Neoadjuvant treatment of er+ breast cancer with lasofoxifene

Abstract

The disclosure provides methods of reducing or eliminating the need for ovarian function suppression (OFS) in a premenopausal or perimenopausal female patient with hormone receptor-positive (HR+) breast cancer. The method comprises the administration of an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof in neoadjuvant and adjuvant treatment.

Description

Atorney Ref: 32524-60115 / WOClient Ref: 016WO-ANEOADJUVANT TREATMENT OF ER+BREAST CANCER WITH LASOFOXIFENE1. BACKGROUND

[0001] Neoadjuvant treatment of breast cancer - treatment before initial surgical resection of the cancer - is the therapeutic approach of choice for many patients with primary breast cancer or locally advanced breast cancer. Neoadjuvant treatment is prescribed to reduce the pre-surgical tumor burden and increase the rate of breast-conserving surgery (BCS) in mastectomy candidates, and / or to allow operability of a previously inoperable tumor (e.g., due to the tumor size). The advantages of BCS include a reduction in surgical morbidity and mortality and improvement in cosmetic outcomes, which can improve patient’s health-related quality of life.

[0002] Neoadjuvant chemotherapy (NCT) is the current standard of care for patients with locally advanced breast cancer. NCT increases the likelihood that breast-conserving surgery will be effective, reducing the need for mastectomy. However, chemotherapy offers limited benefit for patients with hormone receptor-positive / HER2 -negative (HR / HER2 ) tumors. Further, cytotoxic chemotherapy is often poorly tolerated and may have undesirable side effects.

[0003] Approximately 70% of newly diagnosed breast cancers are hormone receptorpositive (HR+). Pre-menopausal women with HR+breast cancer are often treated with ovarian function suppression (OFS) in addition to endocrine therapy, such as aromatase inhibitors (AIs). Despite its efficacy, ovarian function suppression may lead to many side effects that can have a major negative impact on patients’ quality of life. There is, therefore, a need for neoadjuvant therapies for HR+breast cancers, including HR / HER2 breast cancers, that are both effective and that have reduced side effects.2. SUMMARY

[0004] Lasofoxifene is a selective estrogen receptor modulator (SERM). In the ELAINE clinical trial (also called ELAINE 1; NCT03781063), lasofoxifene was shown to be effective in treating advanced or metastatic ER / HER2 breast cancer with acquired gain-of-function mutations in the ESRI gene, which encodes the ERa receptor, and to have a favorableAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A toxicity profile. Data from the ELAINE 2 clinical trial (NCT04432454) demonstrated that lasofoxifene, in combination with the CDK4 / 6 inhibitor abemaciclib, was effective in treating advanced or metastatic ER / HER2 breast cancers with acquired gain-of-function mutations in the ESRI gene, including in patients whose cancers had progressed on prior endocrine therapy and prior CDK4 / 6 inhibitor therapy.

[0005] The LSPY-2 Endocrine Optimization Protocol (EOP) was a sub-study within a phase 2, open-label, randomized, multicenter study I-SPY 2 TRIAL (NCT01042379), designed to evaluate the feasibility, safety, and efficacy of lasofoxifene as neoadjuvant endocrine therapy (NET) among patients with newly diagnosed, molecular low risk, clinical high risk, HR+ / HER2 , locally advanced breast cancer. As described in Example 1 herein, lasofoxifene treatment is effective as neoadjuvant treatment of ER+ / HER2 breast cancer in the absence of ovarian function suppression (OFS) in pre-menopausal women patients.

[0006] Accordingly, in a first aspect, this disclosure provides a method of reducing or eliminating the need for neoadjuvant ovarian function suppression (OFS) in a premenopausal or perimenopausal female patient with hormone receptor-positive (HR+) breast cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, as a neoadjuvant treatment.

[0007] In some embodiments, the HR+breast cancer is hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR 7HER2 ) breast cancer. In some embodiments, the HR+breast cancer is estrogen receptor-positive (ER+) breast cancer. In some embodiments, the HR+breast cancer is ER+ / HER2 breast cancer. In some embodiments, the HR+breast cancer is progesterone receptor-positive (PR+) breast cancer. In some embodiments, the HR+breast cancer is PR+ / HER2 breast cancer. In some embodiments, the HR+breast cancer is ER+ / PR+breast cancer. In some embodiments, the HR+breast cancer is ER+ / PR+ / HER2 breast cancer.

[0008] In some embodiments, the HR+breast cancer is non-invasive, invasive, locally advanced, metastatic, or de novo metastatic. In some embodiments, the HR+breast cancer is locally advanced.

[0009] In some embodiments, the female patient is a premenopausal female patient.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0010] In some embodiments, the pharmaceutically acceptable salt is lasofoxifene tartrate. In some embodiments, lasofoxifene tartrate is administered orally at 5 mg lasofoxifene / day.

[0011] In some embodiments, the functional derivative has the structure of formula III, wherein formula III is:(Formula III).

[0012] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient for at least 3 months prior to a first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient for 6 months prior to a first surgical resection of the cancer.

[0013] In some embodiments, the OFS is selected from the group consisting of: oophorectomy, radiation-induced OFS, and one or more GnRH agonists or analogs thereof. In some embodiments, the GnRH agonists or analogs thereof are selected from the group consisting of: goserelin, triptorelin, histrelin, and leuprorelin. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functionalAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A derivative thereof, reduces the therapeutically required dose of neoadjuvant GnRH agonist or analog thereof.

[0014] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least three weeks.

[0015] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required frequency of treatment with neoadjuvant OFS.

[0016] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, eliminates the need for neoadjuvant OFS.

[0017] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered in combination of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from the group consisting of: abemaciclib, palbociclib, and ribociclib.

[0018] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, decreases the rate of cancer cell proliferation. In some embodiments, the rate of cancer cell proliferation is measured as the percentage of Ki-67 positive cells in a tumor biopsy. In some embodiments, after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In some embodiments, after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells. In some embodiments, after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In some embodiments, after three months of daily administration ofAttomey Ref: 32524-60115 / WOClient Ref: 016WO-A lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells. In some embodiments, after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In some embodiments, after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

[0019] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of cancer cell apoptosis. In some embodiments, the rate of cancer cell apoptosis is measured as the percentage of cells expressing a marker of apoptosis in a tumor biopsy. In some embodiments, the marker of apoptosis is Bcl-2.

[0020] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of breast conservation.

[0021] In some embodiments, the patient has not been diagnosed with osteoporosis.

[0022] In another aspect, this disclosure provides a method of treating a premenopausal or perimenopausal female patient with hormone receptor-positive (HR+) breast cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, as a neoadjuvant treatment.

[0023] In some embodiments, the HR+breast cancer is hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+ / HER2 ) breast cancer. In some embodiments, the HR+breast cancer is estrogen receptor-positive (ER+) breast cancer. In some embodiments, the HR+breast cancer is ER+ / HER2 breast cancer. In some embodiments, the HR+breast cancer is progesterone receptor-positive (PR+) breast cancer. In some embodiments, the HR+breast cancer is PR+ / HER2 breast cancer. In some embodiments, the HR+breast cancer is ER+ / PR+breast cancer. In some embodiments, the HR+breast cancer is ER+ / PR+ / HER2 breast cancer.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0024] In some embodiments, the HR+breast cancer is non-invasive, invasive, locally advanced, metastatic, or de novo metastatic. In some embodiments, the HR+breast cancer is locally advanced.

[0025] In some embodiments, the female patient is a premenopausal female patient.

[0026] In some embodiments, the pharmaceutically acceptable salt is lasofoxifene tartrate. In some embodiments, lasofoxifene tartrate is administered orally at 5 mg lasofoxifene / day.

[0027] In some embodiments, the functional derivative has the structure of formula III, wherein formula III is:(Formula III).

[0028] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient for at least 3 months prior to a first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient for 6 months prior to a first surgical resection of the cancer.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0029] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces or eliminates the need for neoadjuvant ovarian function suppression (OFS).

[0030] In some embodiments, the OFS is selected from the group consisting of: oophorectomy, radiation-induced OFS, and one or more GnRH agonists or analogs thereof. In some embodiments, the GnRH agonists or analogs thereof are selected from the group consisting of: goserelin, triptorelin, histrelin, and leuprorelin. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of neoadjuvant GnRH agonist or analog thereof.

[0031] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least three weeks.

[0032] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required frequency of treatment with neoadjuvant OFS.

[0033] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, eliminates the need for neoadjuvant OFS.

[0034] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered in combination of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from the group consisting of: abemaciclib, palbociclib, and ribociclib.

[0035] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, decreases the rate of cancer cell proliferation. In some embodiments, the rate of cancer cell proliferation is measured as theAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A percentage of Ki-67 positive cells in a tumor biopsy. In some embodiments, after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In some embodiments, after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells. In some embodiments, after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In some embodiments, after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells. In some embodiments, after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In some embodiments, after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

[0036] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of cancer cell apoptosis. In some embodiments, the rate of cancer cell apoptosis is measured as the percentage of cells expressing a marker of apoptosis in a tumor biopsy. In some embodiments, the marker of apoptosis is Bcl-2.

[0037] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of breast conservation.

[0038] In some embodiments, the patient has not been diagnosed with osteoporosis.

[0039] In another aspect, this disclosure provides a method of reducing or eliminating the need for adjuvant ovarian function suppression (OFS) in a premenopausal or perimenopausal female patient with hormone receptor-positive (HR+) breast cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, as an adjuvant treatment.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0040] In some embodiments, the HR+breast cancer is hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+ / HER2 ) breast cancer. In some embodiments, the HR+breast cancer is estrogen receptor-positive (ER+) breast cancer. In some embodiments, the HR+breast cancer is ER+ / HER2 breast cancer. In some embodiments, the HR+breast cancer is progesterone receptor-positive (PR+) breast cancer. In some embodiments, the HR+breast cancer is PR+ / HER2 breast cancer. In some embodiments, the HR+breast cancer is ER+ / PR+breast cancer. In some embodiments, the HR+breast cancer is ER+ / PR+ / HER2 breast cancer.

[0041] In some embodiments, the HR+breast cancer is non-invasive, invasive, locally advanced, metastatic, or de novo metastatic. In some embodiments, the HR+breast cancer is locally advanced.

[0042] In some embodiments, the female patient is a premenopausal female patient.

[0043] In some embodiments, the pharmaceutically acceptable salt is lasofoxifene tartrate. In some embodiments, lasofoxifene tartrate is administered orally at 5 mg lasofoxifene / day.

[0044] In some embodiments, the functional derivative has the structure of formula III, wherein formula III is:(Formula III).Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0045] In some embodiments, the OFS is selected from the group consisting of: oophorectomy, radiation-induced OFS, and one or more GnRH agonists or analogs thereof. In some embodiments, the GnRH agonists or analogs thereof are selected from the group consisting of: goserelin, triptorelin, histrelin, and leuprorelin. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of adjuvant GnRH agonist or analog thereof.

