, the (Z)-endoxifen is formulated as an enteric tablet, an enteric capsule, or an enteric caplet. In some embodiments, the (Z)-endoxifen is formulated as a delayed-release tablet, a delayed-release capsule, or a delayed-release caplet. In some embodiments, the (Z)-endoxifen is formulated as an enteric tablet, an enteric capsule, a delayed-release tablet, or a delayed-release capsule. In some embodiments, the (Z)-endoxifen is formulated as an enteric tablet, an enteric capsule, a delayed- release tablet, or a delayed-release capsule. In some embodiments, the (Z)-endoxifen is formulated -84-KTS Docket No. 1 16771-1529908 (817 WO 1 )as an enteric tablet or a delayed-release tablet. In some embodiments, the (Z)-endoxifen is formulated as an enteric capsule or a delayed-release capsule. In some embodiments, the (Z)- endoxifen is formulated as an enteric tablet. In some embodiments, the (Z)-endoxifen is formulated as an enteric capsule. In some embodiments, the (Z)-endoxifen is formulated as a delayed-release tablet. In some embodiments, the (Z)-endoxifen is formulated as a delayed-release capsule. In some embodiments, the (Z)-endoxifen formulation comprises hydroxypropyl methyl cellulose. In some embodiments, the (Z)-endoxifen formulation comprises from about 10 wt% to about 80 wt% hydroxypropyl methyl cellulose. In some embodiments, the (Z)-endoxifen formulation comprises from about 10 wt% to about 70 wt% hydroxypropyl methyl cellulose. In some embodiments, the (Z)-endoxifen formulation further comprises from about 10 wt% to about 90 wt% microcrystalline cellulose. In some embodiments, the (Z)-endoxifen formulation further comprises less than 5 wt% magnesium stearate.

[0255] In some embodiments, for a method of the present disclosure, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of a compound or pharmaceutically acceptable salt of Formula (I) or Formula (I-Z) is released in the intestines. In some embodiments, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% of the endoxifen is released in the intestines. In some embodiments, at least 40% of the endoxifen is released in the intestines. In some embodiments, at least 50% of the endoxifen is released in the intestines. In some embodiments, at least 60% of the endoxifen is released in the intestines. In some embodiments, at least 70% of the endoxifen is released in the intestines. In some embodiments, at least 80% of the endoxifen is released in the intestines. In some embodiments, at least 90% of the endoxifen is released in the intestines. In some embodiments, at least 40%, at least 50%, at least60%, at least 70%, at least 80%, or at least 90% of the (Z)-endoxifen is released in the intestines.In some embodiments, at least 40% of the (Z)-endoxifen is released in the intestines. In some embodiments, at least 50% of the (Z)-endoxifen is released in the intestines. In some embodiments, at least 60% of the (Z)-endoxifen is released in the intestines. In some embodiments, at least 70% of the (Z)-endoxifen is released in the intestines. In some embodiments, at least 80% of the (Z)-endoxifen is released in the intestines. In some embodiments, at least 90% of the (Z)-endoxifen is released in the intestines.

