Synapse - Clinical and genomic characterization of secondary rectal cancer after radiotherapy for prostate cancer

Clinical and genomic characterization of secondary rectal cancer after radiotherapy for prostate cancer Journal Article

Authors:	Omer, D. M.; Shah, F.; Luthra, A.; Chen, C. T.; Lee, C. I.; Williams, H.; Walch, H.; Verheij, F. S.; Rosen, R.; Alvarez, J.; Firat, C.; Karagkounis, G.; Weiser, M. R.; Widmar, M.; Wei, I. H.; Pappou, E. P.; Nash, G. M.; Smith, J. J.; Chatila, W. K.; Romesser, P. B.; Shia, J.; Paty, P. B.; Garcia-Aguilar, J.; Sanchez-Vega, F.
Article Title:	Clinical and genomic characterization of secondary rectal cancer after radiotherapy for prostate cancer
Abstract:	Importance Patients treated with radiotherapy (RT) for prostate cancer (PC) have increased risk of secondary rectal cancer (SRC) and more limited treatment options. Objective To assess the tumor molecular profile, clinical characteristics, and oncologic outcomes of SRC after PC and compare them with those of primary rectal cancer (PRC). Design, Setting, and Participants This case-control study included patients with SRC diagnosed 5 or more years after RT for PC and patients with PRC who were treated at Memorial Sloan Kettering Cancer Center in New York between February 1, 1994, and September 31, 2022. Main Outcomes and Measures Clinical information and DNA sequencing data were analyzed. Oncologic outcomes were compared between patients with SRC and clinically matched patients with PRC using log-rank tests and Cox proportional hazards regression models. Numerical and categorical variables were compared using the Wilcoxon rank sum test and Fisher exact test, respectively. Results The analysis included 604 male patients with PRC (71.6%; median age, 55 [IQR, 46-66] years) and 64 male patients with SRC (median age, 78 [IQR, 72-82] years). Patients with SRC had more distal rectum (37 of 63 [58.7%] vs 131 of 581 [22.5%]; P < .001) and anterior rectal wall (20 of 57 [35.1%] vs 67 of 496 [13.5%]; P < .001) tumors, were less likely to receive neoadjuvant treatment (33 of 64 [51.6%] vs 570 of 604 [94.4%]), and had shorter 5-year overall survival (45.7% vs 64.9%; P = .01) and disease-free survival (40.3% vs 71.2%; P = .006) compared with clinically matched patients with PRC. Targeted DNA sequencing data from 31 SRC tumors identified lower mutational burden (median, 4.4 [IQR, 3.2-6.7] per megabase [Mb] vs 5.8 [IQR, 4.4-7.0] per Mb; P = .047), lower frequency of APC alterations (15 [48.4%] vs 432 [79.9%]; P < .001), and higher rates of SMAD4 inactivation (8 [25.8%] vs 54 [10.0%]; P = .01) compared with 541 PRC tumors. Whole-exome sequencing data from 17 SRC tumors identified a higher rate of frameshift deletions compared with 28 PRC tumors (median, 5.0 [IQR, 4.0-9.0] vs 2.5 [IQR, 1.0-4.2] variants; P < .001). Conclusions and Relevance In this case-control study, patients with SRC after RT for PC had worse survival and different molecular profiles than patients with PRC. These findings may help improve the clinical management of SRC.
Keywords:	risk; bladder; impact; radiation-therapy; landscape; mutational signatures
Journal Title:	JAMA Network Open
Volume:	8
Issue:	3
ISSN:	2574-3805
Publisher:	American Medical Association
Date Published:	2025-03-01
Start Page:	e251039
Language:	English
ACCESSION:	WOS:001449658600010
DOI:	10.1001/jamanetworkopen.2025.1039
PROVIDER:	wos
PMCID:	PMC11920846
PUBMED:	40100215
Notes:	The MSK Cancer Center Support Grant (P30 CA008748) is acknowledge in the PDF -- Corresponding authors is MSK author: Francisco Sanchez-Vega -- Source: Wos