[0046] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least three weeks.

[0047] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required frequency of treatment with adjuvant OFS.

[0048] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, eliminates the need for adjuvant OFS.

[0049] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered in combination of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from the group consisting of: abemaciclib, palbociclib, and ribociclib.

[0050] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered for 3 months, 6 months, 9 months, or 12 months after a first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered for 2 years, 3 years, 4 years, or 5 years after a first surgical resection of the cancer.

[0051] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, decreases the rate of cancer cellAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A proliferation. In some embodiments, the rate of cancer cell proliferation is measured as the percentage of Ki-67 positive cells in a tumor biopsy. In some embodiments, after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In some embodiments, after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells. In some embodiments, after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In some embodiments, after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells. In some embodiments, after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In some embodiments, after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

[0052] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of cancer cell apoptosis. In some embodiments, the rate of cancer cell apoptosis is measured as the percentage of cells expressing a marker of apoptosis in a tumor biopsy. In some embodiments, the marker of apoptosis is Bcl-2.

[0053] In some embodiments, the patient has not been diagnosed with osteoporosis.

[0054] In another aspect, this disclosure provides a method of treating a premenopausal or perimenopausal female patient with hormone receptor-positive (HR+) breast cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, as an adjuvant treatment.

[0055] In some embodiments, the HR+breast cancer is hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR7HER2 ) breast cancer. In some embodiments, the HR+breast cancer is estrogen receptor-positive (ER+) breast cancer. InAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A some embodiments, the HR+breast cancer is ER+ / HER2 breast cancer. In some embodiments, the HR+breast cancer is progesterone receptor-positive (PR+) breast cancer. In some embodiments, the HR+breast cancer is PR+ / HER2 breast cancer. In some embodiments, the HR+breast cancer is ER+ / PR+breast cancer. In some embodiments, the HR+breast cancer is ER+ / PR+ / HER2 breast cancer.

[0056] In some embodiments, the HR+breast cancer is non-invasive, invasive, locally advanced, metastatic, or de novo metastatic. In some embodiments, the HR+breast cancer is locally advanced.

[0057] In some embodiments, the female patient is a premenopausal female patient.

[0058] In some embodiments, the pharmaceutically acceptable salt is lasofoxifene tartrate. In some embodiments, lasofoxifene tartrate is administered orally at 5 mg lasofoxifene / day.

[0059] In some embodiments, the functional derivative has the structure of formula III, wherein formula III is:(Formula III).Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0060] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces or eliminates the need for adjuvant ovarian function suppression (OFS).

[0061] In some embodiments, the OFS is selected from the group consisting of: oophorectomy, radiation-induced OFS, and one or more GnRH agonists or analogs thereof. In some embodiments, the GnRH agonists or analogs thereof are selected from the group consisting of: goserelin, triptorelin, histrelin, and leuprorelin. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of adjuvant GnRH agonist or analog thereof.

[0062] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least three weeks.

[0063] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required frequency of treatment with adjuvant OFS.

[0064] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, eliminates the need for adjuvant OFS.

[0065] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered in combination of a CDK4 / 6 inhibitor. In some embodiments, the CDK4 / 6 inhibitor is selected from the group consisting of: abemaciclib, palbociclib, and ribociclib.

[0066] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered for 3 months, 6 months, 9 months, or 12 months after a first surgical resection of the cancer. In some embodiments, lasofoxifene, or aAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A pharmaceutically acceptable salt or a functional derivative thereof, is administered for 2 years, 3 years, 4 years, or 5 years after a first surgical resection of the cancer.

[0067] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, decreases the rate of cancer cell proliferation. In some embodiments, the rate of cancer cell proliferation is measured as the percentage of Ki-67 positive cells in a tumor biopsy. In some embodiments, after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In some embodiments, after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells. In some embodiments, after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In some embodiments, after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells. In some embodiments, after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In some embodiments, after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

[0068] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of cancer cell apoptosis. In some embodiments, the rate of cancer cell apoptosis is measured as the percentage of cells expressing a marker of apoptosis in a tumor biopsy. In some embodiments, the marker of apoptosis is Bcl-2.

[0069] In some embodiments, the patient has not been diagnosed with osteoporosis.

[0070] In another aspect, this disclosure provides a method of reducing or eliminating the need for ovarian function suppression (OFS) in a premenopausal or perimenopausal female patient with hormone receptor-positive (HR+) breast cancer. The method comprisesAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, prior to a first surgical resection of the cancer and continuing administration after the first surgical resection of the cancer.

[0071] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered for 3 months, 6 months, 9 months, or 12 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered for 2 years, 3 years, 4 years, or 5 years after the first surgical resection of the cancer.3. BRIEF DESCRIPTION OF THE DRAWINGS

[0072] These and other features, aspects, and advantages of the present invention will become better understood with regard to the following description, and accompanying drawings, where:

[0073] FIG. 1 shows the study schematic of the lasofoxifene arm of the I-SPY-2 Endocrine Optimization Protocol (EOP) clinical trial.4. DETAILED DESCRIPTION4.1. Methods of Treatment

[0074] Disclosed herein are methods of reducing or eliminating the need for ovarian function suppression (OFS) in a female patient with hormone receptor-positive CHR ) breast cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0075] In some embodiments, the method is provided for treating previously-untreated (treatment naive) HR+breast cancer in a patient. In some embodiments, the method reduces or eliminates the need for neoadjuvant ovarian function suppression (OFS). In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as a neoadjuvant treatment.

[0076] In some embodiments, the method reduces or eliminates the need for adjuvant ovarian function suppression (OFS). In some embodiments, lasofoxifene, or aAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A pharmaceutically acceptable salt or a functional derivative thereof, is administered as an adjuvant treatment.

[0077] In some embodiments, the method further comprises the earlier step of determining the menopause status of the patient. In some embodiments, the method further comprises the earlier step of determining that the patient is premenopausal or perimenopausal. In certain embodiments, the method further comprises the earlier step of determining that the patient is premenopausal. In certain embodiments, the method further comprises the earlier step of determining that the patient is perimenopausal.

[0078] In some embodiments, the method further comprises the earlier step of determining that the patient has not been treated with one or more ovarian suppression therapies. In some embodiments, the method further comprises the earlier step of determining that the patient has not been treated with ovarian ablation. In some embodiments, the method further comprises determining that the patient has not been treated with oophorectomy or radiation. In some embodiments, the method further comprises determining that the patient has not been treated with an ovarian suppressor. In some embodiments, the method further comprises determining that the patient has not been treated with one or more GnRH agonists or analogs thereof. In some of these embodiments, the GnRH agonists or analogs thereof are selected from the group consisting of: goserelin, triptorelin, histrelin, and leuprorelin.

[0079] In some embodiments, the method further comprises the earlier step of determining that the patient’s cancer has not metastasized. In some embodiments, the method further comprises the earlier step of determining that the patient’s cancer has metastasized.

[0080] In some embodiments, the method further comprises the earlier step of determining that the patient has not been diagnosed with osteoporosis. In some embodiments, the method further comprises the earlier step of determining that the patient does not have osteoporosis.

[0081] In some embodiments, the method further comprises the earlier step of determining that the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene. In someAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A embodiments, the method further comprises the earlier step of determining that the cancer has one or more ESRI mutations.

[0082] In certain embodiments, the methods further comprise determining one or more characteristics of the patient’s breast cancer. In some embodiments, the one or more characteristics of the cancer are selected from tumor size, grade, metastasis status, hormone- receptor status, HER2 status, gene mutations, and combinations thereof.

[0083] In some embodiments, the method further comprises the earlier step of determining the expression level of one or more clinical breast cancer prognostic biomarkers. In some embodiments, the clinical breast cancer prognostic biomarkers are selected from a cell proliferation marker, a pro- or anti-apoptotic protein, a hormone receptor, and a hormone.

[0084] In certain embodiments, the method further comprises determining the risk of the patient’s breast cancer recurrence.

[0085] In certain embodiments, the method further comprises administering the lasofoxifene, lasofoxifene tartrate, or other pharmaceutically acceptable salt or functional derivative thereof prior to administration of one or more cancer therapies selected from OFS, chemotherapy, one or more additional endocrine therapies, radiation therapy, targeted therapy, and combinations thereof.4.1.1. Patients with HR+Breast Cancer

[0086] In various embodiments, the patient has hormone receptor-positive (HR+) breast cancer. In various embodiments, the HR status can be determined by immunohistochemistry (IHC), by RT-PCR, or by next generation sequencing (NGS) of a patient’s sample. In some embodiments, the sample is a tumor biopsy. In some embodiments, the sample is a liquid biopsy, such as blood, serum, saliva, or other bodily fluids. In certain embodiments, the HR status is determined by immunohistochemistry (IHC) test of a tumor biopsy.

[0087] In some embodiments, the HR+breast cancer is hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR7HER2 ) breast cancer.

[0088] In some embodiments, the HR+breast cancer is estrogen receptor-positive (ER+) breast cancer. In some embodiments, the HR+breast cancer is ER7HER2 breast cancer.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0089] In some embodiments, the HR+breast cancer is progesterone receptor-positive (PR+) breast cancer. In some embodiments, the HR+breast cancer is PR+ / HER2 breast cancer.

[0090] In some embodiments, the HR+breast cancer is ER+ / PR+breast cancer. In some embodiments, the HR+breast cancer is ER / PR / HER2 breast cancer.

[0091] In various embodiments, the HR+breast cancer is non-invasive, invasive, advanced, locally advanced, metastatic, or de novo metastatic. In certain embodiments, the HR+breast cancer is non-invasive. In certain embodiments, the HR+breast cancer is invasive. In certain embodiments, the HR+breast cancer is advanced. In certain embodiments, the HR+breast cancer is locally advanced. In certain embodiments, the HR+breast cancer is metastatic. In certain embodiments, the HR+breast cancer is de novo metastatic.

[0092] In some embodiments, the patient has HR+primary breast cancer. In some embodiments, the patient has HR+locally advanced or metastatic breast cancer. In some embodiments, the patient has HR+locally advanced breast cancer. In some embodiments, the patient has HR+metastatic breast cancer.

[0093] In various embodiments, the ER+breast cancer is non-invasive, invasive, advanced, locally advanced, metastatic, or de novo metastatic. In certain embodiments, the ER+breast cancer is non-invasive. In certain embodiments, the ER+breast cancer is invasive. In certain embodiments, the ER+breast cancer is advanced. In certain embodiments, the ER+breast cancer is locally advanced. In certain embodiments, the ER+breast cancer is metastatic. In certain embodiments, the ER+breast cancer is de novo metastatic.

[0094] In some embodiments, the patient has ER+primary breast cancer. In some embodiments, the patient has ER+locally advanced or metastatic breast cancer. In some embodiments, the patient has ER+locally advanced breast cancer. In some embodiments, the patient has ER+metastatic breast cancer.

