Lasofoxifene treatment of er+ cancers with constitutively active ESR1 mutations

Abstract

The disclosure provides methods for treating estrogen receptor positive (ER+) cancer other than breast and ovarian cancer, including cancer that has acquired gain of function mutations in the ligand binding domain of the Estrogen Receptor 1 (ESR1) gene, which encodes the ERα receptor protein. The methods comprise administering an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof. The disclosure describes the detection of the (ESR1) gene mutations that lead to endocrine resistance in such cancers.

Description

LASOFOXIFENE TREATMENT OF ER+CANCERS WITH CONSTITUTIVELY ACTIVE ESRI MUTATIONS1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of and priority to U.S. Provisional Application No. 63 / 626,968, filed on January 30, 2024, the contents of which are hereby incorporated by reference in their entirety.2. BACKGROUND

[0002] Estrogen receptor positive (ER+) cancers express estrogen receptor a (ERa), which is encoded by the ESRI gene. Approximately 70% of breast cancers are ER+and are, therefore, amenable to treatment with therapies that lower the level of estrogen or block estrogen signaling. However, the effectiveness of these endocrine therapies is limited by intrinsic and acquired endocrine resistance.

[0003] Recent studies have shown evidence for the temporal selection of constitutively active gain-of-function ESRI gene mutations as potential drivers of endocrine resistance during the progression of ER+breast cancer. See Jeselsohn el al.. Clinical Cancer Research 20(7): 1757- 1767 (2014). The mutations in ESRI, the gene encoding ERa, change the conformation of the ERa protein, increasing its interaction with its co-activators, promoting an active form of the receptor in absence of hormone, and assisting tumor cells in evading hormonal treatment. See Thomas and Gustafsson, Trends in Endocrinology and Metabolism 26(9): 467-476 (2015).

[0004] Lasofoxifene, a selective estrogen receptor modulator (SERM), has recently been shown to be effective in vitro in arresting the growth of ER+ovarian and breast cancer cells harboring gain-of-function mutations in the ESRI gene, US Pat. No. 10,258,604; to inhibit tumor growth and metastasis of human ER+breast cancer cells expressing ESRI gain-of- function mutations in a mouse mammary intraductal (MIND) xenograft model of ERa+breast cancer, WO 2019 / 199891; and to be effective in the MIND model in combination with the CDK 4 / 6 inhibitor, palbociclib, WO 2019 / 199891. The efficacy of lasofoxifene as a single agent in the treatment of pre- and postmenopausal women with locally advanced or metastatic ER / HER2 breast cancer with an acquired ESRI mutation is currently being assessed in a phase 2 clinical trial, NCT03781063 (the ELAINE trial). A clinical trial assessing the effectiveness of lasofoxifene in combination with the CDK 4 / 6 inhibitorabemaciclib in a similar population of breast cancer patients has been approved but is not yet open for enrollment, NCT04432454 (the ELAINE II trial).

[0005] Other cancers are known to be ER+and subject to acquisition of ESRI gain-of- function mutations. See Gaillard el al.. Gynecologic Oncology 154: 199-206 (2019) and mycancergenome.org / content / alteration / esrl-mutation. Although lasofoxifene has been proposed to be effective in treating ERa+lung cancers in which the ESRI gene has acquired gain-of-function mutations, WO 2019 / 199891, there is as yet no in vivo demonstration of lasofoxifene’ s effectiveness in ER+cancers other than breast and ovarian cancer. There thus remains a need for therapeutic agents that are effective in inhibiting progression and metastasis of non-breast and non-ovarian cancers harboring gain-of-function mutations in ESRI in patients who have developed resistance to endocrine therapies or who are at risk of developing endocrine resistance.3. SUMMARY

[0006] In vitro and animal model experiments newly demonstrate that lasofoxifene is effective in inhibiting proliferation of ER+cells from cancers other than breast and ovarian cancer and is effective even when the cells have gain-of-function mutations in the ligand binding domain (LBD) of ESRI.

[0007] Accordingly, in a first aspect, a method of treating ER+cancer other than ER+breast or ovarian cancer is presented. The method comprises selecting for treatment a patient who has been diagnosed with estrogen receptor positive (ER+) cancer other than breast or ovarian cancer; and administering to the selected patient an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug or a functional derivative thereof.

[0008] Also provided is the use of lasofoxifene for treating ER+cancer other than ER+breast or ovarian cancer. Further provided is the use of lasofoxifene in the manufacture of a formulation for the treatment of ER+cancer other than ER+breast or ovarian cancer.

[0009] In various embodiments, the ER+cancer is selected from uterine, cervical, peritoneal, vulva, vaginal, lung, esophageal, gastric, small intestine, colon, rectal, colorectal, bladder, brain, skin, renal pelvic, pancreatic, and cancer of unknown primary origin.

[0010] In certain embodiments, the ER+cancer is uterine cancer selected from endometrioid, clear-cell carcinoma, papillary serous, carcinosarcoma, leiomyosarcoma, or endometrial stromal sarcoma (ESS).

[0011] In certain embodiments, the uterine cancer is uterine endometrial stromal sarcoma, uterine endometrial adenosarcoma, uterine adenosquamous carcinoma, uterine leiomyosarcoma or uterine corpus carcinoma.

[0012] In certain embodiments, the ER+cancer is cervical clear-cell carcinoma, vulvar squamous cell carcinoma, vulvar adenocarcinoma, vaginal squamous cell carcinoma or vaginal adenocarcinoma.

[0013] In certain embodiments, the ER+cancer is lung cancer is lung adenosarcoma, squamous cell lung carcinoma or small cell lung carcinoma.

[0014] In certain embodiments, the ER+cancer is esophageal adenocarcinoma, gastric adenocarcinoma, small intestinal adenocarcinoma, small intestinal carcinoid tumor, small intestinal lymphoma, small intestinal sarcoma, small intestinal leiomyosarcoma, malignant small intestinal neoplasm, colon adenocarcinoma, rectal adenocarcinoma, colorectal adenocarcinoma, colorectal mucinous adenocarcinoma, bladder urothelial carcinoma, glioblastoma, conventional glioblastoma multiforme, skin squamous cell carcinoma, melanoma, cutaneous melanoma, infiltrating renal pelvic cancer, or pancreatic adenocarcinoma.

[0015] In various embodiments, the patient has previously been treated with one or more lines of endocrine therapy. In certain embodiments, the patient has previously been treated with a plurality of lines of endocrine therapy. In certain embodiments, the endocrine therapy that the patient has previously been treated with is a selective ER modulator (SERM) other than lasofoxifene.

[0016] In certain embodiments, the SERM is tamoxifen, raloxifene, bazedoxifene, toremifene, or ospemifene.

[0017] In various embodiments, the endocrine therapy that the patient has previously been treated with is a selective ER degrader (SERD).

[0018] In certain embodiments, the SERD is fulvestrant, RAD 1901, ARN-810 (GDC-0810), or AZD9496.

[0019] In various embodiments, the endocrine therapy that the patient has previously been treated with is an aromatase inhibitor (Al).

[0020] In some embodiments, the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®). In certain embodiments, the aromatase inhibitor is exemestane (Aromasin®). In certain embodiments, the aromatase inhibitor is letrozole (Femara®). In certain embodiments, the aromatase inhibitor is anastrozole (Arimidex®).

[0021] In various embodiments, the patient has disease progression after endocrine therapy. In various embodiments, the patient’s cancer is resistant to endocrine therapy other than lasofoxifene. In various embodiments, the patient’s cancer has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene.

[0022] In certain embodiments, the patient has previously been determined to have at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene.

[0023] In various embodiments, the method further comprises the earlier step of determining that the patient has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene.

[0024] In various embodiments, the at least one of gain of function missense mutation is in any one of amino acids D538, Y537, L536, P535, V534, S463, V392, and E380.

[0025] In some embodiments, the at least one gain of function missense mutation is in the amino acid D538. In certain embodiments, the mutation is D538G.

[0026] In various embodiments, the at least one gain of function missense mutation is in the amino acid Y537. In some embodiments, the mutation is Y537S, Y537N, Y537C, or Y537Q. In certain embodiments, the mutation is Y537C. In some embodiments, the at least one gain of function missense mutation is in the amino acid L536. In some embodiments, the mutation is L536R or L536Q.

[0027] In some embodiments, the at least one gain of function missense mutation is in the amino acid P535. In certain embodiments, the mutation is P535H.

[0028] In some embodiments, the at least one gain of function missense mutation is in the amino acid V534. In certain embodiments, the mutation is V534E.

[0029] In some embodiments, the at least one gain of function missense mutation is in the amino acid S463. In certain embodiments, the mutation is S463P.

[0030] In some embodiments, the at least one gain of function missense mutation is in the amino acid V392. In certain embodiments, the mutation is V392I.

[0031] In certain embodiments, the at least one gain of function missense mutation is in the amino acid E380. In certain embodiments, the mutation is E380Q.

[0032] In various embodiments, lasofoxifene is administered as lasofoxifene tartrate. In various embodiments, lasofoxifene is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration. In some embodiments, lasofoxifene is administered byoral administration. In some embodiments, lasofoxifene is administered at about 0.5 mg / day per os to about 10 mg / day per os. In some embodiments, lasofoxifene is administered at about 0.5 mg / day per os to about 5 mg / day per os. In some embodiments, lasofoxifene is administered at about 1 mg / day per os to about 5 mg / day per os. In certain embodiments, lasofoxifene is administered at 1 mg / day per os. In certain embodiments, lasofoxifene is administered at 5 mg / day per os. In certain embodiments, lasofoxifene is administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, or once every month.

[0033] In various embodiments, the method further comprises treating the patient with at least one additional endocrine therapy.

[0034] In some embodiments, the patient is treated with the additional endocrine therapy at original doses. In some embodiments, the patient is treated with the additional endocrine therapy at doses higher than original doses. In some embodiments, the additional endocrine therapy is treatment with a selective ER modulator (SERM) other than lasofoxifene. In certain embodiments, the additional endocrine therapy is treatment with a selective ER degrader (SERD). In some embodiments, the additional endocrine therapy is treatment with an aromatase inhibitor.

[0035] In various embodiments, the method further comprises administering to the patient an effective amount of a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib.

[0036] In various embodiments, the method further comprises administering to the patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor. In some embodiments, the mTOR inhibitor is Everolimus.

[0037] In some embodiments, the method further comprises administering to the patient an effective amount of phosphoinositide 3 -kinase (PI3K) inhibitor or heat shock protein 90 (HSP90) inhibitor.

[0038] In various embodiments, the method further comprises administering to the patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor. In some embodiments, the HER2 inhibitor is trastuzumab (Herceptin®) or ado-trastuzumab emtansine (Kadcyla®).

[0039] In various embodiments, the method further comprises administering to the patient an effective amount of a histone deacetylase (HD AC) inhibitor. In some embodiments, theHD AC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (Farydak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS- 275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ- 26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY-1215), or sulforaphane.

[0040] In various embodiments, the method further comprises administering to the patient an effective amount of a checkpoint inhibitor. In some 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 certain embodiments, the PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). In certain embodiments, the CTLA-4 antibody is ipilimumab (Yervoy®).

[0041] In various embodiments, the method further comprises administering to the patient an effective amount of cancer vaccine.

