Diagnostic and therapeutic methods for the treatment of breast cancer

A method of treating an individual having a breast cancer, the method comprising:

• (a) determining an ER pathway activity score from a sample from the individual, wherein the ER pathway activity score from the sample is determined to be at or above a reference ER pathway activity score;
• and
• (b) administering to the individual an effective amount of an endocrine therapy;
• wherein the endocrine therapy comprises a selective estrogen receptor degrader, a selective estrogen receptor modulator, a selective estrogen receptor covalent antagonist, a selective human estrogen receptor agonist, an aromatase inhibitor, or a combination of two or more thereof.

A method for monitoring the response of an individual having a breast cancer to treatment with an endocrine therapy, the method comprising:

• (a) determining a first estrogen receptor pathway activity score from a sample from the individual at a first time point;
• (b) following step (a), determining a second estrogen receptor pathway activity score from a sample from the individual at a second time point following administration of an endocrine therapy;
• and
• (c) comparing the first estrogen receptor pathway activity score with the second estrogen receptor pathway activity score, wherein a decrease in the second estrogen receptor pathway activity score relative to the first estrogen receptor pathway activity score is predictive of an individual who is likely to respond to treatment with an endocrine therapy.

A method of treating an individual having a breast cancer, the method comprising:

• (a) determining an E2-induced score from a sample from the individual, wherein the E2-induced score from the sample is determined to be at or above a reference E2-induced score;
• and
• (b) administering to the individual an effective amount of an endocrine therapy;
• wherein the endocrine therapy comprises a selective estrogen receptor degrader, a selective estrogen receptor modulator, a selective estrogen receptor covalent antagonist, a selective human estrogen receptor agonist, an aromatase inhibitor, or a combination of two or more thereof.

A method for monitoring the response of an individual having a breast cancer to treatment with an endocrine therapy, the method comprising:

• (a) determining a first E2-induced score from a sample from the individual at a first time point;
• (b) following step (a), determining a second E2-induced score from a sample from the individual at a second time point following administration of an endocrine therapy, wherein the endocrine therapy comprises a selective estrogen receptor degrader, a selective estrogen receptor modulator, a selective estrogen receptor covalent antagonist, a selective human estrogen receptor agonist, an aromatase inhibitor, or a combination of two or more thereof;
• and
• (c) comparing the first E2-induced score with the second E2-induced score, wherein a decrease in the second E2-induced score relative to the first E2-induced score is predictive of an individual who is likely to respond to treatment with an endocrine therapy.

A method of detecting estrogen receptor pathway activity in a subject that has breast cancer, the method comprising detecting:

• (i) an expression level of at least five genes selected from the group consisting of AMZ1, C5AR2, CELSR2, FKBP4, GREB1, OLFM1, SLC9A3R1, and TFF1 and at least five genes selected from the group consisting of BCAS1, CCNG2, IL1R1, PNPLA7, SEMA3E, and STON1;
• (ii) an expression level of at least five genes selected from the group consisting of AMZ1, AREG, C5AR2, CELSR2, FKBP4, FMN1, GREB1, OLFM1, RBM24, SLC9A3R1, and TFF1 and at least five genes selected from the group consisting of BCAS1, CCNG2, IL1R1, NBEA, PNPLA7, SEMA3E, STON1, and TP53INP1;
• or
• (iii) an expression level of at least five genes selected from the group consisting of AGR3, AMZ1, AREG, C5AR2, CELSR2, CT62, FKBP4, FMN1, GREB1, IGFBP4, NOS1AP, NXPH3, OLFM1, PGR, PPM1J, RAPGEFL1, RBM24, RERG, RET, SGK3, SLC9A3R1, TFF1, and ZNF703 and at least five genes selected from the group consisting of BAMBI, BCAS1, CCNG2, DDIT4, EGLN3, FAM171B, GRM4, IL1R1, LIPH, NBEA, PNPLA7, PSCA, SEMA3E, SSPO, STON1, TGFB3, TP53INP1, and TP53INP2.

A method, comprising:

• (i) detecting, by one or more processors, a first expression level of at least five genes selected from the group consisting of AMZ1, C5AR2, CELSR2, FKBP4, GREB1, OLFM1, SLC9A3R1, and TFF1, at least five genes selected from the group consisting of AMZ1, AREG, C5AR2, CELSR2, FKBP4, FMN1, GREB1, OLFM1, RBM24, SLC9A3R1, and TFF1, or at least five genes selected from the group consisting of AGR3, AMZ1, AREG, C5AR2, CELSR2, CT62, FKBP4, FMN1, GREB1, IGFBP4, NOS1AP, NXPH3, OLFM1, PGR, PPM1J, RAPGEFL1, RBM24, RERG, RET, SGK3, SLC9A3R1, TFF1, and ZNF703;
• (ii) detecting, by the one or more processors, a second expression level of at least five genes selected from the group consisting of BCAS1, CCNG2, IL1R1, PNPLA7, SEMA3E, and STON1, at least five genes selected from the group consisting of BCAS1, CCNG2, IL1R1, NBEA, PNPLA7, SEMA3E, STON1, and TP53INP1, or at least five genes selected from the group consisting of BAMBI, BCAS1, CCNG2, DDIT4, EGLN3, FAM171B, GRM4, IL1R1, LIPH, NBEA, PNPLA7, PSCA, SEMA3E, SSPO, STON1, TGFB3, TP53INP1, and TP53INP2;
• and
• (iii) detecting, based at least on the first expression level and/or the second expression level, estrogen receptor (ER) pathway activity in a subject that has cancer.

A kit comprising a plurality of nucleic acids, wherein said plurality of nucleic acids are at least 5 nucleotides in length and are at least 95% identical to a 5 nucleotide continuous sequence or are at least 95% identical to a sequence complementary to said 5 nucleotide continuous sequence within:

• (i) at least five genes selected from the group consisting of AMZ1, C5AR2, CELSR2, FKBP4, GREB1, OLFM1, SLC9A3R1, and TFF1 and at least five genes selected from the group consisting of BCAS1, CCNG2, IL1R1, PNPLA7, SEMA3E, and STON1;
• (ii) at least five genes selected from the group consisting of AMZ1, AREG, C5AR2, CELSR2, FKBP4, FMN1, GREB1, OLFM1, RBM24, SLC9A3R1, and TFF1 and at least five genes selected from the group consisting of BCAS1, CCNG2, IL1R1, NBEA, PNPLA7, SEMA3E, STON1, and TP53INP1;
• or
• (iii) at least five genes selected from the group consisting of AGR3, AMZ1, AREG, C5AR2, CELSR2, CT62, FKBP4, FMN1, GREB1, IGFBP4, NOS1AP, NXPH3, OLFM1, PGR, PPM1J, RAPGEFL1, RBM24, RERG, RET, SGK3, SLC9A3R1, TFF1, and ZNF703 and at least five genes selected from the group consisting of BAMBI, BCAS1, CCNG2, DDIT4, EGLN3, FAM171B, GRM4, IL1R1, LIPH, NBEA, PNPLA7, PSCA, SEMA3E, SSPO, STON1, TGFB3, TP53INP1, and TP53INP2.