[0095] In various embodiments, the ER+ / HER2 breast cancer is non-invasive, invasive, advanced, locally advanced, metastatic, or de novo metastatic. In certain embodiments, the ER / HER2 breast cancer is non-invasive. In certain embodiments, the ER / HER2 breastAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A cancer is invasive. In certain embodiments, the ER / HER2 breast cancer is advanced. In certain embodiments, the ER / HER2 breast cancer is locally advanced. In certain embodiments, the ER / HER2 breast cancer is metastatic. In certain embodiments, the ER+breast cancer is de novo metastatic.

[0096] In some embodiments, the patient has ER+ / HER2 primary breast cancer. In some embodiments, the patient has ER / HER2 locally advanced or metastatic breast cancer. In some embodiments, the patient has ER / HER2 locally advanced breast cancer. In some embodiments, the patient has ER / HER2 metastatic breast cancer.

[0097] In various embodiments, the PR+breast cancer is non-invasive, invasive, advanced, locally advanced, metastatic, or de novo metastatic. In certain embodiments, the PR+breast cancer is non-invasive. In certain embodiments, the PR+breast cancer is invasive. In certain embodiments, the PR+breast cancer is advanced. In certain embodiments, the PR+breast cancer is locally advanced. In certain embodiments, the PR+breast cancer is metastatic. In certain embodiments, the PR+breast cancer is de novo metastatic.

[0098] In some embodiments, the patient has PR+primary breast cancer. In some embodiments, the patient has PR+locally advanced or metastatic breast cancer. In some embodiments, the patient has PR+locally advanced breast cancer. In some embodiments, the patient has PR+metastatic breast cancer.

[0099] In various embodiments, the PR+ / HER2 breast cancer is non-invasive, invasive, advanced, locally advanced, metastatic, or de novo metastatic. In certain embodiments, the PR / HER2 breast cancer is non-invasive. In certain embodiments, the PR / HER2 breast cancer is invasive. In certain embodiments, the PR / HER2 breast cancer is advanced. In certain embodiments, the PR / HER2 breast cancer is locally advanced. In certain embodiments, the PR / HER2 breast cancer is metastatic. In certain embodiments, the PR / HER2 breast cancer is de novo metastatic.

[0100] In some embodiments, the patient has PR+ / HER2 primary breast cancer. In some embodiments, the patient has PR / HER2 locally advanced or metastatic breast cancer. In some embodiments, the patient has PR / HER2 locally advanced breast cancer. In some embodiments, the patient has PR / HER2 metastatic breast cancer.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0101] In various embodiments, the ER+ / PR+breast cancer is non-invasive, invasive, advanced, locally advanced, metastatic, or de novo metastatic. In certain embodiments, the ER+ / PR+breast cancer is non-invasive. In certain embodiments, the ER+ / PR+breast cancer is invasive. In certain embodiments, the ER+ / PR+breast cancer is advanced. In certain embodiments, the ER+ / PR+breast cancer is locally advanced. In certain embodiments, the ER+ / PR+breast cancer is metastatic. In certain embodiments, the ER+ / PR+breast cancer is de novo metastatic.

[0102] In some embodiments, the patient has ER+ / PR+primary breast cancer. In some embodiments, the patient has ER+ / PR+locally advanced or metastatic breast cancer. In some embodiments, the patient has ER+ / PR+locally advanced breast cancer. In some embodiments, the patient has ER+ / PR+metastatic breast cancer.

[0103] In various embodiments, the ER+ / PR+ / HER2 breast cancer is non-invasive, invasive, advanced, locally advanced, metastatic, or de novo metastatic. In certain embodiments, the ER / PR / HER2 breast cancer is non-invasive. In certain embodiments, the ER / PR / HER2 breast cancer is invasive. In certain embodiments, the ER / PR / HER2 breast cancer is advanced. In certain embodiments, the ER / PR / HER2 breast cancer is locally advanced. In certain embodiments, the ER / PR / HER2 breast cancer is metastatic. In certain embodiments, the ER / PR / HER2 breast cancer is de novo metastatic.

[0104] In some embodiments, the patient has ER+ / PR+ / HER2 primary breast cancer. In some embodiments, the patient has ER / PR / HER2 locally advanced or metastatic breast cancer. In some embodiments, the patient has ER / PR / HER2 locally advanced breast cancer. In some embodiments, the patient has ER / PR / HER2 metastatic breast cancer.

[0105] In some embodiments, the patient’s cancer has a low risk of metastasis. In some embodiments, the risk of metastasis is determined by the gene expression profile of the patient’s cancer. In some embodiments, the risk of metastasis is determined by MammaPrint® testing. MammaPrint® test (Agendia) is a diagnostic tool for predicting the risk of breast cancer metastasis using the expression of 70 genes described in Table 1 in Tian et al. (Tian et al. Biomark Insights. Nov 28;5: 129-38 (2010), which is incorporated herein by reference in its entirety). In some embodiments, the patient’s cancer has a MammaPrint®Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A score of Low. In some embodiments, the patient’s cancer has a MammaPrint® score of High 1.

[0106] In some embodiments, the patient’s cancer has a high sensitivity to endocrine therapy. In some embodiments, the sensitivity to endocrine therapy is determined by the gene expression profile of the patient’s cancer. In some embodiments, the sensitivity to endocrine therapy is determined by the sensitivity to endocrine therapy (SET) index. In some embodiments, the patient’s cancer has a high sensitivity to endocrine therapy and a MammaPrint® score of High 1.

[0107] In some embodiments, the patient’s cancer has a tumor size between about 0.1 cm-5 cm. In some embodiments, the patient’s cancer has a tumor size of about 0.1 cm, 0.5 cm, 1.0 cm, 1.5 cm, 2.0 cm, 2.5 cm, 3.0 cm, 3.5 cm, 4.0 cm, 4.5 cm, or 5.0 cm. In some embodiments, the patient’s cancer has a tumor size of no larger than 5.0 cm, such as no larger than 4.5 cm, 4.0 cm, 3.5 cm, 3.0 cm, 2.5 cm, 2 cm, 1.5 cm, 1 cm, or 0.5 cm. In some embodiments, the patient’s cancer has a tumor size of larger than 5.0 cm, such as larger than 6.0 cm, 7 cm, 8 cm, 9 cm, or 10 cm. In some embodiments, the patient’s cancer has a tumor size that is surgically operable (e.g., can be removed with surgery).

[0108] In some embodiments, the patient’s cancer is lymph node-negative. In some embodiments, the patient’s cancer is lymph node-positive. In some embodiments, the patient’s cancer is lymph node-positive with 1-30 positive nodes. In some embodiments, the patient’s cancer is lymph node-positive with no more than 3 positive nodes.

[0109] In some embodiments, the patient has not been diagnosed with osteoporosis. In some embodiments, the patient does not have osteoporosis.

[0110] In some embodiments, the patient’s cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene. In some embodiments, the patient’s cancer has not been determined to have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRJ) gene.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A4.1.2. Neoadjuvant Treatment[OHl] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient as a neoadjuvant treatment.

[0112] In typical embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the HR+breast cancer patient prior to a first surgical resection of the cancer. Non-limiting examples of surgical resection include mastectomy, lumpectomy, lymphadenectomy, breast reconstruction surgery, breast conserving surgery, and combinations thereof.

[0113] In various embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 1 to 12 months prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 1 month prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 2 months prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 3 months prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 4 months prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 5 months prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 6 months prior to the first surgical resection of the cancer.Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A

[0114] In various embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 1 to 12 weeks prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 2 weeks prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 3 weeks prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 4 weeks prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 5 weeks prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 6 weeks prior to the first surgical resection of the cancer.

[0115] In various embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 1 to 12 weeks prior to the first surgical resection of the cancer in the absence of OFS. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks prior to the first surgical resection of the cancer in the absence of OFS. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 2 weeks prior to the first surgical resection of the cancer in the absence of OFS. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 3 weeks prior to the first surgical resection of the cancer in the absence of OFS. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 4 weeks prior to the first surgical resection of the cancer in the absence of OFS. In someAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 5 weeks prior to the first surgical resection of the cancer in the absence of OFS. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 6 weeks prior to the first surgical resection of the cancer in the absence of OFS. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 8 weeks prior to the first surgical resection of the cancer in the absence of OFS. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 10 weeks prior to the first surgical resection of the cancer in the absence of OFS.

[0116] In various embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 1 to 12 weeks prior to the first surgical resection of the cancer as monotherapy. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks prior to the first surgical resection of the cancer as monotherapy. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 2 weeks prior to the first surgical resection of the cancer as monotherapy. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 3 weeks prior to the first surgical resection of the cancer as monotherapy. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 4 weeks prior to the first surgical resection of the cancer as monotherapy. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 5 weeks prior to the first surgical resection of the cancer as monotherapy. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 6 weeks prior to the first surgical resection of the cancer as monotherapy. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 8 weeksAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A prior to the first surgical resection of the cancer as monotherapy. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for at least 10 weeks prior to the first surgical resection of the cancer as monotherapy.

[0117] In various embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for no more than 1 to 12 months prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for no more than 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for no more than 1 month prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for no more than 2 months prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for no more than 3 months prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for no more than 4 months prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for no more than 5 months prior to the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for no more than 6 months prior to the first surgical resection of the cancer.

[0118] In various embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 1 to 12 weeks prior to the first surgical resection of the cancer, such as 1 to 3 weeks, 1 to 6 weeks, 3 to 6 weeks, 3 to 9 weeks, 3 to 12 weeks, 2 to 4 weeks, 4 to 6 weeks, 4 to 8 weeks, or 8 to 12 weeks prior to the first surgical resection of the cancer.Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A

[0119] In various embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 1 to 12 months prior to the first surgical resection of the cancer, such as 1 to 3 months, 1 to 6 months, 3 to 6 months, 3 to 9 months, 3 to 12 months, 2 to 4 months, 4 to 6 months, 4 to 8 months, or 8 to 12 months prior to the first surgical resection of the cancer.4.1.3. Adjuvant Treatment

[0120] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient as an adjuvant treatment.

[0121] In typical embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the HR+breast cancer patient after a first surgical resection of the cancer.

[0122] In various embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 1 to 12 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 1 month after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 2 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 3 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 6 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 9 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceuticallyAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 12 months after the first surgical resection of the cancer.

[0123] In various embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 1 to 10 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 1 year after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 2 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 3 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 4 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 5 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 6 years after the first surgical resection of the cancer.4.1.4. Neoadjuvant and Adjuvant Treatment

[0124] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient with HR+breast cancer as a neoadjuvant and an adjuvant treatment.

