Abstract 6414: Molecular differentiation between complete and incomplete responders to neoadjuvant therapy in rectal cancer
Authors: Huang Fengyuan , McLeod M. Chandler , Irwin Regina Kay , Smithson Mary , Yue Zongliang , Gao Min , Hardiman Karin M. , Chong Zechen 
Published: March 2024

Abstract
Neoadjuvant chemoradiotherapy (nCRT) is the standard treatment for locally advanced rectal cancer, but only 20-40% of patients completely respond to this treatment. This study aims to identify the molecular features associated with a 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. A comprehensive integrated analysis was performed. We found that patients with a complete response have decreased risk of both local recurrence and future metastasis. We identified multiple molecular differences between complete and incomplete responders. Complete responders have a higher tumor mutation burden and more significant co-occurring mutations than the incomplete responders. In addition, mutations in DNA repair genes 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 upregulation of immune checkpoint proteins. Our study directly informs the clinical management of rectal cancer by elucidating the molecular differences between tumors with complete and incomplete responses to neoadjuvant chemoradiotherapy (nCRT), as well as the features of tumors prone to recurrence. We have pinpointed critical molecular markers and clinical indicators—such as tumor size, specific gene mutations, and particular mutation patterns—that are significant predictors of treatment response. These findings offer valuable biomarkers for personalizing treatment strategies. Additionally, the observed mutation enrichment in DNA repair genes among complete responders suggests new avenues for therapeutic innovation. By highlighting the distinct molecular and immune profiles of non-responder tumors at higher recurrence risk, our research supports the advancement of precision oncology approaches, enhancing prognosis and treatment customization in rectal cancer care, ultimately striving to bridge the gap between scientific discovery and clinical application.
Citation Format: Fengyuan Huang, M. Chandler McLeod, Regina Kay Irwin, Mary Smithson, Zongliang Yue, Min Gao, Karin M. Hardiman, Zechen Chong. Molecular differentiation between complete and incomplete responders to neoadjuvant therapy in rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6414.