[0256] In some embodiments, for a method of the present disclosure, the administration of the pharmaceutical composition achieves a mean area under the curve extrapolated to time infinity (AUCo-inf) of (Z)-endoxifen of 200 hr*ng / mL to 10000 hr*ng / mL, of 300 hr*ng / mL to 8000 hr*ng / mL, of 400 hr*ng / mL to 6000 hr*ng / mL or of 700 hr*ng / mL to 6000 hr*ng / mL. In some embodiments, the administration of the pharmaceutical composition achieves a mean area under -85-KTS Docket No. 1 16771-1 29908 (817 WO 1 )the curve extrapolated to time infinity (AUCo-inf) of (Z)-endoxifen of 200 hr*ng / mL to 10000 hr*ng / mL. In some embodiments, the administration of the pharmaceutical composition achieves a mean area under the curve extrapolated to time infinity (AUCo-inf) of (Z)-endoxifen of 300 hr*ng / mL to 8000 hr*ng / mL. In some embodiments, the administration of the pharmaceutical composition achieves a mean area under the curve extrapolated to time infinity (AUCo-inf) of (Z)- endoxifen of 400 hr*ng / mL to 6000 hr*ng / mL. In some embodiments, the administration of the pharmaceutical composition achieves a mean area under the curve extrapolated to time infinity (AUCo-inf) of (Z)-endoxifen of 700 hr*ng / mL to 6000 hr*ng / mL. In some embodiments, a steady state plasma level of endoxifen in the subject is greater than 30 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is less than 30 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is less than 60 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is less than 90 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is less than 120 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is less than 200 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is less than 300 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is less than 500 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is less than 1000 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is from about 30 nM to about 1000 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is from about 100 nM to about 1000 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is from about 200 nM to about 1000 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is from about 400 nM to about 1000 nM. In some embodiments, a steady state plasma level of endoxifen in the subject is from about 1000 nM to about 2000 nM. In some embodiments, a steady state plasma level of endoxifen is achieved within 7 to 21 days of a first administration of the pharmaceutical composition. In some embodiments, a steady state plasma level of endoxifen is achieved within 7 to 14 days of a first administration of the pharmaceutical composition. In some embodiments, a steady state plasma level of endoxifen is achieved within 7 days of a first administration of the pharmaceutical composition. In some embodiments, a steady state plasma level of endoxifen is achieved within 14 days of a first administration of the pharmaceutical composition. In some embodiments, a steady state plasma level of endoxifen is achieved within 21 days of a first administration of the pharmaceutical composition. In some embodiments, a time to maximum plasma levels of endoxifen is from 2 hours to 10 hours or from 4 hours to 8 hours after administering the pharmaceutical composition. In some embodiments, a time to maximum plasma levels of endoxifen is from 2 hours to 10 hours after administering the-86-KTS Docket No. 1 16771-1529908 (817 WO 1 )pharmaceutical composition. In some embodiments, a time to maximum plasma levels of endoxifen ranges is from 4 hours to 8 hours after administering the pharmaceutical composition.

[0257] In some embodiments, for a method of the present disclosure, the mammogram and the further mammogram are separated by a time interv al of about 1 to 5 years. In some embodiments, the mammogram and the further mammogram are separated by a time interval of about 2 years. In some embodiments, the mammogram and the further mammogram are separated by a time interval from about 1 month to about 6 months. In some embodiments, the mammogram and the further mammogram are separated by a time interval from about 1 month to about 12 months. In some embodiments, the mammogram and the further mammogram are separated by a time interval from about 1 month to about 24 months. In some embodiments, the mammogram and the further mammogram are separated by a time interval from about 6 months to about 24 months. In some embodiments, the mammogram and the further mammogram are separated by a time interval from about 1 month to about 36 months. In some embodiments, the mammogram and the further mammogram are separated by a time interval from about 6 months to about 36 months. In some embodiments, the mammogram and the further mammogram are separated by a time interval from about 1 week to about 4 weeks. In some embodiments, the mammogram and the further mammogram are separated by a time interval from about 1 week to about 8 weeks. In some embodiments, the mammogram and the further mammogram are separated by a time interval from about 1 week to about 12 weeks. In some embodiments, the mammogram and the further mammogram are separated by a time interval from about 1 day to about 28 days. In some embodiments, the mammogram and the further mammogram are separated by a time interval from about 1 day to about 14 days. In some embodiments, the mammogram and the further mammogram are separated by a time interval from about 1 day to about 7 days.

[0258] In some embodiments, for a method of the present disclosure, the algorithm-based analysis determines the breast cancer risk score based on an age at screening, cancer incidence rate of a breast region and / or type occurring in a specified population in a given year as a baseline for age risk, a learning model assessment of a breast density and asymmetry of breast density, and a learning model detection of textures, patterns, and radiomic shapes. In some embodiments, the textures, patterns, and radiomic shapes comprises masses and calcifications and / or asymmetries of mammographic features. In some embodiments, the textures, patterns, and radiomic shapes comprises calcifications. In some embodiments, the textures, patterns, and radiomic shapes comprises asymmetries of mammographic features. In some embodiments, the textures, patterns, and radiomic shapes comprises masses. In some embodiments, the algorithm-based analysis comprises generating a risk model from a digital breast tomosynthesis. In some embodiments, the-87-KTS Docket No. 1 16771-1529908 (817 WO 1 )risk model displays a risk of breast cancer higher than a baseline or reference level. In some embodiments, the algorithm-based analysis comprises analyzing the mammogram and the further mammogram to identify a cancer, and wherein the further mammogram presents a densify reduction when compared to the mammogram as a baseline.