[0125] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient with HR+breast cancer prior to a first surgical resection of the cancer, and after the first surgical resection of the cancer.Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A

[0126] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient with HR+breast cancer prior to a first surgical resection of the cancer, and the administration of lasofoxifene is continued after the first surgical resection of the cancer.

[0127] In certain embodiments, the administration lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, to the HR+breast cancer patient is continued after the first surgical resection of the cancer. In some of these embodiments, the administration lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, to the ER+breast cancer patient is continued for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or longer after the first surgical resection of the cancer.

[0128] In some embodiments, the administration lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, to the HR+breast cancer patient is continued as long as the tumor continues downstaging.

[0129] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the HR+breast cancer patient for as long as the cancer is responsive to the treatment, stable, has clinical benefit (CB), or reduced progression.

[0130] In some embodiments, the administration lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, to the HR+breast cancer patient is continued after the first surgical resection of the cancer until the patient’s cancer progresses on therapy, is in full remission, or until the side effects are intolerable.

[0131] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months prior to the first surgical resection of the cancer, and for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 3 months prior to the first surgical resection of the cancer, and for 3 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 3 months prior to the firstAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A surgical resection of the cancer, and for 6 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 3 months prior to the first surgical resection of the cancer, and for 9 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 3 months prior to the first surgical resection of the cancer, and for 12 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 6 months prior to the first surgical resection of the cancer, and for 3 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 6 months prior to the first surgical resection of the cancer, and for 6 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 6 months prior to the first surgical resection of the cancer, and for 9 months after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 6 months prior to the first surgical resection of the cancer, and for 12 months after the first surgical resection of the cancer.

[0132] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months prior to the first surgical resection of the cancer, and for 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 3 months prior to the first surgical resection of the cancer, and for 2 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 3 months prior to the first surgical resection of the cancer, and for 3 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 3 months prior to the first surgicalAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A resection of the cancer, and for 4 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 3 months prior to the first surgical resection of the cancer, and for 5 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 6 months prior to the first surgical resection of the cancer, and for 2 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 6 months prior to the first surgical resection of the cancer, and for 3 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 6 months prior to the first surgical resection of the cancer, and for 4 years after the first surgical resection of the cancer. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the breast cancer patient for 6 months prior to the first surgical resection of the cancer, and for 5 years after the first surgical resection of the cancer.4.1.5. Reduction or Elimination of the Need of OFS

[0133] In various embodiments, the method reduces or eliminates the need for ovarian function suppression (OFS) in a patient with HR+breast cancer.

[0134] In some embodiments, the method reduces or eliminates the need for neoadjuvant OFS in a premenopausal or perimenopausal female patient with HR+breast cancer. In some embodiments, the method reduces the need for neoadjuvant OFS in a premenopausal or perimenopausal female patient with HR+breast cancer. In some embodiments, the method eliminates the need for neoadjuvant OFS in a premenopausal or perimenopausal female patient with HR+breast cancer.

[0135] In some embodiments, the method reduces or eliminates the need for adjuvant OFS in a premenopausal or perimenopausal female patient with HR+breast cancer. In some embodiments, the method reduces the need for adjuvant OFS in a premenopausal or perimenopausal female patient with HR+breast cancer. In some embodiments, the methodAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A eliminates the need for adjuvant OFS in a premenopausal or perimenopausal female patient with HR+breast cancer.

[0136] In various embodiments, the OFS is selected from the group consisting of: oophorectomy, radiation-induced OFS, and one or more GnRH agonists or analogs thereof. In some embodiments, the OFS is ovarian ablation. In some embodiments, the OFS is oophorectomy, such as bilateral oophorectomy. In some embodiments, the OFS is radiation- induced OFS. In certain embodiments, the OFS is the administration of a gonadotropinreleasing hormone (GnRH) agonist or analog thereof. In some of these embodiments, the GnRH agonist or analog thereof is injected periodically (e.g., monthly, every two months, every three months). In some embodiments, the GnRH agonist or analog thereof is injected every 1, 2, 3, 4, 5, or 6 months. Non-limiting examples of GnRH agonist or analog thereof include goserelin, triptorelin, histrelin, and leuprorelin.

[0137] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of neoadjuvant GnRH agonist or analog thereof. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of neoadjuvant GnRH agonist or analog thereof by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% compared to the dose without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of neoadjuvant GnRH agonist or analog thereof by at least 20% compared to the dose without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of neoadjuvant GnRH agonist or analog thereof by at least 50% compared to the dose without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of neoadjuvant GnRH agonist or analog thereof by 10%-90%, 20%-80%, 30%-70%, 40%-60%, 20%-50%, 25%- 75%, or 35%-65% compared to the dose without lasofoxifene.

[0138] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose ofAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A adjuvant GnRH agonist or analog thereof. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of adjuvant GnRH agonist or analog thereof by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99% compared to the dose without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of adjuvant GnRH agonist or analog thereof by at least 20% compared to the dose without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of adjuvant GnRH agonist or analog thereof by at least 50% compared to the dose without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of adjuvant GnRH agonist or analog thereof by 10%-90%, 20%-80%, 30%-70%, 40%-60%, 20%-50%, 25%- 75%, or 35%-65% compared to the dose without lasofoxifene.

[0139] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 1 to 12 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 1 week as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 2 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or aAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 3 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 4 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 6 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 9 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 12 weeks as compared to the duration of treatment without lasofoxifene.

[0140] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 1 to 6 months as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 1, 2, 3, 4, 5, or 6 months as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 1 month as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 2 months as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functionalAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 3 months as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 6 months as compared to the duration of treatment without lasofoxifene.

[0141] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 1 to 12 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 1 week as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 2 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 3 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 4 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 6 weeks as compared to the duration of treatment without lasofoxifene. InAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 9 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 12 weeks as compared to the duration of treatment without lasofoxifene.

[0142] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 1 to 12 months as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 1 month as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 2 months as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 3 months as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 6 months as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 9 months as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functionalAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 12 months as compared to the duration of treatment without lasofoxifene.

[0143] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 1 to 5 years as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 1, 2, 3, 4, or 5 years as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 1 year as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 2 years as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 3 years as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 4 years as compared to the duration of treatment without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least 5 years as compared to the duration of treatment without lasofoxifene.

[0144] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required frequency of treatment with neoadjuvant OFS. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required frequency of neoadjuvant GnRH agonist or analog thereof asAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A compared to the frequency of administration without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the interval for the administration of neoadjuvant GnRH agonist or analog thereof. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the interval between successive administrations of neoadjuvant GnRH agonist or analog thereof, by 50%, 75%, 100% , 200%, 500%, or 1000% as compared to the interval without lasofoxifene.

[0145] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required frequency of treatment with adjuvant OFS. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required frequency of adjuvant GnRH agonist or analog thereof as compared to the frequency without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the interval for the administration of adjuvant GnRH agonist or analog thereof as compared to the frequency without lasofoxifene. In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the interval between successive administrations of adjuvant GnRH agonist or analog thereof, by 50%, 75%, 100%, 200%, 500%, or 1000% as compared to the frequency without lasofoxifene.

[0146] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, eliminates the need for neoadjuvant OFS.

[0147] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, eliminates the need for adjuvant OFS.4.2. Lasofoxifene

[0148] In various embodiments, the selected patient is treated with an effective amount of lasofoxifene, or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a functional derivative thereof.

[0149] Lasofoxifene has the structure of Formula I:Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A(Formula I).

[0150] In some embodiments, lasofoxifene is administered to the selected patient as lasofoxifene tartrate.

[0151] The term “pharmaceutically acceptable salt” refers to non-toxic pharmaceutically acceptable salts. See e.g., Gupta etal. Molecules. Jul 14;23(7): 1719 (2018), incorporated herein by reference in its entirety. Other salts well known to those in the art may, however, be used. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pamoic, 2-naphthalenesulfonic, p- toluenesulfonic, cyclohexanesulfamic, salicylic, saccharinic or trifluoroacetic acid.Representative organic or inorganic bases include, but are not limited to, basic or cationic salts such as benzathine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine, procaine, aluminum, calcium, lithium, magnesium, potassium, sodium and zinc.

[0152] In some embodiments, lasofoxifene is administered as lasofoxifene tartrate.

[0153] Embodiments also include prodrugs of the compounds disclosed herein. In general, such prodrugs include functional derivatives of the compounds described herein which are readily convertible in vivo into the required compound. Thus, in the methods of treatment of the present invention, the term “administering” shall encompass the treatment of the various disorders described with the compound specifically disclosed or with a compound which may not be specifically disclosed, but which converts to the specified compound inAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A vivo after administration to the subject. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in Rautio et al. Nat Rev Drug Discov 7 , 255-270 (2008), incorporated by reference in its entirety.

[0154] In certain embodiments, a functional derivative of lasofoxifene encompasses a proteolysis targeting chimera (PROTAC) comprising a lasofoxifene-derived targeting moiety. In certain embodiments, the functional derivative of lasofoxifene (Formula II) has the following chemical structure:(Formula II), wherein R comprises a ligase binding moiety or functional derivative thereof.

[0155] In certain embodiments, R further comprises a divalent linker that attaches X and the ligase binding moiety. The linker is not limited and is selected from any linkers as described herein or any linker that do not inhibit efficacy of the PROTAC. Such linkers include a carbon chain comprising from 1 to 10 carbon atoms and may also comprise N or O heteroatoms, for example, PEG.

[0156] In certain embodiments, PROTACS are heterobifunctional small molecules with three chemical elements: lasofoxifene, a ubiquitin ligand binding moiety or ULM group, and a linker for conjugating these two elements. In some embodiments, lasofoxifene is covalently conjugated to a ubiquitin ligand binding moiety or ULM group via a linker. Non-limiting examples of such linkers include ester linkers, amide linkers, maleimide or maleimide-based linkers; valine-citrulline linkers; hydrazone linkers; N-succinimidyl-4-(2- pyridyldithiojbutyrate (SPDB) linkers; Succinimidyl-4-(N-maleimidomethyl)cyclohexane-l- carboxylate (SMCC) linkers; vinylsulfone-based linkers; linkers that include polyethyleneAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A glycol (PEG), such as, but not limited to tetraethylene glycol; linkers that include propanols acid; linkers that include caproleic acid, and linkers including any combination thereof. In embodiments, the linker is a chemically-labile linker, such as an acid-cleavable linker that is stable at neutral pH (bloodstream pH 7.3-7.5) but undergoes hydrolysis upon internalization into the mildly acidic endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0) of a target cell (e.g., a cancer cell). Chemically-labile linkers include, but are not limited to, hydrazone-based linkers, oxime-based linkers, carbonate-based linkers, ester-based linkers, etc. In some embodiments, the linker is an enzyme-labile linker, such as an enzyme-labile linker that is stable in the bloodstream but undergoes enzymatic cleavage upon internalization into a target cell, e.g., by a lysosomal protease (such as cathepsin or plasmin) in a lysosome of the target cell (e.g., a cancer cell). Enzyme-labile linkers include, but are not limited to, linkers that include peptidic bonds, e.g., dipeptide-based linkers such as valine-citrulline linkers, such as a maleimidocaproyl-valine-citruline-p-arninobenzyl (MC-vc-PAB) linker, a valyl-alanyl- para-aminobenzyloxy (Val-Ala-PAB) linker, and the like. Chemically-labile linkers, enzyme- labile, and non-cleavable linkers are described in detail, e.g., in Ducry & Stump (2010) Bioconjugate Chem. 21 :5-13, which is hereby incorporated by reference in its entirety, wherein the ULM group is covalently bonded to the linker to which is attached lasofoxifene, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph or prodrug thereof.

