Independent validation of the PAM50-based Chemo-Endocrine Score in hormonal receptor positive HER2-positive breast cancer treated with neoadjuvant therapy.

Background We do not yet have validated biomarkers to predict response and outcome within hormone receptor-positive/HER2-positive (HR+/HER2+) breast cancer (BC). The PAM50-based chemo-endocrine score (CES) predicts chemo-endocrine sensitivity in HR+/HER2-negative BC. Here, we evaluate the relationship of CES with response and survival in HR+/HER2+ BC. Methods Intrinsic subtype and clinicopathological data were obtained from 7 studies in which patients were treated with HER2-targeted therapy either with endocrine therapy (ET) or with chemotherapy (CTX). CES was evaluated as a continuous variable and categorically from low to high scores (CES-C [chemo-sensitive], CES-U [uncertain] and CES-E [endocrine-sensitive]. We first analyzed each dataset individually, and then all combined. Multivariable analyses were used to test CES association with pathologic complete response (pCR) and disease-free survival (DFS). Results 457 patients were included (112 with ET and 345 with CTX). In the combined cohort, CES-C, CES-U and CES-E were identified in 60%, 23% and 17% of the patients, respectively. High CES (i.e. CES-E) was associated with a lower probability of achieving pCR independently of clinical characteristics, therapy, intrinsic subtype, and study (adjusted odd ratio=0.42; p=0.016). 295 patients were analyzed for DFS with a median follow-up of 66 months. High CES was also associated with better DFS (adjusted hazard ratio=0.174, p=0.003) independently of pCR, clinical characteristics and intrinsic subtype. In patients with residual disease, the adjusted DFS hazard ratio of CES was 0.160 (p=0.012). Conclusions In HER2+/HR+ BC, CES is useful for predicting chemo-endocrine sensitivity and provides additional prognostication beyond intrinsic subtype and clinicopathologic characteristics.