[0042] In various embodiments, the patient is a premenopausal woman. In some embodiments, the patient has ER+ / HER2- uterine cancer. In some embodiments, the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.

[0043] In various embodiments, the patient is a perimenopausal woman. In some embodiments, the patient has ER+ / HER2- uterine cancer. In certain embodiments, the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.

[0044] In various embodiments, the patient is a postmenopausal woman. In some embodiments, the patient has ER+ / HER2- uterine cancer. In certain embodiments, the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.

[0045] In another aspect, a method of adjuvant therapy of estrogen receptor positive (ER+) cancer other than breast or ovarian cancer is provided. The method comprises administering to a patient who has received primary treatment for ER+cancer other than breast or ovariancancer, an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0046] In some embodiments, the ER+cancer is selected from uterine, cervical, peritoneal, vulva, vaginal, lung, esophageal, gastric, small intestine, colon, rectal, colorectal, bladder, brain, skin, renal pelvic, pancreatic, and cancer of unknown primary origin. In certain embodiments, the ER+cancer is uterine cancer selected from endometrioid, clear-cell carcinoma, papillary serous, carcinosarcoma, leiomyosarcoma, or endometrial stromal sarcoma (ESS). In certain embodiments, the uterine cancer is uterine endometrial stromal sarcoma uterine endometrial adenosarcoma, uterine adenosquamous carcinoma, uterine leiomyosarcoma or uterine corpus carcinoma. In certain embodiments, the ER+cancer is cervical clear-cell carcinoma, vulvar squamous cell carcinoma, vulvar adenocarcinoma, vaginal squamous cell carcinoma or vaginal adenocarcinoma. In certain embodiments, the ER+cancer is lung cancer is lung adenosarcoma, squamous cell lung carcinoma or small cell lung carcinoma. In certain embodiments, the ER+cancer is esophageal adenocarcinoma, gastric adenocarcinoma, small intestinal adenocarcinoma, small intestinal carcinoid tumor, small intestinal lymphoma, small intestinal sarcoma, small intestinal leiomyosarcoma, malignant small intestinal neoplasm, colon adenocarcinoma, rectal adenocarcinoma, colorectal adenocarcinoma, colorectal mucinous adenocarcinoma, bladder urothelial carcinoma, glioblastoma, conventional glioblastoma multiforme, skin squamous cell carcinoma, melanoma, cutaneous melanoma, infiltrating renal pelvic cancer, or pancreatic adenocarcinoma.

[0047] In various embodiments, lasofoxifene is administered as lasofoxifene tartrate.

[0048] In various embodiments, the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).

[0049] In various embodiments, lasofoxifene is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration. In some embodiments, lasofoxifene is administered by oral administration. In certain embodiments, lasofoxifene is administered at about 0.5 mg / day per os to about 10 mg / day per os. In certain embodiments, lasofoxifene is administered at about 0.5 mg / day per os to about 5 mg / day per os. In certain embodiments, lasofoxifene is administered at about 1 mg / day per os to about 5 mg / day per os. In certain embodiments, lasofoxifene is administered at 1 mg / day per os. In certain embodiments, lasofoxifene is administered at 5 mg / day per os. In various embodiments, lasofoxifene is administered once every day, once every two days, once every three days,once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, or once every month.

[0050] In various embodiments, the method further comprises treating the patient with an additional endocrine therapy. In certain embodiments, the additional endocrine therapy is treatment with a selective ER degrader (SERD).

[0051] In various embodiments, the method further comprises administering to the patient an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In certain embodiments, the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib.

[0052] In various embodiments, the method further comprises administering to the patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor. In certain embodiments, the mTOR inhibitor is Everolimus.

[0053] In various embodiments, the method further comprises administering to the patient an effective amount of phosphoinositide 3 -kinase (PI3K) inhibitor or heat shock protein 90 (HSP90) inhibitor.

[0054] In various embodiments, the method further comprises administering to the patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor. In certain embodiments, the HER2 inhibitor is trastuzumab (Herceptin®) or ado-trastuzumab emtansine (Kadcyla®).

[0055] In various embodiments, the method further comprises administering to the patient an effective amount of a histone deacetylase (HD AC) inhibitor. In certain embodiments, the HD AC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (Farydak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS- 275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ- 26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY-1215), or sulforaphane.

[0056] In various embodiments, the method further comprises administering to the patient an effective amount of checkpoint inhibitor. In certain 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 certain embodiments, the PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). In certain embodiments, the CTLA-4 antibody is ipilimumab (Yervoy®).

[0057] In various embodiments, the method further comprises administering to the patient an effective amount of cancer vaccine.

[0058] In various embodiments, lasofoxifene is administered in an amount and on a schedule sufficient to improve bone mass.

[0059] In various embodiments, the patient is female and lasofoxifene is administered in an amount and on a schedule sufficient to improve symptoms of VVA.

[0060] In various embodiments, the patient is female and is premenopausal.

[0061] In various embodiments, the patient is female and perimenopausal.

[0062] In various embodiments, the patient is female and postmenopausal.

[0063] In another aspect, a method of treating a patient suffering from cancer other than breast or ovarian cancer, who is at risk of acquiring resistance to endocrine therapy, optionally the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (Al) therapy, or (iv) any combination of (i), (ii) and / or (iii). The method comprises administering to the patient an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0064] Also provided is the use of lasofoxifene for treating a patient suffering from cancer other than breast or ovarian cancer, who is at risk of acquiring resistance to endocrine therapy, optionally the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (Al) therapy, or (iv) any combination of (i), (ii) and / or (iii). Further provided is the use of lasofoxifene in the manufacture of a formulation for the treating a patient suffering from cancer other than breast or ovarian cancer, who is at risk of acquiring resistance to endocrine therapy, optionally the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (Al) therapy, or (iv) any combination of (i), (ii) and / or (iii).

[0065] In some embodiments, the patient has been diagnosed with an ER+cancer selected from uterine, cervical, peritoneal, vulva, vaginal, lung, esophageal, gastric, small intestine, colon, rectal, colorectal, bladder, brain, skin, renal pelvic, pancreatic, and cancer of unknown primary origin. In certain embodiments, the cancer is a primary cancer.

[0066] In various embodiments, the patient has been treated with endocrine therapy, optionally the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (Al) therapy, or (iv) any combination of (i), (ii) and / or (iii).

[0067] Accordingly, in another aspect, a method of treating a female patient suffering from estrogen receptor positive (ER+) primary cancer other than breast or ovarian cancer. The method comprises administering to a female patient an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0068] In various embodiments, the patient is at risk of acquiring resistance to endocrine therapy, optionally the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (Al) therapy, or (iv) any combination of (i), (ii) and / or (iii).

[0069] In various embodiments, the primary ER+cancer is selected from uterine, cervical, peritoneal, vulva, vaginal, lung, esophageal, gastric, small intestine, colon, rectal, colorectal, bladder, brain, skin, renal pelvic, pancreatic, and cancer of unknown primary origin.

[0070] In various embodiments, the patient has been treated with endocrine therapy, optionally the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (Al) therapy, or (iv) any combination of (i), (ii) and / or (iii).

[0071] In another aspect, a method of treating a female patient suffering from estrogen receptor positive (ER+) cancer other than breast or ovarian cancer. The method comprises administering to a female patient an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

[0072] Also provided is the use of lasofoxifene for treating a female patient suffering from estrogen receptor positive (ER+) cancer other than breast or ovarian cancer. Further provided is the use of lasofoxifene in the manufacture of a formulation for the treating a female patient suffering from estrogen receptor positive (ER+) cancer other than breast or ovarian cancer.

[0073] In various embodiments, the primary ER+cancer is selected from uterine, cervical, peritoneal, vulva, vaginal, lung, esophageal, gastric, small intestine, colon, rectal, colorectal, bladder, brain, skin, renal pelvic, pancreatic, and cancer of unknown primary origin.

[0074] In various embodiments, the patient has previously been treated with one or more lines of endocrine therapy. In some embodiments, the patient has previously been treated with a plurality of lines of endocrine therapy. In some embodiments, the patient has disease progression after endocrine therapy.

[0075] In some embodiments, the endocrine therapy that the patient has previously been treated with is a selective ER modulator (SERM). In certain embodiments, the SERM is tamoxifen, raloxifene, bazedoxifene, toremifene, or ospemifene.

[0076] In some embodiments, the endocrine therapy that the patient has previously been treated with is a selective ER degrader (SERD). In certain embodiments, the SERD is fulvestrant, RAD1901, ARN-810 (GDC-0810), or AZD9496.

[0077] In some embodiments, the endocrine therapy that the patient has previously been treated with is an aromatase inhibitor. In certain embodiments, the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).

[0078] In various embodiments, the patient has disease progression after endocrine therapy.

[0079] In various embodiments, the patient’s cancer is resistant to endocrine therapy other than lasofoxifene.

[0080] In various embodiments, the patient’s cancer has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene. In some embodiments, the patient has previously been determined to have at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene.

[0081] In various embodiments, the method further comprises the earlier step of determining that the patient has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene.

[0082] In some embodiments, the at least one of gain of function missense mutation is in any one of amino acids D538, Y537, L536, P535, V534, S463, V392, and E380.

[0083] In some embodiments, the at least one gain of function mutation is in the amino acid D538. In certain embodiments, the mutation is D538G.

[0084] In some embodiments, the at least one gain of function mutation is in the amino acid Y537. In some embodiments, the mutation is Y537S, Y537N, Y537C, or Y537Q. In certain embodiments, the mutation is Y537C.

[0085] In some embodiments, the at least one gain of function mutation is in the amino acid L536. In certain embodiments, the mutation is L536R or L536Q.

[0086] In some embodiments, the at least one gain of function mutation is in the amino acid P535. In certain embodiments, the mutation is P535H.

[0087] In some embodiments, the at least one gain of function mutation is in the amino acid V534. In certain embodiments, the mutation is V534E.

[0088] In some embodiments, the at least one gain of function mutation is in the amino acid S463. In certain embodiments, the mutation is S463P.

[0089] In some embodiments, the at least one gain of function mutation is in the amino acid V392. In certain embodiments, the mutation is V392I.

[0090] In some embodiments, the at least one gain of function mutation is in the amino acid E380. In certain embodiments, the mutation is E380Q.

[0091] In various embodiments, lasofoxifene is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration. In some embodiments, lasofoxifene is administered by oral administration. In certain embodiments, lasofoxifene is administered at about 0.5 mg / day per os to about 10 mg / day per os. In certain embodiments, lasofoxifene is administered at about 0.5 mg / day per os to about 5 mg / day per os. In certain embodiments, lasofoxifene is administered at about 1 mg / day per os to about 5 mg / day per os. In certain embodiments, lasofoxifene is administered at 1 mg / day per os. In certain embodiments, lasofoxifene is administered at 5 mg / day per os. In various embodiments, lasofoxifene is administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, or once every month.

[0092] In various embodiments, the method further comprises treating the patient with at least one additional endocrine therapy. In certain embodiments, the patient is treated with the additional endocrine therapy at original doses. In certain embodiments, the patient is treated with the additional endocrine therapy at doses higher than original doses.

