Molecular predictors of treatment resistance and recurrence following neoadjuvant therapy in rectal cancer.

Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer, but only 20–40% of patients completely respond to this treatment. Pre-treatment predictors of response are understudied. To define the molecular features that are associated with response to nCRT, we compared genomic and transcriptomic data from 318 pre-treatment biopsies of microsatellite stable rectal cancers from our own data and from publicly available data. We found that patients with a complete response have decreased risk of both local recurrence and future metastasis. We identified multiple differences in DNA mutations and transcripts between complete and incomplete responders. Different genes contained significantly co-occurring and mutually exclusive mutations between CR and ICR tumors. In addition, complete responders had lower expression of genes enriched with multiple mechanisms of DNA repair indicating that defective DNA repair may be associated with complete response to nCRT. We developed a logistic regression model adjusted for tumor size, stage, and age to determine the relationship co-occurring mutations and tumor complete response and found that the number of certain co-occurring mutations to be highly predictive of CR. When we assessed for predictors of recurrence in incomplete responder tumors, abnormal cell–cell interaction and increased cancer associated fibroblasts were associated with recurrence. Additionally, gene expression analysis identified a subset of immune hot tumors with worse outcomes and upregulation of immune checkpoint proteins. These data provide additional understanding of the molecular features associated with response to nCRT and the underlying molecular differences in responders and non-responders.