Treatment of breast cancer

Abstract

The disclosure provides methods for treating estrogen receptor positive (ER+) cancer in women, and in particular embodiments, methods for treating ER+ cancers having gain of function mutations in the ESR1 ligand binding domain, with an effective amount of a compound selected from the group consisting of raloxifene, bazedoxifene, tamoxifen, etacstil, and fulvestrant, a pharmaceutically acceptable salt thereof, or a prodrug thereof. The disclosure also includes the detection of the Estrogen Receptor 1 (ESR1) gene mutations that lead to endocrine resistance and treatment of endocrine resistant ER+ cancers.

1 . A method of treating locally advanced or metastatic breast cancer in women, comprising:
 a) selecting for treatment a patient who has been diagnosed with estrogen receptor positive (ER + ) locally advanced or metastatic breast cancer; and   b) administering to the selected patient an effective amount of a compound selected from the group consisting of raloxifene, bazedoxifene, tamoxifen, etacstil, and fulvestrant, a pharmaceutically acceptable salt thereof, or a prodrug thereof,   wherein the patient's cancer has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.   
     
     
         2 . The method of  claim 1 , wherein the patient has previously been determined to have at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene. 
     
     
         3 . The method of  claim 1 , further comprising the earlier step of:
 determining that the patient has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.   
     
     
         4 . The method of any one of  claims 1  to  3 , wherein the at least one of gain of function missense mutation is in any one of amino acids D538, Y537, L536, P535, V534, S463, V392, and E380. 
     
     
         5 . The method of  claim 4 , wherein the at least one gain of function missense mutation is in the amino acid D538. 
     
     
         6 . The method of  claim 5 , wherein the mutation is D538G. 
     
     
         7 . The method of  claim 4 , wherein the at least one gain of function missense mutation is in the amino acid Y537. 
     
     
         8 . The method of  claim 7 , wherein the mutation is Y537S, Y537N, Y537C, or Y537Q. 
     
     
         9 . The method of  claim 8 , wherein the mutation is Y537C. 
     
     
         10 . The method of  claim 4 , wherein the at least one gain of function missense mutation is in the amino acid L536. 
     
     
         11 . The method of  claim 10 , wherein the mutation is L536R or L536Q. 
     
     
         12 . The method of  claim 4 , wherein the at least one gain of function missense mutation is in the amino acid P535. 
     
     
         13 . The method of  claim 12 , wherein the mutation is P535H. 
     
     
         14 . The method of  claim 4 , wherein the mutation is in the at least one gain of function missense amino acid V534. 
     
     
         15 . The method of  claim 14 , wherein the mutation is V534E. 
     
     
         16 . The method of  claim 4 , wherein the at least one gain of function missense mutation is in the amino acid S463. 
     
     
         17 . The method of  claim 16 , wherein the mutation is S463P. 
     
     
         18 . The method of  claim 4 , wherein the at least one gain of function missense mutation is in the amino acid V392. 
     
     
         19 . The method of  claim 18 , wherein the mutation is V392I. 
     
     
         20 . The method of  claim 4 , wherein the at least one gain of function missense mutation is in the amino acid E380. 
     
     
         21 . The method of  claim 20 , wherein the mutation is E380Q. 
     
     
         22 . The method of any one of  claims 1  to  21 , wherein the serum estradiol level of the patient is at least 0.35 ng/dL. 
     
     
         23 . The method of any one of  claims 1  to  21 , wherein the serum estradiol level of the patient is about 0.30 ng/dL to about 0.35 ng/dL. 
     
     
         24 . The method of any one of  claims 1  to  21 , wherein the serum estradiol level of the patient is about 0.25 ng/dL to about 0.30 ng/dL. 
     
     
         25 . The method of any one of  claims 1  to  24 , wherein the compound is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration. 
     
     
         26 . The method of any one of  claims 1  to  25 , wherein the compound is administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, or once every month. 
     
     
         27 . The method of any one of  claims 1  to  26 , further comprising treating said patient with at least one additional endocrine therapy. 
     