[0093] In some embodiments, the endocrine therapy that the patient has previously been treated with is a selective ER modulator (SERM). In certain embodiments, the SERM is tamoxifen, raloxifene, bazedoxifene, toremifene, or ospemifene.

[0094] In some embodiments, the endocrine therapy that the patient has previously been treated with is a selective ER degrader (SERD). In certain embodiments, the SERD is fulvestrant, RAD1901, ARN-810 (GDC-0810), or AZD9496.

[0095] In some embodiments, the endocrine therapy that the patient has previously been treated with is an aromatase inhibitor. In certain embodiments, the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).

[0096] In various embodiments, the method further comprises administering to the patient an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In certain embodiments, the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib.

[0097] In various embodiments, the method further comprises administering to the patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor. In certain embodiments, the mTOR inhibitor is Everolimus.

[0098] In various embodiments, the method further comprises administering to the patient an effective amount of phosphoinositide 3 -kinase (PI3K) inhibitor or heat shock protein 90 (HSP90) inhibitor.

[0099] In various embodiments, the method further comprises administering to the patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor. In certain embodiments, the HER2 inhibitor is trastuzumab (Herceptin®) or ado-trastuzumab emtansine (Kadcyla®).

[0100] In various embodiments, the method further comprises administering to the patient an effective amount of a histone deacetylase (HD AC) inhibitor. In some embodiments, the HD AC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (F ary dak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR- 3996, 4SC202, CG200745, rocilinostat (ACY-1215), or sulforaphane.

[0101] In various embodiments, the method further comprises administering to the patient an effective amount of a checkpoint inhibitor. In some 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 certain embodiments, the PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). In certain embodiments, the CTLA-4 antibody is ipilimumab (Yervoy®).

[0102] In various embodiments, the method further comprises administering to the patient an effective amount of cancer vaccine.

[0103] In various embodiments, the patient is premenopausal. In some embodiments, the patient has ER+ / HER2‘ uterine cancer. In certain embodiments, the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.

[0104] In various embodiments, the patient is perimenopausal. In some embodiments, the patient has ER+ / HER2‘ uterine cancer. In certain embodiments, the patient hasprogressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.

[0105] In various embodiments, the patient is postmenopausal. In some embodiments, the patient has ER+ / HER2‘ uterine cancer. In certain embodiments, the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.4. BRIEF DESCRIPTION OF THE DRAWINGS

[0106] 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:

[0107] FIG. 1 shows the chemical structure of lasofoxifene.

[0108] FIG. 2 is a structural diagram of the ERa protein encoded by the ESRI gene that illustrates the known distribution of acquired ESRI mutations in ER+metastatic breast cancers. Provided is a schematic representation of the ERa protein and its functional domains; the position and number of cases (n) of the ESRI (ER) LBD point mutations reported in metastatic ER+breast cancers are indicated. Black circles indicate each mutation at the specific amino acid residue; numbers in parentheses indicate the total number of samples reported to harbor the specific indicated mutations. Abbreviations: AF-1, activation function-1; AF-2, activation function-2; DBD, DNA-binding domain; ERa, oestrogen receptor a; LBD, ligand-binding domain.5. DETAILED DESCRIPTION

[0109] Lasofoxifene, a selective estrogen receptor modulator (SERM), has recently been shown to be effective in vitro in arresting the growth of ER+ovarian and breast cancer cells harboring gain-of-function mutations in the ESRI gene, US Pat. No. 10,258,604; to inhibit tumor growth and metastasis of human ER+breast cancer cells expressing ESRI gain-of- function mutations in a mouse mammary intraductal (MIND) xenograft model of ERa+breast cancer, WO 2019 / 199891; and to be effective in the MIND model in combination with the CDK 4 / 6 inhibitor, palbociclib, WO 2019 / 199891. The effectiveness of lasofoxifene as a single agent in the treatment of pre- and postmenopausal women with locally advanced or metastatic ER / HER2 breast cancer with an acquired ESRI mutation is currently being assessed in a phase 2 clinical trial, NCT03781063 (the ELAINE trial). A clinical trialassessing the effectiveness of lasofoxifene in combination with the CDK 4 / 6 inhibitor, abemaciclib, in a similar population of breast cancer patients has been approved but is not yet open for enrollment, NCT04432454 (the ELAINE II trial).

[0110] Other cancers are known to be ER+and subject to acquisition of ESRI gain-of- function mutations. See Gaillard el al.. Gynecologic Oncology 154: 199-206 (2019) and mycancergenome.org / content / alteration / esrl-mutation. Although lasofoxifene has been proposed to be effective in treating ERa+lung cancers in which the ESRI gene has acquired gain-of-function mutations, WO 2019 / 199891, there is as yet no in vivo demonstration of lasofoxifene’ s effectiveness in ER+cancers other than breast cancer.

[0111] Animal model experiments described herein demonstrate that lasofoxifene is effective in inhibiting proliferation of ER+cells from cancers other than breast or ovarian cancer, and is effective even when the cells have acquired gain-of-function mutations in the ligand binding domain (LBD) of ESRI.5.1. Methods of Treatment

[0112] Accordingly, in a first aspect, disclosed herein is a method of treating ER+cancer other than ER+breast or ovarian cancer. The method comprises (a) selecting for treatment a patient who has been diagnosed with estrogen receptor positive (ER+) cancer other than breast or ovarian cancer; and (b) administering to the selected patient an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.5.1.1. ER+cancers

[0113] In various embodiments, the patient has been diagnosed with ER+cancer by immunohistochemistry (H4C) performed on a sample of the patient’s cancer, by RT-PCR, or by other techniques.

[0114] In certain embodiments, the cancer is a gynecological cancer selected from uterine cancer, cervical cancer, peritoneal cancer, vulva cancer, and vaginal cancer.

[0115] In some embodiments, the patient has been diagnosed with ER+primary uterine cancer. In certain embodiments, the uterine cancer is selected from endometrioid, clear-cell carcinoma, papillary serous, carcinosarcoma, leiomyosarcoma, and endometrial stromal sarcoma (ESS). In certain embodiments, the uterine cancer is uterine endometrial stromal sarcoma uterine endometrial adenosarcoma, uterine adenosquamous carcinoma, uterine leiomyosarcoma or uterine corpus carcinoma.

[0116] In some of these embodiments, the patient has been diagnosed with ER+cervical cancer. In certain embodiments, the cervical cancer is cervical clear-cell carcinoma.

[0117] In some of these embodiments, the patient has been diagnosed with ER+vulvar / vaginal cancer.In certain embodiments, the vulva or vaginal cancer is a squamous cell carcinoma (SCC) or an adenocarcinoma.

[0118] In some of these embodiments, the patient has been diagnosed with ER+lung cancer. In certain embodiments, the lung cancer is lung adenosarcoma, squamous cell lung carcinoma, or small cell lung carcinoma.

[0119] In certain embodiments, the cancer is a gastrointestinal cancer selected from esophageal cancer, gastric cancer,; small intestine cancer, colon cancer, rectal cancer, and colorectal cancer.

[0120] In some embodiments, the patient has been diagnosed with ER+primary esophageal cancer. In certain embodiments, the esophageal cancer is adenocarcinoma or squamous cell carcinoma.

[0121] In some embodiments, the patient has been diagnosed with ER+primary gastric cancer. In certain embodiments, the gastric cancer is gastric adenocarcinoma.

[0122] In some embodiments, the patient has been diagnosed with ER+primary small intestine cancer. In certain embodiments, the small intestine cancer is an adenocarcinoma, carcinoid tumor, lymphoma, or sarcoma such as leiomyosarcoma. In certain embodiments, the small intestine cancer is malignant small intestinal neoplasm.

[0123] In some embodiments, the patient has been diagnosed with ER+primary colon cancer. In certain embodiments, the colon cancer is colon adenocarcinoma.

[0124] In some embodiments, the patient has been diagnosed with ER+primary rectal cancer. In certain embodiments, the rectal cancer is rectal adenocarcinoma;

[0125] In some embodiments, the patient has been diagnosed with ER+primary colorectal cancer. In certain embodiments, the colorectal cancer is colorectal adenocarcinoma and colorectal mucinous adenocarcinoma.

[0126] In certain embodiments, the cancer is selected from bladder cancer, e.g., bladder urothelial carcinoma; glioblastoma, e.g., conventional glioblastoma multiforme; skin cancer, e.g., skin squamous cell carcinoma; melanoma, e.g., cutaneous melanoma; infiltrating renal pelvic cancer; pancreatic cancer, e.g., pancreatic adenocarcinoma and cancer of unknown primary origin.

[0127] In some embodiments, cells of the patient’s cancer have acquired a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene. LBD gain of function mutations are more fully described below in Section 4.1.4.

[0128] In some embodiments, the patient is at risk of acquiring resistance to endocrine therapy. In particular embodiments, the patient is at risk of acquiring resistance to endocrine therapy due to the increased expression of estrogen receptor. In particular embodiments, the patient is at risk of acquiring resistance to endocrine therapy due to the increased expression of co-activators of estrogen receptor. In particular embodiments, the patient is at risk of acquiring resistance to endocrine therapy due to increased phosphorylation level and activity of estrogen receptor and its co-activators. In particular embodiments, the patient is at risk of acquiring resistance to endocrine therapy due to change of tumor microenvironment and other host related factors. In some preferred embodiments, the patient is at risk of acquiring resistance to endocrine therapy due to mutations in the Estrogen Receptor 1 (ESRI) gene.

[0129] In some of these embodiments, the endocrine therapy to which the patient is at risk of acquiring resistance is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor therapy (Al), or (iv) any combination of (i), (ii) and / or (iii).

[0130] In some embodiments, the ER+cancer is a primary cancer. In some embodiments, the ER+cancer is a localized cancer. In some embodiments, the cancer is locally advanced. In some embodiments, the cancer is a metastatic ER+cancer.5.1.2. Previous Treatment with Endocrine Therapy

[0131] In various embodiments, the ER+cancer patient has previously been treated with one or more lines of endocrine therapy. In certain embodiments, the patient has previously been treated with one line of endocrine therapy. In certain other embodiments, the patient has previously been treated with a plurality of lines of endocrine therapy. In some embodiments, the patient has previously been treated with two lines of endocrine therapy. In some embodiments, the patient has previously been treated with three lines of endocrine therapy. In some embodiments, the patient has previously been treated with four or more lines of endocrine therapy.

[0132] In some embodiments, the endocrine therapy that the patient has previously been treated with is a selective ER modulator (SERM). In some embodiments, the selective ERmodulator is selected from tamoxifen, raloxifene, bazedoxifene, toremifene, and ospemifene. In certain embodiments, the selective ER modulator is tamoxifen.

[0133] In some embodiments, the endocrine therapy that the patient has previously been treated with is a selective ER degrader (SERD). In various embodiments, the selective ER degrader binds to the estrogen receptor and leads to the proteasomal degradation of the receptor. In some embodiments, the selective ER degrader is selected from fulvestrant, RAD 1901, ARN-810 (GDC-0810), and AZD9496. In certain embodiments, the selective ER degrader is fulvestrant.

[0134] In some embodiments, the endocrine therapy with which the patient has previously been treated is an aromatase inhibitor (Al). In various embodiments, the aromatase inhibitor blocks the production of estrogen. In some embodiments, the aromatase inhibitor is selected from exemestane (Aromasin®), letrozole (Femara®), and anastrozole (Arimidex®).

