Purpose: Hormone receptor-positive (HR+) breast cancer is clinically and biologically heterogeneous and subgroups with different prognostic and treatment sensitivities need to be identified. Experimental design: Research-based PAM50 subtyping and expression of additional genes was performed on 63 patients with HR+/HER2- disease randomized to neoadjuvant multi-agent chemotherapy versus endocrine therapy in a phase II trial. The biology associated with treatment response was used to derive a PAM50-based Chemo-Endocrine Score (CES). CES's predictive ability was evaluated in 4 independent neoadjuvant datasets (n=675) and 4 adjuvant datasets (n=1,505). The association of CES, intrinsic biology and PAM50 risk of relapse (ROR) was explored across 6,007 tumors. Results: Genes associated with endocrine sensitivity were also found associated with chemotherapy resistance. In the chemotherapy test/validation datasets, CES was independently associated with pathological complete response, even after adjusting for intrinsic subtype. pCR rates of the CES endocrine sensitive (CES-E), uncertain (CES-U) and chemotherapy sensitive (CES-C) groups in both datasets combined were 25%, 11% and 2%, respectively. In the endocrine test/validation datasets, CES was independently associated with response. Compared to ROR, >90% of ROR-low and ROR-high tumors were identified as CES-E and CES-C, respectively; however, each CES-group represented >25% of ROR-intermediate disease. In terms of survival outcome, CES-C was associated with poor relapse-free survival in patients with ROR-intermediate disease treated with adjuvant endocrine therapy-only or no adjuvant systemic therapy, but not in patients treated with (neo)adjuvant chemotherapy. Conclusions: CES is a genomic signature capable of estimating chemo-endocrine sensitivity in HR+ breast cancer beyond intrinsic subtype and risk of relapse.
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