Aleix Prat, Ana Lluch, Arran K. Turnbull, Anita K. Dunbier, Lourdes Calvo, Joan Albanell, Juan de la Haba-Rodríguez, Angels Arcusa, José Ignacio Chacón, Pedro Sánchez-Rovira, Arrate Plazaola, Montserrat Muñoz, Laia Paré, Joel S. Parker, Nuria Ribelles, Begoña Jimenez, Abdul Aziz Bin Aiderus, Rosalía Caballero, Barbara Adamo, Mitch Dowsett, Eva Carrasco, Miguel Martín, J. Michael Dixon, Charles M. Perou, Emilio Alba

Hormone receptor-positive (HR+) breast cancer is clinically and biologically heterogeneous and subgroups with different prognostic and treatment sensitivities need to be identified. 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. 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. CES is a genomic signature capable of estimating chemo-endocrine sensitivity in HR+ breast cancer beyond intrinsic subtype and risk of relapse.