[0135] In some embodiments, the endocrine therapy that the patient has previously been treated with is ovarian suppression. In certain embodiments, ovarian suppression is achieved by oophorectomy. In certain embodiments, ovarian suppression is achieved by administration of a GnRH antagonist.

[0136] In certain embodiments, the patient’s cancer has relapsed or progressed after the previous endocrine therapy treatment. In some embodiments, the patient’s cancer has relapsed or progressed after tamoxifen treatment. In some embodiments, the patient’s cancer has relapsed or progressed after fulvestrant treatment. In some embodiments, the patient’s cancer has relapsed or progressed after aromatase inhibitor treatment. In some of these embodiments, the patient’s cancer has relapsed or progressed after multiple lines of endocrine therapy treatment.

[0137] In some embodiments, the ER+cancer patient has not been treated previously with endocrine therapy.

[0138] In certain embodiments, the patient is resistant to endocrine therapy other than lasofoxifene. In some embodiments, the patient has intrinsic endocrine resistance. In some embodiments, the patient has acquired endocrine resistance. In particular embodiments, the patient is resistant to endocrine therapy due to the increased expression of estrogen receptor. In particular embodiments, the patient is resistant to endocrine therapy due to the increased expression of co-activators of estrogen receptor. In particular embodiments, the patient is resistant to endocrine therapy due to increased phosphorylation level and activity of estrogenreceptor and its co-activators. In particular embodiments, the patient is resistant to endocrine therapy due to change of tumor microenvironment and other host related factors. In some preferred embodiments, the patient is resistant to endocrine therapy due to gene mutations in the Estrogen Receptor 1 (ESRI) gene.

[0139] In various embodiments, the patient is resistant to clinical doses of one or more SERMs other than lasofoxifene. In some of these embodiments, the patient is resistant to clinical doses of tamoxifen. In various embodiments, the patient is resistant to clinical doses of one or more SERDs. In some of these embodiments, the patient is resistant to clinical doses of fulvestrant. In various embodiments, the patient is resistant to clinical doses of one or more aromatase inhibitors. In various embodiments, the patient is resistant to higher than clinical doses of one or more SERMs other than lasofoxifene. In some of these embodiments, the patient is resistant to higher than clinical doses of tamoxifen. In various embodiments, the patient is resistant to higher than clinical doses of one or more SERDs. In some of these embodiments, the patient is resistant to higher than clinical doses of fulvestrant. In various embodiments, the patient is resistant to higher than clinical doses of one or more aromatase inhibitors.

[0140] In certain embodiments, the ER+cancer patient has not been demonstrated to have endocrine resistance. In some of these embodiments, the patient has not been demonstrated to have endocrine resistance due to the limitations of the detection methods.

[0141] In some embodiments, lasofoxifene is administered to the ER+cancer patient after completion of cancer treatment. In some of these embodiments, lasofoxifene is administered to the patient to treat occult micrometastasis.5.1.3. Sex and menopause status

[0142] In some embodiments, the ER+cancer patient is male.

[0143] In some embodiments, the ER+cancer patient is a premenopausal woman. In specific embodiments, the patient is premenopausal and has locally advanced or metastatic ER+cancer. In particular embodiments, the patient is premenopausal and has locally advanced or metastatic ER+cancer other than breast or ovarian cancer.

[0144] In certain embodiments, the ER+cancer patient is a perimenopausal woman. In specific embodiments, the patient is perimenopausal and has locally advanced or metastatic ER+cancer. In particular embodiments, the patient is perimenopausal and has locally advanced or metastatic ER+cancer other than breast or ovarian cancer.

[0145] In certain embodiments, the ER+cancer patient is a postmenopausal woman.

[0146] In certain embodiments, lasofoxifene is administered to a premenopausal woman with locally advanced or metastatic ER+ / HER2‘ cancer other than breast or ovarian cancer. In certain embodiments, lasofoxifene is administered to a premenopausal woman with locally advanced or metastatic ER+ / HER2‘ cancer other than breast or ovarian cancer who has progressed while on her first hormonal treatment with a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.

[0147] In certain embodiments, lasofoxifene is administered to a perimenopausal woman with locally advanced or metastatic ER+ / HER2‘ cancer other than breast or ovarian cancer. In certain embodiments, lasofoxifene is administered to a perimenopausal woman with locally advanced or metastatic ER+ / HER2‘ cancer other than breast or ovarian cancer who has progressed while on her first hormonal treatment with a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.

[0148] In certain embodiments, lasofoxifene is administered to a postmenopausal woman with locally advanced or metastatic ER+ / HER2‘ cancer other than breast or ovarian cancer. In certain embodiments, lasofoxifene is administered to a postmenopausal woman with locally advanced or metastatic ER+ / HER2‘ cancer who has progressed while on her first hormonal treatment with on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.5.1.4. Mutations in ESRI Gene

[0149] In various embodiments, the patient has an ER+cancer, cells of which have at least one mutation in the Estrogen Receptor 1 (ESRI) gene, which encodes the Estrogen Receptor a (ERa) protein. In some embodiments, the mutation leads to the ligandindependent activity of the estrogen receptor. In some embodiments, the mutation leads to enhanced ligand stimulated activity of estrogen receptor. In some embodiments, the mutation leads to resistance to endocrine therapy. In some embodiments, the mutation promotes tumor growth. In some embodiments, the mutation enhances metastatic activity of cancer. In some preferred embodiments, the mutation enhances metastatic activity of ER+metastatic cancer other than breast or ovarian cancer.

[0150] In some embodiments, the mutation arises from a pre-existing clone. In some embodiments, the mutation is acquired de novo during the course of endocrine therapy treatment. In some embodiments, the mutation is acquired de novo after multiple lines ofendocrine therapy treatment. In various embodiments, the mutant clone expands to become a more dominant clone over the course of successive lines of endocrine therapy.

[0151] In some preferred embodiments, the patient has an ER+cancer that has at least one gain of function missense mutation within the ligand binding domain (LBD) of the ESRI gene. In various embodiments, at least one of the mutations is in an amino acid selected from D538, Y537, L536, P535, V534, S463, V392, and E380. (The amino acids are numbered according to the ESRI protein with the NCBI accession number NP 000116.2.)

[0152] In particular embodiments, the mutation increases the stability of the agonist conformation of Helix 12 of the ERa protein. In some of these embodiments, the mutation increases the binding of the estrogen receptor to its co-activators. In some of these embodiments, the mutation leads to hormone independent activity of estrogen receptor. In some of these embodiments, the mutation leads to resistance to tamoxifen, fulvestrant, and / or aromatase inhibitors.

[0153] In certain embodiments, the mutation is in the amino acid D538. In certain preferred embodiments, the mutation is D538G.

[0154] In certain embodiments, the mutation is in the amino acid Y537. In some of these embodiments, the mutation is Y537S, Y537N, Y537C, or Y537Q. In certain preferred embodiments, the mutation is Y537C.

[0155] In some embodiments, the mutation is in the amino acid L536. In certain embodiments, the mutation is L536R or L536Q.

[0156] In some embodiments, the mutation is in the amino acid P535. In certain embodiments, the mutation is P535H.

[0157] In some embodiments, the mutation is in the amino acid V534. In certain embodiments, the mutation is V534E.

[0158] In some embodiments, the mutation is in the amino acid S463. In certain embodiments, the mutation is S463P.

[0159] In some embodiments, the mutation is in the amino acid V392. In certain embodiments, the mutation is V392I.

[0160] In some embodiments, the mutation is in the amino acid E380. In certain embodiments, the mutation is E380Q.5.1.4.1. Detection of the ESRI Gene Mutations

[0161] In various embodiments, the patient’s cancer has been previously determined to have at least one mutation in the ESRI gene. Some embodiments of the methods described herein further include the step of detecting the mutations in ESRI gene.

[0162] In some embodiments, massively parallel next generation sequencing (NGS) is used for detecting the estrogen receptor mutations in the patient’s cancer. In certain embodiments, the entire genome is sequenced. In certain embodiments, selected gene panels of cancer-related genes are sequenced. In certain embodiments, all coding exons within a given set of genes are sequenced. In certain embodiments, known “hotspot” regions within a given set of genes are sequenced. However, the inherent error rate of current next generation sequencing techniques is up to 1%, limiting the sensitivity and specificity of detection. In some embodiments, targeted sequencing is used for detecting the presence of the ESRI mutations. Although targeted sequencing allows deeper sequencing, it is also currently limited by the 1% error rate. In some embodiments, methods with reduced sequencing error rate are used. In a particular embodiment, Safe-Sequencing System (Safe-SeqS) is used, which tags each template molecule to allow for confident identification of rare variants. See Kinde et al.. Proceedings of the National Academy of Sciences 108(23): 9530-9535 (2011). In particular embodiments, ultrasensitive Duplex sequencing is used, which independently tags and sequences each of the two strands of a DNA duplex. See Schmitt et al., Proceedings of the National Academy of Sciences 109(36): 14508-14513 (2012). In some embodiments, digital droplet PCR is used, which emulsifies DNA in thousands to millions of droplets to encapsulate single DNA molecules, designed with mutant specific primers. See Vogelstein and Kinzler, Proceedings of the National Academy of Sciences 96(16): 2322-2326 (1999) and Huggett etal., Clinical Chemistry 61(1): 79-88 (2014).

[0163] In some embodiments, the detection of the ESRI mutations takes place at the initial diagnosis. In some embodiments, the detection of the mutations takes place at the time of disease progression, relapse, or recurrence. In some embodiments, the detection of the mutations takes place at the time of disease progression. In some embodiments, the detection of the mutations takes place at the time when the disease is stable.

[0164] In some embodiments, one or more tissue specimens are obtained for detection of the mutations. In certain embodiments, the tissue specimen is a tumor biopsy. In certain embodiments, the tissue specimen is a biopsy of metastases. In some other embodiments, liquid biopsies are obtained for detection of the mutations. In certain embodiments, the liquidbiopsy comprises circulating tumor cells (CTCs). In other embodiments, the liquid biopsy comprises cell-free DNA from blood samples.

[0165] In specific embodiments, the ESRI mutations are monitored by circulating tumor DNA (ctDNA) analysis. In some embodiments, the ctDNA analysis is performed throughout the course of treatment. In some of these embodiments, the ctDNA is extracted from patient blood samples. In certain embodiments, the ctDNA is evaluated by digital PCR analysis of the ESRI mutations.5.1.5. Estradiol Levels

[0166] In various embodiments, a female patient who is selected for treatment based on presence of ESRI gene mutations is further selected based on serum estradiol level.

[0167] In certain embodiments, the serum estradiol level of the patient with the ER+cancer having an ESRI gene mutation is at least 0.20 ng / dL, such as at least 0.25 ng / dL, at least 0.30 ng / dL, at least 0.35 ng / dL, at least 0.40 ng / dL, at least 0.45 ng / dL, at least 0.50 ng / dL, at least 0.55 ng / dL, at least 0.60 ng / dL, at least 0.65 ng / dL, at least 0.70 ng / dL, at least 0.75 ng / dL, at least 0.80 ng / dL, at least 0.85 ng / dL, at least 0.90 ng / dL, at least 0.95 ng / dL, or at least 1.0 ng / dL.