[0157] In various embodiments, the functional derivative of lasofoxifene is capable of binding to estrogen receptor alpha (ERa), wherein, upon binding of the ERa to the compound, the ERa is ubiquitinated by a ubiquitin ligase.

[0158] In some embodiments, the functional lasofoxifene derivative of formula III, or a hydrate, solvate, or pharmaceutically acceptable salt thereof, is administered, where formula III is:Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A(Formula III).

[0159] Some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included in the present invention. In addition, some of the compounds may form solvates with water (i.e., hydrates) or common organic solvents, and such solvates are intended to be encompassed by some embodiments.

[0160] Where the processes for the preparation of the compounds as disclosed herein give rise to mixtures of stereoisomers, these isomers may be separated by conventional techniques such as preparative chromatography. The compounds may be prepared in racemic form or as individual enantiomers or diastereomers by either stereospecific synthesis or by resolution. The compounds may, for example, be resolved into their component enantiomers or diastereomers by standard techniques, such as the formation of stereoisomeric pairs by salt formation with an optically active base, followed by fractional crystallization and regeneration of the free acid. The compounds may also be resolved by formation of stereoisomeric esters or amides, followed by chromatographic separation and removal of the chiral auxiliary. Alternatively, the compounds may be resolved using a chiral HPLC column. It is to be understood that all stereoisomers, racemic mixtures, diastereomers, cis-trans isomers, and enantiomers thereof are encompassed by some embodiments.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0161] Methods of synthesizing lasofoxifene are described in US Patent Nos. 5,948,809; 6,204,286; 6,232,476; 6,323,345; 6,395,911; 6,906,202; and 7,358,374, the disclosures of which are incorporated herein by reference in their entireties.4.3. Pharmaceutical Compositions

[0162] In some embodiments of the methods described herein, lasofoxifene, or a pharmaceutically acceptable salt thereof, a prodrug thereof, or a functional derivative thereof is administered in a pharmaceutical composition. In addition to lasofoxifene, a pharmaceutically acceptable salt thereof, a prodrug thereof, or functional derivative thereof, the composition further comprises a pharmaceutically acceptable excipient, carrier, buffer, stabilizer or other materials well known to those skilled in the art. Such materials should be non-toxic and should not interfere with the efficacy of the active ingredient. The precise nature of the carrier or other material can depend on the route of administration, e.g., oral, intravenous, transdermal, vaginal topical, or vaginal ring.

[0163] Pharmaceutical compositions for oral administration can be in tablet, capsule, powder or liquid form. A tablet can include a solid carrier such as gelatin or an adjuvant. Liquid pharmaceutical compositions generally include a liquid carrier such as water, petroleum, animal oil, vegetable oil, mineral oil or synthetic oil. Physiological saline solution, dextrose or other saccharide solution or glycols such as ethylene glycol, propylene glycol or polyethylene glycol can also be included.

[0164] For parenteral administration, the lasofoxifene will be in the form of a parenterally acceptable aqueous solution which is pyrogen-free and has suitable pH, isotonicity and stability. Those of relevant skill in the art are well able to prepare suitable solutions using, for example, isotonic vehicles such as Sodium Chloride Injection, Ringer's Injection, Lactated Ringer's Injection. Preservatives, stabilizers, buffers, antioxidants and / or other additives can be included, as required.

[0165] A composition can be administered alone or in combination with other treatments, either simultaneously or sequentially, dependent upon the condition to be treated.4.4. Treatment Regimens4.4.1. Routes and Dosages of AdministrationAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0166] In various embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally, by intravenous injection or infusion, intra-tumoral injection, transdermal administration, vaginal topical administration, or vaginal ring administration. In typical embodiments, lasofoxifene is administered to the patient by oral administration.

[0167] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered at about 0.5 mg lasofoxifene per day to about 10 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered at about 0.5 mg lasofoxifene, about 1 mg lasofoxifene, about 1.5 mg lasofoxifene, about 2 mg lasofoxifene, about 2.5 mg lasofoxifene, about 3 mg lasofoxifene, about 3.5 mg lasofoxifene, about 4 mg lasofoxifene, about 5 mg lasofoxifene, about 5.5 mg lasofoxifene, about 6 mg lasofoxifene, about 6.5 mg lasofoxifene, about 7 mg lasofoxifene, about 7.5 mg lasofoxifene, about 8 mg lasofoxifene, about 8.5 mg lasofoxifene, about 9 mg lasofoxifene, about 9.5 mg lasofoxifene, or about 10 mg lasofoxifene per day.

[0168] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered to the patient orally at a dosage of about 0.5 mg lasofoxifene to about 10 mg lasofoxifene per day, such as about 0.5 mg lasofoxifene to about 5 mg lasofoxifene per day, about 1 mg lasofoxifene to about 5 mg lasofoxifene per day, about 2 mg lasofoxifene to about 5 mg lasofoxifene per day, about 3 mg lasofoxifene to about 5 mg lasofoxifene per day, about 4 mg lasofoxifene to about 5 mg lasofoxifene per day, about 0.5 mg lasofoxifene to about 4 mg lasofoxifene per day, about 1 mg lasofoxifene to about 4 mg lasofoxifene per day, about 2 mg lasofoxifene to about 4 mg lasofoxifene per day, about 3 mg lasofoxifene to about 4 mg lasofoxifene per day, about 0.5 mg lasofoxifene to about 3 mg lasofoxifene per day, about 1 mg lasofoxifene to about 3 mg lasofoxifene per day, about 2 mg lasofoxifene to about 3 mg lasofoxifene per day, about 0.5 mg lasofoxifene to about 2 mg lasofoxifene per day, about 1 mg lasofoxifene to about 2 mg lasofoxifene per day, about 0.5 mg lasofoxifene to about 1 mg lasofoxifene per day, about 2.5 mg lasofoxifene to about 5 mg lasofoxifene per day, about 2.5 mg lasofoxifene to about 7.5 mg lasofoxifene per day, about 5 mg lasofoxifene to about 7.5 mg lasofoxifene per day, or about 7.5 mg lasofoxifene to about 10 mg lasofoxifene per day.Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A

[0169] In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at about 0.5 mg lasofoxifene to about 5 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 0.5 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 1 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 1.5 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 2 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 2.5 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 3 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 3.5 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 4 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 4.5 mg lasofoxifene per day.

[0170] In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at about 5 mg lasofoxifene to about 10 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 5 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 6 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 7 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 8 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally at 9 mg lasofoxifene per day. In some embodiments, lasofoxifene, or a pharmaceuticallyAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A acceptable salt or functional derivative thereof, is administered orally at 10 mg lasofoxifene per day.

[0171] In some preferred embodiments, lasofoxifene tartrate is administered orally at 5 mg lasofoxifene / day.

[0172] In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every day. In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every two days. In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every three days. In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every four days. In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every five days. In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every six days. In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every week. In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every two weeks. In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every three weeks. In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every month.

[0173] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered to the patient by vaginal ring administration. In some of these embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every two weeks. In some of these embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every three weeks. In some of these embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every month. In some of these embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every two months. In some of these embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivativeAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A thereof, is administered once every three months. In some of these embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered once every four months.4.4.2. Lasofoxifene Monotherapy

[0174] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered as monotherapy.

[0175] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered as monotherapy to a patient with neoadjuvant breast cancer.

[0176] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy to a patient with neoadjuvant breast cancer for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy to a patient with neoadjuvant breast cancer for 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 months.

[0177] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered as monotherapy to a patient with adjuvant breast cancer.

[0178] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy to a patient with adjuvant breast cancer for 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy to a patient with adjuvant breast cancer for 1, 2, 3, 4, 5, 6, 7, 8,9, 10, 11, or 12 months. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy to a patient with adjuvant breast cancer for 1, 2, 3, 4, or 5 years.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A4.4.3. Combination Therapy

[0179] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered in combination with an additional therapy.

[0180] In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered in combination with an additional therapy as a neoadjuvant treatment after the administration of lasofoxifene as a neoadjuvant monotherapy. In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered in combination with an additional therapy as an adjuvant treatment after the administration of lasofoxifene as a neoadjuvant monotherapy. In certain embodiments, lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered in combination with an additional therapy as an adjuvant treatment after the administration of lasofoxifene as an adjuvant monotherapy.

[0181] In some embodiments, lasofoxifene and the additional therapy are administered concurrently. In some other embodiments, lasofoxifene and the additional therapy are administered sequentially.

[0182] In some embodiments, the additional therapy is ovarian function suppression (OFS). In various embodiments, the OFS is selected from oophorectomy, radiation, or treatment with a GnRH agonist or analog thereof. In some embodiments, the GnRH agonist or analog thereof is selected from the group consisting of: goserelin, triptorelin, histrelin, and leuprorelin. In some embodiments, the OFS is administered in combination with lasofoxifene after the patient has had lasofoxifene treatment as a monotherapy.

[0183] In certain embodiments, the additional therapy is chemotherapy. In some embodiments, the chemotherapy is selected from anthracyclines, taxanes, 5-fluorouracil, carboplatin, paclitaxel, doxorubicin, epirubicin, cyclophosphamide, and combinations thereof.

[0184] In some embodiments, the additional therapy is an endocrine therapy. In certain embodiments, the endocrine therapy is the treatment with a selective ER modulator (SERM) other than lasofoxifene. In some of these embodiments, the SERM is selected from tamoxifen, raloxifene, bazedoxifene, toremifene, and ospermifene, broparestrol,Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A ormeloxifene, OP-1074, and GDC-0945. In certain embodiments, the endocrine therapy is the treatment with a selective ER degrader (SERD). In some embodiments, the SERD is selected from fulvestrant, elacestrant (RAD 1901), ARN-810 (GDC-0810), giredestrant (GDC-9545), amcenestrant (SAR439859), rintodestrant (G1T48), LSZ102, LY3484356, ZN- c5, D-0502, SHR9549, camizestrant (AZD9833), and AZD9496. In certain embodiments, the endocrine therapy is the treatment with an aromatase inhibitor (Al). In some of these embodiments, the Al is selected from exemestane, letrozole, and anastrozole.

