Abstract P4-01-30: Proteogenomic profiles of HER2-positive breast cancer and response to neoadjuvant anti-HER2 treatment

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Abstract Background: The prospective and randomized PREDIX HER2 (n=202) compared neoadjuvant treatments of docetaxel, trastuzumab, and pertuzumab (DHP) against trastuzumab emtansine (T-DM1) in HER2-positive breast cancer, demonstrating similar pathologic complete response (pCR) rates and disease-free survival between the two groups (Hatschek, JAMA Oncology 2021). In this study, we aimed to elucidate the proteogenomic (PG) characteristics of pre-treatment HER2-positive breast cancer biopsies from the PREDIX HER2 trial, and identified predictive biomarkers for DHP or T-DM1. Methods: We performed high quality shallow whole-genome sequencing (CUTseq), RNA-sequencing (RNA-seq), and mass spectrometry-based (MS) proteomics profiles of pre-treatment core biopsies. Imputed and normalized protein abundance data were used as an input for differential protein abundance analysis using DEqMS. Correlations between mRNA expression (trimmed mean of M-values (TMM) normalized transcript per million reads (TPM)), somatic copy number alterations (SCNA) and normalized protein abundance for each gene-protein pair were measured using Spearman correlation (rho), and a false discovery rate (FDR) lower than 0.05 was considered statistically significant. Furthermore, we assessed the association of biomarkers with pathologic complete response (pCR) in each treatment arm using logistic regression, and evaluated their predictive value by adding the interaction term between biomarker and treatment arm. Results: In total, we identified 9,550 proteins (median (interquartile range): 7,424 (6,655-7,884)), of which 7099 proteins were finally quantified in each of the 137 tumors (70 samples from DHP and 67 samples from T-DM1 arm). We conducted differential protein abundance analysis adjusting for estrogen receptor (ER) status between responders (pCR) and non-responders (i.e., residual disease (RD)) within DHP and T-DM1 arm, respectively. We identified 112 upregulated (e.g., ERBB2, GRB7, CDK12, HLA-B) and 83 downregulated proteins (e.g., MAST4, FBN1, COX11) (nominal P values<0.05, log2 fold-change>0.5) within patients who attained pCR from DHP arm compared to counterparts without reaching pCR. Furthermore, GSEA demonstrated that proliferation (E2F, MYC) and inflammation and immune (IL2-STAT5, inflammatory response, IFN-γ response) pathways were enriched in pCR cases, whereas the epithelial–mesenchymal transition (EMT) pathway was enriched in RD patients. Similarly, we revealed 103 upregulated (e.g., ERBB2, ZNF652, MAPK11, CD3E) and 107 downregulated (e.g., ECM2, COL2A1, PDCD2L) proteins that were enriched in EMT and immune pathways (IFN-γ and IFN-α response, IL6-JAK-STAT3) in T-DM1 arm. We identified significant cis-correlations (rho > 0, FDR < 0.05) for 4706 (71.8%) SCNA–mRNA and 603 (9.2%) SCNA–protein pairs, while trans-effects (FDR < 0.05, for at least 50 genes) were identified in 4,636 (70.8%) and 493 (7.5%) genes at the transcriptional and translational level, respectively. We prioritized 43 putative drivers based on correlated SCNA-mRNA-protein genes, which were located on 1q32.2, 6q21, 8p11.23, 8q23.3, 11q13.3 and 17q12. Amplification of 8p11.23 (ERLIN2, RAB11FIP1) (Pfor interaction=0.02) was associated with pCR in the T-DM1 arm (odds ratio (OR)=1.95, p=0.1), but exhibited a trend towards RD in the DHP arm (OR=0.67, P=0.2). Interestingly, 36 pseudo-HER2+ cases were clustered with 9 HER2-low tumors that were re-evaluated using the 2018 ASCO guidelines, based on protein level of HER2 and its adjacent genes PNMT, MIEN1, GRB7. Patients with pseudo-HER2+ subtype were less likely to attain pCR compared to those with HER2-positive breast cancer (DHP arm, OR=0.16, p=0.001; T-DM1 arm, OR=0.27, p=0.03). Conclusion: This study underscores the importance of PG analysis in predicting the treatment response to chemotherapy, dual blockade or antibody drug conjugate in HER2-positive breast cancer. Citation Format: Kang Wang, Luca Finn Gaessler, Ioannis Zerdes, Yajing Zhu, Emmanouil Sifakis, Dimitrios Salgkamis, Luuk Harbers, Nicola Crosetto, Jonas Bergh, Thomas Hatschek, Henrik J. Johansson, Alexios Matikas, Janne Lehtiö, Theodoros Foukakis. Proteogenomic profiles of HER2-positive breast cancer and response to neoadjuvant anti-HER2 treatment [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P4-01-30.

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