[0168] In certain embodiments, the serum estradiol level of the patient with the ESRI gene mutation is about 0.20 ng / dL to about 1.0 ng / dL, such as about 0.20 ng / dL to about 0.25 ng / dL, about 0.25 ng / dL to about 0.30 ng / dL, about 0.30 ng / dL to about 0.35 ng / dL, about 0.35 ng / dL to about 0.40 ng / dL, about 0.40 ng / dL to about 0.45 ng / dL, about 0.45 ng / dL to about 0.50 ng / dL, about 0.50 ng / dL to about 0.55 ng / dL, about 0.55 ng / dL to about 0.60 ng / dL, about 0.60 ng / dL to about 0.65 ng / dL, about 0.65 ng / dL to about 0.70 ng / dL, about 0.70 ng / dL to about 0.75 ng / dL, about 0.75 ng / dL to about 0.80 ng / dL, about 0.80 ng / dL to about 0.85 ng / dL, about 0.85 ng / dL to about 0.90 ng / dL, about 0.90 ng / dL to about 0.95 ng / dL, about 0.95 ng / dL to about 1.0 ng / dL.5.1.6. Adjuvant Treatment

[0169] In various embodiments, lasofoxifene is administered to the patient as adjuvant treatment. In certain embodiments, lasofoxifene is administered to the patient as adjuvant treatment alone. In certain other embodiments, lasofoxifene is administered to the patient as adjuvant treatment in combination with other endocrine therapies. In some embodiments, lasofoxifene is administered to the patient after the primary treatment. In some of theseembodiments, lasofoxifene is administered to the patient after surgical removal or debulking of the cancer.

[0170] In some embodiments, lasofoxifene is administered to the patient as adjuvant therapy in combination with an aromatase inhibitor (Al). In various embodiments, the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).

[0171] In various embodiments, the aromatase inhibitor predisposes the patient to bone- related toxic effects. In some embodiments, the aromatase inhibitor predisposes the patient to osteoporosis. In some embodiments, the aromatase inhibitor predisposes the patient to bone loss. In some embodiments, the aromatase inhibitor predisposes the patient to bone fractures. In some embodiments, the aromatase inhibitor predisposes the patient to bone pain.

[0172] In various embodiments, the aromatase inhibitor predisposes a female patient to vulvovaginal atrophy (VVA).

[0173] In some embodiments, lasofoxifene is administered continuously during the administration of the aromatase inhibitor. In some other embodiments, lasofoxifene is administered cyclically during the administration of the aromatase inhibitor. In some embodiments, lasofoxifene and the aromatase inhibitor are administered together (simultaneously). In some other embodiments, lasofoxifene and the aromatase inhibitor are administered separately (sequentially).

[0174] In certain embodiments, the dosing regimen of lasofoxifene is different from the dosing regimen of the aromatase inhibitor. In some of these embodiments, the dosing quantity of lasofoxifene is different from the dosing quantity of the aromatase inhibitor. In some embodiments, the dosing schedule of lasofoxifene is different from the dosing schedule of the aromatase inhibitor. In some embodiments, the route of administration of lasofoxifene is different from the route of administration of the aromatase inhibitor.

[0175] In certain embodiments, the dosing regimen of lasofoxifene is the same as the dosing regimen of the aromatase inhibitor. In some embodiments, the dosing quantity of lasofoxifene is the same as the dosing quantity of the aromatase inhibitor. In some embodiments, the dosing schedule of lasofoxifene is the same as the dosing schedule of the aromatase inhibitor. In some embodiments, the route of administration of lasofoxifene is the same as the route of administration of the aromatase inhibitor.

[0176] In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for one year. In some embodiments,lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for two years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for three years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for four years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for five years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for six years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for seven years. I. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for eight years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for nine years. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for ten years. In some other embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to the patient for more than ten years. In certain embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor until the patient’s cancer progresses on therapy.

[0177] In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to increase the disease-free survival of the breast cancer patient. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to decrease the incidence of contralateral breast cancer. In some embodiments, lasofoxifene is administered as adjuvant therapy in combination with an aromatase inhibitor to prevent the recurrence or progression of the cancer.5.2. Lasofoxifene

[0178] In the methods described herein, the selected patient is treated with an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof. Lasofoxifene is a nonsteroidal, naphthalene-derived, third generation, SERM. The IUPAC name is (5R,6S)-6-phenyl-5-[4-(2-pyrrolidin-l-ylethoxy)phenyl]-5, 6,7,8- tetrahydronaphthalen-2-ol. The structure is shown in FIG. 1.

[0179] The term “pharmaceutically acceptable salt” refers to non-toxic pharmaceutically acceptable salts. In some preferred embodiments, lasofoxifene is administered to the selectedpatient as lasofoxifene tartrate. 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.

[0180] Embodiments also include prodrugs of the compounds disclosed herein. In general, such prodrugs will be functional derivatives of the compounds 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 in vivo after administration to the subject.

[0181] 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.

[0182] 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.5.3. Pharmaceutical Compositions

[0183] Methods for treatment of estrogen receptor positive (ER+) cancers include administering a therapeutically effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof. The lasofoxifene, the pharmaceutically acceptable salt, or the prodrug of the invention can be formulated in pharmaceutical compositions. In addition to lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug 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.

[0184] 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.

[0185] 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.

[0186] Pharmaceutical compositions for vaginal topical administration can be in the form of ointment, cream, gel or lotion. The pharmaceutical compositions for vaginal topical administration often include water, alcohol, animal oil, vegetable oil, mineral oil or synthetic oil. Hydrocarbon (paraffin), wool fat, beeswax, macrogols, emulsifying wax or cetrimide can also be included.

[0187] A composition can be administered alone or in combination with other treatments, either simultaneously or sequentially, dependent upon the condition to be treated.5.4. Treatment Regimens

[0188] In the methods of administering an effective amount of lasofoxifene as described above for treatment of ER+cancer other than breast or ovarian cancer, the terms "treatment","treating", and the like are used according to their commonly understood meanings in the oncology art, and therefore do not require complete remission or cure. As used herein the terms “treatment”, “treating”, and the like do not include prevention or prophylaxis of disease. In other embodiments, lasofoxifene is administered prophylactically to completely or partially prevent or slow development of ER+cancers other than breast or ovarian cancer.5.4.1. Routes of Administration

[0189] In various embodiments, lasofoxifene is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration.

[0190] In some embodiments, lasofoxifene is administered to the patient by oral administration. In certain embodiments, lasofoxifene is administered at about 0.5 mg / day per os to about 10 mg / day per os, such as about 0.5 mg / day per os to about 5 mg / day per os, about 0.5 mg / day per os to about 5 mg / day per os, about 1 mg / day per os to about 5 mg / day per os, about 2 mg / day per os to about 5 mg / day per os, about 3 mg / day per os to about 5 mg / day per os, about 4 mg / day per os to about 5 mg / day per os, about 0.5 mg / day per os to about 4 mg / day per os, about 1 mg / day per os to about 4 mg / day per os, about 2 mg / day per os to about 4 mg / day per os, about 3 mg / day per os to about 4 mg / day per os, about 0.5 mg / day per os to about 3 mg / day per os, about 1 mg / day per os to about 3 mg / day per os, about 2 mg / day per os to about 3 mg / day per os, about 0.5 mg / day per os to about 2 mg / day per os, about 1 mg / day per os to about 2 mg / day per os, or about 0.5 mg / day per os to about 1 mg / day per os. In some embodiments, lasofoxifene is administered at about 0.5 mg / day per os. In some embodiments, lasofoxifene is administered at about 1 mg / day per os. In some embodiments, lasofoxifene is administered at about 1.5 mg / day per os. In some embodiments, lasofoxifene is administered at about 2 mg / day per os. In some embodiments, lasofoxifene is administered at about 2.5 mg / day per os. In some embodiments, lasofoxifene is administered at about 3 mg / day per os. In some embodiments, lasofoxifene is administered at about 3.5 mg / day per os. In some embodiments, lasofoxifene is administered at about 4 mg / day per os. In some embodiments, lasofoxifene is administered at about 4.5 mg / day per os. In some embodiments, lasofoxifene is administered at about 5 mg / day per os. In some embodiments, lasofoxifene is administered at about 6 mg / day per os. In some embodiments, lasofoxifene is administered at about 7 mg / day per os. In some embodiments, lasofoxifene is administered at about 8 mg / day per os. In some embodiments, lasofoxifene is administered at about 9 mg / day per os. In some embodiments, lasofoxifene is administered at about 10mg / day per os. In some other embodiments, lasofoxifene is administered at more than 10 mg / day per os.

[0191] In certain embodiments, when lasofoxifene is administered to patient whose cancer has not acquired endocrine resistance, lasofoxifene can be administered at less than 0.5 mg / day per os for prevention of endocrine resistance. In certain embodiments, when lasofoxifene is administered to cancer patient as adjuvant treatment, lasofoxifene can be administered at less than 0.5 mg / day per os for prevention of endocrine resistance.

[0192] In certain embodiments, lasofoxifene is administered once every day. In certain embodiments, lasofoxifene is administered once every two days. In certain embodiments, lasofoxifene is administered once every three days. In certain embodiments, lasofoxifene is administered once every four days. In certain embodiments, lasofoxifene is administered once every five days. In certain embodiments, lasofoxifene is administered once every six days. In certain embodiments, lasofoxifene is administered once every week. In certain embodiments, lasofoxifene is administered once every two weeks. In certain embodiments, lasofoxifene is administered once every three weeks. In certain embodiments, lasofoxifene is administered once every month.

[0193] In some embodiments, lasofoxifene is administered to the patient by vaginal ring administration. In some of these embodiments, lasofoxifene is administered once every two weeks. In some of these embodiments, lasofoxifene is administered once every three weeks. In some of these embodiments, lasofoxifene is administered once every month. In some of these embodiments, lasofoxifene is administered once every two months. In some of these embodiments, lasofoxifene is administered once every three months. In some of these embodiments, lasofoxifene is administered once every four months.

[0194] In some embodiments, lasofoxifene is administered to ER+cancer patient for one year. In some embodiments, lasofoxifene is administered to the patient for two years. In some embodiments, lasofoxifene is administered to the patient for three years. In some embodiments, lasofoxifene is administered to the patient for four years. In some embodiments, lasofoxifene is administered to the patient for five years. In some other embodiments, lasofoxifene is administered to the patient for more than five years. In certain embodiments, lasofoxifene is administered to the patient until the patient’s cancer progresses on therapy.5.4.2. Combination Therapy

[0195] In various embodiments, lasofoxifene is administered either alone or in combination with other therapies. In certain embodiments, lasofoxifene is administered in combination with at least one other therapy. In some embodiments, lasofoxifene and other therapies are administered together (simultaneously). In some other embodiments, lasofoxifene and other therapies are administered at different times (sequentially).

[0196] In particular embodiments, the additional therapy that the patient is treated with is endocrine therapy. In various embodiments, the patient is treated with at least one line of additional endocrine therapy. In some embodiments, the patient is treated with one line of additional endocrine therapy. In some other embodiments, the patient is treated with multiple lines of additional endocrine therapy.

