Treatment of solid cancer with lasofoxifene

Abstract

The disclosure provides methods of treating cancer, such as an estrogen receptor negative (ER–) solid cancer or estrogen receptor-low (ERlow) solid cancer in a patient. The method may include administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

Description

TREATMENT OF SOLID CANCER WITH LASOFOXIFENE 1. CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Patent Application No. 63 / 520,872 filed August 21, 2023; U.S. Provisional Patent Application No.63 / 567,843 filed March 20, 2024; and U.S. Provisional Patent Application No.63 / 636,638 filed April 19, 2024, the entire contents of each of which are hereby incorporated by reference. 2. STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT

[0002] This invention was made with government support under grant BC170954 awarded by the United States Department of Defense. The government has certain rights in the invention. 3. INTRODUCTION

[0003] Immunotherapies, such as immune checkpoint inhibitors (ICIs), have demonstrated substantial benefits in many cancer subtypes, including melanoma, non-small cell lung cancer (NSCLC), and triple negative breast cancer (TNBC). However, only a fraction of patients respond to ICIs. Furthermore, the responses to immune checkpoint blockade (ICB) in multiple cancer types are inferior in female patients compared to male patients.

[0004] Therefore, there is a need to increase the effectiveness of immunotherapies, such ICI treatments, especially in female patients. 4. SUMMARY

[0005] Using tumors derived from murine models of triple negative breast cancer A7C11 and E0771 cells, Lewis lung carcinoma (LLC) cells, and Yumm5.2 melanoma cells propagated in syngeneic hosts, we found that lasofoxifene alone and in combination with ICB is effective in inhibiting tumor growth through the modulation of immune cells in the tumor.

[0006] In a first aspect, methods are provided for increasing the efficacy of immunotherapy in a patient having a solid cancer. The method comprises further administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0007] In some embodiments, the solid cancer is an estrogen receptor negative (ER–) or estrogen receptor-low (ERlow) solid cancer.

[0008] In some embodiments, the solid cancer is estrogen receptor negative (ER–) breast cancer. In some embodiments, the solid cancer is triple-negative breast cancer (TNBC). In some embodiments, the solid cancer is ER–or ERlowovarian cancer. In some embodiments, the solid cancer is ER–or ERlowendometrial cancer. In some embodiments, the solid cancer is a solid cancer other than breast, ovarian, or endometrial cancer. In some embodiments, the solid cancer is head and neck cancer, lung cancer, melanoma, colon cancer, bladder cancer, esophageal cancer, gastric cancer, laryngeal cancer, oral cancer, brain cancer, bone cancer, pancreatic cancer, kidney cancer, glioblastoma, sarcoma, prostate cancer, or liver cancer, or a combination thereof. In some embodiments, the solid cancer is head and neck cancer. In some embodiments, the solid cancer is lung cancer. In some embodiments, the solid cancer is melanoma.

[0009] In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is an inhibitor of PD-1, PD-L1, CTLA-4, LAG- 3, ICOS, BTLA, TIM-3, TIGIT, or NKG2A, or a combination thereof. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of: pembrolizumab, nivolumab, and cemiplimab. In some embodiments, the anti-PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is cemiplimab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of: atezolizumab, avelumab, and durvalumab. In some embodiments, the CTLA-4 inhibitor is an anti-CTLA-4 antibody selected from the group consisting of: ipilimumab and tremelimumab. In some embodiments, the LAG-3 inhibitor is an anti-LAG-3 antibody. In some embodiments, the anti-LAG-3 antibody is relatlimab.

[0010] In some embodiments, lasofoxifene is administered as lasofoxifene tartrate. In some embodiments, lasofoxifene is administered by oral administration. In some embodiments, lasofoxifene is administered orally at about 0.5 mg / lasofoxifene to about 10 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 5 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 10 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered once every day.

[0011] In some embodiments, lasofoxifene and the immunotherapy are administered concurrently. In some embodiments, lasofoxifene and the immunotherapy are administered separately. In some embodiments, lasofoxifene is administered before the start of the immunotherapy.

[0012] In some embodiments, the method further comprises administering to the patient an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib. In some embodiments, the method further comprises administering to the patient an effective amount of a mammalian target of rapamycin (mTOR) inhibitor. In some embodiments, the mTOR inhibitor is everolimus. In some embodiments, the method further comprises administering to the patient an effective amount of a human epidermal growth factor receptor 2 (HER2) inhibitor. In some embodiments, the HER2 inhibitor is an anti-HER2 antibody or an anti-HER2 antibody- drug conjugate (ADC). In some embodiments, the anti-HER2 antibody is trastuzumab. In some embodiments, the anti-HER2 ADC is trastuzumab emtansine or trastuzumab deruxtecan. In some embodiments, the method further comprises administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor. In some embodiments, the HDAC inhibitor is vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, pracinostat, resminostat, givinostat, quisinostat, kevetrin, CUDC-101, AR-42, tefinostat, CHR-3996, 4SC202, CG200745, rocilinostat, or sulforaphane. In some embodiments, the method further comprises administering to the patient an effective amount of a phosphoinositide 3-kinase (PI3K) inhibitor.

[0013] In some embodiments, the administration of lasofoxifene increases the number of immune cells in the solid cancer, as compared to the number of immune cells in the solid cancer prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene increases tumor associated tissue eosinophilia (TATE) in the patient, as compared to the tumor associated tissue eosinophilia (TATE) prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene increases the number of CD8+T cells in the solid cancer, as compared to the number of CD8+T cells in the solid cancer prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene increases the number of effector CD8+T cells in the solid cancer, as compared to the number of effector CD8+T cells in the solid cancer prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene decreases the number of exhaustedCD8+T cells in the solid cancer, as compared to the number of exhausted CD8+T cells in the solid cancer prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene increases the ratio of M1 / M2 macrophages in the solid cancer, as compared to the ratio of M1 / M2 macrophages in the solid cancer prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene decreases the number of M2 tumor- associated macrophages (M2-TAMs) in the solid cancer, as compared to the number of M2- TAMs prior to the lasofoxifene treatment.

[0014] In a second aspect, methods are provided for treating an estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer in a patient. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0015] In another aspect, methods are provided for treating a solid cancer other than estrogen receptor positive (ER+) breast cancer, ER+ovarian cancer, or ER+endometrial cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0016] In another aspect, methods are provided for treating a solid cancer having a low M1 / M2 tumor-associated macrophage (TAM) ratio and / or a high number of M2 tumor- associated macrophages (M2-TAMs) and / or a low number of M1 tumor-associated macrophages (M1-TAMs). The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0017] In another aspect, methods are provided for treating a solid cancer having a low number of CD8+tumor infiltrating lymphocytes (TILs). The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0018] In another aspect, methods are provided for treating a solid cancer having a low number of eosinophils. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0019] In some embodiments, the solid cancer is historically more responsive to an immunotherapy in men than in premenopausal women. In some embodiments, the immunotherapy is an immune checkpoint inhibitor.

[0020] In some embodiments, the solid cancer is estrogen receptor negative (ER–) breast cancer. In some embodiments, the solid cancer is triple-negative breast cancer (TNBC). In some embodiments, the solid cancer is ER–or ERlowovarian cancer. In some embodiments, the solid cancer is ER–or ERlowendometrial cancer. In some embodiments, the solid cancer is a solid cancer other than breast, ovarian, or endometrial cancer. In some embodiments, the solid cancer is head and neck cancer, lung cancer, melanoma, colon cancer, bladder cancer, esophageal cancer, gastric cancer, laryngeal cancer, oral cancer, brain cancer, bone cancer, pancreatic cancer, kidney cancer, glioblastoma, sarcoma, prostate cancer, or liver cancer, or a combination thereof. In some embodiments, the solid cancer is head and neck cancer. In some embodiments, the solid cancer is lung cancer. In some embodiments, the solid cancer is melanoma.

[0021] In some embodiments, the method further comprises administering to the patient an immunotherapy. In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In some embodiments, the checkpoint inhibitor is an inhibitor of PD-1, PD-L1, CTLA-4, LAG-3, ICOS, BTLA, TIM-3, TIGIT, or NKG2A, or a combination thereof. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of: pembrolizumab, nivolumab, and cemiplimab. In some embodiments, the anti- PD-1 antibody is pembrolizumab. In some embodiments, the anti-PD-1 antibody is nivolumab. In some embodiments, the anti-PD-1 antibody is cemiplimab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of: atezolizumab, avelumab, and durvalumab. In some embodiments, the CTLA-4 inhibitor is an anti-CTLA-4 antibody selected from the group consisting of: ipilimumab and tremelimumab. In some embodiments, the LAG-3 inhibitor is an anti-LAG-3 antibody. In some embodiments, the anti-LAG-3 antibody is relatlimab.

[0022] In some embodiments, lasofoxifene is administered as lasofoxifene tartrate. In some embodiments, lasofoxifene is administered by oral administration. In some embodiments, lasofoxifene is administered orally at about 0.5 mg / lasofoxifene to about 10 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 5 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 10 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered once every day.

[0023] In some embodiments, lasofoxifene and the immunotherapy are administered concurrently. In some embodiments, lasofoxifene and the immunotherapy are administeredseparately. In some embodiments, lasofoxifene is administered before the start of the immunotherapy.

[0024] In some embodiments, the method further comprises administering to the patient an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. In some embodiments, the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib. In some embodiments, the method further comprises administering to the patient an effective amount of a mammalian target of rapamycin (mTOR) inhibitor. In some embodiments, the mTOR inhibitor is everolimus. In some embodiments, the method further comprises administering to the patient an effective amount of a human epidermal growth factor receptor 2 (HER2) inhibitor. In some embodiments, the HER2 inhibitor is an anti-HER2 antibody or an anti-HER2 antibody- drug conjugate (ADC). In some embodiments, the anti-HER2 antibody is trastuzumab. In some embodiments, the anti-HER2 ADC is trastuzumab emtansine or trastuzumab deruxtecan. In some embodiments, the method further comprises administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor. In some embodiments, the HDAC inhibitor is vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, pracinostat, resminostat, givinostat, quisinostat, kevetrin, CUDC-101, AR-42, tefinostat, CHR-3996, 4SC202, CG200745, rocilinostat, or sulforaphane.

[0025] In some embodiments, the administration of lasofoxifene increases the number of immune cells in the solid cancer, as compared to the number of immune cells in the solid cancer prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene increases tumor associated tissue eosinophilia (TATE) in the patient, as compared to the tumor associated tissue eosinophilia (TATE) prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene increases the number of CD8+T cells in the solid cancer, as compared to the number of CD8+T cells in the solid cancer prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene increases the number of effector CD8+T cells in the solid cancer, as compared to the number of effector CD8+T cells in the solid cancer prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene decreases the number of exhausted CD8+T cells in the solid cancer, as compared to the number of exhausted CD8+T cells in the solid cancer prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene increases the ratio of M1 / M2 macrophages in the solid cancer, as compared tothe ratio of M1 / M2 macrophages in the solid cancer prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene decreases the number of M2 tumor- associated macrophages (M2-TAMs) in the solid cancer, as compared to the number of M2- TAMs prior to the lasofoxifene treatment.

[0026] In some embodiments, the administration of lasofoxifene increases the biogenesis or survival of eosinophils in the patient, as compared to the biogenesis or survival of eosinophils prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene increases the activity of eosinophils in the patient, as compared to the activity of eosinophils prior to the lasofoxifene treatment.

[0027] In some embodiments, the administration of lasofoxifene decreases the rate of progression of tumor growth, as compared to the rate of progression of tumor growth prior to the lasofoxifene treatment. In some embodiments, the administration of lasofoxifene decreases the rate of cancer metastasis, as compared to the rate of cancer metastasis prior to the lasofoxifene treatment.

[0028] In another aspect, methods are provided for increasing the biogenesis, survival, and / or activity of eosinophils in a patient having estrogen receptor negative (ER–) or estrogen receptor-low (ERlow) solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0029] In another aspect, methods are provided for increasing tumor associated tissue eosinophilia (TATE) in a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0030] In another aspect, methods are provided for increasing the number of CD8+T cells in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0031] In another aspect, methods are provided for increasing the ratio of M1 / M2 macrophages in the cancer of a patient having estrogen receptor negative (ER–) and / orestrogen receptor-low (ERlow) solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0032] In another aspect, methods are provided for decreasing the number of exhausted CD8+T cells in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. In some embodiments, the patient has a mutation in BRCA1 or BRCA2 gene. In some embodiments, the method further comprises administering to the patient an immunotherapy.

[0033] In some embodiments, the patient is a premenopausal female patient. In some embodiments, the patient is a postmenopausal female patient. In some embodiments, the patient is a male patient. 5. BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

[0034] These and other features, aspects, and advantages of the present disclosure will become better understood with regard to the following description and accompanying drawings.

[0035] FIGs.1A and 1B show the growth of A7C11 tumors in ovariectomized female C57BL / 6 mice treated with immune checkpoint blockade (ICB) or a negative control for checkpoint inhibitor antibody (IgG) in the presence of estradiol (E2) or placebo (estrogen negative control), with FIG.1A showing the tumor growth over time and FIG.1B showing the final tumor volume.

[0036] FIGs.2A and 2B show the growth of A7C11 tumors in ovariectomized female C57BL / 6 mice treated with lasofoxifene (Laso) alone, fulvestrant (Fulv) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, Laso in combination with ICB, and Fulv in combination with ICB in the absence of E2, with FIG.2A showing the tumor growth over time and FIG.2B showing the final tumor volume.

[0037] FIGs.3A and 3B show the growth of A7C11 tumors in ovariectomized female C57BL / 6 mice treated with fulvestrant (Fulv) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, and Fulv in combination with ICB in the presence orabsence of E2, with FIG.3A showing the tumor growth over time and FIG.3B showing the final tumor volume.

[0038] FIGs.4A and 4B show the growth of A7C11 tumors in ovariectomized female C57BL / 6 mice treated with lasofoxifene (Laso) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, and Laso in combination with ICB in the presence or absence of E2, with FIG.4A showing the tumor growth over the course of treatment and FIG.4B showing the final tumor volume.

[0039] FIGs.5A and 5B show the ratio of M1 / M2 tumor-associated macrophages in A7C11 tumors after the treatment with lasofoxifene (SERM) or fulvestrant (SERD), immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, or SERM / SERD in combination with ICB in the presence or absence of E2, with FIG.5A showing the M1 / M2 ratio after the treatment with fulvestrant (Fulv) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, or Fulv in combination with ICB and FIG.5B showing the M1 / M2 ratio after the treatment with lasofoxifene (Laso) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, or Laso in combination with ICB.

[0040] FIGs.6A and 6B show the quantification of granulocytic myeloid-derived suppressor cells (G-MDSCs), as the percentage of CD45+cells that are G-MDSCs, in A7C11 tumors after the treatment with SERM / SERD alone, immune checkpoint blockade (ICB with anti- CTLA4 and anti-PD1) alone, or SERM / SERD in combination with ICB in the presence or absence of E2, with FIG.6A showing the quantification of G-MDSC after the treatment with fulvestrant (Fulv) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, or Fulv in combination with ICB and FIG.6B showing the quantification of G-MDSC after the treatment with lasofoxifene (Laso) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, or Laso in combination with ICB.

[0041] FIGs.7A and 7B show the quantification of CD8+T cells, as the percentage of CD45+cells that are CD8+T cells, in A7C11 tumors after the treatment with SERM / SERD alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, or SERM / SERD in combination with ICB in the presence or absence of E2, with FIG.7A showing the quantification of CD8+T cells after the treatment with fulvestrant (Fulv) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, or Fulv incombination with ICB and FIG.7B showing the quantification of CD8+T cells after the treatment with lasofoxifene (Laso) alone, immune checkpoint blockade (ICB with anti- CTLA4 and anti-PD1) alone, or Laso in combination with ICB.

[0042] FIGs.8A and 8B show the percentage of CD8+T cells that are CD8+PD1+T cells in A7C11 tumors after the treatment with SERM / SERD alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, or SERM / SERD in combination with ICB in the presence or absence of E2, with FIG.8A showing the percentage of CD8+T cells that are CD8+PD1+T cells after the treatment with fulvestrant (Fulv) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, or Fulv in combination with ICB and FIG.8B showing the percentage of CD8+T cells that are CD8+PD1+T cells after the treatment with lasofoxifene (Laso) alone, immune checkpoint blockade (ICB with anti- CTLA4 and anti-PD1) alone, or Laso in combination with ICB.

[0043] FIGs.9A and 9B show the growth of Lewis lung carcinoma (LLC) cell-derived tumors in ovariectomized female C57BL / 6 mice treated with IgG or ICB in the presence of placebo or E2, with FIG.9A showing the tumor growth over the course of treatment and FIG.9B showing the final tumor volume.

[0044] FIGs.10A and 10B show the growth of Lewis lung carcinoma (LLC) cell-derived tumors in ovariectomized female C57BL / 6 mice treated with lasofoxifene (Laso) alone, fulvestrant (Fulv) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, Laso in combination with ICB, and Fulv in combination with ICB in the absence of E2, with FIG.10A showing the tumor growth over the course of treatment and FIG.10B showing the final tumor volume.

[0045] FIGs.11A and 11B show the growth of Lewis lung carcinoma (LLC) cell-derived tumors in ovariectomized female C57BL / 6 mice treated with fulvestrant (Fulv) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, and Fulv in combination with ICB in the presence or absence of E2, with FIG.11A showing the tumor growth over time and FIG.11B showing the final tumor volume.

[0046] FIGs.12A and 12B show the growth of Lewis lung carcinoma (LLC) cell-derived tumors in ovariectomized female C57BL / 6 mice treated with lasofoxifene (Laso) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, and Laso incombination with ICB in the presence or absence of E2, with FIG.12A showing the tumor growth over the course of treatment and FIG.12B showing the final tumor volume.

[0047] FIGs.13A and 13B show the quantification of eosinophils, as the percentage of CD45+cells that are eosinophils, in Lewis lung carcinoma (LLC) cell-derived tumors after the treatment with SERM or SERD alone, immune checkpoint blockade (ICB with anti- CTLA4 and anti-PD1) alone, or SERM or SERD in combination with ICB in the presence or absence of E2, with FIG.13A showing the quantification of eosinophils after the treatment with fulvestrant (Fulv) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti- PD1) alone, or Fulv in combination with ICB and FIG.13B showing the quantification of eosinophils after the treatment with lasofoxifene (Laso) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, or Laso in combination with ICB.

[0048] FIGs.14A and 14B show the growth of Yumm5.2 tumors in ovariectomized female C57BL / 6 mice treated with IgG or ICB in the presence of placebo or E2, with FIG.14A showing the tumor growth over the course of treatment and FIG.14B showing the final tumor volume.

[0049] FIGs.15A and 15B show the growth of Yumm5.2 tumors in ovariectomized female C57BL / 6 mice treated with lasofoxifene (Laso) alone, fulvestrant (Fulv) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, Laso in combination with ICB, and Fulv in combination with ICB in the absence of E2, with FIG.15A showing the tumor growth over the course of treatment and FIG.15B showing the final tumor volume.

[0050] FIGs.16A and 16B show the growth of Yumm5.2 tumors in ovariectomized female C57BL / 6 mice treated with fulvestrant (Fulv) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, and Fulv in combination with ICB in the presence or absence of E2, with FIG.16A showing the tumor growth over time and FIG.16B showing the final tumor volume.

[0051] FIGs.17A and 17B show the growth of Yumm5.2 tumors in ovariectomized female C57BL / 6 mice treated with lasofoxifene (Laso) alone, immune checkpoint blockade (ICB with anti-CTLA4 and anti-PD1) alone, and Laso in combination with ICB in the presence or absence of E2, with FIG.17A showing the tumor growth over the course of treatment and FIG.17B showing the final tumor volume.

[0052] FIGs.18A and 18B show the quantification of proliferation of breast cancer cells treated with DMSO or increasing concentrations of E2 (from 10-8to 10-11M), with FIG.18A showing the proliferation of A7C11 cells and FIG.18B showing the proliferation of E0771 cells. Cells were harvested and frozen at various time points (0-4 days post-treatment), lysed, and stained with Hoechst dye. Proliferation was quantified by measuring the fluorescence of the Hoechst dye using a spectrometer.

[0053] FIGs.19A and 19B show the growth of orthotopic A7C11 tumors (2 x 104cells) in ovariectomized female mice supplemented with placebo or E2, with FIG.19A showing the tumor growth over time in C57BL / 6 mice and FIG.19B showing the tumor growth over time in immune compromised NSG mice.

[0054] FIGs.20A and 20B show the growth of orthotopic E0771 tumors (2 x 105cells) in ovariectomized female mice supplemented with placebo or E2, with FIG.20A showing the tumor growth over time in C57BL / 6 mice and FIG.20B showing the tumor growth over time in immune compromised NSG mice.

[0055] FIGs.21A and 21B show the uterine wet weights on the day of sacrifice in A7C11 tumor-bearing mice, with FIG.21A showing the uterine wet weights of C57BL / 6 mice and FIG.21B showing the uterine wet weights of immune compromised NSG mice.

[0056] FIGs.22A and 22B show tumor-infiltrated eosinophils (CD45+Ly6G-SSChiMHCII- CD11b+SiglecF+) in A7C11 breast cancer model, with FIG.22A showing tumor-infiltrated eosinophils in placebo treated mice and FIG.22B showing tumor infiltrated eosinophils in E2 treated mice.

[0057] FIGs.23A and 23B show the quantification of tumor-infiltrated eosinophils, as the percentage of CD45+cells that are eosinophils, with placebo or E2 treatment in breast cancer models, with FIG.23A showing the quantification of tumor-infiltrated eosinophils in A7C11 breast cancer model and FIG.23B showing the quantification of tumor-infiltrated eosinophils in E0771 breast cancer model.

[0058] FIG.24 shows the gating strategy of flow cytometry for tumor-infiltrated eosinophils.

[0059] FIGs.25A and 25B show the quantification of tumor-infiltrating immune cells, as the percentage of CD45+cells that are the immune cells, in A7C11 and E0771 breast cancers(n=8), with FIG.25A showing the quantification of tumor-infiltrating immune cells in A7C11 breast cancer and FIG.25B showing the quantification of tumor-infiltrating immune cells in E0711 breast cancer.

[0060] FIGs.26A and 26B show the quantification of tumor-infiltrated eosinophils, as the percentage of CD45+cells that are eosinophils, with placebo or E2 treatment in melanoma models, with FIG.26A showing the quantification of tumor-infiltrated eosinophils in B16F10 melanoma model and FIG.26B showing the quantification of tumor infiltrated eosinophils in BPD6 melanoma model.

[0061] FIG.27 shows the quantification of tumor-infiltrated eosinophils, as the percentage of CD45+cells that are eosinophils, with placebo or E2 treatment in AKPS colorectal cancer (CRC) model.

[0062] FIGs.28A and 28B show the quantification of blood eosinophil, as the percentage of CD45+cells that are eosinophils, in A7C11 and BPD6 tumor models (n=6), with FIG.28A showing the quantification of blood eosinophil in A7C11 tumor model and FIG.28B showing the quantification of blood eosinophil in BPD6 tumor model.

[0063] FIG.29 shows A7C11 tumor volume (after injecting 2 x 104cells) in ovariectomized C57BL / 6 mice supplemented with E2 or placebo and given s.c. lasofoxifene (10 mg / kg / day), i.m. fulvestrant (25 mg / kg / week), or vehicle starting from day 2 after tumor injection (n=10).

[0064] FIGs.30A and 30B show uterine weights of tumor bearing mice at sacrifice, with FIG.30A showing uterine weights of A7C11 tumor bearing mice treated with E2, E2 plus fulvestrant, and E2 plus lasofoxifene (n=8) and FIG.30B showing uterine weights of E0771 tumor bearing mice treated with E2 and / or lasofoxifene (n=10).

[0065] FIGs.31A and 31B show tumor volume after injection of breast cancer cells in ovariectomized C57BL / 6 mice supplemented with E2 or placebo and given s.c. lasofoxifene (10mg / kg / day) or vehicle daily starting from day 2 after tumor injection, with FIG.31A showing the tumor volume after injection of 2 x 104A7C11 cells and FIG.31B showing the tumor volume after injection of 2 x 105E0771 cells.

[0066] FIGs.32A and 32B show the quantification of tumor eosinophils, as the percentage of CD45+cells that are eosinophils, in ovariectomized C57BL / 6 mice supplemented with E2or placebo and given s.c. lasofoxifene (10mg / kg / day) or vehicle daily, with FIG.32A showing the quantification of tumor eosinophils in mice injected with A7C11 breast cancer cells and FIG.32B showing the quantification of tumor eosinophils in mice injected with E0771 breast cancer cells.

[0067] FIG.33 shows the quantification of tumor eosinophil peroxidase (EPX) levels in A7C11 tumors (n=5).

[0068] FIGs.34A, 34B, and 34C show the depletion of eosinophils with anti-siglecF treatment, with FIG.34A showing the schematic of experimental methods for the eosinophil depletion study along with lasofoxifene treatment, FIG.34B showing the quantification of tumor eosinophils, as the percentage of CD45+cells that are eosinophils, in mice receiving the treatments as indicated, including complete depletion of eosinophils with anti-siglecF treatment (n=7), and FIG.34C showing the quantification of blood eosinophils, as the percentage of CD45+cells that are eosinophils, in mice receiving the treatments as indicated, including complete depletion of eosinophils with anti-siglecF treatment (n=7).

