Proteogenomic analysis of the CALGB 40601 (Alliance) HER2+ breast cancer neoadjuvant trial reveals resistance biomarkers

作者：Eric J. Jaehnig, Aranzazu Fernandez-Martinez, Tanmayi D. Vashist, Matthew V. Holt, LaTerrica Williams, Jonathan T. Lei, Chang In Moon, Beom-Jun Kim, Yongchao Dou, Haoquan Zhao, Viktoriya Korchina, Richard A. Gibbs, Donna M. Muzny, HarshaVardhan Doddapaneni, Charles M. Perou, Lisa A. Carey, Ana I. Robles, Terry Hyslop, Yujia Wen, Linda McCart, Azra Krek, Francesca Petralia, George Miles, Shyam M. Kavuri, Michael A. Gillette, D.R. Mani, Steven A. Carr, Bing Zhang, Matthew J. Ellis, Shankha Satpathy, Meenakshi Anurag · 发表于：Cell Reports Medicine · 年份：2025 · DOI：10.1016/j.xcrm.2025.102154 · 被引用次数：3 · 研究领域：HER2/EGFR in Cancer Research、Breast Cancer Treatment Studies、Bioinformatics and Genomic Networks

Proteogenomic analysis is applied to samples from the CALGB 40601 (Alliance) randomized neoadjuvant trial of trastuzumab, lapatinib, or the combination to identify biomarkers associated with pathological response status. Absence of ERBB2 gene amplification and human epidermal growth factor receptor 2 (HER2) protein overexpression by proteogenomics is associated with non-pathological compete response (pCR) (p < 0.05), highlighting potential false positives from standard diagnostics. Pathway analysis in proteogenomics-confirmed HER2+ samples identifies elevated epithelial-mesenchymal transition (EMT) and WNT-β-catenin signaling in non-pCR cases before treatment. Twenty-four pCR-associated proteins reproduce in a second proteomic dataset, and four (GPRC5A, TPBG, SP140L, and NEU1) are significant in a third. A meta-analysis of ten diverse neoadjuvant anti-HER2 treatment regimens from four independent studies confirms that non-pCR cases express higher levels of mRNA for G protein-coupled receptor class C group 5 member A (GPRC5A, p = 0.0002) and trophoblast glycoprotein (TPBG, p = 0.00008). Thus, proteogenomic analysis identifies negative biomarkers for pCR and alternative plasma membrane targets for treatment-resistant HER2+ breast cancer. This trial is registered at clinicaltrials.gov (NCT00770809).