[0185] In various embodiments, the additional therapy is the administration of an effective amount of a cell cycle inhibitor. In certain embodiments, the cell cycle inhibitor is a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In some embodiments, the additional therapy is a CDK4 / 6 inhibitor selected from the group consisting of abemaciclib, palbociclib, and ribociclib. In certain embodiments, the CDK4 / 6 inhibitor is palbociclib. In certain embodiments, the CDK4 / 6 inhibitor is abemaciclib. In certain embodiments, the CDK4 / 6 inhibitor is ribociclib.

[0186] In some embodiments, the additional therapy is administering to the patient an effective amount of a mammalian target of rapamycin (mTOR) inhibitor. mTOR inhibitors include, for example, an mTORCl inhibitor, an mTORC2 inhibitor, and everolimus. In certain embodiments, the additional therapy is an mTORCl inhibitor. In certain embodiments, the additional therapy is an mTORC2 inhibitor. In some embodiments, the mTOR inhibitor is everolimus.

[0187] In various embodiments, the additional therapy is administrating to the patient an effective amount of a growth factor inhibitor. In some embodiments, the additional therapy is a human epidermal growth factor receptor 2 (HER2) inhibitor. In certain embodiments, the additional therapy is an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate (ADC). In some embodiments, the anti-HER2 antibody is trastuzumab. In some other embodiments, the anti-HER2 ADC is trastuzumab emtansine or trastuzumab deruxtecan.

[0188] In some embodiments, the additional therapy is administering to the patient an effective amount of a histone deacetylase (HD AC) inhibitor. In various embodiments, the HD AC inhibitor is vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, pracinostat, resminostat, givinostat, quisinostat,Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A kevetrin, CUDC-101, AR-42, tefinostat, CHR-3996, 4SC202, CG200745, rocilinostat, and / or sulforaphane. In certain embodiments, the HD AC inhibitor is entinostat with the proviso that the patient is not treated with a HER2 inhibitor. In certain other embodiments, the HD AC inhibitor is vorinostat. In yet certain other embodiments, the HD AC inhibitor is romidepsin.

[0189] In various embodiments, the additional therapy is administrating to the patient an effective amount of a cell cycle inhibitor. In certain embodiments, the additional therapy is administrating to the patient an effective amount of AKT kinase inhibitor. AKT inhibitors include, for example, afuresertib, capivasertib, and ipatasertib. In some embodiments, the additional therapy is a AKT inhibitor selected from the group consisting of afuresertib, capivasertib, and ipatasertib.

[0190] In some embodiments, the additional therapy is administering to the patient an effective amount of a checkpoint inhibitor. In certain embodiments, the checkpoint inhibitor is an antibody. In some of these embodiments, the checkpoint inhibitor is an antibody specific for programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). In some embodiments, the PD-1 antibody is pembrolizumab or nivolumab. In some embodiments, the CTLA-4 antibody is ipilimumab.

[0191] In some embodiments, the additional therapy is administering to the patient an effective amount of denosumab.

[0192] In some embodiments, the additional therapy is administering to the patient an effective amount of a serotonin-norepinephrine reuptake inhibitor (SNRI), a selective serotonin reuptake inhibitor (SSRI), or gabapentin. In certain embodiments, the SNRI is venlafaxine.

[0193] In some embodiments, the additional therapies described in the preceding paragraphs in this section can be used in combination with each other.4.5. Clinical Endpoints

[0194] In some embodiments, the method reduces the therapeutically required dose of neoadjuvant ovarian function suppression (OFS). In some embodiments, the method reduces the therapeutically required dose of neoadjuvant GnRH agonist or analog thereof compared toAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A the dose without lasofoxifene. In some embodiments, the method reduces the therapeutically required duration of treatment with neoadjuvant OFS. In some embodiments, the method reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the method reduces the therapeutically required frequency of treatment with neoadjuvant OFS. In some embodiments, the method reduces the therapeutically required frequency of neoadjuvant GnRH agonist or analog thereof as compared to the frequency of administration without lasofoxifene. In some embodiments, the method eliminates the need of neoadjuvant OFS.

[0195] In some embodiments, the method reduces the therapeutically required dose of adjuvant ovarian function suppression (OFS). In some embodiments, the method reduces the therapeutically required dose of adjuvant GnRH agonist or analog thereof compared to the dose without lasofoxifene. In some embodiments, the method reduces the therapeutically required duration of treatment with adjuvant OFS. In some embodiments, the method reduces the therapeutically required duration of treatment with adjuvant OFS by at least 1, 2,3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 weeks as compared to the duration of treatment without lasofoxifene. In some embodiments, the method reduces the therapeutically required duration of treatment with adjuvant OFS by at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 months as compared to the duration of treatment without lasofoxifene. In some embodiments, the method reduces the therapeutically required frequency of treatment with adjuvant OFS. In some embodiments, the method reduces the therapeutically required frequency of adjuvant GnRH agonist or analog thereof as compared to the frequency of administration without lasofoxifene. In some embodiments, the method eliminates the need of adjuvant OFS.

[0196] In some embodiments, the method increases the rate of breast-conserving surgery (BCS). In some of these embodiments, the breast resection surgery is lumpectomy, quadrantectomy, partial mastectomy, or segmental mastectomy, depending on the amount of breast tissue being removed. In some embodiments, the method decreases the rate of mastectomy. In certain embodiments, the method decreases the rate of unilateral mastectomy. In certain embodiments, the method decreases the rate of bilateral mastectomy.Atomey Ref: 32524-60115 / WOClient Ref: 016WO-AIn some embodiments, the method eliminates the need for unilateral or bilateral mastectomy in a patient with HR+breast cancer.

[0197] In various embodiments, the method changes the level of one or more clinical breast cancer prognostic biomarkers. Non-limiting examples of clinical breast cancer prognostic biomarkers include biomarkers of cell proliferation, biomarkers of apoptosis, hormone receptors, and hormones. In various embodiments, the level of one or more clinical breast cancer prognostic biomarkers is determined prior to the administration of lasofoxifene or pharmaceutically acceptable salt or functional derivative thereof, and at 1 month, 2 months, 3 months, 4 months, 5 months, 6 months, 7 months, 8 months, 9 months, 10 months, 11 months, 12 months, or longer after the administration of lasofoxifene or pharmaceutically acceptable salt or functional derivative thereof.

[0198] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, decreases the rate of cancer cell proliferation. Suitable markers of cancer cell proliferation include, but are not limited to, nuclear-associated antigen Ki-67, proliferating cell nuclear antigen (PCNA), and minichromosome maintenance 2 (MCM2). In various embodiment, the rate of cancer cell proliferation is measured as the percentage of Ki-67 positive cells in a tumor biopsy.

[0199] In some embodiments, after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 30% positive cells, no more than 25% positive cells, no more than 20% positive cells, no more than 15% positive cells, no more than 10% positive cells, no more than 5% positive cells, no more than 2% positive cells, or no more than 1% positive cells. In certain embodiments, after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In certain embodiments, after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

[0200] In some embodiments, after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 30% positive cells, no more than 25% positive cells, noAtorney Ref: 32524-60115 / WOClient Ref: 016WO-A more than 20% positive cells, no more than 15% positive cells, no more than 10% positive cells, no more than 5% positive cells, no more than 2% positive cells, or no more than 1% positive cells. In certain embodiments, after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In certain embodiments, after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

[0201] In some embodiments, after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 30% positive cells, no more than 25% positive cells, no more than 20% positive cells, no more than 15% positive cells, no more than 10% positive cells, no more than 5% positive cells, no more than 2% positive cells, or no more than 1% positive cells. In certain embodiments, after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells. In certain embodiments, after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

[0202] In some embodiments, the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of cancer cell apoptosis. In various embodiments, the rate of cancer cell apoptosis is measured as the percentage of cells expressing a marker of apoptosis in a tumor biopsy. Suitable markers of apoptosis include, but are not limited to, the anti-apoptotic Bel -2 family members (Al, Bcl-2, Bcl-xL, Bcl-w and Mcl-1). In certain embodiments, the marker of apoptosis is Bcl-2.

[0203] In some embodiments, after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Bcl-2 positive cells in a tumor biopsy is no more than 30% positive cells, no more than 25% positive cells, no more than 20% positive cells, no more than 15% positive cells, no more than 10% positive cells, no more than 5% positive cells, no more than 2% positive cells, or no more than 1% positive cells.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0204] In some embodiments, after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Bel - 2 positive cells in a tumor biopsy is no more than 30% positive cells, no more than 25% positive cells, no more than 20% positive cells, no more than 15% positive cells, no more than 10% positive cells, no more than 5% positive cells, no more than 2% positive cells, or no more than 1% positive cells.

[0205] In some embodiments, after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Bcl-2 positive cells in a tumor biopsy is no more than 30% positive cells, no more than 25% positive cells, no more than 20% positive cells, no more than 15% positive cells, no more than 10% positive cells, no more than 5% positive cells, no more than 2% positive cells, or no more than 1% positive cells.

[0206] In various embodiments, the method increases the progression-free survival of the HR+breast cancer patient. In various embodiments, the method increases the duration of progression-free survival of the HR+cancer patient.

[0207] In some embodiments, the method decreases the rate of breast tumor growth. In certain embodiments, the breast tumor growth is measured by the length of the breast tumor. In certain embodiments, the breast tumor growth is measured by the weight of the breast tumor. In certain embodiments, the breast tumor growth is measured by the volume of the breast tumor. In certain embodiments, the breast tumor growth is measured by the length, weight, or volume of the breast tumor before, during, and after the treatment.

[0208] In some embodiments, the method reduces the size of breast tumor. In some embodiments, the method reduces the size of breast tumor by 0.1 cm-5 cm compared to the size of breast tumor prior to treatment. In some embodiments, the method reduces the size of breast tumor by at least O. l cm, 0.5 cm, 1.0 cm, 1.5 cm, 2.0 cm, 2.5 cm, 3.0 cm, 3.5 cm, 4.0 cm, 4.5 cm, 5.0 cm compared to the size of breast tumor prior to treatment. In some embodiments, the method reduces the size of breast tumor by 1%- 100% compared to the size of breast tumor prior to treatment. In some embodiments, the method reduces the breast tumor by at least 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 99%, compared to the size of breast tumor prior to treatment.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0209] In some embodiments, the method reduces the recurrence of HR+breast cancer. In some embodiments, the method increases the time to recurrence of HR+breast cancer

[0210] In some embodiments, the method reduces the rate of metastasis of HR+breast cancer. In certain embodiments, the method reduces the rate of metastasis of HR+breast cancer to the bone. In certain embodiments, the method reduces the rate of metastasis of HR+breast cancer to tissues other than the bone. In certain embodiments, the method reduces the rate of metastasis of HR+breast cancer to the brain. In certain embodiments, the method reduces the rate of metastasis of HR+breast cancer to the lung. In certain embodiments, the method reduces the rate of metastasis of HR+breast cancer to the liver.