[0197] In some embodiments, the patient is treated with the additional endocrine therapy at the original doses. In some other embodiments, the patient is treated with the additional endocrine therapy at doses higher than original doses. In certain embodiments, the patient is treated with the additional endocrine therapy at doses lower than original doses.

[0198] In certain embodiments, the additional endocrine therapy is treatment with a selective ER modulator (SERM) other than lasofoxifene. In some of these embodiments, the selective ER modulator is selected from tamoxifen, raloxifene, bazedoxifene, toremifene, and ospermifene. In certain embodiments, the selective ER modulator is tamoxifen.

[0199] In certain embodiments, the additional endocrine therapy is treatment with a selective ER degrader (SERD). In some of these embodiments, the selective ER degrader is selected from fulvestrant, RAD 1901, ARN-810 (GDC-0810), and AZD9496. In certain embodiments, the selective ER degrader is fulvestrant.

[0200] In certain embodiments, the additional endocrine therapy is treatment with an aromatase inhibitor. In some of these embodiments, the aromatase inhibitor is selected from exemestane (Aromasin®), letrozole (Femara®), and anastrozole (Arimidex®).

[0201] In various embodiments, the additional therapy is administration to the patient of an effective amount of a cell cycle inhibitor. In certain embodiments, the additional therapy is administration of an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In some embodiments, the additional therapy is a CDK4 / 6 inhibitor selected from the group of palbociclib, abemaciclib, and riboci clib.

[0202] In some embodiments, the additional therapy is administration to the patient of an inhibitor of a pathway that cross-talks with and activates the ER transcriptional activity. Incertain embodiments, the additional therapy is a mammalian target of rapamycin (mTOR) inhibitor. In specific embodiments, the mTOR inhibitor is Everolimus. In some of these embodiments, lasofoxifene in combination with Everolimus is administered to a postmenopausal woman with locally advanced or metastatic breast cancer who has progressed on a non-steroidal Al and / or fulvestrant either as monotherapy or in combination with a CDK4 / 6 inhibitor. In various embodiments, the additional therapy is a phosphoinositide 3 -kinase (PI3K) inhibitor or a heat shock protein 90 (HSP90) inhibitor.

[0203] In various embodiments, the additional therapy is administration to the patient of an effective amount of a growth factor inhibitor. In certain embodiments, the additional therapy is a human epidermal growth factor receptor 2 (HER2) inhibitor. In some embodiments, the HER2 inhibitor is trastuzumab (Herceptin®). In some other embodiments, the HER2 inhibitor is ado-trastuzumab emtansine (Kadcyla®).

[0204] 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 (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (Farydak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS- 275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ- 26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY-1215), or sulforaphane. In certain embodiments, the HDAC inhibitor is entinostat (MS-275) with the proviso that the patient is not treated with a HER2 inhibitor. In certain other embodiments, the HDAC inhibitor is vorinostat (Zolinza®). In yet certain other embodiments, the HDAC inhibitor is romidepsin (Istodax®).

[0205] 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 (Keytruda®) or nivolumab (Opdivo®). In some embodiments, the CTLA-4 antibody is ipilimumab (Yervoy®).

[0206] In various embodiments, lasofoxifene or salt or prodrug thereof is administered in combination with drugs and / or radiation respectively approved for treatment of a cancer described in Section 4.1.1 herein.

[0207] In particular embodiments, lasofoxifene or salt or prodrug thereof is administered in combination with drugs and / or radiation regimens respectively approved for treatment of uterine cancer, cervical cancer, peritoneal cancer, vulva cancer, vaginal cancer, or uterine cancer including endometrioid, clear-cell carcinoma, papillary serous, carcinosarcoma, leiomyosarcoma, and endometrial stromal sarcoma (ESS) uterine cancer. In certain embodiments, lasofoxifene or salt or prodrug thereof is administered in combination with drugs and / or radiation regimens approved for uterine cancer, wherein the uterine cancer is endometrial stromal sarcoma uterine endometrial adenosarcoma, uterine adenosquamous carcinoma, uterine leiomyosarcoma or uterine corpus carcinoma.

[0208] In particular embodiments, lasofoxifene or salt or prodrug thereof is administered in combination with drugs and / or radiation regimens respectively approved for treatment of cervical cancer, such as cervical clear-cell carcinoma.

[0209] In particular embodiments, lasofoxifene or salt or prodrug thereof is administered in combination with drugs and / or radiation regimens respectively approved for treatment of vulva or vaginal cancer, including squamous cell carcinoma (SCC) or an adenocarcinoma.

[0210] In particular embodiments, lasofoxifene or salt or prodrug thereof is administered in combination with drugs and / or radiation regimens respectively approved for treatment of esophageal cancer, e.g., esophageal adenocarcinoma; gastric cancer, e.g., gastric adenocarcinoma; small intestine cancer, e.g., adenocarcinomas, carcinoid tumors, lymphomas, sarcoma such as leiomyosarcoma; colon cancer, e.g., colon adenocarcinoma; rectal cancer, e.g., rectal adenocarcinoma; and colorectal cancer, e.g., colorectal adenocarcinoma and colorectal mucinous adenocarcinoma.

[0211] In particular embodiments, lasofoxifene or salt or prodrug thereof is administered in combination with drugs and / or radiation regimens respectively approved for treatment of a cancer selected from bladder cancer, e.g., bladder urothelial cancer; glioblastoma, e.g., conventional glioblastoma; skin cancer, e.g., skin squamous cell carcinoma; melanoma, e.g., cutaneous melanoma; infiltrating renal pelvic cancer; and cancer of unknown primary origin.

[0212] In certain embodiments, the additional therapy is administering to the patient an effective amount of cancer vaccine.

[0213] In some embodiments, the additional therapy is administering to the patient an effective amount of denosumab.

[0214] In some embodiments, the additional therapy is administering to the patient an effective amount of a serotonin-norepinephrine reuptake inhibitor (SNRI), a selectiveserotonin reuptake inhibitor (SSRI), or gabapentin. In certain embodiments, the SNRI is venlafaxine (Effexor®).5.4.3. Clinical Endpoints5.4.3.I. Primary Clinical Endpoints

[0215] In various embodiments, the method comprises administering an amount of lasofoxifene effective to increase the disease-free survival of the ER+cancer patient. In some embodiments, the method comprises administering lasofoxifene in an amount effective to reduce recurrence of ER+cancer. In some embodiments, the method comprises administering lasofoxifene in an amount effective to increase time to recurrence of ER+cancer. In some embodiments, the method comprises administering lasofoxifene in an amount effective to reduce metastasis of ER+cancer. In some embodiments, the method comprises administering lasofoxifene in an amount effective to increase duration of progression-free survival of the ER+cancer patient.

[0216] In various embodiments, the method increases the disease-free survival of the patient who has been diagnosed with an ER+cancer other than breast or ovarian cancer. In certain embodiments, the method reduces recurrence of an ER+cancer described in Section 4.1.1. In certain embodiments, the method increases time to recurrence of an ER+cancer described in Section 4.1.1. In certain embodiments, the method reduces metastasis to bone of an ER+cancer described in Section 4.1.1. In certain embodiments, the method reduces metastasis to tissues other than bone of an ER+cancer described in Section 4.1.1. In certain embodiments, the method increases duration of progression-free survival of the cancer patient with an ER+cancer described in Section 4.1.1.

[0217] In various embodiments, the method increases the disease-free survival in ER+cancer patient with endocrine resistance. In some embodiments, the method reduces recurrence of cancer in patient with endocrine resistance. In some embodiments, the method increases time to recurrence of cancer in patient with endocrine resistance. In some embodiments, the method reduces metastasis of cancer in patient with endocrine resistance. In some embodiments, the method increases duration of progression-free survival in ER+cancer patient with endocrine resistance.

[0218] In some preferred embodiments, the method increases disease-free survival, reduces recurrence, increases time to recurrence, reduces metastasis, and / or increases duration of progression-free survival in patients with ER+locally advanced or metastaticcancer other than breast or ovarian cancer that has developed endocrine resistance. In particular embodiments, the cancer has developed endocrine resistance by acquiring one or more of the ESRI mutations discussed herein. In some embodiments, the method reduces the selective pressure and prevents the expansion of the endocrine resistant clones in ER+locally advanced or metastatic cancer other than breast or ovarian cancer during treatment.5.4.3.2. Secondary Clinical Endpoints

[0219] In some embodiments, the method is effective to prevent fracture and bone loss in women who are concurrently being treated with one or more drugs causing or predisposing to osteoporosis.

[0220] In some embodiments, the method is effective to decrease vaginal pH, increase vaginal lubrication, and / or improve vaginal cell maturation index in women who are concurrently being treated with one or more drugs causing or predisposing to vulvovaginal atrophy (VVA).

[0221] 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.

[0222] In some embodiments, the method treats hot flashes in women who are concurrently being treated with one or more drugs causing or predisposing to hot flashes.

[0223] In some embodiments, the method increases one or more quality of life measures selected from joint ache, urogenital symptoms, bone loss, and bone fractures.5.5. Examples

[0224] 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 ensure accuracy with respect to numbers used (e.g., amounts, temperatures, etc.), but some experimental error and deviation should, of course, be allowed for.

[0225] 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.5.5.1. Example 1: Efficacy of Lasofoxifene on ESRI LBD Mutations in non-breast, non-ovarian cancer cells

[0226] The efficacy of lasofoxifene in inhibiting estrogen signaling in cells from ER+cell lines derived from cancers of tissues other than breast or ovary is tested using the transient transfection assay described in Example 1 of WO 2019 / 199891, incorporated herein by reference in its entirety, adapted as necessary for propagation of the specific cells tested.

[0227] Lasofoxifene is demonstrated to be effective at preventing ER-mediated signaling in uterine cancer cells, cervical cancer cells, lung cancer cells, and colorectal carcinoma cells.5.5.2. Example 2: Lasofoxifene is effective in inhibiting tumor growth in patient-derived xenograft animal models of ER+cancers other than breast or ovarian cancer that have LBD ESRI gain-of-function mutations

[0228] The ability of lasofoxifene to inhibit tumor growth and metastasis of human ER+cancers other than breast or ovarian cancer that have LBD ESRI gain-of-function mutations is tested in a human tumor xenograft mouse model. The mice are immunodeficient and support growth of xenogeneic human tumors.

[0229] Lasofoxifene is demonstrated to inhibit tumor growth and reduce metastasis of human uterine, cervical, lung, and colorectal cancers.5.5.3. Example 3: Lasofoxifene is effective in inhibiting tumor growth in patient-derived 3-dimensional culture models of ER+cancers other than breast or ovarian cancer that have LBD ESRI gain-of- function mutations

[0230] The ability of lasofoxifene to inhibit tumor growth of human ER+cancers other than breast or ovarian cancers that have LBD ESRI gain-of-function mutations is tested in a3-dimensional culture model described in Vasmatzis G., et al. Mayo Clin Proc. 95(2):306-318 (2020). The mice are immunodeficient and support growth of xenogeneic human tumors.

[0231] Lasofoxifene is demonstrated to inhibit tumor growth and reduce metastasis of human uterine, cervical, lung, and colorectal cancers.6. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0232] While the invention has been particularly shown and described with reference to a preferred 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.