     
         28 . The method of  claim 27 , wherein said patient is treated with the additional endocrine therapy at original doses. 
     
     
         29 . The method of  claim 27 , wherein said patient is treated with the additional endocrine therapy at doses higher than original doses. 
     
     
         30 . The method of any one of  claims 27  to  29 , wherein the additional endocrine therapy is treatment with lasofoxifene. 
     
     
         31 . The method of any one of  claims 27  to  29 , wherein the additional endocrine therapy is treatment with an aromatase inhibitor. 
     
     
         32 . The method of any one of  claims 1  to  26 , further comprising administering to said patient an effective amount of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. 
     
     
         33 . The method of  claim 32 , wherein said CDK4/6 inhibitor is palbociclib, abemaciclib, or ribociclib. 
     
     
         34 . The method of any one of  claims 1  to  26 , further comprising administering to said patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor. 
     
     
         35 . The method of  claim 34 , wherein said mTOR inhibitor is Everolimus. 
     
     
         36 . The method of any one of  claims 1  to  26 , further comprising administering to said patient an effective amount of phosphoinositide 3-kinase (PI3K) inhibitor or heat shock protein 90 (HSP90) inhibitor. 
     
     
         37 . The method of any one of  claims 1  to  26 , further comprising administering to said patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor. 
     
     
         38 . The method of  claim 37 , wherein said HER2 inhibitor is trastuzumab (Herceptin®) or ado-trastuzumab emtansine (Kadcyla®). 
     
     
         39 . The method of any one of  claims 1  to  26 , further comprising administering to said patient an effective amount of a histone deacetylase (HDAC) inhibitor. 
     
     
         40 . The method of  claim 39 , wherein said HDAC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (Farydak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY-1215), or sulforaphane. 
     
     
         41 . The method of any one of  claims 1  to  26 , further comprising administering to said patient an effective amount of a checkpoint inhibitor. 
     
     
         42 . The method of  claim 41 , wherein said checkpoint inhibitor is an antibody specific for programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). 
     
     
         43 . The method of  claim 42 , wherein said PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). 
     
     
         44 . The method of  claim 42 , wherein said CTLA-4 antibody is ipilimumab (Yervoy®). 
     
     
         45 . The method of any one of  claims 1  to  26 , further comprising administering to said patient an effective amount of cancer vaccine. 
     
     
         46 . The method of any one of  claims 1  to  45 , wherein the patient is premenopausal. 
     
     
         47 . The method of  claim 46 , wherein the patient has locally advanced or metastatic ER+/HER2− breast cancer. 
     
     
         48 . The method of  claim 47 , wherein the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor. 
     
     
         49 . The method of any one of  claims 1  to  45 , wherein the patient is perimenopausal. 
     
     
         50 . The method of  claim 49 , wherein the patient has locally advanced or metastatic ER+/HER2− breast cancer. 
     
     
         51 . The method of  claim 50 , wherein the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor. 
     
     
         52 . The method of any one of  claims 1  to  45 , wherein the patient is postmenopausal. 
     
     
         53 . The method of  claim 52 , wherein the patient has locally advanced or metastatic ER+/HER2− breast cancer. 
     
     
         54 . The method of  claim 53 , wherein the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor. 
     
     
         55 . A method of treating a female patient suffering from breast cancer who is at risk of acquiring at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene, comprising administering to the female patient an effective amount of a compound selected from the group consisting of raloxifene, bazedoxifene, tamoxifen, etacstil, and fulvestrant, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
     
     
         56 . The method of  claim 55 , wherein the patient is at risk of acquiring resistance to endocrine therapy, optionally wherein the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (AI) therapy, or (iv) any combination of (i), (ii) and/or (iii). 
     
     
         57 . The method of  claim 55  or  claim 56 , wherein the patient has primary breast cancer. 
     
     
         58 . The method of  claim 57 , wherein the primary breast cancer is locally advanced. 
     