[0069] FIGs.35A, 35B, and 35C show A7C11 tumor growth and final day tumor volume in ovariectomized C57BL / 6 mice supplemented with placebo or E2 and given either i.p. IgG or anti-SiglecF antibody (1mg / kg / dose) once every 72 hours and s.c. lasofoxifene (10mg / kg / day) or vehicle given daily from day 2 after tumor injections (n=8), with FIG.35A showing the tumor growth in groups supplemented with placebo, FIG.35B showing the tumor growth in groups supplemented with E2, and , FIG.35B showing the final day tumor volume in groups supplemented with placebo or E2.

[0070] FIGs.36A and 36B show representative zebra plots indicating PD-L1 expression in CD45 negative tumor population in the A7C11 tumors, with FIG.36A showing an A7C11 tumor with low PD-L1 expression and FIG.36B showing an A7C11 tumor with high PD-L1 expression.

[0071] FIGs.37A, 37B, 37C, 37D, and 37E show individual mice A7C11 tumor growth curves in C57BL / 6 mice, with FIG.37A showing A7C11 tumor growth curves of mice that have been ovariectomized and given placebo, FIG.37B showing A7C11 tumor growth curves of mice that have been ovariectomized and given E2 treatment, FIG.37C showing A7C11 tumor growth curves of mice that have been ovariectomized and given E2 treatment, along with s.c. lasofoxifene (10 / mg / kg) daily starting from day 2 after tumor cell injection,FIG.37D showing A7C11 tumor growth curves of mice that have been ovariectomized and given E2 treatment, along with the combination of s.c. lasofoxifene (10 / mg / kg) daily and i.p. ICB (anti-CTLA4 at 5 mg / kg; anti-PD1 at 10mg / kg) once every 72 hours starting from day 2 after tumor cell injection, FIG.37E showing A7C11 tumor growth curves of mice that have been ovariectomized and given E2 treatment, along with i.p. ICB (anti-CTLA4 at 5 mg / kg; anti-PD1 at 10 mg / kg) once every 72 hours starting from day 2 (n=8).

[0072] FIGs.38A, 38B, and 38C show the final tumor volume, quantification of tumor eosinophils, and quantification of tumor CD8+T cells in A7C11 tumor of mice treated with lasofoxifene, ICB, or the combination of lasofoxifene and ICB, with FIG.38A showing the final A7C11 tumor volume, FIG.38B showing the quantification of tumor eosinophils, as the percentage of CD45+cells that are eosinophils, and FIG.38C showing the quantification of tumor CD8+T cells, as the percentage of CD45+cells that are CD8+T cells (n=8).

[0073] FIGs.39A and 39B show the A7C11 tumor growth and final tumor volume in C57BL6 mice that have been ovariectomized and given placebo or E2 treatment along with s.c. lasofoxifene (10 / mg / kg) or s.c. vehicle daily starting from day 2 after tumor cell injection, i.p. ICB (anti-CTLA at 4-5 mg / kg; anti-PD1 at 10 mg / kg) or IgG once every 72 hours starting from day 2, i.m. fulvestrant (25 mg / kg) or vehicle given once weekly starting from day 2 after tumor injections or combination of treatments as indicated (n=8), with FIG. 39A showing the A7C11 tumor growth with the indicated treatments and FIG.39B showing the A7C11 final tumor volume with the indicated treatments.

[0074] FIG.40 shows the uterine weights of tumor-bearing mice receiving various treatments as indicated (n=8).

[0075] FIGs.41A, 41B, and 41C show the effect of various treatments as indicated on the immune cells in the A7C11 tumor, with FIG.41A showing quantification of tumor eosinophils, as the percentage of CD45+cells that are eosinophils, FIG.41B showing quantification of tumor CD8+T cells, as the percentage of CD45+cells that are CD8+T cells, and FIG.41C showing the ratio of M1 / M2 tumor associated macrophages (n=8).

[0076] FIG.42 shows a schematic depiction of the study design for evaluating peripheral blood immune cell counts in breast cancer patients who receive endocrine therapy (ET) (n=69-83).

[0077] FIGs.43A, 43B, 43C, 43D, and 43E show the changes in the prevalence of various blood immune cells obtained from complete differential blood counts in breast cancer patients taken at baseline and an early time point (T1) after the initiation of ET (n=70), with FIG.43A showing the changes in eosinophils, FIG.43B showing the changes in basophils, FIG.43C showing the changes in monocytes, FIG.43D showing the changes in neutrophils, and FIG.43E showing the changes in lymphocytes. *p≤0.05; **p≤0.001; ***p≤0.0001.

[0078] FIGs.44A, 44B, 44C, 44D, 44E, 44F and 44G show the changes in the prevalence of various blood immune cells obtained from complete differential blood counts in breast cancer patients taken at baseline and a late time point (T2) after the initiation of ET (n=69) and the results of two sub-analyses for the effects of chemotherapy and surgery on eosinophil counts, with FIG.44A showing the changes in eosinophils, FIG.44B showing the changes in basophils, FIG.44C showing the changes in monocytes, FIG.44D showing the changes in neutrophils, FIG.44E showing the changes in lymphocytes, FIG.44F showing the changes in the prevalence of blood eosinophils in patients taken at post-chemo baseline compared to ET treatment at T2 (n=41), and FIG.44G showing the changes in the prevalence of blood eosinophils in patients comparing pre- vs post-breast tumor resection surgery (n=25). *p≤0.05; **p≤0.001; ***p≤0.0001.

[0079] FIGs.45A, 45B, 45C, and 45D show the survival analysis (Kaplan–Meier plots) of patients stratified into low and high eosinophil groups, with FIG.45A showing the association between eosinophil gene signature and overall survival in patients with TNBC (n=360), FIG.45B showing the association between the expression of eosinophil-specific EPX gene and overall survival of patients with all breast cancer subtypes, FIG.45C showing the association between the expression of eosinophil-specific Siglec-8 gene and overall survival of patients with all breast cancer subtypes, and FIG.45D showing the association between the expression of eosinophil-specific CCR3 gene and overall survival of patients with all breast cancer subtypes (n=4929).

[0080] FIGs.46A, 46B, and 46C show the depletion of eosinophils in C57BL / 6 mice with anti-SiglecF antibody, with FIG.46A showing the schematic of the eosinophil depletion study, FIG.46B showing the quantification of blood eosinophils indicating depletion of eosinophils with anti-SiglecF antibody, and FIG.46C showing the quantification of tumor eosinophils indicating depletion of eosinophils with anti-SiglecF antibody (n=10).

[0081] FIGs.47A and 47B show A7C11 tumor volume in ovariectomized C57BL6J mice treated with placebo or E2 and given either IgG or anti-SiglecF antibody (1 mg / kg / dose) once every 72 hours (n=10), with FIG.47A showing A7C11 tumor growth and FIG.47B showing A7C11 final day tumor volume.

[0082] FIGs.48A, 48B, and 48C show the A7C11 tumor eosinophils in ΔdblGATA1 mice ovariectomized and supplemented with placebo or E2, with FIG.48A showing the eosinophils in littermate controls ΔdblGATA1- / +mice (n=7), FIG.48B showing the absence of eosinophils in the ΔdblGATA1- / -mice (n=9), and FIG.48C showing the quantification of A7C11 tumor eosinophils, as the percentage of CD45+cells that are eosinophils, in wild type, ΔdblGATA1- / +, or ΔdblGATA1- / -mice ovariectomized and supplemented with placebo or E2.

[0083] FIGs.49A and 49B show the tumor growth and final day tumor weight in ΔdblGATA1- / -, littermate control ΔdblGATA1- / +, or wild type mice ovariectomized and supplemented with placebo or E2 for 7 days before orthotopic injection of A7C11 (2 x 104cells), with FIG.49A showing the A7C11 tumor growth and FIG.49B showing the final day tumor weight of A7C11 tumor.

[0084] FIGs.50A and 50B show the breeding strategy and the ERα expression of EosERWT and EosERKO mice, with FIG.50A showing a schematic of the breeding strategy to generate EosERWT and EosERKO mice and FIG.50B showing a Western blot of ERα expression in eosinophils derived from bone marrow of either EosERWT or EosERKO mice (n=3).

[0085] FIGs.51A and 51B show the tumor growth and the final day tumor volume in EosERKO and EosERWT mice ovariectomized and supplemented with placebo or E2 for 7 days before orthotopic injection of A7C11 (2 x 104cells) (n=9), with FIG.51A showing the A7C11 tumor growth and FIG.51B showing the final day tumor volume of A7C11 tumor.

[0086] FIGs.52A and 52B show the tumor growth and final day tumor volume in EosERKO and EosERWT mice ovariectomized and supplemented with placebo or E2 for 7 days before orthotopic injection of BPD6 (5 x 105cells) (n=8), with FIG.52A showing the BPD6 tumor growth and FIG.52B showing the final day tumor volume of BPD6 tumor.

[0087] FIGs.53A, 53B, and 53C show the quantification of tumor eosinophils and tumor eosinophil peroxidase levels in EosERWT and EosERKO mice, with FIG.53A showing the quantification of tumor infiltrated eosinophils, as the percentage of CD45+cells that areeosinophils, in A7C11 tumors (n=7), FIG.53B showing the quantification of tumor infiltrated eosinophils, as the percentage of CD45+cells that are eosinophils, in BPD6 tumors (n=7), and FIG.53C showing the quantification of tumor eosinophil peroxidase levels (n=3) in A7C11 tumors.

[0088] FIGs.54A, 54B, and 54C show the quantification of tumor-infiltrated immune cells in A7C11 tumors (n=7), with FIG.54A showing the quantification of tumor-infiltrated CD69+CD8 T cells, as the percentage of CD8 T cells that are CD69+CD8 T cells, FIG.54B showing the quantification of tumor-infiltrated IFNȖ+CD8 T cells, as the percentage of CD8 T cells that are IFNȖ+CD8 T cells, and FIG.54C showing the quantification of tumor- infiltrated M2 macrophages, as the percentage of CD45+cells that are M2 macrophages.

[0089] FIGs.55A, 55B, and 55C show the quantification of blood and bone marrow eosinophils, as the percentage of CD45+cells that are eosinophils, in A7C11 tumor bearing and non-tumor bearing healthy C57BL6J mice ovariectomized and supplemented with placebo or E2, with FIG.55A showing blood eosinophils in non-tumor bearing healthy C57BL6J mice ovariectomized and supplemented with placebo or E2 (n=6), FIG.55B showing bone marrow eosinophils in non-tumor bearing healthy C57BL6J mice ovariectomized and supplemented with placebo or E2 (n=6), and FIG.55C showing bone marrow eosinophils in A7C11 tumor bearing C57BL6J mice ovariectomized and supplemented with placebo or E2 (n=6).

[0090] FIGs.56A and 56B show the generation and quantification of bone marrow derived eosinophils, with FIG.56A showing the schematic representation of generating bone marrow derived eosinophils in vitro and FIG.56B showing the quantification of live BMEos at various timepoints (n=3).

[0091] FIGs.57A, 57B, and 57C show the quantification of mature and live eosinophils in bone marrow (BMEos) collected from 8-10 week-old female C57BL / 6 mice, with FIG.57A showing representative zebra plots of SiglecF+SSChi BMEos differentiated in the presence or absence of E2 at 3 time points, FIG.57B showing the quantification of live cells as a percentage of SiglecF+SSChiBMEos (n=3), and FIG.57C showing the quantification of Ki67+BMEos as a percentage of live BMEos at various timepoints (n=3).

[0092] FIGs.58A, 58B, and 58C show the cytotoxicity activity of eosinophils differentiated in presence or absence of E2, with FIG.58A showing a schematic representation of theexperiment used to study eosinophil cytotoxicity activity in vitro, FIG.58B showing the density plot of live, pre-apoptotic, apoptotic, and necrotic A7C11 cells after 5 hours of co- culture with eosinophils differentiated in presence or absence of E2, and FIG.58C showing the quantification of live, pre-apoptotic, apoptotic, and necrotic A7C11 cells after 5 hours of co-culture with eosinophils differentiated in presence or absence of E2 (n=4).

[0093] FIG.59 shows the volcano plot of differentially expressed genes in eosinophils differentiated in presence of E2 or placebo (n=3).

[0094] FIGs.60A and 60B show negative enrichment plots for E2 vs vehicle treatment conditions (n=3), with FIG.60A showing the negative enrichment plot for hallmark Myc target V2 pathway and FIG.60B showing the negative enrichment plot for hallmark G2M checkpoint pathway.

[0095] FIGs.61A, 61B, and 61C show the quantification of gene counts for mRNAs that encode proteins in the cytotoxic granules of eosinophils (n=3), with FIG.61A showing gene counts for mRNAs that encode Ear1 (eosinophil associated RNAse1), FIG.61B showing gene counts for mRNAs that encode Prg2 (major basic protein), and FIG.61C showing gene counts for mRNAs that encode Epx (eosinophil peroxidase).

[0096] FIG.62 shows the GSEA analysis of Hallmark gene pathways obtained from RNAseq of BMEos differentiated in the presence or absence of E2 (n=3).

[0097] FIG.63 shows the qPCR analysis of BMEos differentiated in the presence or absence of E2 (day 11) for the expression of Epx, Ear1, Prg2, Myc, Cdc6 and E2f1 genes (n=4).

[0098] FIG.64 shows the schematic representation for eosinophil recruitment study. 7-week old female C57BL / 6 mice were ovariectomized and supplemented with placebo or E2 in drinking water. A7C11 cells were injected 7 days after ovariectomy, and mice were divided into 2 groups receiving either E2 or placebo in drinking water. CD45.1 BMEos were adoptively transferred via tail vein injections into A7C11 tumor-bearing mice on day 8 post- tumor engraftment (n=5 per group). Mice were sacrificed and analyzed either 24 hrs or 48 hrs post-BMEos transfer as indicated.

[0099] FIGs.65A, 65B, 65C, and 65D show the quantification of CD45.1 eosinophils and total (CD45.1 & CD45.2) eosinophils, with FIG.65A showing the quantification of CD45.1eosinophils in the tumors of mice sacrificed 24 hours post tail vein injection of CD45.1 BMEos, FIG.65B showing the quantification of CD45.1 eosinophils in the tumors of mice sacrificed 48 hours post tail vein injection of CD45.1 BMEos, FIG.65C showing the quantification of total (CD45.1 & CD45.2) eosinophils in the tumors of mice 48 hours post tail vein injection of CD45.1 BMEos (n=5-6), and FIG.65D showing the quantification of CD45.1 eosinophils in the spleens of mice sacrificed at 48 hours (n=5).

[0100] FIG.66 is a heat map of changes of cytokines in A7C11 tumors. Two-way clustering analysis identified different clusters of cytokines whose expression patterns were altered by treatments. The expression of clusters 2, 5 & 7 were up regulated while the clusters 1, 3 ,4 & 6 were down regulated with E2 treatment.

[0101] FIGs.67A and 67B show selected cytokines in the downregulated clusters (pooled from 5 mice), with FIG.67A showing cytokines that have been previously identified for eosinophil recruitment and FIG.67B showing cytokines that have been previously identified for eosinophil survival.

[0102] FIGs.68A, 68B, and 68C show the overall survival for all breast cancer patients as well as ER+and TNBC breast cancer subtypes in Metabric dataset further stratified into low or high using median expression according to the E2-downregulated gene signature score derived from BMEos differentiated in vitro in the presence of E2 or placebo, with FIG.68A showing the overall survival for all breast cancer patients, FIG.68B showing the survival for ER+HER2- breast patients, and FIG.68C showing the survival of TNBC patients. 6. DETAILED DESCRIPTION 6.1. Definitions

[0103] The term “solid cancer” refers to any cancer that is not a hematologic (blood) cancer. Solid cancers include cancers in skin, bones, muscles, and organs. Nonlimiting examples of solid cancer include head and neck cancer, lung cancer, melanoma, colon cancer, bladder cancer, esophageal cancer, gastric cancer, laryngeal cancer, oral cancer, brain cancer, bone cancer, pancreatic cancer, kidney cancer, glioblastoma, sarcoma, prostate cancer, and liver cancer.

[0104] The term “antibody” is used herein in its broadest sense understood in the art, including all polypeptides described as antibodies in Sumit G, Wei W, Tsutomu and SatoshiO, Antibodies, 2013, 2:452-500, incorporated herein by reference. The term “antibody” specifically includes intact antibodies (e.g., intact immunoglobulins and intact monoclonal and polyclonal antibodies) and antibody fragments that include at least one antigen-binding domain. The term “antibody” also includes chimeric antibodies, humanized antibodies, and human antibodies. An “antibody fragment” comprises a portion of an intact antibody, such as the antigen-binding or variable region of an intact antibody. Antibody fragments include, for example, Fv fragments, Fab fragments, F(ab’)2fragments, Fab’ fragments, scFv (sFv) fragments, and scFv-Fc fragments. An “antigen-binding domain” means the portion of an antibody, antibody fragment, or alternative scaffold polypeptide that is capable of specifically binding to an antigen or epitope. One example of an antigen-binding domain is an antigen- binding domain formed by a VH-VLdimer of an antibody. 6.2. Methods of Treatment

[0105] In a first aspect, disclosed herein are methods of treating a solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0106] In some embodiments, the solid cancer is a solid cancer other than estrogen receptor positive (ER+) breast cancer, ER+ovarian cancer, or ER+endometrial cancer. In some embodiments, the solid cancer is an estrogen receptor positive (ER+) cancer. In some embodiments, the ER+ solid cancer has more than 20%, or more than 30%, or more than 40%, or more than 50% cancer cells that stain positive for estrogen receptor (ER) by immunohistochemistry (IHC).

[0107] Also disclosed herein are methods of treating an estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer in a patient. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. In some embodiments, the ER status is determined by immunohistochemistry (IHC). In some embodiments, the ER–or ERlowsolid cancer has no more than 10% cancer cells that stain positive for estrogen receptor (ER) by IHC. In various embodiments, the ER–or ERlowsolid cancer has no more than 9%, no more than 8%, no more than 7%, no more than 6%, no more than 5%, no more than 4%, no more than 3%, no more than 2%, no more than 1%, no more than 0.5%, or no more than 0.1% cancer cells stained positive for ER by IHC. In certain embodiments, the ER–or ERlowsolid cancer has no more than 5% cancer cells stained positive for ER by IHC. In certainembodiments, the ER–or ERlowsolid cancer has no more than 2% cancer cells stained positive for ER by IHC. In certain embodiments, the ER–or ERlowsolid cancer has no more than 1% cancer cells stained positive for ER by IHC. In certain embodiments, the ER–or ERlowsolid cancer has no more than 0.5% cancer cells stained positive for ER by IHC. In certain embodiments, the ER–or ERlowsolid cancer has no more than 0.1% cancer cells stained positive for ER by IHC. In certain embodiments, the solid cancer is an ER negative (ER–) solid cancer.

[0108] Also disclosed herein are methods of treating a solid cancer having a low M1 / M2 tumor-associated macrophage (TAM) ratio and / or a high number of M2 tumor-associated macrophages (M2-TAMs) and / or a low number of M1 tumor-associated macrophages (M1- TAMs). The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. In some embodiments, the solid cancer has a low M1 / M2 tumor-associated macrophage (TAM) ratio. In some embodiments, the solid cancer has a high number of M2 tumor-associated macrophages (M2-TAMs). In some embodiments, the solid cancer has a low number of M1 tumor-associated macrophages (M1-TAMs). In some embodiments, the M1 / M2 ratio, the number of M2-TAMs, and / or the number of M1-TAMs are determined by immunohistochemistry (IHC).

[0109] Also disclosed herein are methods of treating a solid cancer having a low number of CD8+tumor infiltrating lymphocytes (TILs). The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. In some embodiments, the number of CD8+TILs is determined by immunohistochemistry (IHC). In various embodiments, the solid cancer has no more than 10%, such as no more than 5%, no more than 2%, or no more than 1% CD8+T cells of the total cells as determined by IHC.

[0110] Also disclosed herein are methods of treating a solid cancer having a high number of exhausted CD8+T cells. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. In some embodiments, the exhausted CD8+T cells are PD1+CD8+T cells. In some embodiments, the number of exhausted CD8+T cells is measured as the percentage of PD1+CD8+T cells within the population of CD8+T cells.

[0111] Also disclosed herein are methods of treating a solid cancer having a low number of eosinophils. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. In some embodiments, the number of eosinophils in the solid tumor is determined by immunohistochemistry (IHC). In certain embodiments, tumor associated tissue eosinophilia (TATE) is absent in the patient’s solid cancer.

[0112] In some embodiments of the methods described above, the solid cancer affects only women. In some embodiments, the solid cancer affects only men. In certain embodiments, the solid cancer affects both men and women. In some embodiments, the solid cancer is historically more responsive to an immunotherapy in men than in premenopausal women. In some of these embodiments, the immunotherapy is an immune checkpoint inhibitor.

[0113] In some embodiments of the methods described above, the solid cancer is ER–or ERlowbreast cancer. In certain embodiments, the solid cancer is estrogen receptor negative (ER–) breast cancer. In some embodiments, the solid cancer is estrogen receptor negative (ER–) and progesterone receptor negative (PR–), or triple-negative breast cancer (TNBC) that is ER–PR–EGFR–.

[0114] In some embodiments, the solid cancer is ER–or ERlowovarian cancer. In certain embodiments, the solid cancer is estrogen receptor negative (ER–) ovarian cancer.

[0115] In some embodiments, the solid cancer is ER–or ERlowendometrial cancer. In certain embodiments, the solid cancer is estrogen receptor negative (ER–) endometrial cancer.

[0116] In some embodiments, the solid cancer is a solid cancer other than breast, ovarian, or endometrial cancer. In various embodiments, the solid cancer is head and neck cancer, lung cancer, melanoma, colon cancer, bladder cancer, esophageal cancer, gastric cancer, laryngeal cancer, oral cancer, brain cancer, bone cancer, pancreatic cancer, kidney cancer, glioblastoma, sarcoma, prostate cancer, or liver cancer. In certain embodiments, the solid cancer is head and neck cancer. In certain embodiments, the solid cancer is lung cancer. In certain embodiments, the lung cancer is small cell lung cancer. In certain embodiments, the lung cancer is non-small cell lung cancer (NSCLC). In certain embodiments, the solid cancer is melanoma. In certain embodiments, the solid cancer is colon cancer. In certain embodiments, the solid cancer is anal cancer. In certain embodiments, the solid cancer is bladder cancer. In certain embodiments, the solid cancer is esophageal cancer. In certainembodiments, the solid cancer is gastric cancer. In certain embodiments, the solid cancer is laryngeal cancer. In certain embodiments, the solid cancer is oral cancer. In certain embodiments, the solid cancer is brain cancer. In certain embodiments, the solid brain cancer is glioblastoma or high-grade glioma. In certain embodiments, the solid cancer is bone cancer. In certain embodiments, the solid cancer is pancreatic cancer. In certain embodiments, the solid cancer is kidney cancer. In certain embodiments, the solid cancer is sarcoma. In certain embodiments, the solid cancer is prostate cancer. In certain embodiments, the solid cancer is liver cancer.

[0117] Also disclosed herein are methods of increasing the efficacy of immunotherapy in a patient having a solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, in combination with an immunotherapy. In some embodiments, the solid cancer affects only women. In some embodiments, the solid cancer affects only men. In certain embodiments, the solid cancer affects both men and women. In some embodiments, the solid cancer is historically more responsive to an immunotherapy in men than in premenopausal women. In some of these embodiments, the immunotherapy is an immune checkpoint inhibitor.

[0118] Also disclosed herein are methods of increasing the biogenesis, survival, or activity of eosinophils in a patient having estrogen receptor negative (ER–) or estrogen receptor-low (ERlow) solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0119] Also disclosed herein are methods of increasing tumor associated tissue eosinophilia (TATE) in a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0120] Also disclosed herein are methods of increasing the number of CD8+T cells in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0121] Also disclosed herein are methods of increasing the number of effector CD8+T cells in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0122] Also disclosed herein are methods of increasing the ratio of M1 / M2 macrophages in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0123] Also disclosed herein are methods of decreasing the number of exhausted CD8+T cells in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer. The method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0124] In some embodiments, the patient has a mutation in BRCA1 or BRCA2 gene. In certain embodiments, the patient has a mutation in BRCA1 gene. In certain embodiments, the patient has a mutation in BRCA2 gene. In certain embodiments, the patient has a mutation in BRCA1 gene and a mutation in BRCA2 gene.

[0125] For the methods described herein, the patient can be a premenopausal female patient, a postmenopausal female patient, or a male patient. 6.3. SERM / SERD

[0126] In various embodiments, the patient is treated with a SERD and / or a SERM. In some embodiments, the patient is treated with a selective estrogen receptor degrader / downregulator (SERD). In certain embodiments, the SERD is fulvestrant. In some embodiments, the patient is treated with a selective estrogen receptor modulator (SERM). In certain embodiments, the SERM is raloxifene, tamoxifen, bazedoxifene, endoxifene, ospemifene, lasofoxifene, toremifene, levormeloxifene, clomifene, arzoxifene, droloxifene, or acolbifene. In some embodiments, the SERM is lasofoxifene. 6.3.1. Lasofoxifene

[0127] In various embodiments, the patient is treated with an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

[0128] Lasofoxifene has the following structure (Formula I):

[0129] In some embodiments, a pharmaceutically acceptable salt of lasofoxifene is administered, hi some embodiments, the salt is lasofoxifene tartrate.

[0130] The term “pharmaceutically acceptable salt” refers to non-toxic pharmaceutically acceptable salts. See e.g., Gupta et al. Molecules. Jul 14;23(7): 1719 (2018), incorporated by reference in its entirety. Other salts well known to those in the art may, however, be used. Representative organic or inorganic acids include, but are not limited to, hydrochloric, hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric, acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic, tartaric, citric, benzoic, mandelic, methanesulfonic, hydroxyethanesulfonic, benzenesulfonic, oxalic, pantoic, 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.