[0211] In some embodiments, the method prevents fracture and bone loss in women who are concurrently being treated with one or more drugs causing or predisposing to osteoporosis.

[0212] In some embodiments, the method decreases vaginal pH, increases vaginal lubrication, and / or improves vaginal cell maturation index in women who are concurrently being treated with one or more drugs causing or predisposing to vulvovaginal atrophy (VVA).

[0213] In some embodiments, the method reduces one or more symptoms of sexual dysfunction in women who are concurrently being treated with one or more drugs causing or predisposing to sexual dysfunction.

[0214] In some embodiments, the method decreases hot flashes in women who are concurrently being treated with one or more drugs causing or predisposing to hot flashes.

[0215] In some embodiments, the method increases one or more health-related quality of life measures selected from joint ache, urogenital symptoms, bone loss, and bone fractures.5. EXAMPLES

[0216] Below are examples of specific embodiments for carrying out the present invention. The examples are offered for illustrative purposes only and are not intended to limit the scope of the present invention in any way. Efforts have been made to ensureAtomey Ref: 32524-60115 / WOClient Ref: 016WO-A accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0217] The practice of the present invention will employ, unless otherwise indicated, conventional methods of molecular biology, cell biology, biochemistry, genetics, cancer biology, and pharmacology, within the skill of the art. Such techniques are explained fully in the literature.5.1. Example 1. Phase 2 Neoadjuvant Clinical Study5.1.1. Study Design

[0218] The I-SPY-2 Endocrine Optimization Protocol (EOP) is a sub-study within a phase 2, open-label, randomized, multicenter study, Investigation of Serial Studies to Predict Your Therapeutic Response with Imaging And moLecular analysis 2 (I-SPY 2 TRIAL, NCT01042379). I-SPY-2 EOP was designed to evaluate the feasibility, safety, and efficacy of lasofoxifene in subjects with newly diagnosed molecularly-selected hormone receptorpositive (HR+) early stage breast cancer.

[0219] Key inclusion criteria for the EOP study include:• Stage T2 or greater breast tumor, any N category, and MO;• HR+breast cancer (ER+PR ; ER PR ; ER+PR+); >10% positive staining for ER and / or PR based on the most recent tumor biopsy and documented by a local laboratory or medical record;• HER2 breast cancer status based on the most recent tumor biopsy and documented by a local laboratory or medical record;• Biomarker assay profile of breast tumor must include one of the following: a. MammaPrint Low, any SET index score; b. MammaPrint High 1, SET index High;• No clinical or imaging evidence of distant metastases by radiologic modalities (CT, PET / CT, PA and lateral CXR, or radionuclide bone scan).Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A

[0220] As shown in FIG. 1, subjects in the lasofoxifene arm of the study received neoadjuvant treatment of lasofoxifene orally at 5 mg daily for six consecutive 28-day cycles (6 months total). Tumor core biopsy, blood draw, and MRI were performed with each subject at screening, at 3 weeks after treatment, and at 6 months after treatment (preoperative). MRI and blood draw were additionally performed at 12 weeks after treatment.

[0221] Premenopausal women were treated with lasofoxifene without ovarian suppression for the first four weeks, then with ovarian suppression for the remainder of the study.

[0222] The primary endpoint was feasibility, defined as >80% of enrolled patients completing protocol-defined study therapy.

[0223] Secondary endpoints included measurements of safety and tolerability, pathological and clinical response, patient reported outcome (PRO) data, and pharmacokinetics. For the pathological and clinical response, Ki-67% was measured at baseline, after 3 weeks of daily administration of lasofoxifene without ovarian suppression, and then per-surgery. PEPI score and residual cancer burden (RCB) were measured at time of surgery. Rate of pathological complete response (pCR), change in tumor volume, and rate of breast conservation were also measured. Surveys assessing quality of life (QoL) and patient reported outcomes (PROs) were administered at baseline, after 3 months of daily administration of lasofoxifene, and pre-surgery.

[0224] Exploratory endpoints include analysis of ctDNA and blood-based surveillance markers, tumor mutations analysis (i.e. ESRI, PIK3CA, HER2 mutation), and additional biomarker analyses, such as Bcl-2, PR, and ER.5.1.2. Results

[0225] After 3 weeks of daily administration of lasofoxifene without ovarian function suppression (OFS), the percentage of Ki-67 positive cells in the tumor biopsy was reduced in the sole male patient, in postmenopausal women patients, and in premenopausal women patients (Table 1).Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A

[0226] Surprisingly, three weeks of daily administration of lasofoxifene without OFS lasofoxifene reduced the median Ki-67% of premenopausal women patients from 12.5% to 3.0%. Furthermore, 40% premenopausal women patients had less than 2.7% cancers cells stained positive for Ki-67. These results indicate that lasofoxifene has a similar or greater effect in decreasing the rate of HR+breast cancer cell proliferation in premenopausal women patients without OFS, as compared to its effect in postmenopausal women patients.

[0227] Therefore, lasofoxifene is effective in reducing or eliminating the need for OFS in premenopausal women patients with HR+breast cancer.6. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0228] While the invention has been particularly shown and described with reference to a primary embodiment and various alternate embodiments, it will be understood by persons skilled in the relevant art that various changes in form and details can be made therein without departing from the spirit and scope of the invention.

[0229] All references, issued patents, and patent applications cited within the body of the instant specification are hereby incorporated by reference in their entirety, for all purposes.

Claims

Atorney Ref: 32524-60115 / WOClient Ref: 016WO-ACLAIMS1. A method of reducing or eliminating the need for neoadjuvant ovarian function suppression (OFS) in a premenopausal or perimenopausal female patient with hormone receptor-positive (HR+) breast cancer, comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, as a neoadjuvant treatment.

2. The method of claim 1, wherein the HR+breast cancer is hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+ / HER2 ) breast cancer.

3. The method of claim 1 or 2, wherein the HR+breast cancer is estrogen receptorpositive (ER+) breast cancer.

4. The method of claim 3, wherein the HR+breast cancer is ER / HER2 breast cancer.

5. The method of claim 1 or 2, wherein the HR+breast cancer is progesterone receptorpositive (PR+) breast cancer.

6. The method of claim 5, wherein the HR+breast cancer is PR / HER2 breast cancer.

7. The method of any one of claims 1 to 6, wherein the HR+breast cancer is ER+ / PR+breast cancer.

8. The method of claim 7, wherein the HR+breast cancer is ER / PR / HER2 breast cancer.

9. The method of any one of claims 1 to 8, wherein the HR+breast cancer is non- invasive, invasive, locally advanced, metastatic, or de novo metastatic.

10. The method of claim 9, wherein the HR+breast cancer is locally advanced.

11. The method of any one of claims 1 to 10, wherein the female patient is a premenopausal female patient.

12. The method of any one of claims 1 to 11, wherein the pharmaceutically acceptable salt is lasofoxifene tartrate.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A13. The method of claim 12, wherein lasofoxifene tartrate is administered orally at 5 mg lasofoxifene / day.

14. The method of any one of claims 1 to 11, wherein the functional derivative has the structure of formula III, wherein formula III is:(Formula III).

15. The method of any one of claims 1 to 14, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient for at least 3 months prior to a first surgical resection of the cancer.

16. The method of claim 15, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient for 6 months prior to a first surgical resection of the cancer.

17. The method of any one of claims 1 to 16, wherein the OFS is selected from the group consisting of: oophorectomy, radiation-induced OFS, and one or more GnRH agonists or analogs thereof.Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A18. The method of claim 17, wherein the GnRH agonists or analogs thereof are selected from the group consisting of: goserelin, triptorelin, histrelin, and leuprorelin.

19. The method of claim 18, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of neoadjuvant GnRH agonist or analog thereof.

20. The method of any one of claims 1 to 19, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS.

21. The method of claim 20, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least three weeks.

22. The method of any one of claims 1 to 21, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required frequency of treatment with neoadjuvant OFS.

23. The method of any one of claims 1 to 18, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, eliminates the need for neoadjuvant OFS.

24. The method of claim 23, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy.

25. The method of any one of claims 1 to 23, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered in combination of a CDK4 / 6 inhibitor.

26. The method of claim 25, wherein the CDK4 / 6 inhibitor is selected from the group consisting of: abemaciclib, palbociclib, and ribociclib.

27. The method of any one of claims 1 to 26, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, decreases the rate of cancer cell proliferation.Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A28. The method of claim 27, wherein the rate of cancer cell proliferation is measured as the percentage of Ki-67 positive cells in a tumor biopsy.

29. The method of claim 28, wherein after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells.

30. The method of claim 29, wherein after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

31. The method of claim 28, wherein after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells.

32. The method of claim 31, wherein after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

33. The method of claim 28, wherein after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells.

34. The method of claim 33, wherein after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

35. The method of any one of claims 1 to 34, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of cancer cell apoptosis.

36. The method of claim 35, wherein the rate of cancer cell apoptosis is measured as the percentage of cells expressing a marker of apoptosis in a tumor biopsy.

37. The method of claim 36, wherein the marker of apoptosis is Bcl-2.Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A38. The method of any one of claims 1 to 37, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of breast conservation.

39. The method of any one of claims 1 to 38, wherein the patient has not been diagnosed with osteoporosis.

40. A method of treating a premenopausal or perimenopausal female patient with hormone receptor-positive (HR+) breast cancer, comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, as a neoadjuvant treatment.

41. The method of claim 40, wherein the HR+breast cancer is hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+ / HER2 ) breast cancer.

42. The method of claim 40 or 41, wherein the HR+breast cancer is estrogen receptorpositive (ER+) breast cancer.

43. The method of claim 42, wherein the HR+breast cancer is ER / HER2 breast cancer.

44. The method of claim 40 or 41, wherein the HR+breast cancer is progesterone receptor-positive (PR+) breast cancer.

45. The method of claim 44, wherein the HR+breast cancer is PR / HER2 breast cancer.

46. The method of any one of claims 40 to 45, wherein the HR+breast cancer is ER+ / PR+breast cancer.

47. The method of claim 46, wherein the HR+breast cancer is ER / PR / HER2 breast cancer.

48. The method of any one of claims 40 to 47, wherein the HR+breast cancer is non- invasive, invasive, locally advanced, metastatic, or de novo metastatic.

49. The method of claim 48, wherein the HR+breast cancer is locally advanced.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A50. The method of any one of claims 40 to 49, wherein the female patient is a premenopausal female patient.

51. The method of any one of claims 40 to 50, wherein the pharmaceutically acceptable salt is lasofoxifene tartrate.

52. The method of claim 51, wherein lasofoxifene tartrate is administered orally at 5 mg lasofoxifene / day.

53. The method of any one of claims 40 to 50, wherein the functional derivative has the structure of formula III, wherein formula III is:(Formula III).

54. The method of any one of claims 40 to 53, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient for at least 3 months prior to a first surgical resection of the cancer.