     
         59 . The method of any one of  claims 55  to  58 , wherein the patient has been treated with endocrine therapy, optionally wherein the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (AI) therapy, or (iv) any combination of (i), (ii) and/or (iii). 
     
     
         60 . A method of treating a female patient suffering from estrogen receptor positive (ER + ) primary breast cancer, comprising administering to a female patient an effective amount of a compound selected from the group consisting of raloxifene, bazedoxifene, tamoxifen, etacstil, and fulvestrant, a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein the patient has cancer cells with at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene. 
     
     
         61 . The method of  claim 60 , wherein the patient is at risk of acquiring resistance to endocrine therapy, optionally wherein the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (AI) therapy, or (iv) any combination of (i), (ii) and/or (iii). 
     
     
         62 . The method of  claim 60  or  claim 61 , wherein the primary breast cancer is locally advanced. 
     
     
         63 . The method of any one of  claims 60  to  62 , wherein the patient has been treated with endocrine therapy, optionally wherein the endocrine therapy is (i) selective ER modulator (SERM) therapy, (ii) selective ER degrader (SERD) therapy, (iii) aromatase inhibitor (AI) therapy, or (iv) any combination of (i), (ii) and/or (iii). 
     
     
         64 . A method of treating a female patient suffering from estrogen receptor positive (ER + ) locally advanced or metastatic breast cancer, comprising administering to a female patient an effective amount of a compound selected from the group consisting of raloxifene, bazedoxifene, tamoxifen, etacstil, and fulvestrant, a pharmaceutically acceptable salt thereof, or a prodrug thereof, wherein the patient has cancer cells with at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene. 
     
     
         65 . The method of  claims 55  to  64 , wherein the at least one of gain of function missense mutation is in any one of amino acids D538, Y537, L536, P535, V534, S463, V392, and E380. 
     
     
         66 . The method of  claim 65 , wherein the at least one gain of function missense mutation is in the amino acid D538. 
     
     
         67 . The method of  claim 66 , wherein the mutation is D538G. 
     
     
         68 . The method of  claim 65 , wherein the at least one gain of function missense mutation is in the amino acid Y537. 
     
     
         69 . The method of  claim 68 , wherein the mutation is Y537S, Y537N, Y537C, or Y537Q. 
     
     
         70 . The method of  claim 69 , wherein the mutation is Y537C. 
     
     
         71 . The method of  claim 65 , wherein the at least one gain of function missense mutation is in the amino acid L536. 
     
     
         72 . The method of  claim 71 , wherein the mutation is L536R or L536Q. 
     
     
         73 . The method of  claim 65 , wherein the at least one gain of function missense mutation is in the amino acid P535. 
     
     
         74 . The method of  claim 73 , wherein the mutation is P535H. 
     
     
         75 . The method of  claim 65 , wherein the at least one gain of function missense mutation is in the amino acid V534. 
     
     
         76 . The method of  claim 75 , wherein the mutation is V534E. 
     
     
         77 . The method of  claim 65 , wherein the at least one gain of function missense mutation is in the amino acid 5463. 
     
     
         78 . The method of  claim 77 , wherein the mutation is S463P. 
     
     
         79 . The method of  claim 65 , wherein the at least one gain of function missense mutation is in the amino acid V392. 
     
     
         80 . The method of  claim 79 , wherein the mutation is V392I. 
     
     
         81 . The method of  claim 65 , wherein the at least one gain of function missense mutation is in the amino acid E380. 
     
     
         82 . The method of  claim 81 , wherein the mutation is E380Q. 
     
     
         83 . The method of any one of  claims 55  to  82 , wherein the compound is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration. 
     
     
         84 . The method of any one of  claims 55  to  83 , wherein the compound is administered once every day, once every two days, once every three days, once every four days, once every five days, once every six days, once every week, once every two weeks, once every three weeks, or once every month. 
     
     
         85 . The method of any one of  claims 55  to  84 , further comprising treating said patient with at least one additional endocrine therapy. 
     
     
         86 . The method of  claim 85 , wherein said patient is treated with the additional endocrine therapy at original doses. 
     
