Novel estrogen receptor mutations and uses thereof

Abstract

Novel mutant ESR1 molecules and uses are disclosed.

1 . A method of treating a subject having a breast cancer, comprising:
 acquiring knowledge of a presence of a mutant estrogen receptor 1 (ESR1) and an Estrogen Receptor positive (ER+) status, in said subject, wherein the mutant ESR1 comprises a mutation in the ligand binding domain of ESR1; and   responsive to said knowledge, administering to the subject an effective amount of an anti-cancer agent other than a Selective Estrogen Receptor Modulator (SERM), thereby treating the breast cancer in the subject.   
     
     
         2 . The method of  claim 1 , wherein the mutant ESR1 comprises a mutation chosen from one or more of:
 a missense mutation at position 537, 538, 311, 341, 350, 394, 414, 433, or 503 of the amino acid sequence of SEQ ID NO:2 ( FIGS. 2A-2B ),   a deletion of nucleotides 1046-1051 of SEQ ID NO:3, or   an insertion between positions 344 and 345 of SEQ ID NO:2.   
     
     
         3 . The method of  claim 1 , wherein the mutant ESR1 comprises a mutation chosen from one or more of:
 a tyrosine to asparagine substitution at position 537 (a Y537N) of SEQ ID NO: 2;   a tyrosine to cysteine substitution at position 537 (a Y537C) of SEQ ID NO: 2;   an aspartate to glycine substitution at position 538 (a D538G) of SEQ ID NO: 2;   a deletion of amino acids LAD at positions 349-351 of SEQ ID NO:4,   an insertion of H position 349 of SEQ ID NO:3;   a threonine to methionine substitution at position 311 (a T311M) of SEQ ID NO: 2;   a serine to leucine substitution at position 341 (a S341L) of SEQ ID NO: 2;   an alanine to glutamate substitution at position 350 (a A350E) of SEQ ID NO: 2;   an arginine to histidine substitution at position 394 (a R394H) of SEQ ID NO: 2;   a glutamine substitution at position 414 of SEQ ID NO: 2;   an insertion to a stop codon (a Q414*) of SEQ ID NO: 2;   a serine to proline substitution at position 433 (a S433P) of SEQ ID NO: 2;   an arginine to tryptophan substitution at position 503 (a R503W) of SEQ ID NO: 2, or   an insertion of a cysteine between amino acids G344 and L345 of SEQ ID NO:2.   
     
     
         4 . The method of  claim 1 , wherein said subject previously received treatment with a SERM. 
     
     
         5 . The method of  claim 1 , wherein said subject has failed a first or second line of treatment with a SERM. 
     
     
         6 . The method of  claim 1 , wherein said subject has a late stage, metastatic progressive breast cancer. 
     
     
         7 . The method of  claim 1 , wherein said the subject is post-menopausal or pre-menopausal. 
     
     
         8 . The method of  claim 1 , wherein the subject stops treatment with the SERM and begins treatment with an anti-cancer agent that is not a SERM. 
     
     
         9 . The method of  claim 1 , wherein the SERM is chosen from raloxifene, EM652, GW7604, keoxifene, toremifene, tamoxifen, lasofoxifene, levormeloxifene, bazedoxifene, or arzoxifene. 
     
     
         10 . The method of  claim 1 , wherein the anti-cancer agent is a SERD (Selective Estrogen Receptor Degrader), an aromatase inhibitor, an mTOR pathway inhibitor, or a chemotherapeutic agent. 
     
     
         11 . The method of  claim 1 , wherein the subject is postmenopausal, and wherein the subject receives a SERD, an aromatase inhibitor, an mTOR pathway inhibitor, or a chemotherapeutic agent. 
     
     
         12 . The method of  claim 1 , wherein the anti-cancer agent is fulvestrant. 
     
     
         13 . The method of  claim 11 , wherein the aromatase inhibitor is aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole; 4-hydroxyandrostenedione, 1,4,6-androstatrien-3,17-dione (ATD), or 4-Androstene-3,6,17-trione. 
     
