Integrative Molecular Characterization of Resistance to Neoadjuvant Chemoradiation in Rectal Cancer

• DOI: 10.1158/1078-0432.ccr-19-0908
• Publication Date: 2019-06-28T18:55:13Z
• Authors: Sophia C. Kamran; Jochen K. Lennerz; Claire A. Margolis; David Liu; Brendan Reardon; Stephanie A. Wank...; Emily E. Van Seve...; Adam Tracy; Jennifer Y. Wo; Scott L. Carter; Henning Willers; Ryan B. Corcoran; Theodore S. Hong; Eliezer M. Van Allen
• Keywords: Neoadjuvant Therapy

Abstract Purpose: Molecular properties associated with complete response or acquired resistance to concurrent chemotherapy and radiotherapy (CRT) are incompletely characterized. Experimental Design: We performed integrated whole-exome/transcriptome sequencing immune infiltrate analysis on rectal adenocarcinoma tumors prior neoadjuvant CRT (pre-CRT) at time of resection (post-CRT) in 17 patients [8 complete/partial responders, 9 nonresponders (NR)]. Results: was not increased tumor mutational burden neoantigen load did alter the distribution established somatic mutations cancer. Concurrent KRAS/TP53 (KP) NR were enriched for an epithelial–mesenchymal transition transcriptional program. Furthermore, reduced CD4/CD8 T-cell infiltrates a post-CRT M2 macrophage phenotype. Absence any local recurrences, KP/NR status predicted worse progression-free survival, suggesting that escape during after specific genomic features contributes distant progression. Conclusions: Overall, while impact profiles, impacted microenvironment, particularly resistant cases.