Omer Dana M, Shah Farheen, Luthra Anisha, Chen Chin-Tung, Lee Christina I, Williams Hannah, Walch Henry, Verheij Floris S, Rosen Roni, Alvarez Janet, Firat Canan, Karagkounis Georgios, Weiser Martin R, Widmar Maria, Wei Iris H, Pappou Emmanouil P, Nash Garrett M, Smith J Joshua, Chatila Walid K, Romesser Paul B, Shia Jinru, Paty Philip B, Garcia-Aguilar Julio, Sanchez-Vega Francisco
Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York.
Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
JAMA Netw Open. 2025 Mar 3;8(3):e251039. doi: 10.1001/jamanetworkopen.2025.1039.
Patients treated with radiotherapy (RT) for prostate cancer (PC) have increased risk of secondary rectal cancer (SRC) and more limited treatment options.
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.
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.
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).
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.
接受前列腺癌（PC）放射治疗（RT）的患者患继发性直肠癌（SRC）的风险增加，且治疗选择更为有限。
评估PC后SRC的肿瘤分子特征、临床特征和肿瘤学结局，并将其与原发性直肠癌（PRC）的特征进行比较。
设计、设置和参与者：这项病例对照研究纳入了在PC放疗后5年或更长时间被诊断为SRC的患者，以及1994年2月1日至2022年9月31日期间在纽约纪念斯隆凯特琳癌症中心接受治疗的PRC患者。
分析临床信息和DNA测序数据。使用对数秩检验和Cox比例风险回归模型比较SRC患者和临床匹配的PRC患者的肿瘤学结局。分别使用Wilcoxon秩和检验和Fisher精确检验比较数值变量和分类变量。
分析包括604例PRC男性患者（71.6%；中位年龄55岁[四分位间距，46 - 66岁]）和64例SRC男性患者（中位年龄78岁[四分位间距，72 - 82岁]）。SRC患者的直肠远端肿瘤更多（63例中的37例[58.7%] vs 581例中的131例[22.5%]；P <.001），直肠前壁肿瘤更多（57例中的20例[35.1%] vs 496例中的67例[13.5%]；P <.001），接受新辅助治疗的可能性更小（64例中的33例[51.6%] vs 604例中的570例[94.4%]），与临床匹配的PRC患者相比，5年总生存率更低（45.7% vs 64.9%；P =.01），无病生存率更低（40.3% vs 71.2%；P =.006）。来自31例SRC肿瘤的靶向DNA测序数据显示，与541例PRC肿瘤相比，突变负担更低（中位值，每兆碱基[Mb] 4.4个[四分位间距，3.2 - 6.7个] vs 每Mb 5.8个[四分位间距，4.4 - 7.0个]；P =.047），APC改变的频率更低（15例[48.4%] vs 432例[79.9%]；P <.001），SMAD4失活率更高（8例[25.8%] vs 54例[10.0%]；P =.01）。来自17例SRC肿瘤的全外显子测序数据显示，与28例PRC肿瘤相比，移码缺失率更高（中位值，5.0个[四分位间距，4.0 - 9.0个]变异 vs 2.5个[四分位间距，1.0 - 4.2个]变异；P <.001）。
在这项病例对照研究中，PC放疗后SRC患者的生存率比PRC患者更差，分子特征也不同。这些发现可能有助于改善SRC的临床管理。