[0131] Embodiments also include prodrugs of the compounds disclosed herein. In general, such prodrugs include functional derivatives of the compounds described herein which are readily convertible in vivo into the required compound. Thus, in the methods of treatment detailed herein, 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. Conventional procedures for the selection and preparation ofsuitable prodrug derivatives are described, for example, in Rautio etal. Nat Rev Drug Discov 7, 255-270 (2008), incorporated by reference in its entirety.

[0132] In certain embodiments, a functional derivative of lasofoxifene encompasses a proteolysis targeting chimera (PROTAC) comprising a lasofoxifene-derived targeting moiety. In certain embodiments, the functional derivative of lasofoxifene has the following chemical structure (Formula II):wherein R comprises a ligase binding moiety or functional derivative thereof.

[0133] In certain embodiments, R further comprises a divalent linker that attaches X and the ligase binding moiety. The linker is not limited and may be selected from any linkers as described herein or any linker that does not inhibit efficacy of the PROTAC. Such linkers may include a carbon chain comprising from 1 to 10 carbon atoms and may also comprise N or O heteroatoms, for example, PEG.

[0134] In certain embodiments, PROTACs are heterobifunctional small molecules with three chemical elements: lasofoxifene, a ubiquitin ligand binding moiety or ULM group, and a linker for conjugating these two elements. In some embodiments, lasofoxifene is covalently conjugated to a ubiquitin ligand binding moiety or ULM group via a linker. Non-limiting examples of such linkers include ester linkers, amide linkers, maleimide or maleimide-based linkers, valine-citrulline linkers, hydrazone linkers, N-succinimidyl-4-(2- pyridyldithio)butyrate (SPDB) linkers, succinimidyl-4-(N-maleimidomethyl)cyclohexane-1- carboxylate (SMCC) linkers, vinylsulfone-based linkers, linkers that include polyethylene glycol (PEG), such as, but not limited to tetraethylene glycol, linkers that include propanolsacid, linkers that include caproleic acid, and linkers including any combination thereof. In embodiments, the linker is a chemically-labile linker, such as an acid-cleavable linker that is stable at neutral pH (bloodstream pH 7.3-7.5) but undergoes hydrolysis upon internalization into the mildly acidic endosomes (pH 5.0-6.5) and lysosomes (pH 4.5-5.0) of a target cell (e.g., a cancer cell). Chemically-labile linkers include, but are not limited to, hydrazone- based linkers, oxime-based linkers, carbonate-based linkers, ester-based linkers, etc. In some embodiments, the linker is an enzyme-labile linker, such as an enzyme-labile linker that is stable in the bloodstream but undergoes enzymatic cleavage upon internalization into a target cell, e.g., by a lysosomal protease (such as cathepsin or plasmin) in a lysosome of the target cell (e.g., a cancer cell). Enzyme-labile linkers include, but are not limited to, linkers that include peptidic bonds, e.g., dipeptide-based linkers such as valine-citrulline linkers, such as a maleimidocaproyl-valine-citruline-p-arninobenzyl (MC-vc-PAB) linker, a valyl-alanyl- para-aminobenzyloxy (Val-Ala-PAB) linker, and the like. Chemically-labile linkers, enzyme-labile, and non-cleavable linkers are described in detail, e.g., in Ducry & Stump (2010) Bioconjugate Chem.21:5-13, which is hereby incorporated by reference in its entirety. In certain embodiments, the ULM group is covalently bonded to the linker to which is attached to lasofoxifene, or a pharmaceutically acceptable salt, stereoisomer, solvate, polymorph, or prodrug thereof.

[0135] In various embodiments, the functional derivative of lasofoxifene is capable of binding to estrogen receptor alpha (ERα), wherein, upon binding of the ERα to the compound, the ERα is ubiquitinated by a ubiquitin ligase.

[0136] In some embodiments, the functional lasofoxifene derivative of formula III, or a hydrate, solvate, or pharmaceutically acceptable salt thereof is administered, wherein formula III is:

[0137] Some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included. 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.

[0138] 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.

[0139] Methods of synthesizing lasofoxifene are described in U.S. Patent Nos.5,948,809; 6,204,286; 6,232,476; 6,323,345; 6,395,911; 6,906,202; and 7,358,374, the disclosures of which are incorporated herein by reference in their entireties. 6.4. Immunotherapy

[0140] In various embodiments, the patient is treated with an immunotherapy in combination with a selective estrogen receptor modulator (SERM) and / or a selective estrogen receptor degrader (SERD). In some embodiments, the immunotherapy is an immune system modulator. In some embodiments, the immunotherapy is a cytokine, such as interferon α (INFα) and / or interleukin-2 (IL-2). In some embodiments, the immunotherapy is an immunomodulatory agent, such as thalidomide, lenalidomide, pomalidomide, and imiquimod. In some embodiments, the immunotherapy is an antibody. In certain embodiments, the immunotherapy is a monoclonal antibody. In some embodiments, the immunotherapy is an antibody drug conjugate (ADC). 6.4.1. Immune checkpoint inhibitor

[0141] In some embodiments, the immunotherapy is an immune checkpoint inhibitor. In various embodiments, the immune checkpoint inhibitor blocks the functional interaction between immune checkpoint proteins and their binding partners. In some embodiments, the immune checkpoint inhibitor enhances the ability of immune cells to recognize and attack cancer cells.

[0142] In some embodiments, the checkpoint inhibitor is an inhibitor of PD-1, PD-L1, CTLA-4, LAG-3, ICOS, BTLA, TIM-3, TIGIT, or NKG2A. In certain embodiments, the checkpoint inhibitor is an inhibitor of programmed cell death protein 1 (PD-1). In certain embodiments, the checkpoint inhibitor is an inhibitor of programmed death ligand 1 (PD-L1). In certain embodiments, the checkpoint inhibitor is an inhibitor of cytotoxic T lymphocyte associated protein 4 (CTLA-4). In certain embodiments, the checkpoint inhibitor is an inhibitor of lymphocyte activation gene 3 (LAG-3). In certain embodiments, the checkpoint inhibitor is an inhibitor of inducible T cell co-stimulator (ICOS). In certain embodiments, the checkpoint inhibitor is an inhibitor of B and T lymphocyte attenuator (BTLA). In certain embodiments, the checkpoint inhibitor is an inhibitor of T cell immunoglobulin and mucin domain 3 (TIM-3). In certain embodiments, the checkpoint inhibitor is an inhibitor of T-cellimmunoreceptor with Ig and ITIM domains (TIGIT). In certain embodiments, the checkpoint inhibitor is an inhibitor of natural killer group protein 2A (NKG2A).

[0143] In some embodiments, the checkpoint inhibitor is an inhibitor of PD-1 or PD-L1. In various embodiments, the checkpoint inhibitor of PD-1 or PD-L1 blocks the functional interaction between PD-1 and PD-L1. In some embodiments, the PD-1 inhibitor is an anti- PD-1 antibody. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody. In some embodiments, the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of pembrolizumab, nivolumab, and cemiplimab. In certain embodiments, the anti- PD-1 antibody is pembrolizumab. In certain embodiments, the anti-PD-1 antibody is nivolumab. In certain embodiments, the anti-PD-1 antibody is cemiplimab. In some embodiments, the PD-L1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of: atezolizumab, avelumab, and durvalumab. In certain embodiments, the anti- PD-L1 antibody is atezolizumab. In certain embodiments, the anti-PD-L1 antibody is avelumab. In certain embodiments, the anti-PD-L1 antibody is durvalumab.

[0144] In some embodiments, the checkpoint inhibitor is an inhibitor of CTLA-4. In various embodiments, the checkpoint inhibitor of CTLA-4 blocks the functional interaction between CTLA-4 and B7 protein on the antigen-presenting cells (APCs). In some embodiments, the CTLA-4 inhibitor is an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab. In certain embodiments, the anti-CTLA-4 antibody is ipilimumab. In certain embodiments, the anti-CTLA-4 antibody is tremelimumab.

[0145] In some embodiments, the checkpoint inhibitor is an inhibitor of LAG-3. In various embodiments, the checkpoint inhibitor of LAG-3 blocks the functional interaction between LAG-3 and MHC class II on the antigen-presenting cells (APCs). In some embodiments, the LAG-3 inhibitor is an anti-LAG-3 antibody. In certain embodiments, the anti-LAG-3 antibody is relatlimab.

[0146] In some embodiments, the immunotherapy comprises the administration of one immune checkpoint inhibitor. In some embodiments, the immunotherapy comprises the administration of two or more immune checkpoint inhibitors. In certain embodiments, the immunotherapy comprises the administration of a PD-1 inhibitor and a CTLA-4 inhibitor. In certain embodiments, the immunotherapy is the administration of an anti-PD-1 antibody andan anti-CTLA-4 antibody. In certain embodiments, the immunotherapy comprises the administration of a PD-L1 inhibitor and a CTLA-4 inhibitor. In certain embodiments, the immunotherapy is the administration of an anti-PD-L1 antibody and an anti-CTLA-4 antibody. In certain embodiments, the immunotherapy comprises the administration of a PD- 1 inhibitor and a LAG-3 inhibitor. In certain embodiments, the immunotherapy is the administration of an anti-PD-1 antibody and an anti-LAG-3 antibody. In certain embodiments, the immunotherapy comprises the administration of a PD-L1 inhibitor and a LAG-3 inhibitor. In certain embodiments, the immunotherapy is the administration of an anti-PD-L1 antibody and an anti-LAG-3 antibody. In certain embodiments, the immunotherapy comprises the administration of a CTLA-4 inhibitor and a LAG-3 inhibitor. In certain embodiments, the immunotherapy is the administration of an anti-CTLA-4 antibody and an anti-LAG-3 antibody. 6.5. Pharmaceutical Compositions

[0147] Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, can be formulated in pharmaceutical compositions. In addition to lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, the composition may further comprise a pharmaceutically acceptable excipient, carrier, buffer, stabilizer, or other materials well known to those skilled in the art. Such materials are non-toxic and preferably do 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.

[0148] 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 solutions, or glycols such as ethylene glycol, propylene glycol, or polyethylene glycol can also be included.

[0149] For parenteral administration, lasofoxifene may 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, andLactated Ringer's Injection. Preservatives, stabilizers, buffers, antioxidants, and / or other additives can be included, as may be required.

[0150] 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. 6.6. Treatment Regimens 6.6.1. Routes of administration

[0151] In various embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered orally, by intravenous injection or infusion, intra-tumoral injection, transdermal administration, vaginal topical administration, or vaginal ring administration. In typical embodiments, lasofoxifene is administered to the patient by oral administration.

[0152] In various combination treatment embodiments that include administration of an immunotherapy in addition to SERM administration, the immunotherapy is administered by intravenous, oral, topical, or intravesical administration. In some embodiments, immunotherapy is administered to the patient by intravenous administration. In various embodiments, the immune checkpoint inhibitor is administered by intravenous, oral, topical, or intravesical administration. In some embodiments, the immune checkpoint inhibitor is administered to the patient by intravenous administration. 6.6.2. Dosages of lasofoxifene

[0153] In some embodiments, lasofoxifene is administered at about 0.5 mg / lasofoxifene per day to about 10 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered at about 0.5 mg / lasofoxifene, about 1 mg / lasofoxifene, about 1.5 mg / lasofoxifene, about 2 mg / lasofoxifene, about 2.5 mg / lasofoxifene, about 3 mg / lasofoxifene, about 3.5 mg / lasofoxifene, about 4 mg / lasofoxifene, about 5 mg / lasofoxifene, about 5.5 mg / lasofoxifene, about 6 mg / lasofoxifene, about 6.5 mg / lasofoxifene, about 7 mg / lasofoxifene, about 7.5 mg / lasofoxifene, about 8 mg / lasofoxifene, about 8.5mg / lasofoxifene, about 9 mg / lasofoxifene, about 9.5 mg / lasofoxifene, or about 10 mg / lasofoxifene per day.

[0154] In certain embodiments, lasofoxifene is administered orally at about 5 mg / lasofoxifene to about 10 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 5 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 6 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 7 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 8 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 9 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 10 mg / lasofoxifene per day.

[0155] In some embodiments, lasofoxifene is administered to the patient orally at a dosage of about 0.5 mg / lasofoxifene to about 10 mg / lasofoxifene per day, such as about 0.5 mg / lasofoxifene to about 5 mg / lasofoxifene per day, about 1 mg / lasofoxifene to about 5 mg / lasofoxifene per day, about 2 mg / lasofoxifene to about 5 mg / lasofoxifene per day, about 3 mg / lasofoxifene to about 5 mg / lasofoxifene per day, about 4 mg / lasofoxifene to about 5 mg / lasofoxifene per day, about 0.5 mg / lasofoxifene to about 4 mg / lasofoxifene per day, about 1 mg / lasofoxifene to about 4 mg / lasofoxifene per day, about 2 mg / lasofoxifene to about 4 mg / lasofoxifene per day, about 3 mg / lasofoxifene to about 4 mg / lasofoxifene per day, about 0.5 mg / lasofoxifene to about 3 mg / lasofoxifene per day, about 1 mg / lasofoxifene to about 3 mg / lasofoxifene per day, about 2 mg / lasofoxifene to about 3 mg / lasofoxifene per day, about 0.5 mg / lasofoxifene to about 2 mg / lasofoxifene per day, about 1 mg / lasofoxifene to about 2 mg / lasofoxifene per day, about 0.5 mg / lasofoxifene to about 1 mg / lasofoxifene per day, about 2.5 mg / lasofoxifene to about 5 mg / lasofoxifene per day, about 2.5 mg / lasofoxifene to about 7.5 mg / lasofoxifene per day, about 5 mg / lasofoxifene to about 7.5 mg / lasofoxifene per day, or about 7.5 mg / lasofoxifene to about 10 mg / lasofoxifene per day.

[0156] In some embodiments, lasofoxifene is administered orally at 0.5 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 1 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 1.5 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 2 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 2.5 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 3 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 3.5 mg / lasofoxifene per day. Insome embodiments, lasofoxifene is administered orally at 4 mg / lasofoxifene per day. In some embodiments, lasofoxifene is administered orally at 4.5 mg / lasofoxifene per day.

[0157] 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. 6.6.3. Lasofoxifene monotherapy

[0158] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered as monotherapy. 6.6.4. Combination treatment of lasofoxifene and immunotherapy

[0159] In some embodiments, lasofoxifene and an immunotherapy are administered in combination. In some embodiments, lasofoxifene and immunotherapy are administered concurrently. In some of these embodiments, lasofoxifene and the immunotherapy are administered on the same day. In some of these embodiments, lasofoxifene and the immunotherapy are administered during the same week. In some of these embodiments, lasofoxifene and the immunotherapy are administered throughout the same treatment period.

[0160] In some embodiments, lasofoxifene and the immunotherapy are administered separately. In certain embodiments, lasofoxifene is administered before the start of the immunotherapy. In certain embodiments, lasofoxifene is administered both before the start of and during the immunotherapy. In some embodiments, lasofoxifene is administered after the completion of the immunotherapy. In some embodiments, lasofoxifene is administered before, during, and after immunotherapy. 6.6.5. Additional combination therapy

[0161] In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered in combination with an additional therapy otherthan immunotherapy. In certain embodiments, lasofoxifene is administered in combination with at least one other therapy. In some embodiments, lasofoxifene and other therapies are administered concurrently. In some other embodiments, lasofoxifene and other therapies are administered separately. In some embodiments, lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, is administered in combination with an immunotherapy and an additional therapy other than immunotherapy.

[0162] In various embodiments, the additional therapy is the administration of an effective amount of a cell cycle inhibitor to the patient. In certain embodiments, the additional therapy is the administration of an effective amount of a cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. CDK4 / 6 inhibitors include, for example, palbociclib, abemaciclib, and ribociclib. In some embodiments, the additional therapy is a CDK4 / 6 inhibitor selected from the group consisting of palbociclib, abemaciclib, and ribociclib. In certain embodiments, the CDK4 / 6 inhibitor is palbociclib. In certain embodiments, the CDK4 / 6 inhibitor is abemaciclib. In certain embodiments, the CDK4 / 6 inhibitor is ribociclib.

[0163] In some embodiments, the additional therapy is administering to the patient an effective amount of a mammalian target of rapamycin (mTOR) inhibitor. mTOR inhibitors include, for example, an mTORC1 inhibitor, an mTORC2 inhibitor, and everolimus. In certain embodiments, the additional therapy is an mTORC1 inhibitor. In certain embodiments, the additional therapy is an mTORC2 inhibitor. In some embodiments, the mTOR inhibitor is everolimus.

[0164] In various embodiments, the additional therapy is administrating to the patient an effective amount of a growth factor inhibitor. In some embodiments, the additional therapy is a human epidermal growth factor receptor 2 (HER2) inhibitor. In certain embodiments, the additional therapy is an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate (ADC). In some embodiments, the anti-HER2 antibody is trastuzumab. In some other embodiments, the anti-HER2 ADC is trastuzumab emtansine or trastuzumab deruxtecan. In some embodiments, for a patient with TNBC, the method comprises administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, in combination with a checkpoint inhibitor, and further in combination with an anti-HER2 antibody or an anti-HER2 ADC.

[0165] In some embodiments, the additional therapy is administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor. In various embodiments, the HDAC inhibitor is vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, pracinostat, resminostat, givinostat, quisinostat, kevetrin, CUDC-101, AR-42, tefinostat, CHR-3996, 4SC202, CG200745, rocilinostat, and / or sulforaphane. In certain embodiments, the HDAC inhibitor is entinostat with the proviso that the patient is not treated with a HER2 inhibitor. In certain other embodiments, the HDAC inhibitor is vorinostat. In yet certain other embodiments, the HDAC inhibitor is romidepsin.

[0166] In various embodiments, the additional therapy is administrating to the patient an effective amount of a cell cycle inhibitor. In certain embodiments, the additional therapy is administrating to the patient an effective amount of AKT kinase inhibitor. AKT inhibitors include, for example, afuresertib, capivasertib, and ipatasertib. In some embodiments, the additional therapy is a AKT inhibitor selected from the group consisting of afuresertib, capivasertib, and ipatasertib.

[0167] In some embodiments, the additional therapy is administering to the patient an effective amount of denosumab.

[0168] In some embodiments, the additional therapy comprises a GnRH agonist and / or an oophorectomy. For example, lasofoxifene may be administered in combination with a GnRH agonist and / or an oophorectomy to a premenopausal subject.

[0169] In some embodiments, the additional therapy is administering to the patient an effective amount of a serotonin-norepinephrine reuptake inhibitor (SNRI), a selective serotonin reuptake inhibitor (SSRI), or gabapentin. In certain embodiments, the SNRI is venlafaxine.

[0170] In some embodiments, the additional therapies described in the preceding paragraphs in this section can be used in combination with each other. 6.7. Clinical Endpoints

[0171] In various embodiments, the methods described herein increase the disease-free survival of the patient having solid cancer. In some embodiments, the methods increase duration of progression-free survival of the patient having the solid cancer. In some embodiments, the methods decrease the rate of progression of tumor growth. In certainembodiments, the tumor growth is measured by the weight of the solid tumor. In certain embodiments, the tumor growth is measured by the volume of the solid tumor. In certain embodiments, the tumor growth is measured by the volume of the solid tumor before, during, and after the treatment. In some embodiments, the methods reduce recurrence of the solid cancer. In some embodiments, the methods increase time to recurrence of the solid cancer. In some embodiments, the methods decrease the rate of cancer metastasis.

[0172] In some embodiments, the method increases the number of immune cells in the solid cancer, as compared to the number of immune cells in the solid cancer prior to the treatment. In certain embodiments, the method increases tumor associated tissue eosinophilia (TATE) in the patient, as compared to the tumor associated tissue eosinophilia (TATE) prior to the treatment. In certain embodiments, the method increases the number of CD8+T cells in the solid cancer, as compared to the number of CD8+T cells in the solid cancer prior to the treatment. In certain embodiments, the method increases the number of effector CD8+T cells in the solid cancer, as compared to the number of effector CD8+T cells in the solid cancer prior to the treatment.

[0173] In certain embodiments, the method increases the ratio of M1 / M2 macrophages in the solid cancer, as compared to the ratio of M1 / M2 macrophages in the solid cancer prior to the treatment.

[0174] In some embodiments, the method decreases the number of immune cells in the solid cancer, as compared to the number of immune cells in the solid cancer prior to the treatment. In certain embodiments, the method decreases the number of exhausted CD8+T cells in the solid cancer, as compared to the number of exhausted CD8+T cells in the solid cancer prior to the treatment. In certain embodiments, the method decreases the number of PD1+CD8+T cells in the solid cancer, as compared to the number of PD1+CD8+T cells in the solid cancer prior to the treatment. In certain embodiments, the method decreases the number of M2 tumor-associated macrophages (M2-TAMs) in the solid cancer, as compared to the number of M2-TAMs prior to the treatment. In certain embodiments, the method decreases the number of granulocytic myeloid-derived suppressor cells (G-MDSCs) in the solid cancer, as compared to the number of G-MDSCs in the solid cancer prior to the treatment.

[0175] In various embodiments, the number of immune cells, such as the number of eosinophils, the number of CD8+T cells, the number of effector CD8+T cells, the number ofexhausted CD8+T cells, the number of PD1+CD8+T cells, the number of M1-TAMs, and / or the number of M2-TAMs in the solid cancer can be measured by flow cytometry. In some embodiments, the number of immune cells in the solid cancer can be determined from the number of immune cells in peripheral circulation, such as in blood. In some embodiments, the number of immune cells is quantified as the percentage of CD45+cells.

[0176] In various embodiments, the method increases the number of immune cells in the solid cancer by at least 5%, such as by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, at least 90%, at least 100%, at least 150%, or at least 200%. In some embodiments, the method increases the number of immune cells in the solid cancer by at least 2 times, such as by at least 3 times, at least 4 times, at least 5 times, at least 10 times, or at least 20 times.

[0177] In various embodiments, the method decreases the number of immune cells in the solid cancer by at least 5%, such as by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

[0178] In some embodiments, the method increases the biogenesis of eosinophils in the patient, as compared to the biogenesis of eosinophils prior to the treatment. In certain embodiments, the biogenesis of eosinophils is determined by the number of eosinophil progenitor cells. In certain embodiments, the biogenesis of eosinophils is measured by the proliferation rate of eosinophil progenitor cells. In specific embodiment, the proliferation rate of eosinophil progenitor cells is determined by a proliferation assay, such as Ki67 staining.

[0179] In some embodiments, the method increases the survival of eosinophils in the patient, as compared to the survival of eosinophils prior to the treatment. In certain embodiments, the survival of eosinophils is determined by the number of live, pre-apoptotic, or apoptotic eosinophils.

[0180] In some embodiments, the method increases the activity of eosinophils in the patient, as compared to the activity of eosinophils prior to the treatment. In certain embodiments, the activity of eosinophils is assessed by the cytotoxic capability of eosinophils. In certain embodiments, the activity of eosinophils is measured by tumor eosinophil peroxidase (EPX) level. In specific embodiments, cytotoxic capability of eosinophils is quantified by the number / percentage the live, pre-apoptotic, apoptotic, and necrotic cancer cells. In someembodiments, the method increases the recruitment of eosinophils to tumors in the patient, as compared to the recruitment of eosinophils to tumors prior to the treatment.

[0181] 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.

[0182] 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).

[0183] 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.

[0184] 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.

[0185] In some embodiments, the method increases one or more quality of life measures selected from joint ache, urogenital symptoms, bone loss, and bone fractures. 6.8. Additional Description Definitions

[0186] The terms “comprise(s),” “include(s),” “having,” “has,” “can,” “contain(s),” and variants thereof, as used herein, are intended to be open-ended transitional phrases, terms, or words that do not preclude the possibility of additional acts or structures. The singular forms “a,” “and,” and “the” include plural references unless the context clearly dictates otherwise. The present disclosure also contemplates other embodiments “comprising,” “consisting of,” and “consisting essentially of,” the embodiments or elements presented herein, whether explicitly set forth or not.

[0187] For the recitation of numeric ranges herein, each intervening number there between with the same degree of precision is explicitly contemplated. For example, for the range of 6- 9, the numbers 7 and 8 are contemplated in addition to 6 and 9, and for the range 6.0-7.0, the number 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, and 7.0 are explicitly contemplated.

[0188] The term “about” or “approximately” as used herein as applied to one or more values of interest, refers to a value that is similar to a stated reference value, or within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, such as the limitations of the measurement system. In certain aspects, the term “about” refers to a range of values that fall within 20%, 19%, 18%, 17%, 16%, 15%, 14%, 13%, 12%, 11%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, or less in either direction (greater than or less than) of the stated reference value unless otherwise stated or otherwise evident from the context (except where such number would exceed 100% of a possible value). Alternatively, “about” can mean within 3 or more than 3 standard deviations, per the practice in the art. Alternatively, such as with respect to biological systems or processes, the term “about” can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value.

[0189] The term “administration” or “administering,” as used herein refers to providing, contacting, and / or delivery an agent or composition as detailed herein, by any appropriate route to achieve the desired effect. These agents may be administered to a subject in numerous ways and may be used in combination.

[0190] “Amino acid” as used herein refers to naturally occurring and non-natural synthetic amino acids, as well as amino acid analogs and amino acid mimetics that function in a manner similar to the naturally occurring amino acids. Naturally occurring amino acids are those encoded by the genetic code. Amino acids can be referred to herein by either their commonly known three-letter symbols or by the one-letter symbols recommended by the IUPAC-IUB Biochemical Nomenclature Commission. Amino acids include the side chain and polypeptide backbone portions.

