Abstract A026: Identifying unique genomic and clinical characteristics of radiation-associated rectal cancer
Authors: Omer Dana M. R. , Luthra Anisha , Thompson Hannah M. , Yuval Jonathan B. , Romesser Paul B. , Paty Philip B. , Garcia-Aguilar Julio , Sanchez-Vega Francisco 
Published: December 2022

Abstract
Introduction: Prostate cancer patients treated with radiation therapy (RT) are at risk of developing radiation-associated rectal cancer (RARC). Previous literature reports worse overall survival in these patients compared to those with non-radiation associated primary rectal cancer (PRC), yet the genomic and clinical characteristics of RARC are not well understood. We compared molecular profiles of RARC and PRC patients to better understand the mechanism of RARC tumorigenesis and its interplay with clinical outcomes. Methods: We performed a retrospective analysis of 22 patients who had stage I-IV rectal cancer (within 12 cm of the anal verge) and had received previous RT for prostate cancer. Patients were excluded if they had a latency period between cancers of &lt;5 years or additional metachronous cancers. Tumors were profiled using MSK-IMPACT, a targeted DNA-sequencing panel that identifies somatic mutations, copy number changes and fusions in a panel of 341-505 genes using a combination of solid tissue and matched blood specimens. The cohort included patients who had received external beam radiation therapy (EBRT, n=8), brachytherapy (BT, n=7), and combined EBRT-BT (n=7). All the RARC patients were microsatellite stable (MSS). To compare molecular features while accounting for clinical differences, we performed propensity score matching (1:1 ratio) using a background set of 616 patients with MSS PRC who had also been sequenced with MSK-IMPACT. Patients were matched for gender, age at diagnosis, distance from anal verge, tumor size, tumor location (anterior, lateral or posterior) and stage. Results: When compared to the general background set of 616 MSS PRC cases, RARC patients tended to be older at diagnosis (median 74 vs. 54 years, P=&lt;0.0001). RARC tumors were more likely to have size &lt;4cm at diagnosis (70% vs. 36%, P=0.01), to originate in the distal rectum, within 0-4 cm from the anal verge (55% vs. 25%, P=&lt;0.001) and also to develop along the anterior rectal wall (41% vs 22%, P=&lt;0.001). We then compared the genomic features of RARC to the clinically matched PRC set. RARC exhibited lower tumor mutational burden than PRC (median 4.4 vs. 6.0 mut/Mb, P=0.011), but no difference was observed in terms of chromosomal instability measured as the fraction of genome altered by copy number changes [median 0.11 vs. 0.17, P=0.49]. RARC patients also exhibited significantly lower frequency of APC mutations (41% vs. 82%, P=0.012) compared to PRC patients. Conclusion: We have identified clinical and molecular differences between RARC and PRC, including distal and anterior locations as well as lower TMB and lower frequency of APC mutations in RARC patients. The results provide clinically relevant insights into the unique attributes of RARC and may ultimately help to improve prognostication and treatment for this unique population.
Citation Format: Dana M. R. Omer, Anisha Luthra, Hannah M. Thompson, Jonathan B. Yuval, Paul B. Romesser, Philip B. Paty, Julio Garcia-Aguilar, Francisco Sanchez-Vega. Identifying unique genomic and clinical characteristics of radiation-associated rectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A026.