     
         87 . The method of  claim 85 , wherein said patient is treated with the additional endocrine therapy at doses higher than original doses. 
     
     
         88 . The method of any one of  claims 85  to  87 , wherein the additional endocrine therapy is treatment with lasofoxifene. 
     
     
         89 . The method of any one of  claims 85  to  87 , wherein the additional endocrine therapy is treatment with an aromatase inhibitor. 
     
     
         90 . The method of any one of  claims 55  to  84 , further comprising administering to said patient an effective amount of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. 
     
     
         91 . The method of  claim 90 , wherein said CDK4/6 inhibitor is palbociclib, abemaciclib, or ribociclib. 
     
     
         92 . The method of any one of  claims 55  to  84 , further comprising administering to said patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor. 
     
     
         93 . The method of  claim 92 , wherein said mTOR inhibitor is Everolimus. 
     
     
         94 . The method of any one of  claims 55  to  84 , further comprising administering to said patient an effective amount of phosphoinositide 3-kinase (PI3K) inhibitor or heat shock protein 90 (HSP90) inhibitor. 
     
     
         95 . The method of any one of  claims 55  to  84 , further comprising administering to said patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor. 
     
     
         96 . The method of  claim 95 , wherein said HER2 inhibitor is trastuzumab (Herceptin®) or ado-trastuzumab emtansine (Kadcyla®). 
     
     
         97 . The method of any one of  claims 55  to  84 , further comprising administering to said patient an effective amount of a histone deacetylase (HDAC) inhibitor. 
     
     
         98 . The method of  claim 97 , wherein said HDAC inhibitor is vorinostat (Zolinza®), romidepsin (Istodax®), chidamide (Epidaza®), panobinostat (Farydak®), belinostat (Beleodaq®, PXD101), valproic acid (Depakote®, Depakene®, Stavzor®), mocetinostat (MGCD0103), abexinostat (PCI-24781), entinostat (MS-275), pracinostat (SB939), resminostat (4SC-201), givinostat (ITF2357), quisinostat (JNJ-26481585), kevetrin, CUDC-101, AR-42, tefinostat (CHR-2835), CHR-3996, 4SC202, CG200745, rocilinostat (ACY-1215), or sulforaphane. 
     
     
         99 . The method of any one of  claims 55  to  84 , further comprising administering to said patient an effective amount of a checkpoint inhibitor. 
     
     
         100 . The method of  claim 99 , wherein said checkpoint inhibitor is an antibody specific for programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). 
     
     
         101 . The method of  claim 100 , wherein said PD-1 antibody is pembrolizumab (Keytruda®) or nivolumab (Opdivo®). 
     
     
         102 . The method of  claim 100 , wherein said CTLA-4 antibody is ipilimumab (Yervoy®). 
     
     
         103 . The method of any one of  claims 55  to  84 , further comprising administering to said patient an effective amount of cancer vaccine. 
     
     
         104 . The method of any one of  claims 55  to  103 , wherein the patient is premenopausal. 
     
     
         105 . The method of  claim 104 , wherein the patient has locally advanced or metastatic ER+/HER2− breast cancer. 
     
     
         106 . The method of  claim 105 , wherein the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor. 
     
     
         107 . The method of any one of  claims 55  to  103 , wherein the patient is perimenopausal. 
     
     
         108 . The method of  claim 107 , wherein the patient has locally advanced or metastatic ER+/HER2− breast cancer. 
     
     
         109 . The method of  claim 108 , wherein the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor. 
     
     
         110 . The method of any one of  claims 55  to  103 , wherein the patient is postmenopausal. 
     
     
         111 . The method of  claim 110 , wherein the patient has locally advanced or metastatic ER+/HER2− breast cancer. 
     
     
         112 . The method of  claim 111 , wherein the patient has progressed on her first hormonal treatment while on a non-steroid aromatase inhibitor (AI), fulvestrant, AI in combination with a CDK4/6 inhibitor, or fulvestrant in combination with a CDK4/6 inhibitor.