[0191] “Antiprogestogens” and “antiprogestins” as used herein, are used interchangeably and refer those class of drugs / compounds that act as progesterone antagonists or progesterone blockers and prevent progestogens (for example, progesterone) from mediating their biological effects in the body of a subject.

[0192] “Aromatase inhibitor” as used herein refers to the class of compounds / drugs that target aromatase, which is an enzyme involved in the biosynthesis of estrogen. Aromatase inhibitors may block the production of estrogen or block the action of estrogen on receptors.

[0193] The term “disease” as used herein includes, but is not limited to, any abnormal condition and / or disorder of a structure or a function that affects a part of an organism. It may be caused by an external factor, such as an infectious disease, or by internal dysfunctions, such as cancer, cancer metastasis, and the like.

[0194] The terms “cancer”, “cancer cell”, “tumor”, and “tumor cell” are used interchangeably herein and refer generally to a group of diseases characterized by uncontrolled, abnormal growth of cells (e.g., a neoplasia). In some forms of cancer, the cancer cells can spread locally or through the bloodstream and lymphatic system to other parts of the body (“metastatic cancer”). “Cancer” refers to all types of cancer or neoplasm or malignant tumors found in animals, including carcinoma, adenoma, melanoma, sarcoma, lymphoma, leukemia, blastoma, glioma, astrocytoma, mesothelioma, or a germ cell tumor. Cancer may include cancer of, for example, the colon, rectum, stomach, pancreas, bladder, cervix, uterus, vulva, endometrium, salivary gland, skin, epithelium, muscle, kidney, liver, lymph, thyroid, bone, blood, ovary, prostate, lung, brain, head and neck, and / or breast. Cancer may include medullablastoma, non-small cell lung cancer, small cell lung cancer, gastrointestinal, neuroblastoma, glioblastoma, peripheral neuroepithelioma, hepatoma, colorectal cancer, uterine cervical cancer, melanoma, myeloma, and / or mesothelioma. The cancer may include leukemia. The cancer may include any metastasis of the cancer. The term “leukemia” refers to broadly progressive, malignant diseases of the hematopoietic organs / systems and is generally characterized by a distorted proliferation and development of leukocytes and their precursors in the blood and bone marrow. Leukemia diseases include, for example, chronic myeloid leukemia (CML), acute myeloid leukemia (AML), acute nonlymphocytic leukemia, chronic lymphocytic leukemia, acute granulocytic leukemia, chronic granulocytic leukemia, acute promyelocytic leukemia, adult T-cell leukemia, aleukemic leukemia, a leukocythemic leukemia, basophilic leukemia, blast cell leukemia, bovine leukemia, chronic myelocytic leukemia, leukemia cutis, embryonal leukemia, eosinophilic leukemia, Gross' leukemia, Rieder cell leukemia, Schilling's leukemia, stem cell leukemia, subleukemic leukemia, undifferentiated cell leukemia, hairy-cell leukemia, hemoblastic leukemia, hemocytoblastic leukemia, histiocytic leukemia, stem cell leukemia, acute monocytic leukemia, leukopenic leukemia, lymphatic leukemia, lymphoblastic leukemia, lymphocytic leukemia, lymphogenous leukemia, lymphoid leukemia, lymphosarcoma cell leukemia, mast cell leukemia, megakaryocytic leukemia, micromyeloblastic leukemia, monocytic leukemia, myeloblastic leukemia, myelocytic leukemia, myeloid leukemia, myeloid granulocyticleukemia, myelomonocytic leukemia, Naegeli leukemia, plasma cell leukemia, plasmacytic leukemia, and promyelocytic leukemia. In some embodiments, the cancer is selected from melanoma, lung cancer, breast cancer, and colon cancer, and metastatic variations thereof. In some embodiments, the cancer comprises breast cancer, colon cancer, or prostate cancer, bladder cancer, esophageal cancer, gastric cancer, laryngeal cancer, melanoma, oral cancer, or liver cancer, or a combination thereof. In some embodiments, the cancer comprises melanoma. In some embodiments, the cancer comprises breast cancer.

[0195] The terms “control,” “reference level,” and “reference” are used herein interchangeably. The reference level may be a predetermined value or range, which is employed as a benchmark against which to assess the measured result. “Control group” as used herein refers to a group of control subjects. The predetermined level may be a cutoff value from a control group. The predetermined level may be an average from a control group. Cutoff values (or predetermined cutoff values) may be determined by Adaptive Index Model (AIM) methodology. Cutoff values (or predetermined cutoff values) may be determined by a receiver operating curve (ROC) analysis from biological samples of the patient group. ROC analysis, as generally known in the biological arts, is a determination of the ability of a test to discriminate one condition from another, e.g., to determine the performance of each marker in identifying a patient having CRC. A description of ROC analysis is provided in P.J. Heagerty et al. (Biometrics 2000, 56, 337-44), the disclosure of which is hereby incorporated by reference in its entirety. Alternatively, cutoff values may be determined by a quartile analysis of biological samples of a patient group. For example, a cutoff value may be determined by selecting a value that corresponds to any value in the 25th-75th percentile range, preferably a value that corresponds to the 25th percentile, the 50th percentile or the 75th percentile, and more preferably the 75th percentile. Such statistical analyses may be performed using any method known in the art and can be implemented through any number of commercially available software packages (e.g., from Analyse-it Software Ltd., Leeds, UK; StataCorp LP, College Station, TX; SAS Institute Inc., Cary, NC.). The healthy or normal levels or ranges for a target or for a protein activity may be defined in accordance with standard practice. A control may be a subject or cell without a composition as detailed herein. A control may be a subject, or a sample therefrom, whose disease state is known. The subject, or sample therefrom, may be healthy, diseased, diseased prior to treatment, diseased during treatment, or diseased after treatment, or a combination thereof.

[0196] “Effective amount” or “therapeutically effective amount” refers to an amount sufficient to effect beneficial or desirable biological and / or clinical results.

[0197] “Estrogen dependent cancer” or “estrogen receptor positive cancer” as used interchangeably herein refers to a tumor that contains estrogen receptor (ER) positive cells, that is, cells that have estrogen receptors and respond to the presence of estrogen with increased proliferation. Estrogen dependent cancers may include breast cancer, ovarian cancer, or endometrial cancer, for example. “Estrogen receptor positive breast cancer” is a type of breast cancer that is sensitive to estrogen.

[0198] “Estrogen receptor” or “ER” as used interchangeably herein refers to a receptor that is activated by the hormone estrogen and is a member of the nuclear hormone family of intracellular receptors. There are two different forms of estrogen receptor, referred to as α (also referred to as “ERa”) and ȕ (also referred to as “ERb”). ERa and ERb genes are encoded by ESR1 and ESR2 gene, respectively. Hormone-activated estrogen receptors form dimers and may form homodimers or heterodimers. Both ERs are widely expressed in different tissue types.

[0199] “Estrogen receptor negative breast cancer” or “Estrogen independent breast cancer” as used interchangeably herein refers to a tumor that does not contain detectable estrogen receptor positive cells, that is, cells that lack estrogen receptors, and do not depend on the presence of estrogen for ongoing proliferation.

[0200] “Identical” or “identity” as used herein in the context of two or more polynucleotide or polypeptide sequences means that the sequences have a specified percentage of residues that are the same over a specified region. The percentage may be calculated by optimally aligning the two sequences, comparing the two sequences over the specified region, determining the number of positions at which the identical residue occurs in both sequences to yield the number of matched positions, dividing the number of matched positions by the total number of positions in the specified region, and multiplying the result by 100 to yield the percentage of sequence identity. In cases where the two sequences are of different lengths or the alignment produces one or more staggered ends and the specified region of comparison includes only a single sequence, the residues of single sequence are included in the denominator but not the numerator of the calculation. When comparing DNA and RNA,thymine (T) and uracil (U) may be considered equivalent. Identity may be performed manually or by using a computer sequence algorithm such as BLAST or BLAST 2.0.

[0201] “Nucleic acid” or “oligonucleotide” or “polynucleotide” as used herein means at least two nucleotides covalently linked together. The depiction of a single strand also defines the sequence of the complementary strand. Thus, a polynucleotide also encompasses the complementary strand of a depicted single strand. Many variants of a polynucleotide may be used for the same purpose as a given polynucleotide. Thus, a polynucleotide also encompasses substantially identical polynucleotides and complements thereof. A single strand provides a probe that may hybridize to a target sequence under stringent hybridization conditions. Thus, a polynucleotide also encompasses a probe that hybridizes under stringent hybridization conditions. Polynucleotides may be single stranded or double stranded or may contain portions of both double stranded and single stranded sequence. The polynucleotide can be nucleic acid, natural or synthetic, DNA, genomic DNA, cDNA, RNA, mRNA, or a hybrid, where the polynucleotide can contain combinations of deoxyribo- and ribo- nucleotides, and combinations of bases including, for example, uracil, adenine, thymine, cytosine, guanine, inosine, xanthine hypoxanthine, isocytosine, and isoguanine. Polynucleotides can be obtained by chemical synthesis methods or by recombinant methods.

[0202] “Open reading frame” refers to a stretch of codons that begins with a start codon and ends at a stop codon. In eukaryotic genes with multiple exons, introns are removed, and exons are then joined together after transcription to yield the final mRNA for protein translation. An open reading frame may be a continuous stretch of codons. In some embodiments, the open reading frame only applies to spliced mRNAs, not genomic DNA, for expression of a protein.

[0203] “Operably linked” as used herein means that expression of a gene is under the control of a promoter with which it is spatially connected. A promoter may be positioned 5' (upstream) or 3' (downstream) of a gene under its control. The distance between the promoter and a gene may be approximately the same as the distance between that promoter and the gene it controls in the gene from which the promoter is derived. As is known in the art, variation in this distance may be accommodated without loss of promoter function. Nucleic acid or amino acid sequences are “operably linked” (or “operatively linked”) when placed into a functional relationship with one another. For instance, a promoter or enhancer is operably linked to a coding sequence if it regulates, or contributes to the modulation of, thetranscription of the coding sequence. Operably linked DNA sequences are typically contiguous, and operably linked amino acid sequences are typically contiguous and in the same reading frame. However, since enhancers generally function when separated from the promoter by up to several kilobases or more and intronic sequences may be of variable lengths, some polynucleotide elements may be operably linked but not contiguous. Similarly, certain amino acid sequences that are non-contiguous in a primary polypeptide sequence may nonetheless be operably linked due to, for example folding of a polypeptide chain. With respect to fusion polypeptides, the terms “operatively linked” and “operably linked” can refer to the fact that each of the components performs the same function in linkage to the other component as it would if it were not so linked.

[0204] A “peptide” or “polypeptide” is a linked sequence of two or more amino acids linked by peptide bonds. The polypeptide can be natural, synthetic, or a modification or combination of natural and synthetic. Peptides and polypeptides include proteins such as binding proteins, receptors, and antibodies. The terms “polypeptide”, “protein,” and “peptide” are used interchangeably herein. “Primary structure” refers to the amino acid sequence of a particular peptide. “Secondary structure” refers to locally ordered, three dimensional structures within a polypeptide. These structures are commonly known as domains, for example, enzymatic domains, extracellular domains, transmembrane domains, pore domains, and cytoplasmic tail domains. “Domains” are portions of a polypeptide that form a compact unit of the polypeptide and are typically 15 to 350 amino acids long. Exemplary domains include domains with enzymatic activity or ligand binding activity. Typical domains are made up of sections of lesser organization such as stretches of beta-sheet and alpha-helices. “Tertiary structure” refers to the complete three-dimensional structure of a polypeptide monomer. “Quaternary structure” refers to the three-dimensional structure formed by the noncovalent association of independent tertiary units. A “motif” is a portion of a polypeptide sequence and includes at least two amino acids. A motif may be 2 to 20, 2 to 15, or 2 to 10 amino acids in length. In some embodiments, a motif includes 3, 4, 5, 6, or 7 sequential amino acids. A domain may be comprised of a series of the same type of motif.

[0205] “Sample” or “test sample” as used herein can mean any sample in which the presence and / or level of a target is to be detected or determined or any sample comprising a DNA targeting or gene editing system or component thereof as detailed herein. Samples may include liquids, solutions, emulsions, or suspensions. Samples may include a medicalsample. Samples may include any biological fluid or tissue, such as blood, whole blood, fractions of blood such as plasma and serum, muscle, interstitial fluid, sweat, saliva, urine, tears, synovial fluid, bone marrow, cerebrospinal fluid, nasal secretions, sputum, amniotic fluid, bronchoalveolar lavage fluid, gastric lavage, emesis, fecal matter, lung tissue, peripheral blood mononuclear cells, total white blood cells, lymph node cells, spleen cells, tonsil cells, cancer cells, tumor cells, bile, digestive fluid, skin, or combinations thereof. In some embodiments, the sample comprises an aliquot. In other embodiments, the sample comprises a biological fluid. Samples can be obtained by any means known in the art. The sample can be used directly as obtained from a patient or can be pre-treated, such as by filtration, distillation, extraction, concentration, centrifugation, inactivation of interfering components, addition of reagents, and the like, to modify the character of the sample in some manner as discussed herein or otherwise as is known in the art.

[0206] “Selective Estrogen Receptor Degrader or Downregulator” or “SERDs” are used interchangeably and refer to those class of drugs / compounds that bind to the estrogen receptor (ER) and, in the process of doing so, causes the estrogen receptor to be degraded and thus downregulated.

[0207] “Selective Estrogen Receptor Modulators” or “SERMs” refers to the class of drugs / compounds that act on and selectively modulate the estrogen receptor (ER) and are not SERDs.

[0208] “Subject” and “patient” as used herein interchangeably refers to any vertebrate, including, but not limited to, a mammal that wants or is in need of the herein described compositions or methods. The methods and compositions disclosed herein can be used on a sample either in vitro (for example, on isolated cells or tissues) or in vivo in a subject (for example, a living organism, such as a patient). The subject may be a human or a non-human. The subject may be a vertebrate. The subject may be a mammal. The mammal may be a primate or a non-primate. The mammal can be a non-primate such as, for example, cow, pig, camel, llama, hedgehog, anteater, platypus, elephant, alpaca, horse, goat, rabbit, sheep, hamster, guinea pig, cat, dog, rat, and mouse. The mammal can be a primate such as a human. The mammal can be a non-human primate such as, for example, monkey, cynomolgous monkey, rhesus monkey, chimpanzee, gorilla, orangutan, and gibbon. The subject may be of any age or stage of development, such as, for example, an adult, an adolescent, a child, such as age 0-2, 2-4, 2-6, or 6-12 years, or an infant, such as age 0-1years. The subject may be male. The subject may be female. In some embodiments, the subject has a specific genetic marker. The subject may be undergoing other forms of treatment. In some embodiments, the subject has cancer.

[0209] “Substantially identical” can mean that a first and second amino acid or polynucleotide sequence are at least 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98%, or 99%, or less than 100% over a region of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000, 1100 amino acids or nucleotides, respectively.

[0210] “Treatment” or “treating” or “therapy” have the meanings understood by the person of skill in the art of oncology, but does not include prophylaxis or prevention. In some embodiments, when referring to protection of a subject from a disease, these terms mean suppressing, repressing, reversing, alleviating, ameliorating, or inhibiting the progress of disease, or completely eliminating a disease. A treatment may be either performed in an acute or chronic way. The term also refers to reducing the severity of a disease or symptoms associated with such disease prior to affliction with the disease. Treatment may result in a reduction in the incidence, frequency, severity, and / or duration of symptoms of the disease. Suppressing the disease involves administering a composition as detailed herein to a subject after induction of the disease but before its clinical appearance. Repressing or ameliorating the disease involves administering a composition as detailed herein to a subject after clinical appearance of the disease.

[0211] “Variant” used herein with respect to a polynucleotide means (i) a portion or fragment of a referenced nucleotide sequence; (ii) the complement of a referenced nucleotide sequence or portion thereof; (iii) a nucleic acid that is substantially identical to a referenced nucleic acid or the complement thereof; or (iv) a nucleic acid that hybridizes under stringent conditions to the referenced nucleic acid, complement thereof, or a sequence substantially identical thereto.

[0212] “Variant” with respect to a peptide or polypeptide that differs in amino acid sequence by the insertion, deletion, or conservative substitution of amino acids, but retain at least one biological activity. Variant may also mean a protein with an amino acid sequence that is substantially identical to a referenced protein with an amino acid sequence that retains at leastone biological activity. Representative examples of “biological activity” include the ability to be bound by a specific antibody or polypeptide or to promote an immune response. Variant can mean a functional fragment thereof. Variant can also mean multiple copies of a polypeptide. The multiple copies can be in tandem or separated by a linker. A conservative substitution of an amino acid, for example, replacing an amino acid with a different amino acid of similar properties (for example, hydrophilicity, degree and distribution of charged regions) is recognized in the art as typically involving a minor change. These minor changes may be identified, in part, by considering the hydropathic index of amino acids, as understood in the art (Kyte et al., J. Mol. Biol.1982, 157, 105-132). The hydropathic index of an amino acid is based on a consideration of its hydrophobicity and charge. It is known in the art that amino acids of similar hydropathic indexes may be substituted and still retain protein function. In one aspect, amino acids having hydropathic indexes of ±2 are substituted. The hydrophilicity of amino acids may also be used to reveal substitutions that would result in proteins retaining biological function. A consideration of the hydrophilicity of amino acids in the context of a peptide permits calculation of the greatest local average hydrophilicity of that peptide. Substitutions may be performed with amino acids having hydrophilicity values within ±2 of each other. Both the hydrophobicity index and the hydrophilicity value of amino acids are influenced by the particular side chain of that amino acid. Consistent with that observation, amino acid substitutions that are compatible with biological function are understood to depend on the relative similarity of the amino acids, and particularly the side chains of those amino acids, as revealed by the hydrophobicity, hydrophilicity, charge, size, and other properties.

[0213] Unless otherwise defined herein, scientific and technical terms used in connection with the present disclosure shall have the meanings that are commonly understood by those of ordinary skill in the art. For example, any nomenclatures used in connection with, and techniques of, cell and tissue culture, molecular biology, immunology, microbiology, genetics, and protein and nucleic acid chemistry and hybridization described herein are those that are well known and commonly used in the art. The meaning and scope of the terms should be clear; in the event however of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.Eosinophilia

[0214] Eosinophilia is a condition in which abnormally high amounts of eosinophils are in the blood and / or in body tissues. “A subject with eosinophilia,” as used herein, means a subject with greater or increased eosinophil levels compared to a control such as a healthy subject. In some embodiments, a subject with eosinophilia has greater or increased systemic eosinophils compared to a control such as a healthy subject. Systemic eosinophils may be determined by measuring eosinophils in the blood. A subject with eosinophilia may have greater or increased eosinophils in the blood compared to a control such as a healthy subject. “A tumor with eosinophilia,” as used herein, means a tumor with greater or increased eosinophil levels compared to a control tumor. Presence of eosinophils in tumor may be referred to as Tumor Associated Tissue Eosinophilia (TATE). In some instances, a subject having eosinophilia may have an absolute eosinophil count of greater than 500 eosinophils / mL, greater than 500 eosinophils / mm3, greater than 1000 eosinophils / mm3, greater than 1500 eosinophils / mm3, greater than 2000 eosinophils / mm3, greater than 3000 eosinophils / mm3, greater than 4000 eosinophils / mm3, or greater than 5000 eosinophils / mm3. Eosinopenia

[0215] Eosinopenia is a condition in which abnormally low amounts of eosinophils are in the blood and / or in body tissues. “A subject with eosinopenia,” as used herein, means a subject with lower or reduced eosinophil levels compared to a control such as a healthy subject. In some embodiments, a subject with eosinopenia has lower or reduced systemic eosinophils compared to a control such as a healthy subject. “A tumor with eosinopenia,” as used herein, means a tumor with none to lower or reduced eosinophil levels compared to a control tumor, such as a tumor with low to high eosinophil count as measured for a patient and / or tumor type. In some embodiments, the tumor or subject has no detectable level of eosinophils.

[0216] In some instances, a subject having eosinopenia may have an absolute eosinophil count of less than 50 eosinophils / mm3, less than 40 eosinophils / mm3, less than 30 eosinophils / mm3, less than 20 eosinophils / mm3, or less than 10 eosinophils / mm3. Estrogen Receptor (ER) Modulating Drug

[0217] Provided herein are estrogen receptor (ER) modulating drugs, which may also be referred to as an “ER modulator.” The term “estrogen receptor (ER) modulating drug” refersto any drug / compound, or class of drug / compound that is capable of modulating the estrogen receptor on a cell. An ER modulating drug may bind an estrogen receptor. An ER modulating drug may prevent or reduce the binding of a molecule to the estrogen receptor. An ER modulating drug may increase and / or prolong the binding of a molecule to the estrogen receptor. An ER modulating drug may decrease or reduce the activity of the estrogen receptor. An ER modulating drug may increase or enhance the activity of the estrogen receptor.

[0218] An ER modulating drug may modulate an ER receptor by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, relative to a control. An ER modulating drug may modulate an ER receptor by less than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, relative to a control. An ER modulating drug may modulate an ER receptor by about 5-95%, 10-90%, 15-85%, 20-80%, or 1.5-fold to 10-fold, relative to a control.

[0219] An ER modulating drug may have agonist activity against an ER receptor. An ER modulating drug may increase or enhance the activity of an ER receptor by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9- fold, or 10-fold, relative to a control. An ER modulating drug may increase or enhance the activity of an ER receptor by less than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 1.5-fold, 2-fold, 3-fold, 4-fold, 5- fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, relative to a control. An ER modulating drug may increase or enhance the activity of an ER receptor by about 5-95%, 10-90%, 15-85%, 20-80%, or 1.5-fold to 10-fold, relative to a control.

[0220] An ER modulating drug may have antagonist activity against an ER receptor. An ER modulating drug may decrease or inhibit the activity of an ER receptor by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9- fold, or 10-fold, relative to a control. An ER modulating drug may decrease or inhibit the activity of an ER receptor by less than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, relative to a control. An ER modulating drug may decrease or inhibit the activity of an ER receptor by about 5-95%, 10-90%, 15-85%, 20- 80%, or 1.5-fold to 10-fold, relative to a control.

[0221] ER modulating drugs may comprise a small molecule, peptide, polypeptide, antibody, nucleotide, polynucleotide, lipid, or carbohydrate, or a combination thereof. ER modulating drugs may include, for example, a selective estrogen receptor modulator (SERM), a selective estrogen receptor degrader (SERD), an antiprogestin, an aromatase inhibitor, or a combination thereof. The ER may be ER-alpha, or ER-beta, or a combination thereof. An effective amount of the ER modulating drug may be administered. SERM

[0222] SERMs may comprise a small molecule, peptide, polypeptide, antibody, nucleotide, polynucleotide, lipid, or carbohydrate, or a combination thereof. SERMs may be synthesized and / or extracted and / or purified by any suitable means known in the art. SERMs may be commercially available. SERMs may include, for example, lasofoxifene, bazodoxifene, tamoxifen (NOLVADEX®; TAMIFEN®), raloxifene (EVISTA®), toremifene (FARESTON®), or arzoxifene (also known as LY-353381), ospemifene (OSPHENA®; SENSHIO®), clomiphene (also known as clomiphene; CLOMID®; SEROPHENE®), or H3B6545, or a combination thereof. Examples of other SERMS are described in International Patent Application No. PCT / US2015 / 023216 published as WO 2015 / 149045, U.S. Patent No.7,612,114, U.S. Patent No.7,960,412, U.S. Patent No.8,399,520, U.S. Patent Publication No. US 2009-0325930, and U.S. Patent Publication No. US 2006-0116364, the contents of which are incorporated by reference in their entirety. In some embodiments, the SERM comprises lasofoxifene, bazedoxifene, tamoxifen, pipendoxifene, acolbifene, idoxifene, droloxifene, raloxifene, clomiphene, ospemiphene, arzoxifene, toremifene, H3B6545, or a combination thereof. In some embodiments, the SERM comprises lasofoxifene. SERD

[0223] SERDs may comprise a small molecule, peptide, polypeptide, antibody, nucleotide, polynucleotide, lipid, or carbohydrate, or a combination thereof. SERDs may be synthesized and / or extracted and / or purified by any suitable means known in the art. SERDs may be commercially available. SERDs may include, for example, ICI 182780 (also known asfulvestrant; FASLODEX®), LSZ102, LY3484356, giredestrant (also known as GDC9545), camizestrant (also known as AZD-9833), AZD9496, GDC0927, D-052, AC0682, SAR439859 (also known as amcenestrant), RAD1901 (also known as elacestrant), G1T48 (also known as rintodestrant), Zn-c5, ARV-471 (also known as vepdegestrant), or OP-1250, or a combination thereof. In some embodiments, the SERD comprises fulvestrant. Antiprogestin

[0224] Antiprogestins may comprise a small molecule, peptide, polypeptide, antibody, nucleotide, polynucleotide, lipid, or carbohydrate, or a combination thereof. Antiprogestins may be synthesized and / or extracted and / or purified by any suitable means known in the art. Antiprogestins may be commercially available. Antiprogestins may include, for example, mifepristone (also known as RU-486; MIFEGYNE®), asoprisnil, onapristone, or telapristone (PROELLEX®), or a combination thereof. Aromatase Inhibitor

[0225] Aromatase inhibitors may comprise a small molecule, peptide, polypeptide, antibody, nucleotide, polynucleotide, lipid, or carbohydrate, or a combination thereof. Aromatase inhibitors may be synthesized and / or extracted and / or purified by any suitable means known in the art. Aromatase inhibitors may be commercially available. Aromatase inhibitors may include, for example, letrozole (FEMARA®), anastrozole (ARIMIDEX®), Exemestane (AROMASIN®), vorozole, formestane (LENTARON®), fadrozole (AFEMA®), testolactone (TESLAC®), aminoglutethimide (ELIPTEN®; CYTADREN®; ORIMETEN®), androstatrienedione, or 4-androstene-3,6,17-trione (also known as 4-AT; 6-Oxo, 6-OXO™), or a combination thereof. Additional Therapies

[0226] In some embodiments, the at least one ER modulating drug is combined with at least one additional cancer therapy. As used herein, the term “standard of care treatment” or “additional therapy” or “additional treatment” are used interchangeably and refer to any other standard cancer treatments / additional cancer treatments that do not include ER modulating drugs. Additional cancer therapies may comprise a small molecule, peptide, polypeptide, antibody, nucleotide, polynucleotide, lipid, or carbohydrate, or a combination thereof. Additional cancer therapies may be synthesized and / or extracted and / or purified by anysuitable means known in the art. Additional cancer therapies may be commercially available. Additional cancer therapies may include, for example, chemotherapy, immunotherapy, radiation therapy, hormone therapy, targeted drug therapy, cryoablation, and surgery, or a combination thereof. Hormone therapy, for example, may block hormone synthesis such as blocking estrogen synthesis. An effective amount of the additional therapy may be administered.