[0259] In some embodiments, for a method of the present disclosure, the method further comprises plotting a risk model resulting from the breast cancer risk score.

[0260] In some embodiments, for a method of the present disclosure, treating the breast cancer comprises shrinking a size of a tumor, reducing a risk of the breast cancer, preventing the breast cancer, or any combination thereof. In some embodiments, treating the breast cancer comprises shrinking a size of a tumor, reducing a risk of the breast cancer, or preventing the breast cancer. In some embodiments, treating the breast cancer comprises shrinking a size of a tumor. In some embodiments, treating the breast cancer comprises reducing a risk of the breast cancer. In some embodiments, treating the breast cancer comprises preventing the breast cancer. In some embodiments the breast cancer is an interval breast cancer. In some embodiments, the breast cancer is an occult breast cancer. In some embodiments, treating the breast cancer comprises preventing the formation of a tumor.

[0261] In some embodiments, for a method of the present disclosure, the method further comprises reducing a breast densify score from about 5% to 90%. In some embodiments, method further comprises reducing a breast densify score from about 5% to 80%. In some embodiments, method further comprises reducing a breast densify score from about 5% to 70%. In some embodiments, method further comprises reducing a breast densify score from about 5% to 60%. In some embodiments, method further comprises reducing a breast densify score from about 5% to 50%. In some embodiments, method further comprises reducing a breast densify' score from about 15% to 80%. In some embodiments, method further comprises reducing a breast densify score from about 15% to 70%. In some embodiments, method further comprises reducing a breast densify score from about 15% to 60%. In some embodiments, method further comprises reducing a breast densify score from about 15% to 50%. In some embodiments, method further comprises reducing a breast densify score from about 15% to 90%. In some embodiments, method further comprises reducing a breast densify score from about 20% to 90%. In some embodiments, method further comprises reducing a breast densify score from about 30% to 90%. In some embodiments, method further comprises reducing a breast densify score by greater than 30%. In some embodiments, method further comprises reducing a breast densify score by greater than 40%. In some embodiments, method further comprises reducing a breast densify score by greater than 50%.-88-KTS Docket No. 1 16771-1529908 (817 WO 1 )EXAMPLESExample 1: Training of the Machine Algorithm

[0262] This example describes training of a mammogram screening test that identifies patients at high risk of cancer, and also identifies cancers that other screening methods miss.

[0263] An algorithm was developed through training with a dataset of mammograms from women followed through several years. The training process involved using a large dataset of mammograms from the KARMA cohort, which includes detailed mammographic images from approximately 70,000 women followed over several years, of which 3,000 to 4,000 have developed breast cancer. The algorithm was trained to compare mammograms of women who developed breast cancer with those who did not, extracting features such as mammographic density and microcalcifications to be able to identify breast cancer and risk of breast cancer with high accuracy.

[0264] The training process included several steps: data preprocessing, feature extraction, model training, and validation. Data preprocessing involved normalizing the mammogram images and segmenting the breast tissue to focus on relevant areas. Feature extraction was performed using advanced image processing techniques to identify key characteristics associated with breast cancer risk. The model was then trained using supervised learning techniques, where the algorithm learned to distinguish between mammograms of women with and without breast cancer based on the extracted features. Validation was conducted using a separate set of mammograms to ensure the accuracy and reliability of the algorithm. The algorithm demonstrated high sensitivity and specificity in identifying patterns associated with increased breast cancer risk, making it a valuable tool for analyzing mammographic breast densify in the KARISMA study.Example 2: Interval Mammographic Cancer Study

[0265] Mammographic data is collected from a cohort of female patients to diagnosis and treat potential patients suffering from interval and occult mammographic cancers. Each patient has multiple mammograms from both breasts spanning over a time period of about 2 years.

