The Role of Proliferation in Determining Response to Neoadjuvant Chemotherapy in Breast Cancer: A Gene Expression-Based Meta-Analysis.

PURPOSE To provide further insight into the role of proliferation and other cellular processes in chemosensitivity and resistance, we evaluated the association of a diverse set of gene expression signatures with response to neoadjuvant chemotherapy (NAC) in breast cancer. EXPERIMENTAL DESIGN Expression data from primary breast cancer biopsies for 1,419 patients in 17 studies prior to NAC were identified and aggregated using common normalization procedures. Clinicopathologic characteristics, including response to NAC, were collected. Scores for 125 previously published breast cancer-related gene expression signatures were calculated for each tumor. RESULTS Within each receptor-based subgroup or PAM50 subtype, breast tumors with high proliferation signature scores were significantly more likely to achieve pathologic complete response to NAC. To distinguish "proliferation-associated" from "proliferation-independent" signatures, we used correlation and linear modeling approaches. Most signatures associated with response to NAC were proliferation associated: 90.5% (38/42) in ER+/HER2- and 63.3% (38/60) in triple-negative breast cancer (TNBC). Proliferation-independent signatures predictive of response to NAC in ER+/HER2- breast cancer were related to immune activity, while those in TNBC comprised a diverse set of signatures, including immune, DNA damage, signaling pathways (PI3K, AKT, Ras, and EGFR), and "stemness" phenotypes. CONCLUSIONS Proliferation differences account for the vast majority of predictive capacity of gene expression signatures in neoadjuvant chemosensitivity for ER+/HER2- breast cancers and, to a lesser extent, TNBCs. Immune activation signatures are proliferation-independent predictors of pathologic complete response in ER+/HER2- breast cancers. In TNBCs, significant proliferation-independent signatures include gene sets that represent a diverse set of cellular processes. Clin Cancer Res; 22(24); 6039-50. ©2016 AACR.