Abstract 349: Association of DNA damage response capacity with neoadjuvant chemoradiation response in locally advanced rectal cancer

Abstract

Abstract Background: Locally advanced rectal cancer (RC) cases are ~60% of newly diagnosed RCs, with neoadjuvant chemoradiation therapy (nCRT) followed by surgery as the standard of care. While nCRT is highly toxic, it is also beneficial. Recent prospective trials reported that up to 59% locally advanced RC cases exhibit complete clinical response, suggesting these patients as ideal candidates for organ preservation. However, currently there is no biomarker to predict who will or will not benefit from nCRT. The goal of this study was to establish a predictive biomarker for benefit from nCRT, based on the hypothesis that inherent DNA damage response (DDR) capacity contributes to nCRT response in RC. Methods: To gain insight into inherent DDR capacity, we profiled primary peripheral blood lymphocytes (pPBLs) from RC patients by quantitative immunofluorescence, Luminex-multianalyte assay, and pPBL DNA whole exome sequencing (WES). RC patients analyzed were segregated by neoadjuvant rectal (NAR) score: NAR<1, complete responders (CRs), n=21; NAR>14, poor responders (PoRs), n=21; 1<NAR<14, partial responders (PRs), n=12. Conditional inference trees were used to establish optimal cut points for the nCRT response outcomes data. Single nucleotide variants from WES data were annotated and analyzed for variation in genes involved in DDR, and associated pathways. The variants were annotated as predicted-pathogenic based on the consensus of four variant effect prediction programs. Results: pPBLs from CRs showed significantly elevated γH2AX foci (a hallmark of double strand breaks) vs. PoRs (P<0.001, Kruskal-Wallis test). Multianalyte DDR panel testing revealed significantly increased expression or activation of 6 DDR proteins (ATR, MDM2, phosphorylated H2AXS139 (γ), p53S15, Chk1S345, and Chk2T68) in pPBLs from CRs versus PoRs (p<0.01, logistic regression model) and significantly increased protein levels of 4 DDR proteins (ATR, MDM2, p53S15, Chk2T68) in pPBLs from CRs vs. pPBLs from PRs (p<0.05, logistic regression model). We generated a combined DDR Score which positively and significantly correlated with CR vs. PoR (P<0.001, ordinal logistic regression model). From the combined DDR score, using mean score >0.082 as a cutpoint, we could include 90% patients with a CR. Finally, WES analysis of pPBL DNA from 15 CRs and 15 PoRs revealed that CRs were enriched in predicted-pathogenic variants in base excision repair genes vs. PoRs (p<0.01, q<0.025, FDR). Conclusion and future work: Overall, our data suggests inherent DDR capacity testing may predict the magnitude of benefit from nCRT and assist in patient selection for treatment. Validation in a larger RC patient population is needed to confirm these findings. Biological studies testing the impact of the identified variants in base excision repair on inherent DDR capacity are warranted. Citation Format: Elena V. Demidova, Randy W. Lesh, Vladimir Avkshtol, Margret B. Einarson, Erica A. Golemis, Sanjeevani Arora, Joshua E. Meyer. Association of DNA damage response capacity with neoadjuvant chemoradiation response in locally advanced rectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 349.