Molecular differentiation between complete and incomplete responders to neoadjuvant therapy in rectal cancer

TL;DR

This study identifies molecular differences between rectal cancer patients who fully respond to treatment and those who do not, offering insights for precision therapy.

Contribution

The study reveals novel molecular predictors and mechanisms of response to neoadjuvant therapy in rectal cancer.

Findings

Complete responders have higher tumor mutation burden and co-occurring mutations compared to incomplete responders.

Defective DNA repair is associated with complete response to neoadjuvant therapy.

Immune hot tumors with upregulated immune checkpoints are linked to worse outcomes in non-responders.

Abstract

Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer, but only 20–40% of patients completely respond to this treatment.

To define the molecular features that are associated with response to nCRT, we generated and collected genomic and transcriptomic data from 712 cancers prior to treatment 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. Complete responder tumors have a higher tumor mutation burden and more significant co-occurring mutations than the incomplete responder tumors. In addition, mutations in DNA repair genes (across multiple mechanisms of repair) were enriched in complete responders and they also had lower expression of these genes indicating that defective DNA repair is associated with complete response to nCRT. Using logistic regression, we identified three significant predictors of complete response: tumor size, mutations within specific network genes, and the existence of three or more specific co-occurrent mutations. In incompletely 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 upregulated of immune checkpoint proteins.

Overall, our study provides a comprehensive understanding of the molecular features associated with response to nCRT and the molecular differences in non-responder tumors that later reoccur. This knowledge may provide critical insight for the development of precision therapy for rectal cancer.

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