[0233] 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

CLAIMS1. A method of treating ER+cancer other than ER+breast or ovarian cancer, the method comprising: a) selecting for treatment a patient who has been diagnosed with estrogen receptor positive (ER+) cancer other than breast or ovarian cancer; and b) administering to the selected patient an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

2. The method of claim 1, wherein the ER+cancer is selected from uterine, cervical, peritoneal, vulva, vaginal, lung, esophageal, gastric, small intestine, colon, rectal, colorectal, bladder, brain, skin, renal pelvic, pancreatic, and cancer of unknown primary origin.

3. The method of claim 2, wherein the ER+cancer is uterine cancer selected from endometrioid, clear-cell carcinoma, papillary serous, carcinosarcoma, leiomyosarcoma, or endometrial stromal sarcoma (ESS).

4. The method of claim 3, wherein the uterine cancer is uterine endometrial stromal sarcoma, uterine endometrial adenosarcoma, uterine adenosquamous carcinoma, uterine leiomyosarcoma or uterine corpus carcinoma.

5. The method of claim 2, wherein the ER+cancer is cervical clear-cell carcinoma, vulvar squamous cell carcinoma, vulvar adenocarcinoma, vaginal squamous cell carcinoma or vaginal adenocarcinoma.

6. The method of claim 2, wherein the ER+cancer is lung cancer is lung adenosarcoma, squamous cell lung carcinoma or small cell lung carcinoma.

7. The method of claim 2, wherein the ER+cancer is esophageal adenocarcinoma, gastric adenocarcinoma, small intestinal adenocarcinoma, small intestinal carcinoid tumor, small intestinal lymphoma, small intestinal sarcoma, small intestinal leiomyosarcoma, malignant small intestinal neoplasm, colon adenocarcinoma, rectal adenocarcinoma, colorectal adenocarcinoma, colorectal mucinous adenocarcinoma, bladder urothelial carcinoma, glioblastoma, conventional glioblastoma multiforme, skin squamous cell carcinoma, melanoma, cutaneous melanoma, infiltrating renal pelvic cancer, or pancreatic adenocarcinoma.

8. The method of any one of claims 1-7, wherein the patient has previously been treated with one or more lines of endocrine therapy.

9. The method of claim 8, wherein the patient has previously been treated with a plurality of lines of endocrine therapy.

10. The method of claim 8 or claim 9, wherein the endocrine therapy that the patient has previously been treated with is a selective ER modulator (SERM) other than lasofoxifene.

11. The method of claim 10, wherein the SERM is tamoxifen, raloxifene, bazedoxifene, toremifene, or ospemifene.

12. The method of claim 8 or claim 9, wherein the endocrine therapy that the patient has previously been treated with is a selective ER degrader (SERD).

13. The method of claim 12, wherein the SERD is fulvestrant, RAD1901, ARN-810 (GDC-0810), or AZD9496.

14. The method of claim 8 or claim 9, wherein the endocrine therapy that the patient has previously been treated with is an aromatase inhibitor (Al).

15. The method of claim 14, wherein the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).

16. The method of any one of claims 8 to 15, wherein the patient has disease progression after endocrine therapy.

17. The method of any one of claims 1 to 16, wherein the patient’s cancer is resistant to endocrine therapy other than lasofoxifene.

18. The method of any one of claims 1 to 17, wherein the patient’s cancer has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene.

19. The method of claim 18, wherein the patient has previously been determined to have at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene.

20. The method of claim 19, further comprising the earlier step of: determining that the patient has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene.

21. The method of any one of claims 18 to 20, wherein the at least one of gain of function missense mutation is in any one of amino acids D538, Y537, L536, P535, V534, S463, V392, and E380.

22. The method of claim 21, wherein the at least one gain of function missense mutation is in the amino acid D538.

23. The method of claim 22, wherein the mutation is D538G.

24. The method of claim 21, wherein the at least one gain of function missense mutation is in the amino acid Y537.

25. The method of claim 24, wherein the mutation is Y537S, Y537N, Y537C, or Y537Q.

26. The method of claim 25, wherein the mutation is Y537C.

27. The method of claim 21, wherein the at least one gain of function missense mutation is in the amino acid L536.

28. The method of claim 27, wherein the mutation is L536R or L536Q.

29. The method of claim 21, wherein the at least one gain of function missense mutation is in the amino acid P535.

30. The method of claim 29, wherein the mutation is P535H.

31. The method of claim 21, wherein the at least one gain of function missense mutation is in the amino acid V534.

32. The method of claim 31, wherein the mutation is V534E.

33. The method of claim 21, wherein the at least one gain of function missense mutation is in the amino acid S463.

34. The method of claim 33, wherein the mutation is S463P.

35. The method of claim 21, wherein the at least one gain of function missense mutation is in the amino acid V392.

36. The method of claim 35, wherein the mutation is V392I.

37. The method of claim 21, wherein the at least one gain of function missense mutation is in the amino acid E380.

38. The method of claim 37, wherein the mutation is E380Q.

39. The method of any one of claims 1 to 38, wherein lasofoxifene is administered as lasofoxifene tartrate.

40. The method of any one of claims 1 to 39, wherein lasofoxifene is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration.

41. The method of claim 40, wherein lasofoxifene is administered by oral administration.

42. The method of claim 41, wherein lasofoxifene is administered at about 0.5 mg / day per os to about 10 mg / day per os.

43. The method of claim 42, wherein lasofoxifene is administered at about 0.5 mg / day per os to about 5 mg / day per os.

44. The method of claim 43, wherein lasofoxifene is administered at about 1 mg / day per os to about 5 mg / day per os.

45. The method of claim 43, wherein lasofoxifene is administered at 1 mg / day per os.

46. The method of claim 43, wherein lasofoxifene is administered at 5 mg / day per os.

47. The method of any one of claims 1 to 46, wherein lasofoxifene is administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, or once every month.

48. The method of any one of claims 1 to 47, further comprising treating said patient with at least one additional endocrine therapy.

49. The method of claim 48, wherein said patient is treated with the additional endocrine therapy at original doses.

50. The method of claim 48, wherein said patient is treated with the additional endocrine therapy at doses higher than original doses.

51. The method of any one of claims 48 to 50, wherein the additional endocrine therapy is treatment with a selective ER modulator (SERM) other than lasofoxifene.

52. The method of any one of claims 48 to 50, wherein the additional endocrine therapy is treatment with a selective ER degrader (SERD).

53. The method of any one of claims 48 to 50, wherein the additional endocrine therapy is treatment with an aromatase inhibitor.

54. The method of any one of claims 1 to 47, further comprising administering to said patient an effective amount of a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor.

55. The method of claim 54, wherein said CDK4 / 6 inhibitor is palbociclib, abemaciclib, or riboci clib.

56. The method of any one of claims 1 to 47, further comprising administering to said patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor.

57. The method of claim 56, wherein said mTOR inhibitor is Everolimus.

58. The method of any one of claims 1 to 47, further comprising administering to said patient an effective amount of phosphoinositide 3 -kinase (PI3K) inhibitor or heat shock protein 90 (HSP90) inhibitor.

59. The method of any one of claims 1 to 47, further comprising administering to said patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor.

60. The method of claim 59, wherein said HER2 inhibitor is trastuzumab (Herceptin®) or ado-trastuzumab emtansine (Kadcyla®).

61. The method of any one of claims 1 to 47, further comprising administering to said patient an effective amount of a histone deacetylase (HD AC) inhibitor.

62. The method of claim 61, wherein said HD AC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (F ary dak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC- 101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY- 1215), or sulforaphane.

63. The method of any one of claims 1 to 47, further comprising administering to said patient an effective amount of a checkpoint inhibitor.

64. The method of claim 63, wherein said 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).

65. The method of claim 64, wherein said PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®).

66. The method of claim 64, wherein said CTLA-4 antibody is ipilimumab (Yervoy®).

67. The method of any one of claims 1 to 66, further comprising administering to said patient an effective amount of cancer vaccine.

68. The method of any one of claims 1 to 67, wherein the patient is a premenopausal woman.

69. The method of claim 68, wherein the patient has ER / HER2 uterine cancer.

70. The method of claim 68, wherein the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.

71. The method of any one of claims 1 to 67, wherein the patient is a perimenopausal woman.

72. The method of claim 71, wherein the patient has ER / HER2 uterine cancer.

73. The method of claim 72, wherein the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.

74. The method of any one of claims 1 to 67, wherein the patient is a postmenopausal woman.

75. The method of claim 74, wherein the patient has ER / HER2 uterine cancer.

76. The method of claim 75, wherein the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.

77. A method of adjuvant therapy of estrogen receptor positive (ER+) cancer other than breast or ovarian cancer, the method comprising: administering to a patient who has received primary treatment for ER+cancer other than breast or ovarian cancer, an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

78. The method of claim 77, wherein the ER+cancer is selected from uterine, cervical, peritoneal, vulva, vaginal, lung, esophageal, gastric, small intestine, colon, rectal, colorectal, bladder, brain, skin, renal pelvic, pancreatic, and cancer of unknown primary origin.

79. The method of claim 78, wherein the ER+cancer is uterine cancer selected from endometrioid, clear-cell carcinoma, papillary serous, carcinosarcoma, leiomyosarcoma, or endometrial stromal sarcoma (ESS).

80. The method of claim 78 or claim 79, wherein the uterine cancer is uterine endometrial stromal sarcoma uterine endometrial adenosarcoma, uterine adenosquamous carcinoma, uterine leiomyosarcoma or uterine corpus carcinoma.

81. The method of claim 77, wherein the ER+cancer is cervical clear-cell carcinoma, vulvar squamous cell carcinoma, vulvar adenocarcinoma, vaginal squamous cell carcinoma or vaginal adenocarcinoma.

82. The method of claim 77, wherein the ER+cancer is lung cancer is lung adenosarcoma, squamous cell lung carcinoma or small cell lung carcinoma.

83. The method of claim 77, wherein the ER+cancer is esophageal adenocarcinoma, gastric adenocarcinoma, small intestinal adenocarcinoma, small intestinal carcinoid tumor, small intestinal lymphoma, small intestinal sarcoma, small intestinal leiomyosarcoma, malignant small intestinal neoplasm, colon adenocarcinoma, rectal adenocarcinoma, colorectal adenocarcinoma, colorectal mucinous adenocarcinoma, bladder urothelial carcinoma, glioblastoma, conventional glioblastoma multiforme, skin squamous cell carcinoma, melanoma, cutaneous melanoma, infiltrating renal pelvic cancer, or pancreatic adenocarcinoma.

84. The method of any one of claims 77 to 83 wherein lasofoxifene is administered as lasofoxifene tartrate.

85. The method of any one of claims 77 to 84, wherein the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).

86. The method of any one of claims 77 to 85, wherein lasofoxifene is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration.

87. The method of claim 86, wherein lasofoxifene is administered by oral administration.

88. The method of claim 87, wherein lasofoxifene is administered at about 0.5 mg / day per os to about 10 mg / day per os.

89. The method of claim 88, wherein lasofoxifene is administered at about 0.5 mg / day per os to about 5 mg / day per os.

