Lasofoxifene treatment of breast cancer

Abstract

The disclosure provides methods for treating estrogen receptor positive (ER + ) cancer in women with an effective amount of lasofoxifene, 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 lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.   
     
     
         2 . The method of  claim 1 , wherein the patient has previously been treated with one or more lines of endocrine therapy. 
     
     
         3 . The method of  claim 2 , wherein the patient has previously been treated with a plurality of lines of endocrine therapy. 
     
     
         4 . The method of  claim 2 , wherein the endocrine therapy that the patient has previously been treated with is a selective ER modulator (SERM). 
     
     
         5 . The method of  claim 4 , wherein the SERM is tamoxifen, raloxifene, bazedoxifene, toremifene, or ospemifene. 
     
     
         6 . The method of  claim 2 , wherein the endocrine therapy that the patient has previously been treated with is a selective ER degrader (SERD). 
     
     
         7 . The method of  claim 6 , wherein the SERD is fulvestrant, RAD1901, ARN-810 (GDC-0810), or AZD9496. 
     
     
         8 . The method of  claim 2 , wherein the endocrine therapy that the patient has previously been treated with is an aromatase inhibitor. 
     
     
         9 . The method of  claim 8 , wherein the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®). 
     
     
         10 . The method of  claim 2 , wherein the patient has disease progression after endocrine therapy. 
     
     
         11 . The method of  claim 1 , wherein the patient's locally advanced or metastatic cancer is resistant to endocrine therapy other than lasofoxifene. 
     
     
         12 . The method of  claim 1 , wherein the patient's locally advanced or metastatic cancer has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene. 
     
     
         13 . The method of  claim 12 , 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. 
     
     
         14 . The method of  claim 13 , 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.   
     
     
         15 . The method of  claim 12 , 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. 
     
     
         16 . The method of  claim 15 , wherein the at least one gain of function missense mutation is in the amino acid D538. 
     
     
         17 . The method of  claim 16 , wherein the mutation is D538G. 
     
     
         18 . The method of  claim 15 , wherein the at least one gain of function missense mutation is in the amino acid Y537. 
     
     
         19 . The method of  claim 18 , wherein the mutation is Y537S, Y537N, Y537C, or Y537Q. 
     
     
         20 . The method of  claim 19 , wherein the mutation is Y537C. 
     
     
         21 . The method of  claim 15 , wherein the at least one gain of function missense mutation is in the amino acid L536. 
     
     
         22 . The method of  claim 21 , wherein the mutation is L536R or L536Q. 
     
     
         23 . The method of  claim 15 , wherein the at least one gain of function missense mutation is in the amino acid P535. 
     
     
         24 . The method of  claim 23 , wherein the mutation is P535H. 
     
     
         25 . The method of  claim 15 , wherein the at least one gain of function missense mutation is in the amino acid V534. 
     
     
         26 . The method of  claim 25 , wherein the mutation is V534E. 
     
     
         27 . The method of  claim 15 , wherein the at least one gain of function missense mutation is in the amino acid S463. 
     
     
         28 . The method of  claim 27 , wherein the mutation is S463P. 
     
     
         29 . The method of  claim 15 , wherein the at least one gain of function missense mutation is in the amino acid V392. 
     
     
         30 . The method of  claim 29 , wherein the mutation is V392I. 
     
     
         31 . The method of  claim 15 , wherein the at least one gain of function missense mutation is in the amino acid E380. 
     
     
         32 . The method of  claim 31 , wherein the mutation is E380Q. 
     
     
         33 - 35 . (canceled) 
     
     
         36 . The method of  claim 1 , wherein lasofoxifene is administered as lasofoxifene tartrate. 
     
     
         37 . The method of  claim 1 , wherein lasofoxifene is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration. 
     
     
         38 . The method of  claim 37 , wherein lasofoxifene is administered by oral administration. 
     
     
         39 - 44 . (canceled) 
     
     
         45 . The method of  claim 1 , further comprising treating said patient with at least one additional endocrine therapy. 
     
     
         46 - 50 . (canceled) 
     
     
         51 . The method of  claim 1 , further comprising administering to said patient an effective amount of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. 
     
     
         52 . (canceled) 
     
     
         53 . The method of  claim 1 , further comprising administering to said patient an effective amount of mammalian target of rapamycin (mTOR) inhibitor. 
     
     
         54 - 55 . (canceled) 
     
     
         56 . The method of  claim 1 , further comprising administering to said patient an effective amount of human epidermal growth factor receptor 2 (HER2) inhibitor. 
     
     
         57 . (canceled) 
     
     
         58 . The method of  claim 1 , further comprising administering to said patient an effective amount of a histone deacetylase (HDAC) inhibitor. 
     
     
         59 . (canceled) 
     
     
         60 . The method of  claim 1 , further comprising administering to said patient an effective amount of a checkpoint inhibitor. 
     
     
         61 - 64 . (canceled) 
     
     
         65 . The method of  claim 1 , wherein the patient is premenopausal. 
     
     
         66 . The method of  claim 65 , wherein the patient has locally advanced or metastatic ER + /HER2− breast cancer. 
     
     
         67 . The method of  claim 65 , 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. 
     
     
         68 . The method of  claim 1 , wherein the patient is perimenopausal. 
     
     
         69 . The method of  claim 68 , wherein the patient has locally advanced or metastatic ER + /HER2− breast cancer. 
     
     
         70 . The method of  claim 69 , 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. 
     
     
         71 . The method of  claim 1 , wherein the patient is postmenopausal. 
     
     
         72 . The method of  claim 71 , wherein the patient has locally advanced or metastatic ER + /HER2− breast cancer. 
     
     
         73 . The method of  claim 72 , 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. 
     
     
         74 . A method of treating primary breast cancer in women, comprising:
 a) selecting for treatment a patient who has been diagnosed with estrogen receptor positive (ER + ) primary breast cancer; and   b) administering to the selected patient an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.   
     
     
         75 - 106 . (canceled) 
     
     
         107 . A method of adjuvant therapy of estrogen receptor positive (ER + ) breast cancer, comprising:
 administering to a patient who has received primary treatment for ER +  breast cancer an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof, in combination with an aromatase inhibitor.   
     
     
         108 - 141 . (canceled) 
     
     
         142 . A method of treating cancers other than breast cancer in women, comprising:
 a) selecting for treatment a patient who has been diagnosed with estrogen receptor positive (ER + ) cancer, other than breast cancer, and has at least one gain of function mutations in the Estrogen Receptor 1 (ESR1) gene; and   b) administering to the selected patient an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof.   
     
     
         143 - 176 . (canceled) 
     
     
         177 . A method of treating a female patient suffering from breast cancer who is at risk of acquiring a 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 lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
     
     
         178 . A method of treating a female patient suffering from breast cancer who 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), comprising administering to the female patient an effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
     
     
         179 - 181 . (canceled) 
     
     
         182 . 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 lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
     
     
         183 - 185 . (canceled) 
     
     
         186 . 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 lasofoxifene, a pharmaceutically acceptable salt thereof, or a prodrug thereof. 
     
     
         187 - 256 . (canceled)