[0266] An image-derived risk model is implemented to determine a screening mammogram-based future breast cancer risk estimate based on algorithm-based analysis of a multitude of factors, including age at the time of screening, incidence data from population-based cancer registries, mortality tables as well as an assessment of breast densify and asymmetry of breast densify from the collected mammographic data. The risk model detects textures, patterns, and radiomic shapes, including masses and calcifications and mammographic asymmetries.-89-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0267] Patients with a positive breast cancer risk score generated by the risk model analysis are administered a low dose of (Z)-endoxifen, resulting in a reduction in breast cancer morbidity in the cohort as compared to a control.Example3: Breast Density Reduction Study

[0268] This example describes a clinical trial designed to show the effect of endoxifen on breast mammographic breast density.

[0269] A randomized, double-blind, placebo-controlled trial evaluates the effect of endoxifen on mammographic breast density in women. A cohort of 240 women identified as having high breast density are randomized to receive either endoxifen or a placebo. Mammographic breast density is used as a proxy for therapy response, showing that (Z)-endoxifen reduces breast density' more significantly than a placebo. The study measures changes in mammographic breast density over a specified period due to treatment with (Z)-endoxifen. The primary endpoint is the change in mammographic breast density from baseline to the end of the study period, while the secondary endpoint is the incidence of breast cancer in participants over the follow-up period.

[0270] Patients identified with high breast density by the risk model analysis are administered a regimen of selective estrogen receptor modulators (SERMs) or aromatase inhibitors, which are known to reduce breast density. The inters ention aims to lower breast density and, consequently, the associated breast cancer risk. The effectiveness of the treatment is monitored through followup mammograms and compared to a control group that does not receive the intervention. The study aims to demonstrate a significant reduction in breast density and a corresponding decrease in breast cancer incidence in the treated cohort.

[0271] The patients are randomized to be treated with either placebo, 1 mg (Z)-endoxifen, or 2 mg (Z)-endoxifen. Patients experience greater than 10% reduction in breast density'.

[0272] Mammograms are analyzed using a screening method that includes an algorithm trained to identify patterns and features associated with increased breast cancer risk. The mammogram screening method extracts features such as mammographic density and microcalcifications and tests them to categorize them as high or low risk, as well as to identify levels of density. Participants are monitored for two to five years, with regular mammograms to assess changes in breast density and the incidence of breast cancer. The study demonstrates that (Z)-endoxifen significantly reduces mammographic breast density compared to a placebo. A successful outcome supports the use of (Z)-endoxifen as a preventive measure for breast cancer in high-risk women. The findings lead to improved breast cancer prevention strategies and personalized screening protocols, reducing the incidence of breast cancer in high-risk populations. This study represents a significant step forward in breast cancer prevention and treatment.-90-KTS Docket No. 1 16771-1529908 (817 WO 1 )Example 4: Cancer Treatment of High-Risk Patients

[0273] This example describes treatment and prevention of breast cancer in patients identified as high risk of breast cancer. A clinical study designed to show the efficacy and safety of (Z)- endoxifen for the treatment of patients at high risk is conducted. The trial includes a diverse population of participants who are identified as high risk of breast cancer through the previously- described screening methods. Participants are randomly assigned to receive 1 mg (Z)-endoxifen, 2 mg (Z)-endoxifen, or a placebo, and the trial measures breast density, risk of breast cancer, and incidences of detected breast cancer over a specified period.

[0274] Results may include a significant reduction in breast density among participants treated with both 1 mg and 2 mg doses of (Z)-endoxifen compared to those who received the placebo. This reduction in breast density7is a promising indicator, as higher breast density is a known risk factor for breast cancer. Furthermore, the risk of developing breast cancer may be notably lower in both (Z)-endoxifen groups, showcasing the drug's potential in preventive applications. The incidences of detected breast cancer may also be fewer in the (Z)-endoxifen groups, underscoring the drug's efficacy in reducing the occurrence of the disease.