[0227] Chemotherapies may include, for example, an antimitotic agent, an alkylating agent, an antimetabolite, an antimicrotubule agent, a topoisomerase inhibitor, a cytotoxic agent, a cell cycle inhibitor, a growth factor inhibitor, a histone deacetylase (HDAC) inhibitor, or an inhibitor of a pathway that cross-talks with and activates ER transcriptional activity, or a combination thereof.

[0228] Alkylating agents may include, for example, cisplatin (PLATINOL®), oxaliplatin (ELOXATIN®), chlorambucil (LEUKERAN®), procarbazine (MATULANE®; NATULAN®), or carmustine (BiCNU®), or a combination thereof. Antimetabolites may include, for example, methotrexate (also known as amethopterin), 5-fluorouracil, cytarabine (also known as cytosine arabinoside or ara-C; CYTOSAR®), or gemcitabine (GEMZAR®), or a combination thereof. Antimicrotubule agents may include, for example, vinblastine (VELBAN®; VELBE®), or paclitaxel (TAXOL®), or a combination thereof. Topoisomerase inhibitors may include, for example, etoposide (VEPESID®), or doxorubicin (ADRIAMYCIN®; MYOCET®), or a combination thereof. Cytotoxic agents may include, for example, bleomycin (BLENOXANE®). Growth factor inhibitors may include, for example, human epidermal growth factor receptor 2 (HER2) inhibitors. HER2 inhibitors include, for example, trastuzumab (HERCEPTIN®), deruxtecan, sacitizumab, and / or ado- trastuzumab emtansine (KADCYLA®). HDAC inhibitors may include, for example, vorinostat (ZOLINZA®), romidepsin (ISTODAX®), chidamide (also known as tucidinostat; EPIDAZA®; HIYASTA™), panobinostat (FARYDAK®), belinostat (also known as BELEODAQ®or PXD101), valproic acid (DEPAKOTE®; DEPAKENE®; STAVZOR®), mocetinostat (also known as MGCD0103), abexinostat (also known as PCI-24781), entinostat (also known as SNDX-275 or MS-275), pracinostat (also known as SB939), resminostat (also known as 4SC-201 or RAS2410), givinostat (also known as gavinostat or ITF2357), quisinostat (also known as JNJ-26481585), kevetrin, CUDC-101, AR-42, tefinostat (also known as CHR-2845), nanatinostat (also known as CHR-3996), domatinostat (also known as4SC-202), ivaltinostat (also known as CG-200745), rocilinostat (also known as ACY-1215), or sulforaphane, or a combination thereof. Inhibitors of a pathway that cross-talks with and activates ER transcriptional activity may include, for example, a phosphoinositide 3-kinase (PI3K) inhibitor, a heat shock protein 90 (HSP90) inhibitor, or a mammalian target of rapamycin (mTOR) inhibitor. mTOR inhibitors include, for example, everolimus (AFINITOR®; VOTUBIA®; ZORTRESS®). In some embodiments, the HDAC inhibitor comprises vorinostat (ZOLINZA®). In some embodiments, the HDAC inhibitor comprises romidepsin (ISTODAX®). In some embodiments, the method further comprises administering to the patient an effective amount of a phosphoinositide 3-kinase (PI3K) inhibitor.

[0229] Immunotherapies may include, for example, a checkpoint inhibitor, or denosumab (PROLIA®; XGEVA®), or a combination thereof. “Checkpoint inhibitor” or “immune checkpoint inhibitor” may also be referred to as an immune checkpoint blockade (ICB) therapy. Checkpoint inhibitors may comprise an antibody. Checkpoint inhibitors may include, for example, an antibody to programmed cell death protein 1 (PD1) (anti-PD1), or an antibody to cytotoxic T-lymphocyte-associated protein 4 (CTLA4) (anti-CTLA4), or an antibody to programmed death-ligand 1 (PDL1) (anti-PDL1), or DMXAA (sting agonist; also known as ASA404, vadimezan, or dimethylxanthone acetic acid) or a combination thereof. “Anti-PD1” refers to an antibody that binds PD1, “anti-CTLA4” refers to an antibody that binds CTLA4, and “anti-PDL1” refers to an antibody that binds PDL1. In some embodiments, the PD-1 antibody comprises pembrolizumab (KEYTRUDA®) or nivolumab (OPDIVO®). In some embodiments, the CTLA-4 antibody comprises ipilimumab (YERVOY®). In some embodiments, the checkpoint inhibitor comprises anti-PD1, anti- CTLA4, anti-PDL1, or DMXAA, or a combination thereof.

[0230] Targeted drug therapies may include, for example, vemurafenib (ZELBORAF®), anti- EGFR targeted therapies (such as, for example, erlotinib (TARCEVA®), and / or gefitinib (IRESSA®)), a serotonin-norepinephrine reuptake inhibitor (SNRI; such as venlafaxine (EFFEXOR XR®)), a selective serotonin reuptake inhibitor (SSRI), or gabapentin (NEURONTIN®), or a combination thereof.

[0231] In some embodiments, the at least one ER modulating drug is combined with anti- PD1. In some embodiments, the at least one ER modulating drug is combined with anti-CTLA4. In some embodiments, the at least one ER modulating drug is combined with anti- PD1 and anti-CTLA4. Pharmaceutical Compositions

[0232] Further provided herein are pharmaceutical compositions comprising the above- described ER modulating drug(s). The pharmaceutical composition may further include at least one additional cancer therapy. In some embodiments, the pharmaceutical composition may comprise about 1 ng to about 10 mg of ER modulating drug, or about 1 ng to about 10 mg of ER modulating drug and additional cancer therapy. The ER modulating drug as detailed herein, with or without at least one additional cancer therapy, may be formulated into pharmaceutical compositions in accordance with standard techniques well known to those skilled in the pharmaceutical art. The pharmaceutical compositions can be formulated according to the mode of administration to be used. In cases where pharmaceutical compositions are injectable pharmaceutical compositions, they are sterile, pyrogen free, and particulate free. An isotonic formulation is preferably used. Generally, additives for isotonicity may include sodium chloride, dextrose, mannitol, sorbitol and lactose. In some cases, isotonic solutions such as phosphate buffered saline are preferred. Stabilizers include gelatin and albumin. In some embodiments, a vasoconstriction agent is added to the formulation. 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. For parenteral administration, the ER modulating drug 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. 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 syntheticoil. Hydrocarbon (paraffin), wool fat, beeswax, macrogols, emulsifying wax or cetrimide can also be included.

[0233] The composition may further comprise a pharmaceutically acceptable excipient. The pharmaceutically acceptable excipient may be functional molecules as vehicles, adjuvants, carriers, or diluents. The term “pharmaceutically acceptable carrier,” may be a non-toxic, inert solid, semi-solid or liquid filler, diluent, encapsulating material or formulation auxiliary of any type. Pharmaceutically acceptable carriers include, for example, diluents, lubricants, binders, disintegrants, colorants, flavors, sweeteners, antioxidants, preservatives, glidants, solvents, suspending agents, wetting agents, surfactants, emollients, propellants, humectants, powders, pH adjusting agents, and combinations thereof. The pharmaceutically acceptable excipient may be a transfection facilitating agent, which may include surface active agents, such as immune-stimulating complexes (ISCOMS), Freunds incomplete adjuvant, LPS analog including monophosphoryl lipid A, muramyl peptides, quinone analogs, vesicles such as squalene and squalene, hyaluronic acid, lipids, liposomes, calcium ions, viral proteins, polyanions, polycations, or nanoparticles, or other known transfection facilitating agents. The transfection facilitating agent may be a polyanion, polycation, including poly-L- glutamate (LGS), or lipid. The transfection facilitating agent may be poly-L-glutamate, and more preferably, the poly-L-glutamate may be present in the composition at a concentration less than 6 mg / mL.

[0234] The ER modulating drug and / or additional cancer therapy may be present or formulated as a pharmaceutically acceptable salt thereof, or a prodrug thereof. The term “pharmaceutically acceptable salt” refers to non-toxic pharmaceutically acceptable salts (see Gould, International Journal of Pharmaceutics 1986, 33, 201-217; and Berge et al., Journal of Pharmaceutical Sciences 1977, 66, 1-19). 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.

[0235] 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 as detailed herein, 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. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in “Design of Prodrugs”, H. Bundgaard, Elsevier, 1985.

[0236] Some of the crystalline forms for the compounds may exist as polymorphs and as such are intended to be included. 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.

[0237] 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.

[0238] In embodiments wherein the pharmaceutical composition comprises both the at least one ER modulating drug and the at least one additional cancer therapy, they may be present in the pharmaceutical composition in a variety of molar ratios. The molar ratio between the at least one ER modulating drug and the at least one additional cancer therapy may be 1:1, or1:15, or from 5:1 to 1:10, or from 1:1 to 1:5. The molar ratio between the at least one ER modulating drug and the at least one additional cancer therapy may be at least 1:1, at least 1:2, at least 1:3, at least 1:4, at least 1:5, at least 1:6, at least 1:7, at least 1:8, at least 1:9, at least 1:10, at least 1:15, or at least 1:20. The molar ratio between the at least one ER modulating drug and the at least one additional cancer therapy may be less than 20:1, less than 15:1, less than 10:1, less than 9:1, less than 8:1, less than 7:1, less than 6:1, less than 5:1, less than 4:1, less than 3:1, less than 2:1, or less than 1:1. Administration

[0239] The ER modulating drug as detailed herein, with or without at least one additional cancer therapy as detailed herein, or the pharmaceutical compositions comprising the same, may be administered to a subject. Such compositions can be administered in dosages and by techniques well known to those skilled in the medical arts taking into consideration such factors as the age, sex, weight, and condition of the particular subject, and the route of administration. The presently disclosed ER modulating drug, with or without at least one additional cancer therapy, or compositions comprising the same, may be administered to a subject by different routes including orally, ocularly, nasally, parenterally, sublingually, transdermally, rectally, transmucosally, topically, intranasal, intravaginal, via inhalation, via buccal administration, intrapleurally, intravenous, intraarterial, intraperitoneal, subcutaneous, intradermally, epidermally, intramuscular, intranasal, intrathecal, intracranial, and intraarticular or combinations thereof. In some embodiments, administration is via aerosol or suppository. In certain embodiments, the ER modulating drug, with or without at least one additional cancer therapy, or compositions comprising the same, is administered to a subject orally, intravenously, vaginally, or transdermally, or a combination thereof. The composition may be injected into any organ or tissue of the subject. In some embodiments, the ER modulating drug, with or without at least one additional cancer therapy, or compositions comprising the same, is administered to the subject by vaginal ring administration.

[0240] In some embodiments, the ER modulating drug is administered either alone or in combination with one or more additional therapies. The at least one ER modulating drug and the at least one additional cancer therapy may be administered in a variety of molar ratios. The molar ratio between the at least one ER modulating drug and the at least one additional cancer therapy may be 1:1, or 1:15, or from 5:1 to 1:10, or from 1:1 to 1:5. The molar ratio between the at least one ER modulating drug and the at least one additional cancer therapymay be at least 1:1, at least 1:2, at least 1:3, at least 1:4, at least 1:5, at least 1:6, at least 1:7, at least 1:8, at least 1:9, at least 1:10, at least 1:15, or at least 1:20. The molar ratio between the at least one ER modulating drug and the at least one additional cancer therapy may be less than 20:1, less than 15:1, less than 10:1, less than 9:1, less than 8:1, less than 7:1, less than 6:1, less than 5:1, less than 4:1, less than 3:1, less than 2:1, or less than 1:1.

[0241] In some embodiments, the ER modulating drug is administered to the subject by oral administration (orally, or “os”). In certain embodiments, ER modulating drug 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, the ER modulating drug is administered at about 0.5 mg / day per os. In some embodiments, the ER modulating drug is administered at about 1 mg / day per os. In some embodiments, the ER modulating drug is administered at about 1.5 mg / day per os. In some embodiments, the ER modulating drug is administered at about 2 mg / day per os. In some embodiments, the ER modulating drug is administered at about 2.5 mg / day per os. In some embodiments, the ER modulating drug is administered at about 3 mg / day per os. In some embodiments, the ER modulating drug is administered at about 3.5 mg / day per os. In some embodiments, the ER modulating drug is administered at about 4 mg / day per os. In some embodiments, the ER modulating drug is administered at about 4.5 mg / day per os. In some embodiments, the ER modulating drug is administered at about 5 mg / day per os. In some embodiments, the ER modulating drug is administered at about 6 mg / day per os.some embodiments, the ER modulating drug is administered at about 7 mg / day per os. In some embodiments, the ER modulating drug is administered at about 8 mg / day per os. In some embodiments, the ER modulating drug is administered at about 9 mg / day per os. In some embodiments, the ER modulating drug is administered at about 10 mg / day per os. In some other embodiments, the ER modulating drug is administered at more than 10 mg / day per os.

[0242] In certain embodiments, when the ER modulating drug is administered to a subject whose cancer has not acquired endocrine resistance, the ER modulating drug can be administered at less than 0.5 mg / day per os for prevention of endocrine resistance. In certain embodiments, when the ER modulating drug is administered to cancer patient as adjuvant treatment, the ER modulating drug can be administered at less than 0.5 mg / day per os for prevention of endocrine resistance.

[0243] A composition can be administered alone or in combination with other treatments, either simultaneously or sequentially, dependent upon the condition to be treated. The at least one ER modulating drug and the at least one additional therapy may be administered together or simultaneously, they may be administered at different times or sequentially. The at least one ER modulating drug and the at least one additional therapy and the Vemurafenib may be administered simultaneously or sequentially.

[0244] The at least one ER modulating drug, with or without the at least one additional therapy, may be administered to the subject once every day, once every 2 days, once every 3 days, once every 4 days, once every 5 days, once every 6 days, once every 7 days, once every week, once every 2 weeks, once every 3 weeks, once every 4 weeks, once every 5 weeks, once every 6 weeks, once every 7 weeks, once every 8 weeks, once every month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months. The at least one ER modulating drug may be administered to the subject for 1 year, 2 years, 3 years, 4 years, 5 years, or more than 5 years. In some embodiments, the ER modulating drug, with or without the at least one additional therapy, is administered to the subject until the subject's cancer progresses on therapy. Methods Methods of Diagnosis

[0245] Provided herein are methods of diagnosing subjects with eosinophilia and eosinopenia. The methods may involve quantifying eosinophil levels in a sample from the subject. Various methods may be used to quantify the eosinophils in a blood and / or tissue sample from the subject, such as a sample comprising blood and / or a tumor biopsy. Methods for quantifying eosinophil levels may involve staining the sample and analyzing the stained sample under a microscope or other biochemical methods such as immunohistochemistry or activity assays for enzyme activity. In some instances, the level of eosinophils is determinedby measuring or staining for eosinophils, measuring or staining for eosinophilic granular protein contents, measuring or staining for eosinophilic major basic protein, or determining the level of eosinophil peroxidase in the sample, or a combination thereof.

[0246] The methods may involve determining in a sample from the subject or from a tumor of the subject the level of eosinophils greater than the level in an eosinopenia or normal control, thereby identifying the subject or the tumor as having eosinophilia. Alternatively, the methods may involve determining in a sample from the subject or from a tumor of the subject the level of eosinophils lower than the level in a normal control, thereby identifying the subject or the tumor as having eosinopenia. In some embodiments, the method further includes administering a selective estrogen receptor modulator (SERM) and / or a selective estrogen receptor degrader (SERD) to a subject determined as having eosinopenia or eosinophilia. Methods of Treatment

[0247] Provided herein are methods of treating cancer in a subject. The subject may be a subject with eosinopenia. Alternatively, the subject may be a subject with eosinophilia. The methods may include administering to the subject at least one ER modulating drug, as detailed herein. In some embodiments, the method includes administering a selective estrogen receptor modulator (SERM) and / or a selective estrogen receptor degrader (SERD) to the subject. The methods may further include administering to the subject at least one additional therapy, as detailed herein. Further provided herein are methods of treating a disease in a subject to increase eosinophils in the subject, such as, for example, in a subject with an infection and / or Cushing’s disease.

[0248] Further provided herein are methods of increasing eosinophils in a tumor in a subject. The methods may include administering to the subject at least one ER modulating drug, as detailed herein. In some embodiments, the method includes administering a selective estrogen receptor modulator (SERM) and / or a selective estrogen receptor degrader (SERD) to the subject. The methods may further include administering to the subject at least one additional therapy, as detailed herein.

[0249] The compositions and methods may increase the amount or level of eosinophils or eosinophil activity in a subject or tumor, relative to a control. For example, the amount of eosinophils in blood or in a tumor may be increased, relative to a control. The compositionsand methods may suppress growth of a tumor in a subject, relative to a control. The compositions and methods may suppress growth of a tumor with eosinopenia in the subject, relative to a control. The compositions and methods may increase the generation of eosinophils in the bone marrow of a subject, relative to a control. The compositions and methods may increase the cytotoxic activity of an eosinophil in a subject or in a tumor, relative to a control. The compositions and methods may increase the activity of an eosinophil in a subject or in a tumor, relative to a control, such as, for example, increasing the cytotoxic activity of an eosinophil or increasing the ability of an eosinophil to recruit other immune cells (for example, CD8 T cells) to indirectly suppress cancer growth. The compositions and methods may increase the migration of eosinophils into blood or into a tumor, relative to a control.

[0250] In some embodiments, the at least one ER modulating drug comprises a selective estrogen receptor modulator (SERM). In some embodiments, the ER modulating drug comprises lasofoxifene. In some embodiments, the at least one ER modulating drug comprises a selective estrogen receptor modulator (SERD). In some embodiments, the SERD comprises fulvestrant. In some embodiments, the at least one ER modulating drug is administered with anti-PD1. In some embodiments, the at least one ER modulating drug is administered with anti-CTLA4. In some embodiments, the at least one ER modulating drug is administered with anti-PD1 and anti-CTLA4.

[0251] The compositions and methods detailed herein may have a variety of effects in the subject, relative to a control. Tumor growth may be decreased. Tumor size may be decreased. Circulating tumor cells may be reduced. Cancer metastasis may be reduced.

[0252] The at least one ER modulating drug, or the at least one additional therapy, or a combination thereof, may treat cancer. The at least one ER modulating drug, or the at least one additional therapy, or a combination thereof, may reduce cancer. Reducing cancer may include reducing tumor size, reducing tumor growth, reducing cancer metastasis, or a combination thereof. In some embodiments, the at least one ER modulating drug, or the at least one additional therapy, or a combination thereof, reduces cancer by at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, relative to a control. The cancer may be reduced by less than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold, relative to a control. The cancer may be reduced by about 5-95%, 10-90%, 15-85%, 20-80%, or 1.5-fold to 10-fold, relative to a control. Methods of Improving Effectiveness of ICB Therapies

[0253] Provided herein are methods of improving the effectiveness of ICB therapies. The methods may include administering to the subject at least one ER modulating drug, as detailed herein. The methods may further include administering to the subject at least one additional therapy, as detailed herein.

[0254] Provided herein are methods of treating cancer in a subject. The method may include administering to the subject at least one estrogen receptor (ER) modulating drug such that the effectiveness of an ICB therapy is increased relative to a control. The method may further include administering to the subject the ICB therapy. In some embodiments, the ICB therapy is selected from anti-PD1, anti-CTLA4, anti-PDL1, and DMXAA, or a combination thereof. In some embodiments, the method further comprises administering to the subject at least one additional therapy.

[0255] In some embodiments, the at least one ER modulating drug is administered with anti- PD1. In some embodiments, the at least one ER modulating drug is administered with anti- CTLA4. In some embodiments, the at least one ER modulating drug is administered with anti-PD1 and anti-CTLA4. In some embodiments, the at least one ER modulating drug is administered with anti-PD1 and vemurafenib. In some embodiments, the at least one ER modulating drug is administered with anti-CTLA4 and vemurafenib. In some embodiments, the at least one ER modulating drug is administered with anti-PD1, anti-CTLA4, and vemurafenib.

[0256] The at least one ER modulating drug, or the at least one additional therapy, or a combination thereof, may increase the effectiveness of an ICB therapy. In some embodiments, the at least one ER modulating drug, or the at least one additional therapy, or a combination thereof, increases the effectiveness of an ICB therapy by at least about 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9- fold, or 10-fold, relative to a control. The effectiveness of an ICB therapy may be increased by less than about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%,75%, 80%, 85%, 90%, 95%, 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9- fold, or 10-fold, relative to a control. The effectiveness of an ICB therapy may be increased by about 5-95%, 10-90%, 15-85%, 20-80%, or 1.5-fold to 10-fold, relative to a control. 6.9. Additional Embodiments

[0257] Embodiment 1: A method of increasing eosinophils in a tumor in a subject, the method comprising: administering to the subject a selective estrogen receptor modulator (SERM) and / or a selective estrogen receptor degrader (SERD).

[0258] Embodiment 2: A method of treating cancer in a subject with eosinopenia, the method comprising: administering a selective estrogen receptor modulator (SERM) and / or a selective estrogen receptor degrader (SERD) to the subject with eosinopenia to increase the level of eosinophils in the subject.

[0259] Embodiment 3: A method of suppressing growth of a tumor with eosinopenia in a subject, the method comprising: administering a selective estrogen receptor modulator (SERM) and / or a selective estrogen receptor degrader (SERD) to the subject to increase the level of eosinophils in the tumor.

[0260] Embodiment 4: A method of treating cancer in a subject with eosinophilia, the method comprising: administering a selective estrogen receptor modulator (SERM) and / or a selective estrogen receptor degrader (SERD) to the subject with eosinophilia.

[0261] Embodiment 5: A method of suppressing growth of a tumor with eosinophilia in a subject, the method comprising: administering a selective estrogen receptor modulator (SERM) and / or a selective estrogen receptor degrader (SERD) to the subject.

[0262] Embodiment 6: A method of diagnosing and treating a subject with eosinophilia, the method comprising: determining in a sample from the subject or from a tumor of the subject the level of eosinophils greater than the level in an eosinopenia or normal control, thereby identifying the subject or the tumor as having eosinophilia; and administering a selective estrogen receptor modulator (SERM) and / or a selective estrogen receptor degrader (SERD) to the subject having eosinophilia.

[0263] Embodiment 7: The method of embodiment 6, wherein the level of eosinophils is determined by staining for eosinophils or eosinophilic granular protein contents, or stainingfor eosinophilic major basic protein, or determining the level of eosinophil peroxidase in the sample.

[0264] Embodiment 8: The method of embodiment 6 or 7, wherein the sample comprises blood and / or a tumor biopsy.

[0265] Embodiment 9: The method of any one of embodiments 1-8, wherein the SERM comprises lasofoxifene, bazedoxifene, tamoxifen, pipendoxifene, acolbifene, idoxifene, droloxifene, raloxifene, clomiphene, ospemiphene, arzoxifene, toremifene, H3B6545, or a combination thereof.

[0266] Embodiment 10: The method of embodiment 9, wherein the SERM comprises lasofoxifene.

[0267] Embodiment 11: The method of any one of embodiments 1-10, wherein the SERD comprises fulvestrant, giredestrant, camizestrant, amcenestrant, elacestrant, rintodestrant, vepdegestrant, LSZ102, LY3484356, AZD9496, GDC0927, D-052, AC0682, Zn-c5, or OP- 1250, or a combination thereof.

[0268] Embodiment 12: The method of embodiment 11, wherein the SERD comprises fulvestrant.

[0269] Embodiment 13: The method of any one of embodiments 1-12, wherein, upon administration of the SERM and / or the SERD, the migration of eosinophils into the blood or into the tumor or into a tumor in the subject is increased.

[0270] Embodiment 14: The method of any one of embodiments 1-13, wherein, upon administration of the SERM and / or the SERD, the amount of eosinophils in the blood or in the tumor or in a tumor in the subject is increased.

[0271] Embodiment 15: The method of any one of embodiments 1-14, wherein, upon administration of the SERM and / or the SERD, the generation of eosinophils in the bone marrow of the subject is increased.

[0272] Embodiment 16: The method of any one of embodiments 1-15, wherein, upon administration of the SERM ad / or the SERD, the activity of an eosinophil in the subject or in the tumor is increased.

[0273] Embodiment 17: The method of any one of embodiments 1-16, wherein the cancer comprises breast cancer, colon cancer, prostate cancer, bladder cancer, esophageal cancer, gastric cancer, laryngeal cancer, melanoma, oral cancer, or liver cancer, or a combination thereof.

[0274] Embodiment 18: The method of embodiment 17, wherein the cancer is estrogen receptor negative breast cancer.

