{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T17:26:27Z","timestamp":1780507587001,"version":"3.54.1"},"reference-count":41,"publisher":"American Medical Association (AMA)","issue":"3","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JAMA Netw Open"],"abstract":"Importance<\/jats:title>Patients treated with radiotherapy (RT) for prostate cancer (PC) have increased risk of secondary rectal cancer (SRC) and more limited treatment options.<\/jats:p><\/jats:sec>Objective<\/jats:title>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).<\/jats:p><\/jats:sec>Design, Setting, and Participants<\/jats:title>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.<\/jats:p><\/jats:sec>Main Outcomes and Measures<\/jats:title>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.<\/jats:p><\/jats:sec>Results<\/jats:title>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<\/jats:italic>\u2009&amp;lt;\u2009.001) and anterior rectal wall (20 of 57 [35.1%] vs 67 of 496 [13.5%]; P<\/jats:italic>\u2009&amp;lt;\u2009.001) 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<\/jats:italic>\u2009=\u2009.01) and disease-free survival (40.3% vs 71.2%; P<\/jats:italic>\u2009=\u2009.006) 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<\/jats:italic>\u2009=\u2009.047), lower frequency of APC<\/jats:italic> alterations (15 [48.4%] vs 432 [79.9%]; P<\/jats:italic>\u2009&amp;lt;\u2009.001), and higher rates of SMAD4<\/jats:italic> inactivation (8 [25.8%] vs 54 [10.0%]; P<\/jats:italic>\u2009=\u2009.01) 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<\/jats:italic>\u2009&amp;lt;\u2009.001).<\/jats:p><\/jats:sec>Conclusions and Relevance<\/jats:title>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.<\/jats:p><\/jats:sec>","DOI":"10.1001\/jamanetworkopen.2025.1039","type":"journal-article","created":{"date-parts":[[2025,3,18]],"date-time":"2025-03-18T15:01:05Z","timestamp":1742310065000},"page":"e251039","source":"Crossref","is-referenced-by-count":2,"title":["Clinical and Genomic Characterization of Secondary Rectal Cancer After Radiotherapy for Prostate Cancer"],"prefix":"10.1001","volume":"8","author":[{"given":"Dana M.","family":"Omer","sequence":"first","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Farheen","family":"Shah","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"},{"name":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anisha","family":"Luthra","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin-Tung","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina I.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Williams","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Henry","family":"Walch","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Floris S.","family":"Verheij","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roni","family":"Rosen","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Janet","family":"Alvarez","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Canan","family":"Firat","sequence":"additional","affiliation":[{"name":"Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Georgios","family":"Karagkounis","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin R.","family":"Weiser","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Widmar","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iris H.","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanouil P.","family":"Pappou","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Garrett M.","family":"Nash","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J. Joshua","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Walid K.","family":"Chatila","sequence":"additional","affiliation":[{"name":"Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul B.","family":"Romesser","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinru","family":"Shia","sequence":"additional","affiliation":[{"name":"Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip 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