Spatial proteomic characterization of HER2-positive breast tumors through neoadjuvant therapy predicts response

Abstract

Addition of HER2-targeted agents to neoadjuvant chemotherapy has dramatically improved pathological complete response (pCR) rates in early-stage HER2-positive breast cancer. Still, up to 50% of patients have residual disease following treatment, while others are likely overtreated. Here, we performed multiplex spatial proteomic characterization of 122 samples from 57 HER2-positive breast tumors from the neoadjuvant TRIO-US B07 clinical trial sampled pre-treatment, after 14-21 days of HER2-targeted therapy, and at surgery. We demonstrate that proteomic changes following a single cycle of HER2-targeted therapy aids the identification of tumors that ultimately undergo pCR, outperforming pre-treatment measures or transcriptomic changes. We further developed and validated a classifier that robustly predicts pCR using a single marker, CD45, measured on-treatment, and show that CD45-positive cell counts measured via conventional immunohistochemistry perform comparably. These results demonstrate novel biomarkers to enable the stratification of sensitive tumors early during neoadjuvant HER2-targeted therapy with implications for tailoring subsequent therapy.