Genomic index of sensitivity to endocrine therapy for breast cancer

Abstract

Purpose: We hypothesize that measurement of gene expression related to estrogen receptor α (ER; gene name ESR1) within a breast cancer sample represents intrinsic tumoral sensitivity to adjuvant endocrine therapy.

Methods: A genomic index for sensitivity to endocrine therapy (SET) index was defined from genes coexpressed with ESR1 in 437 microarray profiles from newly diagnosed breast cancer, unrelated to treatment or outcome. The association of SET index and ESR1 levels with distant relapse risk was evaluated from microarrays of ER-positive breast cancer in two cohorts who received 5 years of tamoxifen alone as adjuvant endocrine therapy (n = 225 and 298, respectively), a cohort who received neoadjuvant chemotherapy followed by tamoxifen and/or aromatase inhibition (n = 122), and two cohorts who received no adjuvant systemic therapy (n = 208 and 133, respectively).

Results: The SET index (165 genes) was significantly associated with distant relapse or death risk in both tamoxifen-treated cohorts (hazard ratio [HR] = 0.70, 95% CI, 0.56 to 0.88, P = .002; and HR = 0.76, 95% CI, 0.63 to 0.93, P = .007) and in the chemo-endocrine-treated cohort (HR = 0.19; 95% CI, 0.05 to 0.69, P = .011) independently from pathologic response to chemotherapy, but was not prognostic in two untreated cohorts. No distant relapse or death was observed after tamoxifen alone if node-negative and high SET or after chemo-endocrine therapy if intermediate or high SET.

Conclusion: The SET index of ER-related transcription predicted survival benefit from adjuvant endocrine therapy, not inherent prognosis. Prior chemotherapy seemed to enhance the efficacy of adjuvant endocrine therapy related to SET index.

Fig 1.

Hazard rate for distant relapse or death in 225 estrogen receptor (ER) –positive tamoxifen-treated patients from first validation cohort as a function of the genomic sensitivity to endocrine therapy (SET) index (A) and log2-transformed ESR1 expression (B). (C, D) Corresponding profiles for the 298 ER-positive tamoxifen-treated patients from the second validation cohort. The dashed lines show the 95% pointwise CIs of the hazard rates. A risk of 1.0 corresponds to lack of covariate effect. P values are from the likelihood ratio test.

Fig 2.

Kaplan-Meier estimates of relapse-free survival in patients treated with adjuvant tamoxifen in (A) the first validation cohort, with follow-up censored at 8 years, to define the thresholds for sensitivity to endocrine therapy (SET) index categories, and (B) the second independent validation cohort presented in toto with complete follow-up, and presented separately for the subsets with (C) node-negative and (D) node-positive breast cancer. Endocrine sensitivity groups were defined by the SET index. P values are from the log-rank test.

Fig 3.

Kaplan-Meier estimates of relapse-free survival in (A, B) two cohorts of estrogen receptor (ER) –positive, node-negative patients who did not receive any prior hormonal therapy, and (C) in patients with clinically higher-risk ER-positive breast cancer who received neoadjuvant chemotherapy (paclitaxel, fluorouracil, doxorubicin, and cyclophosphamide) followed by adjuvant endocrine therapy. Endocrine sensitivity groups were defined by the SET index. P values are from the log-rank test. (D) Contour plot depicting the dependence of the hazard rate of distant relapse or death on residual cancer burden after neoadjuvant chemotherapy (RCB index) and endocrine sensitivity (SET index) according to the Cox regression model of Table 3 estimated from the cohort in (C).