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 reducing the progression of estrogen receptor positive human epidermal growth factor receptor 2 negative (ER + /HER2 − ) locally advanced or metastatic breast cancer in a patient, wherein the cancer has at least one gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene, the method comprising:
 administering a therapeutically effective amount of lasofoxifene, a pharmaceutically acceptable salt thereof, or a functional derivative thereof to the patient.   
     
     
         2 . (canceled) 
     
     
         3 . The method of  claim 1 , wherein the patient has previously been treated with an aromatase inhibitor. 
     
     
         4 . The method of  claim 3 , wherein the aromatase inhibitor is exemestane, letrozole, or anastrozole. 
     
     
         5 . The method of  claim 1 , wherein lasofoxifene is administered as lasofoxifene tartrate. 
     
     
         6 . The method of  claim 1 , wherein lasofoxifene is administered by oral administration. 
     
     
         7 . The method of  claim 6 , wherein lasofoxifene is administered at 5 mg/day per os. 
     
     
         8 . The method of  claim 1 , further comprising administering to the patient an additional agent selected from the group consisting of an aromatase inhibitor, a CDK4/6 inhibitor, an mTOR inhibitor, a PI3K inhibitor, an HSP90 inhibitor, a HER2 inhibitor, and an HDAC inhibitor. 
     
     
         9 . The method of  claim 8 , wherein the additional agent is an aromatase inhibitor. 
     
     
         10 . The method of  claim 8 , wherein the additional agent is a CDK4/6 inhibitor. 
     
     
         11 . The method of  claim 8 , wherein the additional agent is an mTOR inhibitor. 
     
     
         12 . The method of  claim 8 , wherein the additional agent is a PI3K inhibitor. 
     
     
         13 . The method of  claim 8 , wherein the additional agent is an HSP90 inhibitor. 
     
     
         14 . The method of  claim 8 , wherein the additional agent is a HER2 inhibitor. 
     
     
         15 . The method of  claim 8 , wherein the additional agent is an HDAC inhibitor. 
     
     
         16 . The method of  claim 1 , wherein the patient is postmenopausal. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . The method of  claim 1 , wherein the patient's cancer has progressed 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. 
     
     
         21 . The method of  claim 1 , wherein the at least one gain of function missense mutation is in any one of amino acids D538, Y537, L536, P535, V534, S463, V392, and E380 of the ERα protein. 
     
     
         22 . The method of  claim 21 , wherein the at least one gain of function missense mutation is D538G, Y537S, Y537N, Y537C, Y537Q, L536R, L536Q, P535H, V534E, S463P, V392I, or E380Q. 
     
     
         23 . The method of  claim 21 , wherein the at least one gain of function missense mutation is in amino acid D538 or Y537 of the ERα protein. 
     
     
         24 . The method of  claim 23 , wherein the at least one of gain of function missense mutation is D538G, Y537S, Y537N, Y537C, or Y537Q.