Methods and compositions for modulating estrogen receptor mutants

1. A method for treating an ER-related disease or condition comprising administering an estrogen receptor modulator compound to a patient having a mutation in the ESR1 gene,

wherein the ER-related disease or condition is breast cancer;

the mutation in the ESR1 gene is an amino acid substitution in the ligand binding domain of the estrogen receptor selected from E380Q, L536R, L536P, Y537C, Y537N, Y537S and D538G of SEQ ID NO:2;

and the estrogen receptor modulator compound has the structure:

or a pharmaceutically acceptable salt, or solvate thereof.

2. The method of claim 1 wherein the breast cancer is metastatic, hormone resistant, estrogen receptor positive, estrogen receptor negative, progesterone receptor negative, HER2 positive, or HER2 negative breast cancer.

3. The method of claim 2 wherein the breast cancer is resistant to treatment with an aromatase inhibitor.

4. The method of claim 3 wherein the aromatase inhibitor is anastrozole, letrozole, or exemestane.

5. The method of claim 1 wherein the breast cancer is Basal or Luminal subtype.

6. The method of claim 1 wherein the patient is a pre-menopausal or post-menopausal female patient.

7. The method of claim 1 wherein the patient has failed one or more anti-cancer therapies.

8. The method of claim 1 wherein the mutation in the ESR1 gene is a somatic mutation.

9. The method of claim 1 wherein the patient expresses a wild-type ER and a mutant ER.

10. The method of claim 1 wherein the patient expresses a homodimer of two mutant ER-α polypeptides.

11. The method of claim 1 wherein the patient expresses a homodimer of two wild-type ER-α polypeptides.

12. The method of claim 1 wherein the patient expresses a heterodimer of one wild-type ER-α polypeptide and one mutant ER-α polypeptide, or a heterodimer of one wild-type ER-β polypeptide and one mutant ER-α polypeptide.

13. The method of claim 12 wherein the patient has a tumor and a plurality of cells of the tumor express the mutant ER.

14. The method of claim 1 wherein the patient has received a chemotherapeutic agent, a biological therapy, a cancer vaccine, an angiogenesis inhibitor, hormone therapy, radiation therapy, surgery, or any combination thereof.

15. The method of claim 14 wherein the biological therapy is a peptide, a cytokine, an antibody, a therapeutic virus, a therapeutic bacterium, gene therapy, siRNA, adoptive T-cell transfer, or any combination thereof.

16. The method of claim 1 wherein the patient has received an aromatase inhibitor, a selective estrogen receptor modulator (SERM), a selective estrogen degrader (SERD), a PI3 kinase/mTOR pathway inhibitor, a CDK 4/6 inhibitor, a HER-2 inhibitor, an EGFR inhibitor, a PD-1 inhibitor, poly ADP-ribose polymerase (PARP) inhibitor, a histone deacetylase (HDAC) inhibitor, an HSP90 inhibitor, a VEGFR inhibitor, an AKT inhibitor, chemotherapy, or any combination thereof.

17. The method of claim 1 wherein the patient has received fulvestrant, tamoxifen, anastrozole, letrozole, exemestane, goserelin, leuprolide, raloxifene, toremifene, megestrol acetate, bazedoxifene, or any combination thereof.

18. The method of claim 1 wherein the patient has received an anthracycline, a taxane, a platinum agent, an epothilone, or a nucleoside analog.

19. The method of claim 1 wherein the patient has received cisplatin, carboplatin, capecitabine, cyclophosphamide, docetaxel, doxorubicin, epirubicin, eribulin, fluorouracil, gemcitabine, ixabepilone, mitoxantrone, methotrexate, paclitaxel, pamidronate, vinorelbine, or any combination thereof.

20. The method of claim 1 wherein the patient has received pertuzumab, trastuzumab, lapatinib, everolimus, bevacizumab, temsirolimus, or any combination thereof.

21. The method of claim 1 wherein the ESR1 mutation results in a substitution, insertion or deletion of one or more amino acids in the ER polypeptide.

22. The method of claim 21 wherein the ESR1 mutation results in an amino acid substitution in the N-terminal domain, the DNA binding domain, the hinge region or the ligand binding domain of the estrogen receptor.

23. The method of claim 1 wherein the amino acid substitution is selected from among L536R, Y537N, Y537C, Y537S, and D538G.

24. The method of claim 1 wherein the patient is selected for treatment with the estrogen receptor modulator compound by the steps of:

a) detecting a mutation in the ESR1 gene in a sample comprising nucleic acid from the patient; and

b) selecting the patient for treatment with the estrogen receptor modulator compound if the patient has the ESR1 mutation.

25. The method of claim 24 wherein the nucleic acid is RNA or DNA.

26. The method of claim 25 wherein the DNA is genomic DNA.

27. The method of claim 24 wherein the method further comprises isolating mRNA from the nucleic acid sample.

28. The method of claim 24 wherein the method further comprises amplifying a nucleic molecule comprising the mutation from the nucleic acid sample.

29. The method of claim 28 wherein amplification is by polymerase chain reaction (PCR) or digital PCR.

30. The method of claim 29 wherein PCR amplification comprises using a pair of oligonucleotide primers that flank the region comprising the mutation.

31. The method of claim 24 comprising contacting the nucleic acid with a sequence specific nucleic acid probe, wherein the sequence specific nucleic acid probe that binds to the nucleic acid having the mutation and does not bind to the wild-type nucleic acid.

32. The method of claim 24 wherein the sample comprises nucleic acid from one or more tumor cells.

33. The method of claim 32 wherein the tumor cell is taken from a tumor biopsy sample, a blood sample, a serum sample, a lymph sample, or a bone marrow aspirate.

34. The method of claim 33 wherein the tumor cell is a circulating tumor cell.

35. The method of claim 34 wherein the sample comprises circulating tumor DNA (ctDNA).