[0275] Embodiment 19: The method of embodiment 17, wherein the cancer is estrogen receptor positive breast cancer.

[0276] Embodiment 20: The method of any one of embodiments 1-19, wherein the method further comprises administering an immunotherapy.

[0277] Embodiment 21: The method of embodiment 20, wherein the immunotherapy comprises a checkpoint inhibitor.

[0278] Embodiment 22: The method of embodiment 21, wherein the checkpoint inhibitor comprises anti-PD1, anti-CTLA4, anti-PDL1, and DMXAA, or a combination thereof.

[0279] Embodiment 23: The method of any one of embodiments 20-22, wherein the immunotherapy is administered before, concurrently with, and / or after the SERM and / or the SERD. EXAMPLES

[0280] The foregoing may be better understood by reference to the following examples, which are presented for purposes of illustration and are not intended to limit the scope of the disclosure. The present disclosure has multiple aspects and embodiments, illustrated by the appended non-limiting examples. 7.1. Methods Mice

[0281] C57BL / 6 and ΔdblGATA1 female mice were purchased from the Jackson Laboratories (Bar Harbor, ME). Age-matched mice (7-12 weeks old) were used for all the studies. EpxCre mice were obtained from Mayo Clinic (see Doyle, A.D., et al., Homologous recombination into the eosinophil peroxidase locus generates a strain of mice expressing Crerecombinase exclusively in eosinophils. Journal of Leukocyte Biology, 2013.94(1): 17-24, which is incorporated by reference in its entirety.) and were bred to Esr1f / f mice to generate Esr1f / fEpxCre and littermate controls EpxCre and Esr1f / f mice. Mice were housed in a secure animal facility on a 12-hr light:dark cycle at temperature around 25°C and 70% humidity. Throughout the study, the mice had access to ad-libitum food and water. NSG (NOD.Cg-PrkdcscidIl2rgtm1Wjl / SzJ) mice were purchased from the Division of Laboratory Animal Resources (Duke University). The NSG animals were fed with GL3 diet and were kept in pathogen-free conditions. All animal experiments were performed according to guidelines from Duke Institutional Animal Care and Use Committee (IACUC). Tumor models and cells

[0282] Mouse cell lines A7C11, EO771, B16F10, and AKPS were purchased from American Type Culture Collection (ATCC, Manassas, VA). A7C11 cells were maintained in RPMI- 1640 media (Sigma-Aldrich) supplemented with 2-Mercaptoethanol (Cat #ST-0000002415; 1:1000), 8% fetal bovine serum (FBS), 0.1mM non-essential amino acids (NEAA) and 1mM Sodium pyruvate (NaPy). E0771 cells were maintained in RPMI-1640 media (Sigma- Aldrich) supplemented with 8% FBS, 0.1mM NEAA, and 1mM NaPy. The cells were split 3 times / week at a 1:10 ratio when confluent and were kept in 37°C incubator at 5% CO2. For breast tumor models, A7C11 (2 x 104cells) and E0771 (2 x 105cells) cells were subcutaneously injected into the right upper mammary fat pad of mice. Tumors were measured thrice weekly with an electronic caliper. Tumor volume was calculated by the formula: Volume=Length x (Width x Width) / 2. For tumor growth rate studies, mice were euthanized when the tumors reach 2000mm3, as specified by Duke IACUC. Ovariectomy and estrogen supplementation

[0283] Eight days prior to tumor inoculation, 7-week-old C57BL6 / J female mice were subjected to ovariectomy. Mice were first anesthetized in an inhalation chamber (2% Isoflurane) and subsequently maintained in half the dose of isoflurane (1%) via nose cone throughout the surgical process. Prior to surgery, mice were administered with 5mg / kg dose of carprofen subcutaneously. The area on the back of the mice below the ribs was shaved with an electronic razor and the skin was sterilized by rubbing with betadine and alcohol 3X alternating. This was followed by a horizontal incision through the skin above the ovary fat pad, and then a vertical incision through the abdominal muscle wall. The ovary was externalized and removed using cauterizing scissors. The fat pad was replaced, muscle wallswere realigned and sutured (1-2 stitches), and 1 drop of Bupivacaine (0.25%) was added on top of the incision site. The skin was realigned, and a wound clip was placed on the incision site. The steps were repeated for the other ovary. Subsequently, the mice were removed from anesthesia and kept in a clean cage and monitored until it regained consciousness. The mice were monitored for recovery for 10 days. Drug treatments

[0284] The treatments with E2 were started on day 2 after ovariectomy. E2 was dissolved in drinking water at 2.72 mcg / mL, and the placebo group received vehicle (ethyl alcohol) at 2 mL / liter water. Lasofoxifene was dissolved in 10% DMSO / 40% PEG400 / 50% sterile water and injected subcutaneously once daily from day 2 after tumor injections until the end of the study. Fulvestrant was dissolved in corn oil and given once a week intramuscularly at 25 mg / kg. The ICB treatments were a combination of anti-PD1 at 10 mg / kg (cat # BE0146; Bio X Cell, Lebanon, NH) and anti-CTLA4 at 5 mg / kg (cat # BE0164, Bio X Cell, Lebanon, NH) given intraperitonially once every 3 days starting at day 2 after tumor injections. IgG (cat # BE0089; Bio X Cell, Lebanon, NH) was used as the control for ICB treatments. Eosinophil depletion studies

[0285] For the purposes of eosinophil depletion, C57BL / 6 mice were injected with mouse SiglecF antibody (clone #238047; R&D Cat #MAB17061) at 1mg / kg / dose or monoclonal rat IgG2Aisotype control (clone #54447; R&D Cat #MAB006) reconstituted at 0.05 mg / mL in sterile PBS. Antibody injections were performed 24 hours before tumor injections and once every 72 hours after the first dose. The efficacy of eosinophil depletion was analyzed at the end of the experiment by collecting cardiac blood as well as tumor-infiltrating immune cells and performing flow cytometry for eosinophil subpopulation. In vitro bone marrow eosinophil differentiation

[0286] Bone marrow-derived cells were aseptically collected from 8-10 week-old female C57BL / 6 mice by crushing the leg bones in PBS containing 1% FBS and 2 mM EDTA. The solution was filtered through a 40 μm strainer to remove bone pieces. Cells were subjected to ACK buffer to lyse the red blood cells. After centrifugation, the cells were washed once in PBS containing 0.1% BSA. The bone marrow cells were cultured at 106 / mL in media containing RPMI 1640 (Invitrogen) with 20% charcoal-stripped FBS, 100 IU / mL penicillin and 10 μg / mL streptomycin (Cellgro), 2 mM glutamine (Invitrogen), 25 mM HEPES, 0.1mM NEAA, 1 mM sodium pyruvate (Gibco) and 50 μM β-mercaptoethanol (#ST- 0000002415). Cells were supplemented with either E2 (1nM) or DMSO throughout the differentiation process and with 100 ng / mL stem-cell factor (SCF; PeproTech Cat #250-03), and 100 ng / mL FLT3-Ligand (FLT3-L; PeproTech Cat #250-31L) from day 0 to day 4. On day 4, the media containing SCF and FLT3-L was replaced with media containing 10 ng / mL recombinant mouse interleukin-5 (rmIL-5; R&D Systems) only. On day 8, the cells were moved to new flasks and maintained in fresh media supplemented with rmIL-5. Every other day, the media was replaced with fresh media containing rmIL-5, and the concentration of the cells was adjusted each time to 106 / mL. Cells were enumerated at day 0 and on days indicated thereafter using a hemocytometer. Quantitative PCR of eosinophils

[0287] RNA was isolated using Aurum total RNA mini kit (Cat# 7326820, Bio-Rad, Hercules, CA) followed by cDNA synthesis using iScript cDNA synthesis kit (Cat# 170- 7691, Bio-Rad, Hercules, CA) as per the manufacturer’s instructions. Quantitative amplification was performed with Sybr Green (Cat# 1725124, Bio-Rad, Hercules, CA) using CFX- 384 Real Time PCR detection system. The 36B4 gene expression was used as an internal control, and the expression levels of each target gene were normalized to 36B4, then to vehicle (DMSO) treated controls. The corresponding primers are shown in Table 1 below.Proliferation assays

[0288] A7C11 or E0771 cells were plated in RPMI media (without phenol red) supplemented with 10% charcoal-stripped FBS (with further addition of 2-mercaptoethanol for A7C11). Cells were plated at a concentration of 1000 cells / well on a 96-well plate and incubated for 2 days in 200 μL of media. After 2 days, 50 μL of media was removed and replenished with 50 μL of fresh media containing 4X concentration of vehicle (DMSO), E2, or E2+fulvestrant, thus maintaining the original concentration. Cells were collected every 24 hours by discarding the media from the plates and then freezing plates at -80°C. Frozen plates were thawed at room temperature, and 100 μL of water was added to each plate for 1 hour at 37°C to mediate cell lysis. DNA content in each well was determined by the addition of Hoechst dye (Hoechst 33258 Cat #H3570 Thermo Fisher Scientific, Waltham, MA) in TNE buffer for 45 minutes at RT, and the fluorescence was read at excitation of 346 nm and emission at 460 nm using a microplate reader. Flow cytometry staining

[0289] Single cell suspensions (106cells in 50 μL) were incubated with Live / dead fixable dead cell stain in PBS for 10 mins at 4°C. Cells were spun down at 2000 RPM and were incubated with anti-CD16 / 32 (1:100; Catalog# 14-0161-85, Thermo Fisher Scientific, Waltham MA) in flow buffer (made by dissolving 10 grams BSA in 1L PBS) for 15 mins. Cells were stained with antibody cocktails in BV buffer (Cat# 566349, Thermo Fisher Scientific, Waltham MA) for 30 minutes at 4°C. The antibodies used are listed in Table 2 below. For intracellular staining, cells were fixed and permeabilized using transcription factor staining kit buffer (Cat# 00-5523-00, Thermo Fisher Scientific, Waltham, MA), followed by intracellular staining with the desired antibodies for 30 minutes at 4°C. Multicolor flow cytometry was performed using the BD Fortessa 16 color analyzer. Results were analyzed using FlowJo_V10 software (FlowJo, LLC).Immunoblotting

[0290] Cells were washed three times with 2 mL of ice-cold PBS and lysed with 0.15 mL of phospho-RIPA lysis buffer (Tris-Cl pH 7.5, 50 mM; NaCl, 150 mM; NP-40, 1%; Sodium deoxycholate, 0.5%; SDS, 0.05%; EDTA, 5 mM; Sodium fluoride, 50 mM; Sodium pyrophosphate, 15 mM; ß-glycerophosphate, 10 mM; Sodium orthovanadate, 1 mM) with Protease inhibitor cocktail (Millipore-Sigma, P-8340). Equal amounts of protein per sample / lane were denatured and resolved by SDS-PAGE. Proteins were transferred toImmuno-Blot PVDF membranes (Bio-Rad Cat #1620177). Primary antibodies used were anti-ER-α (1:1000, cat # 6F11 Leica in milk) and anti-b-actin (Cell Signaling, cat no #8457, dilution 1:20000). The secondary antibodies used were HRP-conjugated goat anti-mouse IgG (Bio-Rad cat #1706516; dilution 1:10,000) and HRP-conjugated goat anti-rabbit (cat #1706515; Bio-Rad; dilution 1:15000). Bulk RNAseq

[0291] Day 11 BMEos differentiated in the presence of vehicle or E2 were flow sorted for live cells, followed by RNA isolation using the RNeasy Micro kit from Qiagen. Following RNA QC, library preparation was performed using stranded KAPA hyperPrep kit followed by high throughput sequencing to obtain paired-end 50 bp reads using Illumina NovaSeq 6000. RNAseq reads were trimmed by Trim Galore (https: / / www.bioinformatics.babraham.ac.uk / projects / trim_galore / ) and trimmed reads were aligned to mouse genome (GRCm38) using STAR (version 2.7.7a) (see Dobin, A., et al., STAR: ultrafast universal RNA-seq aligner. Bioinformatics, 2013.29(1): 15-21, which is incorporated by reference in its entirety). Quantification of gene expression was obtained by Subread featureCounts (version 2.0.1) (see Liao, Y., et al., featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics, 2014.30(7): 923-30, which is incorporated by reference in its entirety). Differential expression analysis using gene counts was performed by DESeq2 (see Love, M.I., et al., Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biology, 2014.15(12): 550, which is incorporated by reference in its entirety). Data wrangling were performed and plots were generated using tidyverse (https: / / www.tidyverse.org / ), EnhancedVolcano (https: / / github.com / kevinblighe / EnhancedVolcano) and base R packages. Pathway enrichment analysis was performed using ClusterProfiler (see Yu, G., et al., clusterProfiler: an R package for comparing biological themes among gene clusters. Omics, 2012.16(5): 284-7, which is incorporated by reference in its entirety) and Gene Set Enrichment Analyses (see Subramanian, A., et al., Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proceedings of the National Academy of Sciences, 2005.102(43): 15545-15550, which is incorporated by reference in its entirety).Epx ELISA

[0292] Tumor eosinophil peroxidase (EPX) levels were quantified using mouse the Epx ELISA Kit from Biomatik corporation (cat #501502404 / EKN4503096 Tests), following manufacturer’s protocol. An equal amount of protein isolated from tumor homogenates (prepared according to manufacturer’s recommendations) was used along with protein standards provided by the kit in a sandwich enzyme immunoassay to quantify EPX levels. Optical density was measured at 450 nm using a TECAN microplate reader. Measurement of tumor cytokine levels

[0293] Protein from tumor homogenates were subjected to cytokine ELISA array (Ray Biotech) analysis for 96 different cytokines. The membranes were probed according to the manufacturer's protocol and quantified by scanning densitometry. Analysis of human correlates

[0294] Bulk RNA sequencing was performed on murine bone marrow-derived eosinophils differentiated in the presence of E2 or placebo. The top 30 genes that were upregulated in E2 group and the top 30 genes that were downregulated with E2 based on fold-change and p- value were identified. The human analogues of these genes were used to create an “E2- upregulated” gene signature and an “E2 downregulated” gene signature. Survival analyses were performed using the ‘survival’ package’ analysis with R. Patient populations were partitioned using median expression values and compared using the log-rank test. Retrospective chart review study

[0295] The SlicerDicer tool, a feature of the Epic Electronic Medical Record, was used to identify a group of 135 patients within the Duke University Health System who satisfy the following criteria. Inclusion criteria: females with a breast cancer diagnosis between October 2018 and October 2023, age younger than 45 at time of diagnosis, at least two complete blood counts (CBC) with differential within 12 months of diagnosis, and either (A) concurrent treatment with a GnRH agonist and an aromatase inhibitor or (B) concurrent treatment with a GnRH agonist and tamoxifen. Exclusion criteria: diagnosis of distant metastases (stage IV disease), diagnosis of menopause or menopause symptoms prior to breast cancer diagnosis, previous breast cancer diagnoses, and any history of treatment with CDK4 / 6 inhibitors. For each patient, three CBCs with differential were identified: a “baseline” CBC collected prior to chemotherapy but no more than 3 months prior todiagnosis, an “early endocrine therapy (ET)” CBC collected 1-6 months after the end of chemotherapy and the initiation of both GnRH agonist and AI / tamoxifen, and a “late ET” CBC collected 6-24 months after the same timepoint referenced above. Six measurements were recorded from each CBC: total WBC count, neutrophil count, lymphocyte count, monocyte count, eosinophil count, and basophil count. 52 of the original 135 patients were excluded from the study due to incomplete information in the chart or notes indicating non- compliance with ET. Study data were securely recorded and managed using Research Electronic Data Capture (REDCap) tools hosted at Duke University (see Harris, P.A., et al., Research electronic data capture (REDCap)--a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform, 2009. 42(2): 377-81 and Harris, P.A., et al., The REDCap consortium: Building an international community of software platform partners. J Biomed Inform, 2019.95: 103208, each of which is incorporated by reference in its entirety). Statistics

[0296] Description of samples (mice, cell number, and biological replicates) are provided in the figure legends. Data was plotted and analyzed using Graph Pad Prism 8.0 software. Statistical significance was calculated by either two-tailed Student’s T test, one-way ANOVA or two-way ANOVA as indicated in the legends. For both one-way and two-way ANOVA, post-test analysis was performed using Tukey’s multiple correction. Evaluation of the separate and combined effects of lasofoxifene and immune checkpoint blockade

[0297] A7C11 tumors were implanted orthotopically by subcutaneous injection of cells into the flank of ovariectomized C57BL6 / J mice receiving placebo (n=60) or estrogen (E2, n=60) treatment. Two days later, treatment groups were further subdivided to receive vehicle, lasofoxifene (Laso, 3 mg / kg sc qd) or fulvestrant (Fulv, 25 mg / kg sc q5d). These groups were then further subdivided to receive IgG control (15 mg / kg ip q3d) or ICB (anti-CTLA4, 5 mg / kg ip q3d; anti-PD1, 10 mg / kg ip q3d) treatment, for a total of 12 treatment groups with n=10 mice in each group (see Table 3 below). These treatments were continued for 14 days, at which point the average tumor volume recorded for group 7 (estradiol / vehicle / IgG) control exceeded 1 cm3. Mice were euthanized on day 17 (for A7C11 tumors and Yumm5.2 tumors) or day 19 (for LLC tumors), and plasma and tumors were retained for analysis.Tumors were dispersed by collagenase and DNase digestion to enable enumeration of immune cell populations by flow cytometry.7.2. Example 1: Selective Estrogen Receptor Modulator (SERM) Lasofoxifene Suppresses Breast Cancer Growth by Modulating the Functionality of Immune Cells

[0298] The impact of ER signaling on tumor growth was evaluated with tumors derived from mouse triple negative breast cancer A7C11 cells propagated in syngeneic hosts that did not produce estrogen. As shown in FIGs.1A and 1B, the presence of estrogen significantly increased A7C11 tumor growth and the final tumor volume. The immune checkpoint blockade (ICB) treatment demonstrated anti-tumor activity only in the presence of estrogen.

[0299] The effect of pharmacological inhibition of ER signaling was determined with lasofoxifene and fulvestrant. Fulvestrant (Fulv) is a clinically approved injectable selective estrogen receptor degrader (SERD) for the treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer. Lasofoxifene (Laso), an oral selective estrogen receptor modulator (SERM) is in late-stage clinical development as a treatment for metastatic breast cancer. As shown in FIGs.2A and2B, neither fulvestrant nor lasofoxifene had effect on A7C11 tumor growth and the final tumor volume in the absence of estrogen.

[0300] In the presence of estrogen, fulvestrant exhibited anti-tumor activity alone and together with ICB (FIGs.3A and 3B). However, ICB did not further inhibit the A7C11 tumor growth significantly when administered in combination with fulvestrant. As shown in FIGs.4A and 4B, in the presence of estrogen, lasofoxifene also inhibited A7C11 tumor growth alone and in combination with ICB. ICB further inhibited the A7C11 tumor growth significantly when administered in combination with lasofoxifene.

[0301] The effect of ER inhibition was further evaluated on immune cell repertoire in tumors derived from mouse triple negative breast cancer A7C11 cells propagated in syngeneic hosts. As shown in FIGs.5A and 5B, M1 / M2 ratio increased with the combination treatment of fulvestrant and ICB or lasofoxifene and ICB, despite not statistically significant. FIGs.6A and 6B show that lasofoxifene, but not fulvestrant, significantly decreased tumor-promoting granulocytic myeloid-derived suppressor cells (G-MDSCs). In the presence of estrogen, the combination treatment of lasofoxifene and ICB dramatically increased CD8+T cells compared to the control group and compared to the group treated with lasofoxifene alone (FIG.7B). In contract, the dramatic increase of CD8+T cells was not observed with the combination of fulvestrant and ICB (FIG.7A). Furthermore, the combination treatment of lasofoxifene and ICB dramatically decreased the percentage of PD1+CD8+T cells within the population of CD8+T cells compared to the control group (FIG.8B), while such effect was not observed with the combination of fulvestrant and ICB (FIG.8A), indicating that the combination of lasofoxifene and ICB is effective in decreasing CD8+T cell exhaustion.

[0302] Taken together, the results demonstrate that in the triple negative breast cancer (TNBC) model, lasofoxifene alone and in combination with ICB is effective in inhibiting tumor growth through the modulation of immune cells in the tumor. Furthermore, the efficacy of lasofoxifene on the TNBC model is superior to the effect of fulvestrant treatment. 7.3. Example 2: Selective Estrogen Receptor Modulator (SERM) Lasofoxifene Suppresses Lung Carcinoma Growth by Modulating the Functionality of Immune Cells

[0303] The impact of ER signaling on tumor growth was evaluated with tumors derived from mouse Lewis lung carcinoma (LLC) cells propagated in syngeneic hosts that did not produce estrogen. As shown in FIGs.9A and 9B, the presence of estrogen significantly increasedLLC tumor growth and the final tumor volume. The immune checkpoint blockade (ICB) treatment did not significantly inhibit the estrogen-stimulated LLC tumor growth.

[0304] The effect of pharmacological inhibition of ER signaling was determined with lasofoxifene and fulvestrant. Neither fulvestrant nor lasofoxifene had effect on LLC tumor growth and the final tumor volume in the absence of estrogen (FIGs.10A and 10B). In contrast, in the presence of estrogen, both fulvestrant and lasofoxifene exhibited anti-tumor activity alone and together with ICB (FIGs.11A and 11B; FIGs.12A and 12B). ICB did not further reduce the LLC tumor significantly when administered in combination with fulvestrant (FIGs.11A and 11B). In contrast, ICB further reduced the A7C11 tumor significantly when administered in combination with lasofoxifene (FIGs.12A and 12B).

[0305] The effect of ER inhibition was further evaluated with eosinophils in tumors derived from LLC cells propagated in syngeneic hosts. As shown in FIGs.13A and 13B, the number of eosinophils in the tumor increased significantly with the combination treatment of fulvestrant and ICB or lasofoxifene and ICB.

[0306] Taken together, the results demonstrate that lasofoxifene alone and in combination with ICB is effective in inhibiting Lewis lung carcinoma (LLC) growth through the modulation of immune cells in the tumor. 7.4. Example 3: Selective Estrogen Receptor Modulator (SERM) Lasofoxifene Suppresses Melanoma Growth by Modulating the Functionality of Immune Cells

[0307] The impact of ER signaling on tumor growth was evaluated with tumors derived from Yumm5.2 mouse melanoma cells propagated in syngeneic hosts that did not produce estrogen. As shown in FIGs.14A and 14B, the presence of estrogen significantly increased Yumm5.2 tumor growth and the final tumor volume. The immune checkpoint blockade (ICB) treatment was not effective in inhibiting the estrogen-stimulated Yumm5.2 tumor growth.

[0308] The effect of pharmacological inhibition of ER signaling was determined with lasofoxifene and fulvestrant. Neither fulvestrant nor lasofoxifene had effect on Yumm5.2 tumor growth and the final tumor volume in the absence of estrogen (FIGs.15A and 15B). However, in the presence of estrogen, both fulvestrant and lasofoxifene exhibited significant anti-tumor activity alone and together with ICB (FIGs.16A and 16B; FIGs.17A and 17B).ICB did not further reduce the Yumm5.2 tumor volume significantly when the administered in combination with fulvestrant or lasofoxifene.

[0309] Taken together, the results demonstrate that lasofoxifene alone and in combination with ICB is effective in inhibiting Yumm5.2 melanoma growth. 7.5. Example 4: Estrogens decrease the number of eosinophils in tumors and in the blood and increase tumor growth

[0310] The impact of ER signaling was evaluated on immune cell repertoire and activity in tumors derived from A7C11 and E0771 breast cancer cells propagated in syngeneic hosts. The proliferation of these breast cancer cells was not directly influenced by estrogens in vitro (FIGs.18A and 18B), allowing the assessment of extrinsic effects of estrogens, selective estrogen receptor modulators (SERMs) and selective estrogen receptor degraders (SERDs) on tumor pathology and tumor immunobiology.

[0311] Cancer cells were injected into the mammary fat pad of ovariectomized C57BL / 6 mice (to accomplish estrogen deprivation) or ovariectomized mice supplemented with 17β- estradiol (E2, estrogen replete). E2 promoted tumor growth in both the A7C11 and E0771 models when compared to placebo (FIGs.19A and 20A). The growth of these tumors was unaffected by E2 when propagated in the mammary fat pads of immune compromised NOD scid gamma (NSG) mice (FIGs.19B and 20B). Notably, the stimulatory effect of estrogens on uterine wet weights, a measure of water imbibition and hypertrophy in response to E2, were similar in both C57BL / 6 and NSG mice (FIGs.21A and 21B). These data suggest that an intact immune system is required for the tumor promoting effects of E2 in these models.

[0312] Immune profiling of tumors was performed and a decrease in the frequencies of tumor associated eosinophils (CD45+SSChighSiglecF+CD11b+Ly6G-MHCIIlow) (FIGs.22A and 22B; FIGs.23A and 23B; FIG.24) was observed. An E2-dependent increase in the M2 / M1 macrophage ratio was also observed (FIGs.25A and 25B). E2 also decreased the number of intratumoral eosinophils in melanoma models B16F10 and BPD6 (FIGs.26A and 26B). E2 also decreased eosinophil number in a syngeneic model of colorectal cancer (CRC) (FIG. 27). The decreased tumor eosinophil number reflected a similar decrease in blood eosinophil number in tumor bearing mice receiving E2 treatment (FIGs.28A and 28B).

