Multiomic factor analysis for pathologic complete response after pembrolizumab + trastuzumab + pertuzumab in HER2-enriched early breast cancer: WSG-Keyriched-1 trial

Abstract Purpose: We performed multiomic factor analysis of biomarkers potentially associated with pathologic complete response (pCR) after chemotherapy-free combination of immunotherapy and dual HER2 blockade. Experimental Design: 48 patients with HER2 2+ (ISH+) or 3+ early breast cancer (eBC), stage I-III and HER2-enriched subtype received pembrolizumab, trastuzumab biosimilar, and pertuzumab. Primary outcome was pCR (ypT0/is ypN0). Multiomic factors representing combined markers from pooling different translational research marker data were identified based on the eigenvalue >1 criteria. Additionally, logistic regressions with elastic net regularization were performed using all single markers, multiomic factors, and clinical characteristics to evaluate their association with pCR. Results: The multiomic factor involving genes related to immune response and tumorigenesis, multiplexed immunohistochemistry (mIHC) markers related to immune response and HER2 in the stroma, and stromal tumor-infiltrating lymphocytes (sTILs) were associated with pCR. pCR rates were 66.7% and 28.6% in the high (>median) and low (≤median) factor score groups, respectively (unadjusted OR 5.00, 95%CI 1.35, 18.56; nominal p=.016). In the analysis using standardized values for all individual markers from gene expression analysis, mIHC analysis in the stroma, and sTIL, markers with the greatest impact on pCR were genes FNBP1, CD36, MYCN, and SIX1 (OR between 1.43 and 1.62), and progesterone receptor status (OR 0.65), which surpassed grade (OR 1.22) and nodal status (OR 0.90). Conclusions: Our multiomic analysis uncovered mechanisms of tumor response to immunotherapy combined with dual HER2 blockade. These results could inform the design of larger trials investigating chemotherapy-free regimens in selected patients with HER2+ eBC.