Identification and Construction of Combinatory Cancer Hallmark-Based Gene Signature Sets to Predict Recurrence and Chemotherapy Benefit in Stage II Colorectal Cancer
Identification and Construction of Combinatory Cancer Hallmark-Based Gene Signature Sets to Predict Recurrence and Chemotherapy Benefit in Stage II Colorectal Cancer
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DOI：
10.1001/jamaoncol.2015.3413
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发表时间：
2016-01-01
期刊：
影响因子：
28.4
通讯作者：
Wang, Edwin
中科院分区：
文献类型：
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作者：
Gao, Shanwu;Tibiche, Chabane;Wang, Edwin
在过去的20年里，关于II期结直肠癌（CRC）患者辅助治疗的决策一直是肿瘤学中最具挑战性和争议性的问题之一。目的开发强大的基于癌症标志物的组合基因签名集（CSS集），更准确地预测预后，并确定一个子集的II期CRC患者谁可以获得生存的好处，从辅助化疗。和参与者13个回顾性研究与II期结直肠癌患者进行了临床随访和辅助化疗进行了分析。分别将来自2个和11个独立队列的总计162名和843名患者分别用作发现和验证队列。13个队列共纳入1005例II期CRC患者。其中，在3个独立的队列中，416例患者中有84例接受了基于氟尿嘧啶的辅助化疗。主要结果和指标确定CSS集以预测无复发生存率，并确定一个II期CRC患者子集，这些患者可以从基于氟尿嘧啶的辅助化疗中获得实质性的生存益处。（各30个基因）被鉴定并用于构建用于确定预后的CSS集。CSS集在11个独立队列的767例未接受辅助化疗的II期CRC患者中进行了验证。CSS将患者准确地分为低风险、中等风险和高风险组。5年无复发生存率分别为94%、78%和45%，分别占II期患者的60%、28%和12%。416例CSS组定义的高风险II期CRC患者接受氟尿嘧啶为基础的辅助化疗，显示出从治疗中获得的生存益处（即5年内复发率降低30%-40%）。它们对于预后预测更加准确和稳健，并有助于识别可以从基于氟尿嘧啶的辅助化疗中获得生存益处的II期疾病患者。
IMPORTANCE Decisions regarding adjuvant therapy in patients with stage II colorectal cancer (CRC) have been among the most challenging and controversial in oncology over the past 20 years.OBJECTIVE To develop robust combinatory cancer hallmark-based gene signature sets (CSS sets) that more accurately predict prognosis and identify a subset of patients with stage II CRC who could gain survival benefits from adjuvant chemotherapy.DESIGN, SETTING, AND PARTICIPANTS Thirteen retrospective studies of patients with stage II CRC who had clinical follow-up and adjuvant chemotherapy were analyzed. Respective totals of 162 and 843 patients from 2 and 11 independent cohorts were used as the discovery and validation cohorts, respectively. A total of 1005 patients with stage II CRC were included in the 13 cohorts. Among them, 84 of 416 patients in 3 independent cohorts received fluorouracil-based adjuvant chemotherapy.MAIN OUTCOMES AND MEASURES Identification of CSS sets to predict relapse-free survival and identify a subset of patients with stage II CRC who could gain substantial survival benefits from fluorouracil-based adjuvant chemotherapy.RESULTS Eight cancer hallmark-based gene signatures (30 genes each) were identified and used to construct CSS sets for determining prognosis. The CSS sets were validated in 11 independent cohorts of 767 patients with stage II CRC who did not receive adjuvant chemotherapy. The CSS sets accurately stratified patients into low-, intermediate-, and high-risk groups. Five-year relapse-free survival rates were 94%, 78%, and 45%, respectively, representing 60%, 28%, and 12% of patients with stage II disease. The 416 patients with CSS set-defined high-risk stage II CRC who received fluorouracil-based adjuvant chemotherapy showed a substantial gain in survival benefits from the treatment (ie, recurrence reduced by 30%-40% in 5 years).CONCLUSIONS AND RELEVANCE The CSS sets substantially outperformed other prognostic predictors of stage 2 CRC. They are more accurate and robust for prognostic predictions and facilitate the identification of patients with stage II disease who could gain survival benefit from fluorouracil-based adjuvant chemotherapy.