[0313] Taken together, E2 decreases TATE in well validated models of breast cancer and in models of other solid cancers and this activity correlates with increased tumor growth.7.6. Example 5: Pharmacological inhibition of ER signaling with lasofoxifene increases TATE to suppress tumor growth

[0314] The effects of systemically inhibiting estrogen signaling was evaluated using two different classes of clinically relevant ER modulators: fulvestrant (fulv), a clinically approved injectable SERD and lasofoxifene (laso), an oral SERM that is in late-stage clinical development as a treatment for metastatic breast cancer. In the A7C11 model, lasofoxifene inhibited E2 induced tumor growth. Fulvestrant also decreased tumor growth but in general its effects were less robust and not sustained (FIG.29), despite adequate drug exposure demonstrated by the results that fulv (and laso) inhibited E2 stimulated increases in uterine wet weight (FIGs.30A and 30B). Considering its superior efficacy and excellent pharmaceutical properties, a more comprehensive evaluation of laso as a regulator of TATE / tumor growth was conducted.

[0315] The efficacy of laso given alone or in combination with E2 was evaluated in two triple negative breast cancer models (A7C11 and E0771). In both models, laso reduced tumor growth below that observed in placebo treated mice and reversed E2 induced tumor growth (FIGs.31A and 31B). Lasofoxifene also reversed the inhibitory effects of E2 on eosinophil numbers in the A7C11 model and with a trend in this direction noted in studies performed in the E0771 model (FIGs.32A and 32B). The E2 dependent suppression of tumor eosinophil activity, as measured by tumor eosinophil peroxidase (EPX) levels, was rescued by laso treatment (FIG.33). The extent to which the protective effect of laso on tumor growth was dependent on tumor associated eosinophils was evaluated by the efficacy of laso in tumor models in which eosinophils had been depleted using an anti-siglecF antibody (FIG.34A). Quantification of blood and tumor eosinophils confirmed that anti- SiglecF antibody treatment efficiently depleted eosinophils in mice (FIGs.34B and 34C). Importantly, the depletion of eosinophils completely abrogated the antitumor activity of laso (FIGs.35A, 35B, and 35C).

[0316] Taken together, lasofoxifene inhibits E2 induced tumor growth by increasing the number and activity of eosinophils in the tumor. 7.7. Example 6: Lasofoxifene enhances the antitumor efficacy of immune checkpoint inhibitors

[0317] The extent to which manipulating eosinophil function using lasofoxifene could influence ICB efficacy was determined in E2 treated A7C11 cell derived tumors whichexpress PD-L1 (FIG.36B). In this model ICB treatment (anti-PD1-10mg / kg & anti-CTLA4- 5mg / kg) alone demonstrated modest antitumor activity (FIGs.37A-37E and FIG.38A). E2 decreased TATE in this model which was reversed upon treatment with laso and was unaffected by treatment with ICB alone (FIG.38B). E2 also decreased the number of CD8+T cells and this was reversed by treatment with either laso or ICB (FIG.38C). Importantly, the number of CD8+T cells was substantially increased by co-treatment with ICB and laso.

[0318] The antitumor activity of lasofoxifene (laso) was compared with the SERD fulvestrant (fulv) in the E2 treated A7C11 model. Both laso and fulv increased ICB efficacy in inhibiting tumor growth, with lasofoxifene increasing the ICB efficacy to a greater extent (FIGs.39A and 39B). The ability of both fulv and laso to decrease uterine wet weights was used to confirm adequate drug exposure in these animals (FIG.40). Laso and fulv were both effective in reversing E2-dependent decreases in intratumoral eosinophilia and CD8+T cells (FIGs.41A and 41B). However, lasofoxifene in combination with ICB showed greater increase of CD8+T cells compared to the combination of fulvestrant and ICB. Laso and fulv were both effective in increasing the ratio of M1 / M2 tumor associated macrophages (FIG. 41C). However, lasofoxifene in combination with ICB showed greater increase of M1 / M2 ratio compared to the combination of fulvestrant and ICB.

[0319] Taken together, lasofoxifene enhances the efficacy of ICB treatment in E2 treated A7C11 cell derived tumor model through increasing intratumoral eosinophilia, CD8+T cells, and the ratio of M1 / M2 tumor associated macrophages. 7.8. Example 7: Endocrine therapies increase the number of peripheral eosinophils in patients with breast cancer

[0320] A retrospective analysis of patient data to explore how ovarian suppression and endocrine therapies (GnRH agonists, and aromatase inhibitors and / or tamoxifen) impact peripheral immune cell repertoire in premenopausal women with ER-positive breast cancer was performed (FIG.42). These studies were focused on premenopausal women as they experience a very acute and sustained inhibition of ER signaling upon commencement of endocrine therapy (ET). A relevant cohort of patients with breast cancer was identified and compared each patient’s pre-ET (“baseline”) blood cell counts to blood cell counts collected 1-6 months after ET initiation (“early ET” or “T1”) and to blood cell counts collected 6-24 months after ET initiation (“late ET” or “T2”). Importantly, of the cell types examined, the most robust (and sustained) increase occurred in blood eosinophils both at the early timepoint / early ET (FIGs.43A-43E) and at the late point / late ET (FIGs.44A-44E). A very small increase in the number of basophils was also observed in patients after treatment with ET.

[0321] To control for the effects of chemotherapy and surgery on eosinophil counts, two sub- analyses within the patient cohort were performed. First, each patient’s post-chemotherapy CBC (collected at least 1 month after the completion of chemotherapy but prior to start of ET) was compared to their post-ET CBC collected 6-24 months after the initiation of ET. Despite the greatly reduced sample size (N value), a statistically significant increase in eosinophil counts was observed post-ET compared to post-chemotherapy, suggesting that ET, not chemotherapy, led to the increase in the number of eosinophils noted (FIG.44F). Second, 25 patients who underwent surgery before other treatments were identified and their pre-surgery CBC was compared to a post-surgery CBC collected at least one month after surgery but prior to any additional treatments. This sub-analysis showed no independent effect of surgery on eosinophil count, suggesting that surgery is not an important confounding variable (FIG.44G). 7.9. Example 8: Eosinophils have antitumorigenic properties in murine models of breast cancer

[0322] To assess whether tumor eosinophil number is also prognostic of outcome independent of treatment with immunotherapies, the expression of an eosinophil signature in the Molecular Taxonomy of Breast Cancer (Metabric) dataset was assessed. Higher activity of an intratumoral eosinophil gene signature was associated with a survival advantage in patients with TNBC (FIG.45A). Similar advantages in survival were also observed in patients whose tumors expressed EPX, Siglec-8, or CCR3, proteins whose expression is restricted to eosinophils (FIGs.45B-45D). The potential cause-and-effect relationships between estrogen deprivation, increased TATE, and decreased growth of tumors were assessed in syngeneic cancer models.

[0323] An eosinophil depletion study using an anti-SiglecF antibody was performed (FIG. 46A) and a quantitative depletion of eosinophils was observed in both the blood and within tumors in mice (FIGs.46B and 46C). Depletion of eosinophils abrogated the protective effects of estrogen deprivation (ovariectomized mice) noted in the murine A7C11 tumor model (FIGs.47A and 47B). The specific involvement of eosinophils was confirmed using the ΔdblGATA1 mouse model which lack eosinophils (FIGs.48A-48C). While estrogendeprivation reduced tumor growth compared to estrogen-treated mice in the littermate control ΔdblGATA1- / +and WT mice, the protective effects of estrogen deprivation was lost in the ΔdblGATA1- / -mice (FIGs.49A and 49B). When taken together these data highlight how estrogens, through their actions in eosinophils, impact primary tumor growth in established models of breast cancer. 7.10. Example 9: Inhibiting ERα signaling in eosinophils promotes their antitumorigenic activity

[0324] To define the role of eosinophil intrinsic estrogen signaling in regulating eosinophil functionality in tumors, mice that lack ERα expression in eosinophils were generated. Specifically, EpxCre mice were crossed with Esr1flox / floxmice to generate EpxCre+Esr1f / f(EosERKO) mice and EpxCre+Esr1w / w(EosERWT) control mice (FIG.50A). Mature eosinophils derived from the bone marrow of EosERKO mice significantly reduced ERα expression compared to those from the control mice (FIG.50B). The specific role(s) of ERα signaling on the biology of mature eosinophils were determined using the mouse model. In this model, the growth of the syngeneic A7C11 cell derived breast tumors were significantly impaired in EosERKO mice when compared to EosERWT control mice, in placebo treated, estrogen deprived mice (FIGs.51A and 51B). Similar observations were made in another model of solid tumor, where the growth of BPD6-cell derived melanoma tumors was also compromised in EosERKO mice compared to EosERWT control mice (FIGs.52A and 52B). The impact of estrogens on tumor growth in the EosERKO mice were also attenuated when compared to control mice. However, depletion of ERα in mature eosinophils did not reverse the negative effects of estrogens on tumor eosinophilia (FIGs.53A and 53B). Despite the decrease in tumor eosinophilia observed with E2 in EosERKO mice, the expression of tumor eosinophil peroxidase, a marker of eosinophil activity, was not suppressed by E2 treatment in EosERKO mice (FIG.53C). These results suggest that estrogens, acting through ERα, suppress the antitumorigenic properties of mature eosinophils.

[0325] An increase in the number of effector CD8+T cells (CD69+CD8+and IFNγ+CD8+cells) in placebo treated EosERKO mice was observed. This change was accompanied by a decrease in protumorigenic M2 macrophages in E2 treated EosERKO mice (FIGs.54A- 54C).7.11. Example 10: E2 regulates both biogenesis and the activity of eosinophils

[0326] Both blood and bone marrow eosinophil numbers were decreased in tumor bearing and healthy mice upon E2 treatment suggesting that this hormone regulates fundamental aspects of the biology of these immune cells (FIGs.55A and 55B). Eosinophils are produced and mature within the bone marrow. E2 decreased bone marrow eosinophil numbers in both healthy and tumor-bearing mice (FIGs.55B and 55C). The impact of E2 on the biogenesis and differentiation of bone marrow-derived eosinophils (BMEos) in vitro was determined.

[0327] The standard BMEos differentiation protocol was modified to enable a specific assessment of the role of E2 (FIG.56A). Aliquots of cells were taken on days 8, 11 and 14 during the differentiation assay to assess cell viability and the expression of markers that read on differentiation. The results of this analysis demonstrated that E2 decreased the total number of live progenitors and fully matured eosinophils throughout the time course of the differentiation protocol (FIG.56B). Among the live cells, the number of mature eosinophils (cells expressing siglecF) was similar between vehicle treated cultures and those that were treated with E2 (FIG.57A). However, the viability of BMEos (FIG.57B), as well as proliferation of live BMEos as measured by Ki67 staining (FIG.57C), was suppressed by E2 treatment. The results suggested that E2 treatment reduced both the viability and proliferative potentials of mature eosinophils likely explaining the reduction in the numbers of eosinophils in circulation and within tumors in E2 treated mice.

[0328] The effects of E2 on eosinophil cytotoxicity was assessed. An equal number of live BMEos, differentiated in the presence or absence of E2, were cocultured with A7C11 cancer cells at 1:15 ratio for 5 hours. The number of live, pre-apoptotic, apoptotic, and necrotic cancer cells in the co-culture were quantified using Annexin V and Sytox staining. The cytotoxic capability of E2 treated BMEos was reduced compared to vehicle treated cells resulting in a significantly reduced number of necrotic cancer cells (FIGs.58A-58C).

[0329] To elucidate the mechanisms by which estrogens affect eosinophil biology, RNAseq analysis of BMEos differentiated was performed in the presence of E2 or vehicle control. The approach to study ER-target gene expression in BMEos was validated by confirming the expression of Pgr and Tgm2, two canonical ER / E2 target genes (FIG.59). Pathway analysis indicated that E2 treatment downregulated the expression of genes that are associated with proliferation (Myc) cell cycle (G2M checkpoint) and with eosinophil cytotoxicity (eosinophil peroxidase (Epx), eosinophil-associated ribonucleases (Ear1), and eosinophil major basicprotein (Prg2)) (FIGs.60A-60B, FIGs.61A-61C, and FIG.62). The expression of these genes was confirmed in a separate experiment using qPCR (FIG.63). Paradoxically, E2 treatment was also found to regulate pathways associated with increased innate immune cell activation and inflammatory responses (FIG.62). This was unexpected given that BMEos differentiated in the presence of E2 have reduced cytotoxic capabilities. Thus, it appears that the effects of estrogens on different aspects of ER regulated biology are not the same; an observation that highlights a potential clinical utility of SERMs or SERDs that can differentially regulate these biologies.

[0330] In addition to reduced eosinophil biogenesis, adoptive transfer of equal numbers of CD45.1 bone marrow derived eosinophils into CD45.2 tumor bearing mice indicated that E2 treatment is associated with decreased eosinophil recruitment to tumors (FIG.64, FIGs. 65A-65C). Recruitment of adoptively transferred eosinophils to other organs such as spleen was not affected, indicating that E2 affects TATE specifically (FIG.65D). The decreased TATE observed may relate to changes in the expression of CCL11, CCL24 and CCL5 in the tumors; cytokines that have been shown to be important for eosinophil recruitment (FIG.66, FIGs.67A-67B). Therefore, E2 decreases eosinophil production in the bone marrow and inhibit their activity in tumors.

[0331] To assess the potential clinical significance of estrogen signaling in eosinophils, two gene signatures from the E2 (a) up- and (b) down-regulated genes were generated from RNAseq analysis. The top 30 up- or down-regulated differentially expressed genes (DEG’s) based on fold change with a significant adjusted p-value (<0.01) were used to generate mouse E2 up- and down-regulated gene signatures. The human corollary of the mouse signature was used for subsequent studies. The signature derived from the E2 downregulated genes appears to have prognostic value. Specifically, higher activity (increase expression of the E2 downregulated genes) of this signature predicts better survival in patients with breast cancer when analyzed as a group and more specifically in patients with ER+breast tumors. A trend in the same direction was noted in patients with TNBC, a likely reflection of the low numbers of samples available for analysis (FIGs.68A-68C), suggesting that downregulation / inhibition of ER signaling in eosinophils may be beneficial. Together, these results suggest that estrogens directly suppress eosinophil proliferation, survival, and cytotoxicity by affecting the expression of genes associated with these functions and that inhibition of ER signaling in eosinophils increase the antitumorigenic effects of eosinophils.8. EQUIVALENTS AND INCORPORATION BY REFERENCE

[0332] While the disclosure 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 disclosure.