[0275] In terms of safety, (Z)-endoxifen is w ell-tolerated among participants, with adverse effects being minimal and comparable to those observed in placebo groups. (Z)-endoxifen, whether administered at 1 mg or 2 mg, is not only effective but also safe for use in high-risk populations. The trial's outcomes will highlight the potential of innovative screening methods for identifying high risk patients and preventing the development of cancer. The studies also identify (Z)- endoxifen as a valuable therapeutic option for individuals at high risk of breast cancer, paving the way for further research and clinical applications.Example 5: (Z)-Endoxifen Shown to Significantly Reduce Mammographic Breast DensityStudy design

[0276] KARISMA Endoxifen, was a proof of concept, dose determining, double-blinded, randomized, placebo-controlled, three-armed, phase II trial of oral (Z)-endoxifen in premenopausal women. Participants were randomized to daily capsules of placebo (methyl crystalline cellulose capsules administered orally at 3 mg daily), 1 mg or 2 mg (Z)-endoxifen for six months. This superiority study aimed at providing evidence that one or both active doses of (Z)-endoxifen were superior to placebo in reducing MBD area. Participants visited the clinic 5 times (Screening, Day 1, Months 1, 3 and 6), and made 3 self-reported visits (months 2, 4, and 5).-91-KTS Docket No. 1 16771-1529908 (817 WO 1 )Standard of care mammograms were used for the screening mammogram, as well as the 24 month follow up visit. Two study mammograms (each equivalent to the dose of half a normal mammogram) were perfomred at 3 and 6 months. Clinical labs, vital signs, and responses to questionares were used to assess safety and tolerability. Treatment was daily for 6 months.Participants and procedures

[0277] Women aged 40 to 55 years conducting a screening mammogram at three hospitals in Stockholm, Sweden, were invited. Recruitment began in December 2021 and ended in November 2023. Full-field digital mammograms of the mediolateral oblique view, from left and right breasts, were collected at baseline, 3, 6 months or at early discontinuation. MBD was assessed as area density (cm2) using the fully automated STRATUS method. Each participant’s MBD area of left and right breasts was measured and combined. Before MBD area measurements and comparisons were done, images of the same breast were aligned to reduce technical differences between images.Randomization and masking

[0278] A total of 240 participants were block randomized (block size = 6) to a 1: 1: 1 ratio to receive placebo, 1 mg or 2 mg of (Z)-endoxifen. All study participants, personnel, clinicians, and investigators w ere blinded to treatment allocation. When follow-up ended for the last participant, the database was locked and randomisation information and plasma concentrations of (Z)- endoxifen added to the dataset.Statistical methods

[0279] This was a improvement study, which aimed to provide evidence that one or both of the active doses of (Z)-endoxifen are improved to a placebo for reducing MBD area. The original total sample size estimation indicated 165 participants were required to provide 90% power with alpha of 0.05 assuming an absolute effect size of 6.9 cm2and standard deviation of 12 cm2, with the intention of using the Williams test to identity2the minimum effective dose. This w2as inflated to 80 per arm to allow for dropouts, hence a total recruitment target of 240. However, partway through the trial, and before any outcome data had been assessed, it was decided to use relative change in MBD, rather than absolute change, and to use a gatekeeping approach for the statistical analysis. The power was recalculated and found to be 86%, assuming the equivalent relative effect of 24.6 percentage points and shared standard deviation of 42 and allowing for the same dropout rate. Assessment of the primary outcome was performed using a pre-specified gatekeeping approach, described in a Statistical Analysis Plan (SAP) which was uploaded to clinicaltrials.gov-92-KTS Docket No. 1 16771-1529908 (817 WO 1 )prior to unblinding of the data. We first compared the 0 mg with the 2 mg group; if and only if that showed evidence (p<0.05) of efficacy did we compare 1 mg with placebo. Comparisons were made using separate linear regression models, with the percentage reduction in MBD area as the outcome, an indicator of randomized arm (placebo or active) and adjusting for baseline MBD area. No other covariates were taken into consideration. As a secondary analysis we compared absolute change, using a linear regression model and adjusting for baseline MBD area. Tolerability was measured through change in Likert score from baseline to end of treatment, using linear regression with separate models for the two active doses and adjusting for baseline Likert score. Analyses were performed on both the modified intention-to-treat population (ITT) and per protocol population (PP), but the primary analyses were done using the ITT population. ITT population was equal to the number of randomized participants. The modified ITT population was defined as women with an MBD measured at baseline and at end of treatment (75 women in each arm). The PP population was defined as women who received at least 80% of the study drug to which they were randomized to (measured through pill count), had no major protocol deviations, conducted a baseline mammogram, and had at least one post-baseline mammogram. Safety endpoints were reported on the safety population, which consisted of all women who received at least one dose of their randomized treatment. All analyses followed the SAP. All p-values are two-sided and confidence intervals (CI) are at the 95% level. Analyses were conducted in SPSS version 28 and Stata vl8.0.Results

