Lasofoxifene treatment of aromatase-resistant er+ cancer

Abstract

The disclosure provides methods for treating estrogen receptor positive (ER + ) cancer in a patient who has progressed on an aromatase inhibitor. Of particular interest are ER + cancers that do not harbor a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene. The provided methods involve the administration of an effective amount of lasofoxifene, a pharmaceutically acceptable salt, prodrug or functional derivative thereof.

1 . A method of reducing the progression of estrogen receptor positive (ER) cancer in a patient who has progressed on an aromatase inhibitor, wherein the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene, the method comprising:
 administering to the patient an effective amount of lasofoxifene or a pharmaceutically acceptable salt, prodrug, or functional derivative thereof.   
     
     
         2 . The method of  claim 1 , wherein the ER +  cancer is locally advanced or metastatic breast cancer, optionally wherein the cancer is HER2 − . 
     
     
         3 . The method of any previous claim, wherein the aromatase inhibitor is exemestane (Aromasin®), letrozole (Femara®), or anastrozole (Arimidex®). 
     
     
         4 . The method of any previous claim, further comprising the earlier step of:
 determining that the cancer does not have a gain of function missense mutation within the ligand binding domain (LBD) of the Estrogen Receptor 1 (ESR1) gene.   
     
     
         5 . The method of any previous claim, wherein lasofoxifene is administered as lasofoxifene tartrate. 
     
     
         6 . The method of any previous claim, wherein lasofoxifene is administered by oral, intravenous, transdermal, vaginal topical, or vaginal ring administration. 
     
     
         7 . The method of any previous claim, wherein lasofoxifene is administered by oral administration. 
     
     
         8 . The method of  claim 7 , wherein lasofoxifene is administered orally in a dose of 5 mg/day to about 10 mg/day. 
     
     
         9 . The method of any previous claim, further comprising treating said patient with at least one additional endocrine therapy. 
     
     
         10 . The method of any previous claim, further comprising administering to said patient an effective amount of cyclin-dependent kinase 4/6 (CDK4/6) inhibitor. 
     
     
         11 . The method of  claim 10 , wherein said CDK4/6 inhibitor is palbociclib, abemaciclib, or ribociclib, preferably wherein said inhibitor is abemaciclib. 
     
     
         12 . The method of any one of  claims 1 - 9 , further comprising administering to said patient an effective amount of an AKT inhibitor. 
     
     
         13 . The method of  claim 12 , wherein the AKT inhibitor is afuresertib. 
     
     
         14 . The method of any one of  claims 1 - 9 , further comprising administering to said patient an effect amount of an mTor inhibitor.