55. The method of claim 54, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered to the patient for 6 months prior to a first surgical resection of the cancer.Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A56. The method of any one of claims 40 to 55, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces or eliminates the need for neoadjuvant ovarian function suppression (OFS).

57. The method of claim 56, wherein the OFS is selected from the group consisting of: oophorectomy, radiation-induced OFS, and one or more GnRH agonists or analogs thereof.

58. The method of claim 57, wherein the GnRH agonists or analogs thereof are selected from the group consisting of: goserelin, triptorelin, histrelin, and leuprorelin.

59. The method of claim 58, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of neoadjuvant GnRH agonist or analog thereof.

60. The method of any one of claims 56 to 59, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS.

61. The method of claim 60, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with neoadjuvant OFS by at least three weeks.

62. The method of any one of claims 56 to 61, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required frequency of treatment with neoadjuvant OFS.

63. The method of any one of claims 56 to 58, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, eliminates the need for neoadjuvant OFS.

64. The method of claim 63, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy.

65. The method of any one of claims 40 to 63, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered in combination of a CDK4 / 6 inhibitor.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A66. The method of claim 65, wherein the CDK4 / 6 inhibitor is selected from the group consisting of: abemaciclib, palbociclib, and ribociclib.

67. The method of any one of claims 40 to 66, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, decreases the rate of cancer cell proliferation.

68. The method of claim 67, wherein the rate of cancer cell proliferation is measured as the percentage of Ki-67 positive cells in a tumor biopsy.

69. The method of claim 68, wherein after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells.

70. The method of claim 69, wherein after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

71. The method of claim 68, wherein after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells.

72. The method of claim 71, wherein after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

73. The method of claim 68, wherein after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells.

74. The method of claim 73, wherein after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A75. The method of any one of claims 40 to 74, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of cancer cell apoptosis.

76. The method of claim 75, wherein the rate of cancer cell apoptosis is measured as the percentage of cells expressing a marker of apoptosis in a tumor biopsy.

77. The method of claim 76, wherein the marker of apoptosis is Bcl-2.

78. The method of any one of claims 40 to 77, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of breast conservation.

79. The method of any one of claims 40 to 78, wherein the patient has not been diagnosed with osteoporosis.

80. A method of reducing or eliminating the need for adjuvant ovarian function suppression (OFS) in a premenopausal or perimenopausal female patient with hormone receptor-positive (HR+) breast cancer, comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, as an adjuvant treatment.

81. The method of claim 80, wherein the HR+breast cancer is hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+ / HER2 ) breast cancer.

82. The method of claim 80 or 81, wherein the HR+breast cancer is estrogen receptorpositive (ER+) breast cancer.

83. The method of claim 82, wherein the HR+breast cancer is ER / HER2 breast cancer.

84. The method of claim 80 or 81, wherein the HR+breast cancer is progesterone receptor-positive (PR+) breast cancer.

85. The method of claim 84, wherein the HR+breast cancer is PR / HER2 breast cancer.

86. The method of any one of claims 80 to 85, wherein the HR+breast cancer is ER+ / PR+breast cancer.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A87. The method of claim 86, wherein the HR+breast cancer is ER+ / PR+ / HER2 breast cancer.

88. The method of any one of claims 80 to 87, wherein the HR+breast cancer is non- invasive, invasive, locally advanced, metastatic, or de novo metastatic.

89. The method of claim 88, wherein the HR+breast cancer is locally advanced.

90. The method of any one of claims 80 to 89, wherein the female patient is a premenopausal female patient.

91. The method of any one of claims 80 to 90, wherein the pharmaceutically acceptable salt is lasofoxifene tartrate.

92. The method of claim 91, wherein lasofoxifene tartrate is administered orally at 5 mg lasofoxifene / day.

93. The method of any one of claims 80 to 90, wherein the functional derivative has the structure of formula III, wherein formula III is:(Formula III).Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A94. The method of any one of claims 80 to 93, wherein the OFS is selected from the group consisting of: oophorectomy, radiation-induced OFS, and one or more GnRH agonists or analogs thereof.

95. The method of claim 94, wherein the GnRH agonists or analogs thereof are selected from the group consisting of: goserelin, triptorelin, histrelin, and leuprorelin.

96. The method of claim 95, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of adjuvant GnRH agonist or analog thereof.

97. The method of any one of claims 80 to 96, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS.

98. The method of claim 97, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least three weeks.

99. The method of any one of claims 80 to 98, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required frequency of treatment with adjuvant OFS.

100. The method of any one of claims 80 to 95, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, eliminates the need for adjuvant OFS.

101. The method of claim 100, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy.

102. The method of any one of claims 80 to 100, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered in combination of a CDK4 / 6 inhibitor.

103. The method of claim 102, wherein the CDK4 / 6 inhibitor is selected from the group consisting of: abemaciclib, palbociclib, and ribociclib.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A104. The method of any one of claims 82 to 103, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered for 3 months, 6 months, 9 months, or 12 months after a first surgical resection of the cancer.

105. The method of any one of claims 82 to 103, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered for 2 years, 3 years, 4 years, or 5 years after a first surgical resection of the cancer.

106. The method of any one of claims 82 to 105, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, decreases the rate of cancer cell proliferation.

107. The method of claim 106, wherein the rate of cancer cell proliferation is measured as the percentage of Ki-67 positive cells in a tumor biopsy.

108. The method of claim 107, wherein after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells.

109. The method of claim 108, wherein after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

110. The method of claim 107, wherein after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells.

111. The method of claim 110, wherein after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

112. The method of claim 107, wherein after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells.Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A113. The method of claim 112, wherein after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

114. The method of any one of claims 82 to 113, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of cancer cell apoptosis.

115. The method of claim 114, wherein the rate of cancer cell apoptosis is measured as the percentage of cells expressing a marker of apoptosis in a tumor biopsy.

116. The method of claim 115, wherein the marker of apoptosis is Bcl-2.

117. The method of any one of claims 82 to 116, wherein the patient has not been diagnosed with osteoporosis.

118. A method of treating a premenopausal or perimenopausal female patient with hormone receptor-positive (HR+) breast cancer, comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, as an adjuvant treatment.

119. The method of claim 118, wherein the HR+breast cancer is hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+ / HER2 ) breast cancer.

120. The method of claim 118 or 119, wherein the HR+breast cancer is estrogen receptorpositive (ER+) breast cancer.

121. The method of claim 120, wherein the HR+breast cancer is ER / HER2 breast cancer.

122. The method of claim 118 or 119, wherein the HR+breast cancer is progesterone receptor-positive (PR+) breast cancer.

123. The method of claim 122, wherein the HR+breast cancer is PR / HER2 breast cancer.

124. The method of any one of claims 118 or 119, wherein the HR+breast cancer is ER+ / PR+breast cancer.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A125. The method of claim 124, wherein the HR+breast cancer is ER+ / PR+ / HER2 breast cancer.

126. The method of any one of claims 118 to 125, wherein the HR+breast cancer is non- invasive, invasive, locally advanced, metastatic, or de novo metastatic.

127. The method of claim 126, wherein the HR+breast cancer is locally advanced.

128. The method of any one of claims 118 to 127, wherein the female patient is a premenopausal female patient.

129. The method of any one of claims 118 to 128, wherein the pharmaceutically acceptable salt is lasofoxifene tartrate.

130. The method of claim 129, wherein lasofoxifene tartrate is administered orally at 5 mg lasofoxifene / day.

131. The method of any one of claims 118 to 128, wherein the functional derivative has the structure of formula III, wherein formula III is:(Formula III).Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A132. The method of any one of claims 118 to 131, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces or eliminates the need for adjuvant ovarian function suppression (OFS).

133. The method of claim 132, wherein the OFS is selected from the group consisting of: oophorectomy, radiation-induced OFS, and one or more GnRH agonists or analogs thereof.

134. The method of claim 133, wherein the GnRH agonists or analogs thereof are selected from the group consisting of: goserelin, triptorelin, histrelin, and leuprorelin.

135. The method of claim 134, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required dose of adjuvant GnRH agonist or analog thereof.

136. The method of any one of claims 132 to 135, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS.

137. The method of claim 136, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required duration of treatment with adjuvant OFS by at least three weeks.

138. The method of any one of claims 132 to 137, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, reduces the therapeutically required frequency of treatment with adjuvant OFS.

139. The method of any one of claims 132 to 134, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, eliminates the need for adjuvant OFS.

140. The method of claim 139, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered as monotherapy.

141. The method of any one of claims 118 to 139, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered in combination of a CDK4 / 6 inhibitor.Atorney Ref: 32524-60115 / WOClient Ref: 016WO-A142. The method of claim 141, wherein the CDK4 / 6 inhibitor is selected from the group consisting of: abemaciclib, palbociclib, and ribociclib.

143. The method of any one of claims 118 to 142, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered for 3 months, 6 months, 9 months, or 12 months after a first surgical resection of the cancer.

144. The method of any one of claims 118 to 142, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered for 2 years, 3 years, 4 years, or 5 years after a first surgical resection of the cancer.

145. The method of any one of claims 118 to 144, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, decreases the rate of cancer cell proliferation.

146. The method of claim 143, wherein the rate of cancer cell proliferation is measured as the percentage of Ki-67 positive cells in a tumor biopsy.

147. The method of claim 146, wherein after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells.

148. The method of claim 147, wherein after three weeks of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

149. The method of claim 146, wherein after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells.

150. The method of claim 149, wherein after three months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.Atomey Ref: 32524-60115 / WOClient Ref: 016WO-A151. The method of claim 146, wherein after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 10% positive cells.

152. The method of claim 151, wherein after six months of daily administration of lasofoxifene or a pharmaceutically acceptable salt or a functional derivative thereof, the percentage of Ki-67 positive cells is no more than 5% positive cells.

153. The method of any one of claims 118 to 152, wherein the administration of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, increases the rate of cancer cell apoptosis.

154. The method of claim 153, wherein the rate of cancer cell apoptosis is measured as the percentage of cells expressing a marker of apoptosis in a tumor biospy.

155. The method of claim 154, wherein the marker of apoptosis is Bcl-2.

156. The method of any one of claims 118 to 155, wherein the patient has not been diagnosed with osteoporosis.

157. A method of reducing or eliminating the need for ovarian function suppression (OFS) in a premenopausal or perimenopausal female patient with hormone receptor-positive (HR+) breast cancer, comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, prior to a first surgical resection of the cancer and continuing administration after the first surgical resection of the cancer.

158. The method of claim 157, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered for 3 months, 6 months, 9 months, or 12 months after the first surgical resection of the cancer.

159. The method of claim 157, wherein lasofoxifene, or a pharmaceutically acceptable salt or a functional derivative thereof, is administered for 2 years, 3 years, 4 years, or 5 years after the first surgical resection of the cancer.

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