[0280] In total. 126,670 women were invited to the trial, 410 (0.3%) were screened for eligibility and 240 (0.2%) women were randomized. One hundred seventy participants were screening failures or excluded for other reasons. The most common reasons for non-eligibility were postmenopausal status (n=50) or a BMI > 30 (n=28). In addition, 32 women were entered into the electronic case report form (eCRF) but consent was not recorded, and 31 women gave consent, were found eligible but withdrew their consent prior to randomization. A total of 42 participants discontinued and 26 of these women did not perform an exit examination, leaving 214 women in the PP population. No major differences in age at study entry , menarche, BMI, smoking prevalence or family history- of breast cancer yvere seen (Table 3). Additionally, no clinically significant changes in safety tests (serum chemistry, haematology, coagulation, urinalysis) or vital signs (physical examination including blood pressure and heart rate) yvere noted during the trial period (data not shoyvn).-93-KTS Docket No. 1 16771-1529908 (817 WO 1 )

[0281] The mean MBD area at baseline did not differ greatly between arms (43.8, 48.9, 43.9 cm2 in the placebo, 1 mg and 2 mg arms; Table 4). By the end of the trial there was substantial difference between the arms (44.7, 34.6, 29.8 cm2, respectively). There was evidence of efficacy in the 2 mg, with an estimated MBD decrease of -26.5% (CI: -38.8%, -14.1%; p <0.001). As this cleared the pre-specified gatekeeping approach, the 1 mg arm was analysed. In the 1 mg group the treatment effect was -19.3% (95% CI: -32.4%, -6.1%; p=0.004; Table 4). Similar results were seen when analyses were restricted to the PP population (effect sizes were -28.8% and -18.2% in the 2 mg and 1 mg arms respectively). When we compared absolute change in MBD the results were a reduction of 5.9 cm2 (CI: -10.3, -1.4) and 7.1 cm2 (CI: -11.0, -3.2) in the 1 mg and 2 mg groups, respectively.

[0282] Positive topline data from the KARISMA-Endoxifen Phase 2 study of (Z)-endoxifen in premenopausal women with mammographic breast density (MBD) has been released. The study demonstrated that low doses of (Z)-endoxifen significantly reduced MBD and were generally well tolerated.

[0283] The trial included healthy women who were randomized to receive a daily placebo or 1 and 2 mg of (Z)-endoxifen. Each study arm consisted of 80 women, and the study duration was six months. Mammographic breast density decrease was used as a proxy for therapy response, with measurements at six months or early terminations compared to baseline density. No significant differences in age, BMI, or other background factors were observed between the randomization arms.

[0284] The relative significant density change was -19.3 percent and -26.5 percent for the 1 and 2 mg arms, respectively, using the placebo arm as a reference. No significant difference was observed when comparing the 1 and 2 mg arms. In a 2011 study, women with a breast density decrease of 10 percent or greater after taking tamoxifen for one year had a 62 percent reduction in breast cancer incidence after five years.

[0285] No changes in hematological safety tests or vital signs were noted during the trial period. The mean endoxifen plasma concentration was 5.18 ng / mL in the I mg arm and 10.87 ng / mL in the 2 mg arm after one month of therapy, with plasma concentrations remaining stable at three and six months. The number of women who discontinued the study due to drug-related side effects was 4, 5, and 12 in the placebo, 1 mg, and 2 mg arms, respectively. Vasomotor symptoms were not reported as a reason for discontinuation.

[0286] A validated questionnaire with 36 questions and a five-graded Likert scale was used for self-assessment of symptoms. Only vasomotor symptoms (night and cold sweats and hot flushes)-94-KTS Docket No. 1 16771-1529908 (817 WO 1 )increased during the study period in the active arms, but not substantially, with a mean score of 1.4 on a 10-point scale.