90. The method of claim 89, wherein lasofoxifene is administered at about 1 mg / day per os to about 5 mg / day per os.

91. The method of claim 89, wherein lasofoxifene is administered at 1 mg / day per os.

92. The method of claim 89, wherein lasofoxifene is administered at 5 mg / day per os.

93. The method of any one of claims 77 to 92, wherein lasofoxifene is administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, or once every month.

94. The method of any one of claims 77 to 93, further comprising treating said patient with an additional endocrine therapy.

95. The method of claim 94, wherein the additional endocrine therapy is treatment with a selective ER degrader (SERD).

96. The method of any one of claims 77 to 93, further comprising administering to said patient an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor.

97. The method of claim 96, wherein said CDK4 / 6 inhibitor is palbociclib, abemaciclib, or riboci clib.

98. The method of any one of claims 77 to 93, further comprising administering to said patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor.

99. The method of claim 98, wherein said mTOR inhibitor is Everolimus.

100. The method of any one of claims 77 to 93, further comprising administering to said patient an effective amount of phosphoinositide 3 -kinase (PI3K) inhibitor or heat shock protein 90 (HSP90) inhibitor.

101. The method of any one of claims 77 to 93, further comprising administering to said patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor.

102. The method of claim 101, wherein said HER2 inhibitor is trastuzumab (Herceptin®) or ado-trastuzumab emtansine (Kadcyla®).

103. The method of any one of claims 77 to 93, further comprising administering to said patient an effective amount of a histone deacetylase (HD AC) inhibitor.

104. The method of claim 103, wherein said HDAC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (F ary dak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC- 101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY- 1215), or sulforaphane.

105. The method of any one of claims 77 to 93, further comprising administering to said patient an effective amount of checkpoint inhibitor.

106. The method of claim 105, wherein said 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).

107. The method of claim 106, wherein said PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®).

108. The method of claim 106, wherein said CTLA-4 antibody is ipilimumab (Yervoy®).

109. The method of any one of claims 77 to 93, further comprising administering to said patient an effective amount of cancer vaccine.

110. The method of any one of claims 77 to 109, wherein lasofoxifene is administered in an amount and on a schedule sufficient to improve bone mass.

111. The method of any one of claims 77 to 109, wherein the patient is female and lasofoxifene is administered in an amount and on a schedule sufficient to improve symptoms of VVA.

112. The method of any one of claims 77 to 111, wherein the patient is female and is premenopausal.

113. The method of any one of claims 77 to 111, wherein the patient is female and perimenopausal.

114. The method of any one of claims 77 to 111, wherein the patient is female and postmenopausal.

115. A method of treating a patient suffering from cancer other than breast or ovarian cancer, who is at risk of acquiring resistance to endocrine therapy, optionally wherein theendocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (Al) therapy, or (iv) any combination of (i), (ii) and / or (iii), the method comprising administering to the patient an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

116. The method of claim 115, wherein the patient has been diagnosed with an ER+cancer selected from uterine, cervical, peritoneal, vulva, vaginal, lung, esophageal, gastric, small intestine, colon, rectal, colorectal, bladder, brain, skin, renal pelvic, pancreatic, and cancer of unknown primary origin.

117. The method of claim 116, wherein the cancer is a primary cancer.

118. The method of any one of claims 115117, wherein the patient has been treated with endocrine therapy, optionally wherein the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (Al) therapy, or (iv) any combination of (i), (ii) and / or (iii).

119. A method of treating a female patient suffering from estrogen receptor positive (ER+) primary cancer other than breast or ovarian cancer, comprising administering to a female patient an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

120. The method of claim 119, wherein the patient is at risk of acquiring resistance to endocrine therapy, optionally wherein the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (Al) therapy, or (iv) any combination of (i), (ii) and / or (iii).

121. The method of claim 119 or claim 120, wherein the primary ER+cancer is selected from uterine, cervical, peritoneal, vulva, vaginal, lung, esophageal, gastric, small intestine, colon, rectal, colorectal, bladder, brain, skin, renal pelvic, pancreatic, and cancer of unknown primary origin.

122. The method of any one of claims 119 to 121, wherein the patient has been treated with endocrine therapy, optionally wherein the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (Al) therapy, or (iv) any combination of (i), (ii) and / or (iii).

123. A method of treating a female patient suffering from estrogen receptor positive (ER+) cancer other than breast or ovarian cancer comprising administering to a female patient aneffective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.

124. The method of claim 123, wherein the primary ER+cancer is selected from uterine, cervical, peritoneal, vulva, vaginal, lung, esophageal, gastric, small intestine, colon, rectal, colorectal, bladder, brain, skin, renal pelvic, pancreatic, and cancer of unknown primary origin.

125. The method of claim 123 or 124, wherein the patient has previously been treated with one or more lines of endocrine therapy.

126. The method of any one of claims 123-125, wherein the patient has previously been treated with a plurality of lines of endocrine therapy.

127. The method of any one of claims 123 to 126, wherein the patient has disease progression after endocrine therapy.

128. The method of any one of claims 123 to 126, wherein the endocrine therapy that the patient has previously been treated with is a selective ER modulator (SERM).

129. The method of claim 128, wherein the SERM is tamoxifen, raloxifene, bazedoxifene, toremifene, or ospemifene.

130. The method any one of claims 123 to 126, wherein the endocrine therapy that the patient has previously been treated with is a selective ER degrader (SERD).

131. The method of claim 130, wherein the SERD is fulvestrant, RAD1901, ARN-810 (GDC-0810), or AZD9496.

132. The method of any one of claims 123 to 126, wherein the endocrine therapy that the patient has previously been treated with is an aromatase inhibitor.

133. The method of claim 132, wherein the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®).

134. The method of any one of claims 125 to 133, wherein the patient has disease progression after endocrine therapy.

135. The method of any one of claims 123 to 134, wherein the patient’s cancer is resistant to endocrine therapy other than lasofoxifene.

136. The method of any one of claims 123 to 135, wherein the patient’s cancer has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene.

137. The method of claim 136, wherein the patient has previously been determined to have at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene.

138. The method of claim 137, further comprising the earlier step of: determining that the patient has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESRI) gene.

139. The method of any one of claims 136 to 138, wherein the at least one of gain of function missense mutation is in any one of amino acids D538, Y537, L536, P535, V534, S463, V392, and E380.

140. The method of claim 139, wherein the at least one gain of function mutation is in the amino acid D538.

141. The method of claim 140, wherein the mutation is D538G.

142. The method of claim 139, wherein the at least one gain of function mutation is in the amino acid Y537.

143. The method of claim 142, wherein the mutation is Y537S, Y537N, Y537C, or Y537Q.

144. The method of claim 143, wherein the mutation is Y537C.

145. The method of claim 139, wherein the at least one gain of function mutation is in the amino acid L536.

146. The method of claim 145, wherein the mutation is L536R or L536Q.

147. The method of claim 139, wherein the at least one gain of function mutation is in the amino acid P535.

148. The method of claim 147, wherein the mutation is P535H.

149. The method of claim 139, wherein the at least one gain of function mutation is in the amino acid V534.

150. The method of claim 149, wherein the mutation is V534E.

151. The method of claim 139, wherein the at least one gain of function mutation is in the amino acid S463.

152. The method of claim 151, wherein the mutation is S463P.

153. The method of claim 139, wherein the at least one gain of function mutation is in the amino acid V392.

154. The method of claim 153, wherein the mutation is V392I.

155. The method of claim 139, wherein the at least one gain of function mutation is in the amino acid E380.

156. The method of claim 155, wherein the mutation is E380Q.

157. The method of any one of claims 123 to 156, wherein lasofoxifene is administered as lasofoxifene tartrate.

158. The method of any one of claims 123 to 157, wherein lasofoxifene is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration.

159. The method of claim 158, wherein lasofoxifene is administered by oral administration.

160. The method of claim 159, wherein lasofoxifene is administered at about 0.5 mg / day per os to about 10 mg / day per os.

161. The method of claim 160, wherein lasofoxifene is administered at about 0.5 mg / day per os to about 5 mg / day per os.

162. The method of claim 161, wherein lasofoxifene is administered at about 1 mg / day per os to about 5 mg / day per os.

163. The method of claim 161, wherein lasofoxifene is administered at 1 mg / day per os.

164. The method of claim 161, wherein lasofoxifene is administered at 5 mg / day per os.

165. The method of any one of claims 123 to 164, wherein lasofoxifene is administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, or once every month.

166. The method of any one of claims 123 to 165, further comprising treating said patient with at least one additional endocrine therapy.

167. The method of claim 166, wherein said patient is treated with the additional endocrine therapy at original doses.

168. The method of claim 166, wherein said patient is treated with the additional endocrine therapy at doses higher than original doses.

169. The method of any one of claims 166 to 168, wherein the additional endocrine therapy is treatment with a selective ER modulator (SERM) other than lasofoxifene.

170. The method of any one of claims 166 to 168, wherein the additional endocrine therapy is treatment with a selective ER degrader (SERD).

171. The method of any one of claims 166 to 168, wherein the additional endocrine therapy is treatment with an aromatase inhibitor.

172. The method of any one of claims 123 to 165, further comprising administering to said patient an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor.

173. The method of claim 172, wherein said CDK4 / 6 inhibitor is palbociclib, abemaciclib, or riboci clib.

174. The method of any one of claims 123 to 165, further comprising administering to said patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor.

175. The method of claim 174, wherein said mTOR inhibitor is Everolimus.

176. The method of any one of claims 123 to 165, further comprising administering to said patient an effective amount of phosphoinositide 3 -kinase (PI3K) inhibitor or heat shock protein 90 (HSP90) inhibitor.

177. The method of any one of claims 123 to 165, further comprising administering to said patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor.

178. The method of claim 177, wherein said HER2 inhibitor is trastuzumab (Herceptin®) or ado-trastuzumab emtansine (Kadcyla®).

179. The method of any one of claims 123 to 165, further comprising administering to said patient an effective amount of a histone deacetylase (HD AC) inhibitor.

180. The method of claim 179, wherein said HD AC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (F ary dak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat(MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC- 101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY- 1215), or sulforaphane.

181. The method of any one of claims 123 to 165, further comprising administering to said patient an effective amount of a checkpoint inhibitor.

182. The method of claim 181, wherein said 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).

183. The method of claim 182, wherein said PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®).

184. The method of claim 182, wherein said CTLA-4 antibody is ipilimumab (Yervoy®).

185. The method of any one of claims 123 to 165, further comprising administering to said patient an effective amount of cancer vaccine.

186. The method of any one of claims 123 to 185, wherein the patient is premenopausal.

187. The method of claim 186, wherein the patient has ER+ / HER2‘ uterine cancer.

188. The method of claim 187, wherein the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.

189. The method of any one of claims 123 to 185, wherein the patient is perimenopausal.

190. The method of claim 189, wherein the patient has ER+ / HER2‘ uterine cancer.

191. The method of claim 190, wherein the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.

192. The method of any one of claims 123 to 185, wherein the patient is postmenopausal.

193. The method of claim 192, wherein the patient has ER+ / HER2‘ uterine cancer.

194. The method of claim 193, wherein the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (Al), fulvestrant, Al in combination with a CDK4 / 6 inhibitor, or fulvestrant in combination with a CDK4 / 6 inhibitor.