Estrogen receptor mutations and uses thereof

1. A method of treating a subject having a breast cancer, comprising:

detecting in a sample from the subject:

(a) a mutant estrogen receptor 1 (ESR1) polypeptide or a nucleic acid molecule encoding the mutant ESR1 polypeptide, and

(b) an Estrogen Receptor positive (ER+) breast cancer;

wherein the mutant ESR1 polypeptide, or the nucleic acid molecule encoding the mutant ESR1 polypeptide, comprises one or more of:

one or more missense mutations at amino acid position 311, 341, 350, 394, 414, 433, 503, or 538 of SEQ ID NO: 2,

a deletion of nucleotides 1046-1051 of SEQ ID NO: 1, or

an insertion between amino acid positions 344 and 345 of SEQ ID NO: 2; and

administering to the subject an effective amount of an anti-cancer agent other than a Selective Estrogen Receptor Modulator (SERM), wherein the anti-cancer agent is a Selective Estrogen Receptor Degrader (SERD),

thereby treating the breast cancer in the subject.

2. The method of claim 1 , wherein the mutant ESR1 polypeptide comprises one or more of:

an aspartate to glycine substitution at amino acid position 538 (D538G) of SEQ ID NO: 2;

a deletion of amino acids Leu-Ala-Asp (LAD) at positions 349-351 of SEQ ID NO:2;

an insertion of a histidine at amino acid position 349 of SEQ ID NO:2;

a threonine to methionine substitution at amino acid position 311 (T311M) of SEQ ID NO: 2;

a serine to leucine substitution at amino acid position 341 (S341L) of SEQ ID NO: 2;

an alanine to glutamate substitution at amino acid position 350 (A350E) of SEQ ID NO: 2;

an arginine to histidine substitution at amino acid position 394 (R394H) of SEQ ID NO: 2;

a glutamine substitution at amino acid position 414 of SEQ ID NO: 2;

a serine to proline substitution at amino acid position 433 (S433P) of SEQ ID NO: 2;

an arginine to tryptophan substitution at amino acid position 503 (R503W) of SEQ ID NO: 2; or

an insertion of a cysteine between amino acid positions 344 and 345 of SEQ ID NO:2.

3. The method of claim 1 , wherein said subject:

(i) has previously received a treatment with a SERM;

(ii) has failed a first or second line of treatment with a SERM;

(iii) has a late stage, metastatic progressive breast cancer;

(iv) is postmenopausal or premenopausal;

(v) stops a treatment with a SERM prior to administration of the anti-cancer agent other than a SERM;

(vi) is premenopausal and an oophorectomy is performed on the subject;

or any combination of (i)-(vi).

4. The method of claim 1 , wherein the SERM is raloxifene, EM652, GW7604, keoxifene, toremifene, tamoxifen, lasofoxifene, levormeloxifene, bazedoxifene, or arzoxifene.

5. The method of claim 1 , wherein the subject is postmenopausal.

6. The method of claim 1 , wherein the anti-cancer agent is fulvestrant.

7. The method of claim 1 , wherein the anti-cancer agent is administered in combination with a different therapeutic agent or a different therapeutic modality.

8. The method of claim 7 , wherein the different therapeutic agent or modality is selected according to a determination of the presence of a mutation other than the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide, and wherein the mutation other than the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide is a HER2 mutation, a p53 mutation, a BRCA mutation, an NF1 mutation, an EGFR/myc mutation, a PIK3CA mutation, a CCND1 mutation, a CDH1 mutation, or any combination thereof.

9. The method of claim 1 , wherein the detecting step comprises determining the presence of the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide by sequencing.

10. The method of claim 1 , wherein the subject was previously tested for the presence of a mutant ESR1 polypeptide or a nucleic acid molecule encoding the mutant ESR1 polypeptide, wherein the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide was not detected during the previous testing,

and wherein the subject was administered a SERM based on the knowledge that the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide was not detected during the previous testing.

11. The method of claim 1 , wherein the subject was previously tested at intervals for the presence of a mutant ESR1 polypeptide or a nucleic acid molecule encoding the mutant ESR1 polypeptide, wherein the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide was not detected during the previous testing,

and wherein the subject continued a treatment with a SERM based on the knowledge that the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide was not detected during the previous testing.

12. The method of claim 1 , wherein the subject was previously tested or is being tested for the presence of a mutant ESR1 polypeptide or a nucleic acid molecule encoding the mutant ESR1 polypeptide at 6 month or one-year intervals.

13. The method of claim 1 , wherein the subject was previously tested at intervals for the presence of a mutant ESR1 polypeptide or a nucleic acid molecule encoding the mutant ESR1 polypeptide, wherein the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide was detected during the previous testing,

and wherein the subject stopped a treatment with a SERM based on the knowledge that the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide was detected during the previous testing.

14. The method of claim 1 , further comprising generating a personalized cancer treatment report, by:

obtaining the sample from the subject,

detecting the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide in the sample, and

selecting a treatment based on the ESR1 mutation detected.

15. The method of claim 1 , further comprising:

(i) identifying, selecting, or obtaining information or knowledge that the subject has participated in a clinical trial or has been treated for cancer; and

(ii) acquiring genotype information that identifies a mutant ESR1 polypeptide or a nucleic acid molecule encoding the mutant ESR1 polypeptide as being in the subject,

wherein the presence of the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide identifies the subject as having an increased risk for, or having, a cancer associated with the mutant ESR1 polypeptide or the nucleic acid molecule encoding the mutant ESR1 polypeptide.