[0287] Nearly 50 percent of women receiving mammograms in the United States have dense breasts. While common and not considered abnormal, dense breasts make it harder to detect tumors on mammograms and are an independent risk factor for developing breast cancer. Identification of high risk patients and treatment with (Z)-endoxifen reduces risk of cancer, in a significant step forward for patients.

[0288] Both 1 and 2 mg of (Z)-endoxifen significantly reduced mammographic breast density to a degree comparable to the established 20 mg dose of tamoxifen. The 1 mg dosage of (Z)- endoxifen indicate improved tolerability.Table 3 - Participant DemographicsSD = standard deviation, BESS = Breast Cancer Prevention Trial (BCPT) Eight Symptom ScaleTable 4 - Baseline mean Mammographic breast density data (MBD)-95-KTS Docket No. 1 16771-1529908 (817 WO 1 )*Regression analyses were done in a two-model approach comparing active dose to placebo and adjusted for baseline density. SD = standard deviation, CI = Confidence interval

[0289] While preferred embodiments of the present invention have been shown and described herein, it will be apparent to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.KTS Docket No. 1 16771-1529908 (817 WO 1 )

Claims

1. CLAIMSWhat is claimed is:

1. A method of reducing a risk of a breast cancer in a subject in need thereof, the method comprising: presenting a mammogram from one or more breasts of the subject; and subsequently administering a therapeutically effective amount of an estrogen receptormodulating pharmaceutical to the subject in need thereof, thereby reducing a risk of a breast cancer in the subject in need thereof.

2. The method of claim 1, wherein the breast cancer is an interval breast cancer.

3. The method of claim 1 or claim 2, wherein the method prevents an interval breast cancer in the subject in need thereof.

4. A method of treating an occult breast cancer in a subject in need thereof, the method comprising: presenting a mammogram from one or more breasts of the subject in need thereof; and subsequently administering a therapeutically effective amount of an estrogen receptormodulating pharmaceutical to the subject, thereby treating the occult breast cancer in the subject in need thereof.

5. A method of treating a breast cancer in a subject in need thereof, the method comprising: presenting a mammogram from one or more breasts of the subject in need thereof; performing an algorithm-based analysis of the mammogram, the algorithm-based analysis producing a breast cancer risk score; determining that the subject in need thereof has a higher breast cancer risk score than a baseline or reference breast cancer risk score; and administering a therapeutically effective amount of an estrogen receptor-modulating pharmaceutical to the subject in need thereof, wherein the breast cancer is treated.

6. The method of claim 5, wherein the breast cancer is an occult breast cancer.

7. The method of any one of claims 1 to 6, wherein the method further comprises presenting a further mammogram on the one or more breasts of the subj ect in need thereof-97-KTS Docket No. 1 16771-1529908 (817 WO 1 )following administering the therapeutically effective amount of the estrogen receptormodulating pharmaceutical to the subject.

8. The method of any one of claims 1 to 7, wherein the method further comprises performing an analysis of the mammogram, the analysis determining that a breast density score is higher than a baseline or reference score.

9. The method of any one of claims 1 to 8, wherein the estrogen receptormodulating pharmaceutical comprises a compound of Formula (I):Formula (I), or a pharmaceutically acceptable salt thereof, wherein: the compound or pharmaceutically acceptable salt of Formula (I) is endoxifen; and the endoxifen is greater than 95% (Z)-endoxifen.

10. The method of any one of claims 7 to 9, wherein the mammogram and the further mammogram are separated by a time interval of about 1 to 5 years.

11. The method of any one of claims 7 to 10, wherein the mammogram and the further mammogram are separated by a time interval of about 2 years.

12. The method of any one of claims 5 to 11, wherein the algorithm-based analysis comprises analyzing the mammogram to identify a cancer.

13. The method of any one of claims 5 to 12, wherein the algorithm-based analysis determines the breast cancer risk score based on an age at screening, cancer incidence rate of a breast region and / or type occurring in a specified population in a given year as a baseline for age risk, a learning model assessment of a breast density and asymmetry of breast density, and a learning model detection of textures, patterns, and radiomic shapes.