[0333] 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. FURTHER EMBODIMENTS: Clause 1. A method of increasing the efficacy of immunotherapy in a patient having a solid cancer, the method comprising: further administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 2. The method of clause 1, wherein the solid cancer is an estrogen receptor negative (ER–) or estrogen receptor-low (ERlow) solid cancer. Clause 3. The method of clause 1 or 2, wherein the solid cancer is estrogen receptor negative (ER–) breast cancer. Clause 4. The method of clause 3, wherein the solid cancer is triple-negative breast cancer (TNBC). Clause 5. The method of clause 1 or 2, wherein the solid cancer is ER–or ERlowovarian cancer. Clause 6. The method of clause 1 or 2, wherein the solid cancer is ER–or ERlowendometrial cancer. Clause 7. The method of clause 1 or 2, wherein the solid cancer is a solid cancer other than breast, ovarian, or endometrial cancer. Clause 8. The method of clause 7, wherein the solid cancer is head and neck cancer, lung cancer, melanoma, colon cancer, bladder cancer, esophageal cancer, gastric cancer, laryngeal cancer, oral cancer, brain cancer, bone cancer, pancreatic cancer, kidney cancer, glioblastoma, sarcoma, prostate cancer, or liver cancer, or a combination thereof.Clause 9. The method of clause 8, wherein the solid cancer is head and neck cancer. Clause 10. The method of clause 8, wherein the solid cancer is lung cancer. Clause 11. The method of clause 8, wherein the solid cancer is melanoma. Clause 12. The method of any one of clauses 1 to 11, wherein the immunotherapy is an immune checkpoint inhibitor. Clause 13. The method of clause 12, wherein the checkpoint inhibitor is an inhibitor of PD- 1, PD-L1, CTLA-4, LAG-3, ICOS, BTLA, TIM-3, TIGIT, or NKG2A, or a combination thereof. Clause 14. The method of clause 13, wherein the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of: pembrolizumab, nivolumab, and cemiplimab. Clause 15. The method of clause 14, wherein the anti-PD-1 antibody is pembrolizumab. Clause 16. The method of clause 14, wherein the anti-PD-1 antibody is nivolumab. Clause 17. The method of clause 14, wherein the anti-PD-1 antibody is cemiplimab. Clause 18. The method of clause 13, wherein the PD-L1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of: atezolizumab, avelumab, and durvalumab. Clause 19. The method of clause 13, wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody selected from the group consisting of: ipilimumab and tremelimumab. Clause 10. The method of clause 13, wherein the LAG-3 inhibitor is an anti-LAG-3 antibody. Clause 21. The method of clause 20, wherein the anti-LAG-3 antibody is relatlimab. Clause 22. The method of any one of clauses 1 to 21, wherein lasofoxifene is administered as lasofoxifene tartrate. Clause 23. The method of any one of clauses 1 to 22, wherein lasofoxifene is administered by oral administration.Clause 24. The method of clause 23, wherein lasofoxifene is administered orally at about 0.5 mg / lasofoxifene to about 10 mg / lasofoxifene per day. Clause 25. The method of clause 24, wherein lasofoxifene is administered orally at 5 mg / lasofoxifene per day. Clause 26. The method of clause 24, wherein lasofoxifene is administered orally at 10 mg / lasofoxifene per day. Clause 27. The method of any one of clauses 23 to 26, wherein lasofoxifene is administered once every day. Clause 28. The method of any one of clauses 1 to 27, wherein lasofoxifene and the immunotherapy are administered concurrently. Clause 29. The method of any one of clauses 1 to 27, wherein lasofoxifene and the immunotherapy are administered separately. Clause 30. The method of clause 29, wherein lasofoxifene is administered before the start of the immunotherapy. Clause 31. The method of any one of clauses 1 to 30, further comprising administering to the patient an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. Clause 32. The method of clause 31, wherein the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib. Clause 33. The method of any one of clauses 1 to 30, further comprising administering to the patient an effective amount of a mammalian target of rapamycin (mTOR) inhibitor. Clause 34. The method of clause 33, wherein the mTOR inhibitor is everolimus. Clause 35. The method of any one of clauses 1 to 30, further comprising administering to the patient an effective amount of a human epidermal growth factor receptor 2 (HER2) inhibitor. Clause 36. The method of clause 35, wherein the HER2 inhibitor is an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate (ADC). Clause 37. The method of clause 36, wherein the anti-HER2 antibody is trastuzumab.Clause 38. The method of clause 36, wherein the anti-HER2 ADC is trastuzumab emtansine or trastuzumab deruxtecan. Clause 39. The method of any one of clauses 1 to 30, further comprising administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor. Clause 40. The method of clause 39, wherein the HDAC inhibitor is vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, pracinostat, resminostat, givinostat, quisinostat, kevetrin, CUDC-101, AR-42, tefinostat, CHR-3996, 4SC202, CG200745, rocilinostat, or sulforaphane. Clause 41. The method of any one of clauses 1 to 40, wherein the administration of lasofoxifene increases the number of immune cells in the solid cancer, as compared to the number of immune cells in the solid cancer prior to the lasofoxifene treatment. Clause 42. The method of any one of clauses 1 to 41, wherein the administration of lasofoxifene increases tumor associated tissue eosinophilia (TATE) in the patient, as compared to the tumor associated tissue eosinophilia (TATE) prior to the lasofoxifene treatment. Clause 43. The method of any one of clauses 1 to 42, wherein the administration of lasofoxifene increases the number of CD8+T cells in the solid cancer, as compared to the number of CD8+T cells in the solid cancer prior to the lasofoxifene treatment. Clause 44. The method of clause 43, wherein the administration of lasofoxifene increases the number of effector CD8+T cells in the solid cancer, as compared to the number of effector CD8+T cells in the solid cancer prior to the lasofoxifene treatment. Clause 45. The method of any one of clauses 1 to 44, wherein the administration of lasofoxifene decreases the number of exhausted CD8+T cells in the solid cancer, as compared to the number of exhausted CD8+T cells in the solid cancer prior to the lasofoxifene treatment. Clause 46. The method of any one of clauses 1 to 45, wherein the administration of lasofoxifene increases the ratio of M1 / M2 macrophages in the solid cancer, as compared to the ratio of M1 / M2 macrophages in the solid cancer prior to the lasofoxifene treatment.Clause 47. The method of any one of clauses 1 to 46, wherein the administration of lasofoxifene decreases the number of M2 tumor-associated macrophages (M2-TAMs) in the solid cancer, as compared to the number of M2-TAMs prior to the lasofoxifene treatment. Clause 48. A method of treating an estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer in a patient, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 49. A method of treating a solid cancer other than estrogen receptor positive (ER+) breast cancer, ER+ovarian cancer, or ER+endometrial cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 50. A method of treating a solid cancer having a low M1 / M2 tumor-associated macrophage (TAM) ratio and / or a high number of M2 tumor-associated macrophages (M2- TAMs) and / or a low number of M1 tumor-associated macrophages (M1-TAMs), the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 51. A method of treating a solid cancer having a low number of CD8+tumor infiltrating lymphocytes (TILs), the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 52. A method of treating a solid cancer having a low number of eosinophils, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 53. The method of any one of clause 48 to 52, wherein the solid cancer is historically more responsive to an immunotherapy in men than in premenopausal women. Clause 54. The method of clause 53, wherein the immunotherapy is an immune checkpoint inhibitor. Clause 55. The method of any one of clauses 48 to 54, wherein the solid cancer is estrogen receptor negative (ER–) breast cancer.Clause 56. The method of clause 55, wherein the solid cancer is triple-negative breast cancer (TNBC). Clause 57. The method of any one of clauses 48 to 54, wherein the solid cancer is ER–or ERlowovarian cancer. Clause 58. The method of any one of clauses 48 to 54, wherein the solid cancer is ER–or ERlowendometrial cancer. Clause 59. The method of any one of clauses 48 to 54, wherein the solid cancer is a solid cancer other than breast, ovarian, or endometrial cancer. Clause 60. The method of clause 59, wherein the solid cancer is head and neck cancer, lung cancer, melanoma, colon cancer, bladder cancer, esophageal cancer, gastric cancer, laryngeal cancer, oral cancer, brain cancer, bone cancer, pancreatic cancer, kidney cancer, glioblastoma, sarcoma, prostate cancer, or liver cancer, or a combination thereof. Clause 61. The method of clause 60, wherein the solid cancer is head and neck cancer. Clause 62. The method of clause 60, wherein the solid cancer is lung cancer. Clause 63. The method of clause 60, wherein the solid cancer is melanoma. Clause 64. The method of any one of clauses 48 to 63, further comprising administering to the patient an immunotherapy. Clause 65. The method of clause 64, wherein the immunotherapy is an immune checkpoint inhibitor. Clause 66. The method of clause 65, wherein the checkpoint inhibitor is an inhibitor of PD- 1, PD-L1, CTLA-4, LAG-3, ICOS, BTLA, TIM-3, TIGIT, or NKG2A, or a combination thereof. Clause 67. The method of clause 66, wherein the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of: pembrolizumab, nivolumab, and cemiplimab. Clause 68. The method of clause 67, wherein the anti-PD-1 antibody is pembrolizumab. Clause 69. The method of clause 67, wherein the anti-PD-1 antibody is nivolumab.Clause 70. The method of clause 67, wherein the anti-PD-1 antibody is cemiplimab. Clause 71. The method of clause 66, wherein the PD-L1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of: atezolizumab, avelumab, and durvalumab. Clause 72. The method of clause 66, wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody selected from the group consisting of: ipilimumab and tremelimumab. Clause 73. The method of clause 66, wherein the LAG-3 inhibitor is an anti-LAG-3 antibody. Clause 74. The method of clause 73, wherein the anti-LAG-3 antibody is relatlimab. Clause 75. The method of any one of clauses 48 to 74, wherein lasofoxifene is administered as lasofoxifene tartrate. Clause 76. The method of any one of clauses 48 to 75, wherein lasofoxifene is administered by oral administration. Clause 77. The method of clause 76, wherein lasofoxifene is administered orally at about 0.5 mg / lasofoxifene to about 10 mg / lasofoxifene per day. Clause 78. The method of clause 77, wherein lasofoxifene is administered orally at 5 mg / lasofoxifene per day. Clause 79. The method of clause 77, wherein lasofoxifene is administered orally at 10 mg / lasofoxifene per day. Clause 80. The method of any one of clauses 76 to 79, wherein lasofoxifene is administered once every day. Clause 81. The method of any one of clauses 64 to 74, and clauses 75 to 80 as depend from clauses 64 to 74, wherein lasofoxifene and the immunotherapy are administered concurrently. Clause 82. The method of any one of clauses 64 to 74, and clauses 75 to 80 as depend from clauses 64 to 74, wherein lasofoxifene and the immunotherapy are administered separately. Clause 83. The method of clause 82, wherein lasofoxifene is administered before the start of the immunotherapy.Clause 84. The method of any one of clauses 48 to 83, further comprising administering to the patient an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. Clause 85. The method of clause 84, wherein the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib. Clause 86. The method of any one of clauses 48 to 83, further comprising administering to the patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor. Clause 87. The method of clause 86, wherein the mTOR inhibitor is everolimus. Clause 88. The method of any one of clauses 48 to 83, further comprising administering to the patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor. Clause 89. The method of clause 88, wherein the HER2 inhibitor is an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate (ADC). Clause 90. The method of clause 89, wherein the anti-HER2 antibody is trastuzumab. Clause 91. The method of clause 89, wherein the anti-HER2 ADC is trastuzumab emtansine or trastuzumab deruxtecan. Clause 92. The method of any one of clauses 48 to 83, further comprising administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor. Clause 93. The method of clause 92, wherein the HDAC inhibitor is vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, pracinostat, resminostat, givinostat, quisinostat, kevetrin, CUDC-101, AR-42, tefinostat, CHR-3996, 4SC202, CG200745, rocilinostat, or sulforaphane. Clause 94. The method of any one of clauses 48 to 93, wherein the administration of lasofoxifene increases the number of immune cells in the solid cancer, as compared to the number of immune cells in the solid cancer prior to the lasofoxifene treatment. Clause 95. The method of any one of clauses 48 to 94, wherein the administration of lasofoxifene increases tumor associated tissue eosinophilia (TATE) in the patient, ascompared to the tumor associated tissue eosinophilia (TATE) prior to the lasofoxifene treatment. Clause 96. The method of any one of clauses 48 to 95, wherein the administration of lasofoxifene increases the number of CD8+T cells in the solid cancer, as compared to the number of CD8+T cells in the solid cancer prior to the lasofoxifene treatment. Clause 97. The method of clause 96, wherein the administration of lasofoxifene increases the number of effector CD8+T cells in the solid cancer, as compared to the number of effector CD8+T cells in the solid cancer prior to the lasofoxifene treatment. Clause 98. The method of any one of clauses 48 to 97, wherein the administration of lasofoxifene decreases the number of exhausted CD8+T cells in the solid cancer, as compared to the number of exhausted CD8+T cells in the solid cancer prior to the lasofoxifene treatment. Clause 99. The method of any one of clauses 48 to 98, wherein the administration of lasofoxifene increases the ratio of M1 / M2 macrophages in the solid cancer, as compared to the ratio of M1 / M2 macrophages in the solid cancer prior to the lasofoxifene treatment. Clause 100. The method of any one of clauses 48 to 99, wherein the administration of lasofoxifene decreases the number of M2 tumor-associated macrophages (M2-TAMs) in the solid cancer, as compared to the number of M2-TAMs prior to the lasofoxifene treatment. Clause 101. The method of any one of clauses 48 to 100, wherein the administration of lasofoxifene increases the biogenesis or survival of eosinophils in the patient, as compared to the biogenesis or survival of eosinophils prior to the lasofoxifene treatment. Clause 102. The method of any one of clauses 48 to 101, wherein the administration of lasofoxifene increases the activity of eosinophils in the patient, as compared to the activity of eosinophils prior to the lasofoxifene treatment. Clause 103. The method of any one of clauses 48 to 102, wherein the administration of lasofoxifene decreases the rate of progression of tumor growth, as compared to the rate of progression of tumor growth prior to the lasofoxifene treatment.Clause 104. The method of any one of clauses 48 to 103, wherein the administration of lasofoxifene decreases the rate of cancer metastasis, as compared to the rate of cancer metastasis prior to the lasofoxifene treatment. Clause 105. A method of increasing the biogenesis, survival, and / or activity of eosinophils in a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 106. A method of increasing tumor associated tissue eosinophilia (TATE) in a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 107. A method of increasing the number of CD8+T cells in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 108. A method of increasing the ratio of M1 / M2 macrophages in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 109. A method of decreasing the number of exhausted CD8+T cells in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 110. The method of clause 109, wherein the patient has a mutation in BRCA1 or BRCA2 gene. Clause 111. The method of clause 109 or 110, further comprising administering to the patient an immunotherapy. Clause 112. The method of any one of clauses 1 to 111, wherein the patient is a premenopausal female patient.Clause 113. The method of any one of clauses 1 to 111, wherein the patient is a postmenopausal female patient. Clause 114. The method of any one of clauses 1 to 111, wherein the patient is a male patient. FURTHER EMBODIMENTS: Clause 1. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of treating a solid cancer in a patient that is receiving immunotherapy, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 2. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 1, wherein the solid cancer is an estrogen receptor negative (ER–) or estrogen receptor-low (ERlow) solid cancer. Clause 3. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 1 or 2, wherein the solid cancer is estrogen receptor negative (ER–) breast cancer. Clause 4. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 3, wherein the solid cancer is triple-negative breast cancer (TNBC). Clause 5. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 1 or 2, wherein the solid cancer is ER–or ERlowovarian cancer. Clause 6. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 1 or 2, wherein the solid cancer is ER–or ERlowendometrial cancer. Clause 7. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 or 2, wherein the solid cancer is a solid cancer other than breast, ovarian, or endometrial cancer. Clause 8. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 7, wherein the solid cancer is head and neck cancer, lung cancer, melanoma, colon cancer, bladder cancer, esophageal cancer, gastric cancer, laryngeal cancer,oral cancer, brain cancer, bone cancer, pancreatic cancer, kidney cancer, glioblastoma, sarcoma, prostate cancer, or liver cancer, or a combination thereof. Clause 9. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 8, wherein the solid cancer is head and neck cancer. Clause 10. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 8, wherein the solid cancer is lung cancer. Clause 11. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 8, wherein the solid cancer is melanoma. Clause 12. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 to 11, wherein the immunotherapy is an immune checkpoint inhibitor. Clause 13. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 12, wherein the checkpoint inhibitor is an inhibitor of PD-1, PD- L1, CTLA-4, LAG-3, ICOS, BTLA, TIM-3, TIGIT, or NKG2A, or a combination thereof. Clause 14. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 13, wherein the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of: pembrolizumab, nivolumab, and cemiplimab. Clause 15. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 14, wherein the anti-PD-1 antibody is pembrolizumab. Clause 16. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 14, wherein the anti-PD-1 antibody is nivolumab. Clause 17. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 14, wherein the anti-PD-1 antibody is cemiplimab. Clause 18. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 13, wherein the PD-L1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of: atezolizumab, avelumab, and durvalumab.Clause 19. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 13, wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody selected from the group consisting of: ipilimumab and tremelimumab. Clause 20. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 13, wherein the LAG-3 inhibitor is an anti-LAG-3 antibody. Clause 21. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 20, wherein the anti-LAG-3 antibody is relatlimab. Clause 22. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 to 21, wherein lasofoxifene is administered as lasofoxifene tartrate. Clause 23. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 to 22, wherein lasofoxifene is administered by oral administration. Clause 24. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 23, wherein lasofoxifene is administered orally at about 0.5 mg / lasofoxifene to about 10 mg / lasofoxifene per day. Clause 25. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 24, wherein lasofoxifene is administered orally at 5 mg / lasofoxifene per day. Clause 26. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 24, wherein lasofoxifene is administered orally at 10 mg / lasofoxifene per day. Clause 27. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 23 to 26, wherein lasofoxifene is administered once every day. Clause 28. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 to 27, wherein lasofoxifene and the immunotherapy are administered concurrently.Clause 29. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 to 27, wherein lasofoxifene and the immunotherapy are administered separately. Clause 30. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 29, wherein lasofoxifene is administered before the start of the immunotherapy. Clause 31. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 to 30, further comprising administering to the patient an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. Clause 32. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 31, wherein the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib. Clause 33. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 to 30, further comprising administering to the patient an effective amount of a mammalian target of rapamycin (mTOR) inhibitor. Clause 34. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 33, wherein the mTOR inhibitor is everolimus. Clause 35. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 to 30, further comprising administering to the patient an effective amount of a human epidermal growth factor receptor 2 (HER2) inhibitor. Clause 36. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 35, wherein the HER2 inhibitor is an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate (ADC). Clause 37. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 36, wherein the anti-HER2 antibody is trastuzumab. Clause 38. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 36, wherein the anti-HER2 ADC is trastuzumab emtansine or trastuzumab deruxtecan.Clause 39. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 to 30, further comprising administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor. Clause 40. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 39, wherein the HDAC inhibitor is vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, pracinostat, resminostat, givinostat, quisinostat, kevetrin, CUDC-101, AR-42, tefinostat, CHR-3996, 4SC202, CG200745, rocilinostat, or sulforaphane. Clause 41. A combination of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, and immunotherapy for use in a method of treating a solid cancer in a patient. Clause 42. A combination of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, and immunotherapy for use of clause 41, wherein lasofoxifene and the immunotherapy are administered separately. Clause 43. A combination of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, and immunotherapy for use of clause 42, wherein lasofoxifene is administered before the start of the immunotherapy. Clause 44. A combination of immunotherapy and lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of treating a solid cancer in a patient. Clause 45. A combination of immunotherapy and lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use of clause 44, wherein the immunotherapy and lasofoxifene are administered separately. Clause 46. A combination of immunotherapy and lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use of clause 45, wherein the immunotherapy is administered after the start of lasofoxifene. Clause 47. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of increasing the efficacy of immunotherapy in a patient having asolid cancer, the method comprising: further administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 48. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of treating an estrogen receptor negative (ER–) or estrogen receptor-low (ERlow) solid cancer in a patient, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 49. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of treating a solid cancer other than estrogen receptor positive (ER+) breast cancer, ER+ovarian cancer, or ER+endometrial cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 50. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of treating a solid cancer having a low M1 / M2 tumor-associated macrophage (TAM) ratio and / or a high number of M2 tumor-associated macrophages (M2- TAMs) and / or a low number of M1 tumor-associated macrophages (M1-TAMs), the method comprising: administering to the patient an effective amount of the lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 51. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of treating a solid cancer having a low number of CD8+tumor infiltrating lymphocytes (TILs), the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 52. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use in a method of treating a solid cancer having a low number of eosinophils, the method comprising: administering to the patient an effective amount of the lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 53. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use of any one of clauses 48 to 52, wherein the solid cancer is historically more responsive to an immunotherapy in men than in premenopausal women.Clause 54. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 53, wherein the immunotherapy is an immune checkpoint inhibitor. Clause 55. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 48 to 54, wherein the solid cancer is estrogen receptor negative (ER–) breast cancer. Clause 56. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 55, wherein the solid cancer is triple-negative breast cancer (TNBC). Clause 57. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 48 to 54, wherein the solid cancer is ER–or ERlowovarian cancer. Clause 58. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof for the use of any one of clauses 48 to 54, wherein the solid cancer is ER–or ERlowendometrial cancer. Clause 59. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 48 to 54, wherein the solid cancer is a solid cancer other than breast, ovarian, or endometrial cancer. Clause 60. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 59, wherein the solid cancer is head and neck cancer, lung cancer, melanoma, colon cancer, bladder cancer, esophageal cancer, gastric cancer, laryngeal cancer, oral cancer, brain cancer, bone cancer, pancreatic cancer, kidney cancer, glioblastoma, sarcoma, prostate cancer, or liver cancer, or a combination thereof. Clause 61. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 60, wherein the solid cancer is head and neck cancer. Clause 62. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 60, wherein the solid cancer is lung cancer.Clause 63. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 60, wherein the solid cancer is melanoma. Clause 64. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 48 to 63, further comprising administering to the patient an immunotherapy. Clause 65. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 64, wherein the immunotherapy is an immune checkpoint inhibitor. Clause 66. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 65, wherein the checkpoint inhibitor is an inhibitor of PD-1, PD- L1, CTLA-4, LAG-3, ICOS, BTLA, TIM-3, TIGIT, or NKG2A, or a combination thereof. Clause 67. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 66, wherein the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of: pembrolizumab, nivolumab, and cemiplimab. Clause 68. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 67, wherein the anti-PD-1 antibody is pembrolizumab. Clause 69. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 67, wherein the anti-PD-1 antibody is nivolumab. Clause 70. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 67, wherein the anti-PD-1 antibody is cemiplimab. Clause 71. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 66, wherein the PD-L1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of: atezolizumab, avelumab, and durvalumab. Clause 72. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 66, wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody selected from the group consisting of: ipilimumab and tremelimumab. Clause 73. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 66, wherein the LAG-3 inhibitor is an anti-LAG-3 antibody.Clause 74. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 73, wherein the anti-LAG-3 antibody is relatlimab. Clause 75. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 48 to 74, wherein lasofoxifene is administered as lasofoxifene tartrate. Clause 76. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 48 to 75, wherein lasofoxifene is administered by oral administration. Clause 77. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 76, wherein lasofoxifene is administered orally at about 0.5 mg / lasofoxifene to about 10 mg / lasofoxifene per day. Clause 78. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 77, wherein lasofoxifene is administered orally at 5 mg / lasofoxifene per day. Clause 79. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 77, wherein lasofoxifene is administered orally at 10 mg / lasofoxifene per day. Clause 80. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 76 to 79, wherein lasofoxifene is administered once every day. Clause 81. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 64 to 74, and clauses 75 to 80 as depend from clauses 64 to 74, wherein lasofoxifene and the immunotherapy are administered concurrently. Clause 82. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 64 to 74, and clauses 75 to 80 as depend from clauses 64 to 74, wherein lasofoxifene and the immunotherapy are administered separately.Clause 83. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 82, wherein lasofoxifene is administered before the start of the immunotherapy. Clause 84. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 48 to 83, further comprising administering to the patient an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor. Clause 85. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 84, wherein the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib. Clause 86. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 48 to 83, further comprising administering to the patient an effective amount of a mammalian target of rapamycin (mTOR) inhibitor. Clause 87. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 86, wherein the mTOR inhibitor is everolimus. Clause 88. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 48 to 83, further comprising administering to the patient an effective amount of a human epidermal growth factor receptor 2 (HER2) inhibitor. Clause 89. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 88, wherein the HER2 inhibitor is an anti-HER2 antibody or an anti-HER2 antibody-drug conjugate (ADC). Clause 90. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 89, wherein the anti-HER2 antibody is trastuzumab. Clause 91. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 89, wherein the anti-HER2 ADC is trastuzumab emtansine or trastuzumab deruxtecan. Clause 92. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 48 to 83, further comprising administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor.Clause 93. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 92, wherein the HDAC inhibitor is vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, pracinostat, resminostat, givinostat, quisinostat, kevetrin, CUDC-101, AR-42, tefinostat, CHR-3996, 4SC202, CG200745, rocilinostat, or sulforaphane. Clause 94. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of increasing the biogenesis, survival, and / or activity of eosinophils in a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of the lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 95. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of increasing tumor associated tissue eosinophilia (TATE) in a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 96. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of increasing the number of CD8+T cells in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 97. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of increasing the ratio of M1 / M2 macrophages in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof. Clause 98. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of decreasing the number of exhausted CD8+T cells in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of the lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.Clause 99. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 98, wherein the patient has a mutation in BRCA1 or BRCA2 gene. Clause 100. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of clause 98 or 99, further comprising administering to the patient an immunotherapy. Clause 101. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 to 100, wherein the patient is a premenopausal female patient. Clause 102. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 to 100, wherein the patient is a postmenopausal female patient. Clause 103. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of clauses 1 to 100, wherein the patient is a male patient.

Claims

CLAIMS WHAT IS CLAIMED IS:

1. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of treating a solid cancer in a patient that is receiving immunotherapy, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

2. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 1, wherein the solid cancer is an estrogen receptor negative (ER–) or estrogen receptor-low (ERlow) solid cancer.

3. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 1 or 2, wherein the solid cancer is estrogen receptor negative (ER–) breast cancer.

4. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 3, wherein the solid cancer is triple-negative breast cancer (TNBC).

5. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 1 or 2, wherein the solid cancer is ER–or ERlowovarian cancer.

6. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 1 or 2, wherein the solid cancer is ER–or ERlowendometrial cancer.

7. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 or 2, wherein the solid cancer is a solid cancer other than breast, ovarian, or endometrial cancer.

8. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 7, wherein the solid cancer is head and neck cancer, lung cancer, melanoma, colon cancer, bladder cancer, esophageal cancer, gastric cancer, laryngeal cancer, oral cancer, brain cancer, bone cancer, pancreatic cancer, kidney cancer, glioblastoma, sarcoma, prostate cancer, or liver cancer, or a combination thereof.

9. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 8, wherein the solid cancer is head and neck cancer.

10. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 8, wherein the solid cancer is lung cancer.

11. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 8, wherein the solid cancer is melanoma.

12. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 to 11, wherein the immunotherapy is an immune checkpoint inhibitor.

13. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 12, wherein the checkpoint inhibitor is an inhibitor of PD-1, PD-L1, CTLA-4, LAG-3, ICOS, BTLA, TIM-3, TIGIT, or NKG2A, or a combination thereof.

14. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 13, wherein the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of: pembrolizumab, nivolumab, and cemiplimab.

15. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 14, wherein the anti-PD-1 antibody is pembrolizumab.

16. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 14, wherein the anti-PD-1 antibody is nivolumab.

17. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 14, wherein the anti-PD-1 antibody is cemiplimab.

18. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 13, wherein the PD-L1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of: atezolizumab, avelumab, and durvalumab.

19. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 13, wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody selected from the group consisting of: ipilimumab and tremelimumab.

20. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 13, wherein the LAG-3 inhibitor is an anti-LAG-3 antibody.

21. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 20, wherein the anti-LAG-3 antibody is relatlimab.

22. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 to 21, wherein lasofoxifene is administered as lasofoxifene tartrate.

23. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 to 22, wherein lasofoxifene is administered by oral administration.

24. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 23, wherein lasofoxifene is administered orally at about 0.5 mg / lasofoxifene to about 10 mg / lasofoxifene per day.

25. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 24, wherein lasofoxifene is administered orally at 5 mg / lasofoxifene per day.

26. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 24, wherein lasofoxifene is administered orally at 10 mg / lasofoxifene per day.

27. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 23 to 26, wherein lasofoxifene is administered once every day.

28. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 to 27, wherein lasofoxifene and the immunotherapy are administered concurrently.

29. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 to 27, wherein lasofoxifene and the immunotherapy are administered separately.

30. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 29, wherein lasofoxifene is administered before the start of the immunotherapy.

31. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 to 30, further comprising administering to the patient an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor.

32. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 31, wherein the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib.

33. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 to 30, further comprising administering to the patient an effective amount of a mammalian target of rapamycin (mTOR) inhibitor.

34. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 33, wherein the mTOR inhibitor is everolimus.

35. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 to 30, further comprising administering to the patient an effective amount of a human epidermal growth factor receptor 2 (HER2) inhibitor.

36. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 35, wherein the HER2 inhibitor is an anti-HER2 antibody or an anti- HER2 antibody-drug conjugate (ADC).

37. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 36, wherein the anti-HER2 antibody is trastuzumab.

38. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 36, wherein the anti-HER2 ADC is trastuzumab emtansine or trastuzumab deruxtecan.

39. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 to 30, further comprising administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor.

40. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 39, wherein the HDAC inhibitor is vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, pracinostat, resminostat, givinostat, quisinostat, kevetrin, CUDC-101, AR-42, tefinostat, CHR-3996, 4SC202, CG200745, rocilinostat, or sulforaphane.

41. A combination of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, and immunotherapy for use in a method of treating a solid cancer in a patient.

42. A combination of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, and immunotherapy for use of claim 41, wherein lasofoxifene and the immunotherapy are administered separately.

43. A combination of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, and immunotherapy for use of claim 42, wherein lasofoxifene is administered before the start of the immunotherapy.

44. A combination of immunotherapy and lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of treating a solid cancer in a patient.

45. A combination of immunotherapy and lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use of claim 44, wherein the immunotherapy and lasofoxifene are administered separately.

46. A combination of immunotherapy and lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use of claim 45, wherein the immunotherapy is administered after the start of lasofoxifene.

47. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of increasing the efficacy of immunotherapy in a patient having a solid cancer, the method comprising: further administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

48. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of treating an estrogen receptor negative (ER–) or estrogen receptor-low (ERlow) solid cancer in a patient, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

49. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of treating a solid cancer other than estrogen receptor positive (ER+) breast cancer, ER+ovarian cancer, or ER+endometrial cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

50. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of treating a solid cancer having a low M1 / M2 tumor-associated macrophage (TAM) ratio and / or a high number of M2 tumor-associated macrophages (M2- TAMs) and / or a low number of M1 tumor-associated macrophages (M1-TAMs), the method comprising: administering to the patient an effective amount of the lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

51. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of treating a solid cancer having a low number of CD8+tumor infiltrating lymphocytes (TILs), the method comprising:administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

52. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use in a method of treating a solid cancer having a low number of eosinophils, the method comprising: administering to the patient an effective amount of the lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

53. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use of any one of claims 48 to 52, wherein the solid cancer is historically more responsive to an immunotherapy in men than in premenopausal women.

54. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 53, wherein the immunotherapy is an immune checkpoint inhibitor.

55. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 48 to 54, wherein the solid cancer is estrogen receptor negative (ER–) breast cancer.

56. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 55, wherein the solid cancer is triple-negative breast cancer (TNBC).

57. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 48 to 54, wherein the solid cancer is ER–or ERlowovarian cancer.

58. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof for the use of any one of claims 48 to 54, wherein the solid cancer is ER– or ERlowendometrial cancer.

59. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 48 to 54, wherein the solid cancer is a solid cancer other than breast, ovarian, or endometrial cancer.

60. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 59, wherein the solid cancer is head and neck cancer, lung cancer, melanoma, colon cancer, bladder cancer, esophageal cancer, gastric cancer, laryngeal cancer, oral cancer, brain cancer, bone cancer, pancreatic cancer, kidney cancer, glioblastoma, sarcoma, prostate cancer, or liver cancer, or a combination thereof.

61. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 60, wherein the solid cancer is head and neck cancer.

62. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 60, wherein the solid cancer is lung cancer.

63. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 60, wherein the solid cancer is melanoma.

64. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 48 to 63, further comprising administering to the patient an immunotherapy.

65. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 64, wherein the immunotherapy is an immune checkpoint inhibitor.

66. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 65, wherein the checkpoint inhibitor is an inhibitor of PD-1, PD-L1, CTLA-4, LAG-3, ICOS, BTLA, TIM-3, TIGIT, or NKG2A, or a combination thereof.

67. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 66, wherein the PD-1 inhibitor is an anti-PD-1 antibody selected from the group consisting of: pembrolizumab, nivolumab, and cemiplimab.

68. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 67, wherein the anti-PD-1 antibody is pembrolizumab.

69. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 67, wherein the anti-PD-1 antibody is nivolumab.

70. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 67, wherein the anti-PD-1 antibody is cemiplimab.

71. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 66, wherein the PD-L1 inhibitor is an anti-PD-L1 antibody selected from the group consisting of: atezolizumab, avelumab, and durvalumab.

72. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 66, wherein the CTLA-4 inhibitor is an anti-CTLA-4 antibody selected from the group consisting of: ipilimumab and tremelimumab.

73. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 66, wherein the LAG-3 inhibitor is an anti-LAG-3 antibody.

74. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 73, wherein the anti-LAG-3 antibody is relatlimab.

75. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 48 to 74, wherein lasofoxifene is administered as lasofoxifene tartrate.

76. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 48 to 75, wherein lasofoxifene is administered by oral administration.

77. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 76, wherein lasofoxifene is administered orally at about 0.5 mg / lasofoxifene to about 10 mg / lasofoxifene per day.

78. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 77, wherein lasofoxifene is administered orally at 5 mg / lasofoxifene per day.

79. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 77, wherein lasofoxifene is administered orally at 10 mg / lasofoxifene per day.

80. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 76 to 79, wherein lasofoxifene is administered once every day.

81. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 64 to 74, and claims 75 to 80 as depend from claims 64 to 74, wherein lasofoxifene and the immunotherapy are administered concurrently.

82. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 64 to 74, and claims 75 to 80 as depend from claims 64 to 74, wherein lasofoxifene and the immunotherapy are administered separately.

83. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 82, wherein lasofoxifene is administered before the start of the immunotherapy.

84. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 48 to 83, further comprising administering to the patient an effective amount of cyclin-dependent kinase 4 / 6 (CDK4 / 6) inhibitor.

85. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 84, wherein the CDK4 / 6 inhibitor is palbociclib, abemaciclib, or ribociclib.

86. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 48 to 83, further comprising administering to the patient an effective amount of a mammalian target of rapamycin (mTOR) inhibitor.

87. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 86, wherein the mTOR inhibitor is everolimus.

88. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 48 to 83, further comprising administering to the patient an effective amount of a human epidermal growth factor receptor 2 (HER2) inhibitor.

89. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 88, wherein the HER2 inhibitor is an anti-HER2 antibody or an anti- HER2 antibody-drug conjugate (ADC).

90. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 89, wherein the anti-HER2 antibody is trastuzumab.

91. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 89, wherein the anti-HER2 ADC is trastuzumab emtansine or trastuzumab deruxtecan.

92. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 48 to 83, further comprising administering to the patient an effective amount of a histone deacetylase (HDAC) inhibitor.

93. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 92, wherein the HDAC inhibitor is vorinostat, romidepsin, chidamide, panobinostat, belinostat, valproic acid, mocetinostat, abexinostat, entinostat, pracinostat, resminostat, givinostat, quisinostat, kevetrin, CUDC-101, AR-42, tefinostat, CHR-3996, 4SC202, CG200745, rocilinostat, or sulforaphane.

94. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of increasing the biogenesis, survival, and / or activity of eosinophils in a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of the lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

95. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of increasing tumor associated tissue eosinophilia (TATE) in a patienthaving estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

96. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of increasing the number of CD8+T cells in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

97. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of increasing the ratio of M1 / M2 macrophages in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

98. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for use in a method of decreasing the number of exhausted CD8+T cells in the cancer of a patient having estrogen receptor negative (ER–) and / or estrogen receptor-low (ERlow) solid cancer, the method comprising: administering to the patient an effective amount of the lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof.

99. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 98, wherein the patient has a mutation in BRCA1 or BRCA2 gene.

100. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of claim 98 or 99, further comprising administering to the patient an immunotherapy.

101. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 to 100, wherein the patient is a premenopausal female patient.

102. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 to 100, wherein the patient is a postmenopausal female patient.

103. Lasofoxifene, or a pharmaceutically acceptable salt or functional derivative thereof, for the use of any one of claims 1 to 100, wherein the patient is a male patient.

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