Multiomic characterization of response and resistance to neoadjuvant chemoradiotherapy in esophageal squamous cell carcinoma

<h4>Background</h4>In neoadjuvant chemoradiotherapy (NCRT), only 1/3 of patients with esophageal squamous cell carcinoma (ESCC) achieve pathologic complete response (pCR). Here, we aimed to depict the biological landscape of ESCC with different responses to NCRT and identify biomarkers to facilitate clinical decision-making.<h4>Methods</h4>Tumor specimens before NCRT were obtained for whole exome sequencing (WES), RNA sequencing, and data-independent acquisition (DIA) mass spectrometry. Genomic data were analyzed for significantly mutated genes (SMGs), copy number alterations, microsatellite instability (MSI), tumor mutation burden (TMB), and mutational signatures. Transcriptomic and proteomic data were used to examine differentially activated pathways. Gene set enrichment analysis (GSEA) and ActivePathways were used for single omics and joint multiomics analyses, respectively. Treatment-resistance biomarkers were identified and confirmed in a separate cohort using immunohistochemistry (IHC).<h4>Results</h4>FBXW7 mutation (Fisher's exact test, P=0.03) and 9p21.3 cytoband loss (q-value =0.001) are the significant genetic variations in the pCR group. Combined transcriptomic and proteomic analyses revealed that the type I interferon signaling pathways and retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) signaling pathways were enriched in non-pCR tumors. A biomarker panel of 12 proteins predictive of non-pCR tumors was identified, 10 of which were verified using multiplex IHC (mIHC) in an independent cohort.<h4>Conclusions</h4>We described the multiomic biological characteristics of ESCC with distinct responses to NCRT and proposed a panel of proteins as predictive biomarkers for non-pCR patients.