14. The method of claim 13, wherein the textures, patterns, and radiomic shapes comprises masses and calcifications and / or asymmetries of mammographic features.-98-KTS Docket No. 1 16771-1 29908 (817 WO 1 )15. The method of any one of claims 5 to 14, wherein the method further comprises plotting a risk model resulting from the breast cancer risk score.

16. The method of any one of claims 5 to 15, wherein the algorithm-based analysis comprises generating a risk model from a digital breast tomosynthesis.

17. The method of claim 15 or claim 16, wherein the risk model displays a risk of breast cancer higher than a baseline or reference level.

18. The method of any one of claims 5 to 17, wherein the algorithm-based analysis comprises analyzing the mammogram and the further mammogram to identify a cancer, and wherein the further mammogram presents a density reduction when compared to the mammogram as a baseline.

19. The method of any one of claim 4 to 18, wherein treating the breast cancer comprises shrinking a size of a tumor, reducing a risk of the breast cancer, or preventing the breast cancer.

20. A method of reducing breast densify in a subject in need thereof, the method comprising: presenting a mammogram from one or more breasts of the subject in need thereof; subsequently performing an analysis of the mammogram, the analysis determining that a breast densify score is higher than a baseline or reference score; and administering a therapeutically effective amount of an estrogen receptor-modulating pharmaceutical to the subject in need thereof.

21. The method of any one of claims 1 to 20, wherein the method further comprises reducing a breast densify score from about 5% to 90%.

22. The method of any one of claims 9 to 21, wherein the (Z)-endoxifen is formulated as a suspension, a tablet, a capsule, a caplet, a liquid, or a gel.

23. The method of any one of claims 9 to 22, wherein the (Z)-endoxifen is formulated as an enteric oral formulation.

24. The method of any one of claims 9 to 23, wherein the (Z)-endoxifen is formulated as an enteric caplet, an enteric capsule, a delayed-release tablet, a delayed-release caplet, or a delayed-release capsule.-99-KTS Docket No. 1 16771-1529908 (817 WO 1 )25. The method of any one of claims 22 to 24, wherein the (Z)-endoxifen formulation comprises hydroxypropyl methyl cellulose.

26. The method of any one of claims 9 to 25 wherein the (Z)-endoxifen is administered orally.

27. The method of any one of claims 9 to 26, wherein the therapeutically effective amount of (Z)-endoxifen is from about 0.01 mg to 360 mg.

28. The method of any one of claims 9 to 27, wherein the therapeutically effective amount of (Z)-endoxifen is from about 0.5 mg to 10 mg.

29. The method of any one of claims 9 to 28, wherein the therapeutically effective amount of (Z)-endoxifen is 0.5 mg, 1 mg, 1.5 mg, 2 mg, 2.5 mg, 3 mg, 3.5 mg, 4 mg, 4.5 mg, 5 mg, 5.5 mg, 6 mg, 6.5 mg, 7 mg, 7.5 mg, 8 mg, 8.5 mg, 9 mg, 9.5 mg, or 10 mg.

30. The method of any one of claims 9 to 29, wherein the therapeutically effective amount of (Z)-endoxifen is from about 0.01 mg to 200 mg, about 0.1 mg to 100 mg, about 0. 1 mg to 50 mg, about 0. 1 mg to 20 mg, or about 1 mg to 20 mg.

31. The method of any one of claims 9 to 30, wherein the (Z)-endoxifen is administered at a unit dose from about 0.05 to 0.5 mg / kg, 0.5 to 1 mg / kg, 1 to 1.5 mg / kg, 1.5 to 2 mg / kg, 2 to 5 mg / kg, 5 to 10 mg / kg, or 10 to 20 mg / kg.

32. The method of any one of claims 9 to 31, wherein the (Z)-endoxifen is administered at a unit dose of about 0.05 mg / kg, 0.1 mg / kg, 0.5 mg / kg, 1 mg / kg, 1 .5 mg / kg, or 2.0 mg / kg.

33. The method of any one of claims 9 to 32, wherein the (Z)-endoxifen is administered daily for at least about 1 month, at least about 2 months, at least about 3 months, at least about 4 months, at least about 5 months, at least about 6 months, or greater.-100-KTS Docket No. 1 16771-1529908 (817 WO 1 )

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