Neupane Achal, Liu Qi, Taneja Siddhant, French Jennifer, Ehrhardt Matthew J, Brinkman Tara M, Webster Rachel, Yang Jun J, Im Cindy, Turcotte Lucie M, Neglia Joseph P, Gramatges M Monica, Howell Rebecca M, Bhatia Smita, Ness Kirsten K, Hudson Melissa M, Armstrong Gregory T, Robison Leslie L, Yasui Yutaka, Sapkota Yadav
Department of Epidemiology and Cancer Control, St Jude Children's Research Hospital, Memphis, TN, USA.
School of Public Health, University of Alberta, Edmonton, AB, Canada.
Lancet Oncol. 2025 Jun;26(6):806-816. doi: 10.1016/S1470-2045(25)00157-3.
Survivors of childhood cancer are at risk of subsequent neoplasms (SNs) associated with exposure to radiotherapy and chemotherapy, as well as with genetic predisposition. We aimed to estimate the relative contributions of these risk factors to the total SN burden in survivor populations.
We analysed data from two retrospectively constructed cohorts with ongoing recruitment and prospective follow-up: the St Jude Lifetime Cohort (SJLIFE; 4401 participants; NCT00760656) and the Childhood Cancer Survivor Study (CCSS; 7943 participants; NCT01120353). We used multivariable piecewise-exponential models to calculate attributable fractions to assess the contributions of radiotherapy and chemotherapy exposures, genetic predisposition (comparing the top two tertiles with the lowest tertile of polygenic risk scores [PRSs] where the tertile is from external general population corresponding to SN outcome) and lifestyle factors (physical activity, smoking, alcohol consumption, obesity, and diet) to incident of the first occurrences of SNs as the primary outcome.
The study was conducted between Jan 1, 2024, and Sept 30, 2024. Of the 12 344 survivors eligible for analysis, median attained age was 33·0 years (IQR 24·1-42·1) in SJLIFE and 36·0 years (29·5-43·6) in CCSS; 6127 (49·6%) were men and 6217 (50·4%) were women. Most patients were White (10 907 [88·4%]). The median follow-up from primary cancer diagnosis was 24·2 years (IQR 11·7-35·4) in SJLIFE (from Sept 13, 2007 to April 20, 2020) and 28·0 years (8·9-37·2) in CCSS (from Jan 1, 1975 to Dec 31, 2023). Cancer treatments and genetic risk jointly contributed to a substantial proportion of incident SN cases with attributable fractions ranging from 30% (95% CI 6-49; sarcoma) to 92% (89-94; meningioma). Higher exposure levels of radiotherapy contributed most, particularly in older (≥35 years; SJLIFE proportion of SNs 44·7% [95% CI 41·9-47·5]) compared with younger (<35 years; 40·0% [37·1-43·3]) follow-up age periods. Elevated genetic risk based on the PRSs accounted for a notable proportion, ranging from 1% (95% CI 0-7; meningioma) to 52% (39-62; thyroid cancer), surpassing contributions of chemotherapies, ranging from 3% (1-6; SMNs) to 35% (19-49; sarcoma). Lifestyle factors contributed negligibly.
Cancer treatments and genetic predisposition are primary contributors to the risk of SNs in childhood cancer survivors, and lifestyle factors seem to have a minimal effect. These results highlight the crucial need to consider both treatment history and genetic factors in developing effective risk assessment and surveillance strategies for this vulnerable population.
US National Institutes of Health and the American Lebanese Syrian Associated Charities.
儿童癌症幸存者有发生继发肿瘤（SNs）的风险，这与放疗、化疗暴露以及遗传易感性有关。我们旨在评估这些风险因素对幸存者群体中SNs总负担的相对贡献。
我们分析了两个回顾性构建的队列数据，这两个队列持续招募并进行前瞻性随访：圣裘德终身队列（SJLIFE；4401名参与者；NCT00760656）和儿童癌症幸存者研究（CCSS；7943名参与者；NCT01120353）。我们使用多变量分段指数模型计算归因分数，以评估放疗和化疗暴露、遗传易感性（将多基因风险评分[PRSs]最高的两个三分位数与最低三分位数进行比较，其中三分位数来自与SN结果对应的外部普通人群）和生活方式因素（身体活动、吸烟、饮酒、肥胖和饮食）对首次发生SNs事件的贡献，将其作为主要结局。
该研究于2024年1月1日至2024年9月30日进行。在12344名符合分析条件的幸存者中，SJLIFE队列的中位年龄为33.0岁（四分位间距24.1 - 42.1），CCSS队列的中位年龄为36.0岁（29.5 - 43.6）；6127名（49.6%）为男性，6217名（50.4%）为女性。大多数患者为白人（10907名[88.4%]）。SJLIFE队列（从2007年9月13日至2020年4月20日）自原发癌诊断后的中位随访时间为24.2年（四分位间距11.7 - 35.4），CCSS队列（从1975年1月1日至2023年12月31日）的中位随访时间为28.0年（8.9 - 37.2）。癌症治疗和遗传风险共同导致了相当比例的SNs发病病例，归因分数范围从30%（95%置信区间6 - 49；肉瘤）到92%（89 - 94；脑膜瘤）。放疗暴露水平较高的贡献最大，尤其是在年龄较大（≥35岁；SJLIFE队列中SNs的比例为44.7%[95%置信区间41.9 - 47.5]）的随访年龄段，而年龄较小（<35岁；40.0%[37.1 - 43.3]）的随访年龄段贡献相对较小。基于PRSs的遗传风险升高占显著比例，范围从1%（95%置信区间0 - 7；脑膜瘤）到52%（39 - 62；甲状腺癌），超过了化疗的贡献，化疗的贡献范围从3%（1 - 6；SMNs）到35%（19 - 49；肉瘤）。生活方式因素的贡献可忽略不计。
癌症治疗和遗传易感性是儿童癌症幸存者发生SNs风险的主要因素，生活方式因素似乎影响极小。这些结果凸显了在为这一脆弱人群制定有效的风险评估和监测策略时，同时考虑治疗史和遗传因素的迫切需求。
美国国立卫生研究院和美国黎巴嫩叙利亚联合慈善机构。