     
         14 . The method of  claim 11 , wherein the mTOR pathway inhibitor is chosen from rapamycin, temsirolimus, everolimus, ridaforolimus, AP23573, AZD8055, BEZ235, BGT226, XL765, PF-4691502, GDC0980, SF1126, OSI-027, GSK1059615, KU-0063794, WYE-354, INK128, temsirolimus, Palomid 529, PF-04691502, or PKI-587. 
     
     
         15 . The method of  claim 1 , wherein the anti-cancer agent is administered in combination with a different therapeutic agent or a different therapeutic modality. 
     
     
         16 . The method of  claim 15 , wherein the different therapeutic agent or modality is selected based on a mutation chosen from one or more of HER2 mutation, a HER2 amplification, a p53 mutation, a BRCA mutation, an NF1 mutation, an EGFR/myc gain, a PIK3CA mutation, a CCND1 mutation or a CDH1 mutation. 
     
     
         17 . The method of  claim 1 , wherein the acquiring knowledge step comprises determining the presence of the ESR1 mutation by sequencing. 
     
     
         18 . The method of  claim 1 , wherein the subject was tested at intervals for the presence of a mutant ESR1, and wherein a mutation in the ligand binding domain of ESR1 was not detected and the subject continued treatment with a SERM based on the knowledge that a mutation in the ligand binding domain of ESR1 was not detected. 
     
     
         19 . The method of  claim 1 , wherein the subject was tested for the presence of the mutant ESR1 at 6 month or one year intervals. 
     
     
         20 . The method of  claim 1 , wherein the subject was tested at intervals for the presence of a mutant ESR1, and wherein a mutation in the ligand binding domain of ESR1 was detected and the subject stopped treatment with the SERM based on the knowledge that a mutation in the ligand binding domain of ESR1 was detected. 
     
     
         21 . A method of treating a subject having a metastatic ER+ breast cancer, comprising:
 acquiring knowledge of the presence of a constitutively activating estrogen receptor 1 (ESR1) mutation in said subject; and   administering to the subject an effective amount of an alternative therapy chosen from a SERD, an aromatase inhibitor, an anti-estrogen, a non-steroidal ERα antagonist, a tamoxifen analogue, or a combination thereof,   
       thereby treating the breast cancer in the subject. 
     
     
         22 . The method of  claim 21 , wherein the ESR1 mutation comprises a mutation chosen from a mutation at amino acid 537 or 538, or a combination thereof, of SEQ ID NO: 2. 
     
     
         23 . The method of  claim 21 , wherein said subject has been previously treated with tamoxifen. 
     
     
         24 . The method of  claim 23 , wherein said subject is ER+ and has a late stage, metastatic progressive breast cancer. 
     
     
         25 . The method of  claim 24 , wherein the agent is a SERD. 
     
     
         26 . The method of  claim 24 , wherein the anti-estrogen is fulvestrant. 
     
     
         27 . The method of  claim 24 , wherein the aromatase inhibitor is aminoglutethimide, testolactone, anastrozole, letrozole, exemestane, vorozole, formestane, fadrozole, 4-hydroxyandrostenedione, 1,4,6-androstatrien-3,17-dione (ATD), or 4-Androstene-3,6,17-trione. 
     
     
         28 . The method of  claim 24 , wherein the agent is a non-steroidal ER.alpha. antagonist or a tamoxifen analogue. 
     
     
         29 . A method of treating a subject having a breast cancer, comprising:
 acquiring knowledge of a presence of a mutant estrogen receptor 1 (ESR1) and an Estrogen Receptor positive (ER+) status, in said subject, wherein the mutant ESR1 comprises a mutation in the ligand binding domain of ESR1; and   responsive to said knowledge, administering to the subject an effective amount of a SERD.   
     
     
         30 . The method of  claim 15 , wherein the different therapeutic agent or a different therapeutic modality is an mTOR pathway inhibitor.