Department of Surgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul, South Korea; Department of Biochemistry & Molecular Biology, Yonsei University College of Medicine, Seoul, South Korea; Yonsei Biomedical Research Institute, Seoul, South Korea; Brain Korea 21 PLUS Project for Medical Science, Seoul, South Korea.
Department of Surgery and Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
Lancet Oncol. 2018 May;19(5):629-638. doi: 10.1016/S1470-2045(18)30108-6. Epub 2018 Mar 19.
Adjuvant chemotherapy after surgery improves survival of patients with stage II-III, resectable gastric cancer. However, the overall survival benefit observed after adjuvant chemotherapy is moderate, suggesting that not all patients with resectable gastric cancer treated with adjuvant chemotherapy benefit from it. We aimed to develop and validate a predictive test for adjuvant chemotherapy response in patients with resectable, stage II-III gastric cancer.
In this multi-cohort, retrospective study, we developed through a multi-step strategy a predictive test consisting of two rule-based classifier algorithms with predictive value for adjuvant chemotherapy response and prognosis. Exploratory bioinformatics analyses identified biologically relevant candidate genes in gastric cancer transcriptome datasets. In the discovery analysis, a four-gene, real-time RT-PCR assay was developed and analytically validated in formalin-fixed, paraffin-embedded (FFPE) tumour tissues from an internal cohort of 307 patients with stage II-III gastric cancer treated at the Yonsei Cancer Center with D2 gastrectomy plus adjuvant fluorouracil-based chemotherapy (n=193) or surgery alone (n=114). The same internal cohort was used to evaluate the prognostic and chemotherapy response predictive value of the single patient classifier genes using associations with 5-year overall survival. The results were validated with a subset (n=625) of FFPE tumour samples from an independent cohort of patients treated in the CLASSIC trial (NCT00411229), who received D2 gastrectomy plus capecitabine and oxaliplatin chemotherapy (n=323) or surgery alone (n=302). The primary endpoint was 5-year overall survival.
We identified four classifier genes related to relevant gastric cancer features (GZMB, WARS, SFRP4, and CDX1) that formed the single patient classifier assay. In the validation cohort, the prognostic single patient classifier (based on the expression of GZMB, WARS, and SFRP4) identified 79 (13%) of 625 patients as low risk, 296 (47%) as intermediate risk, and 250 (40%) as high risk, and 5-year overall survival for these groups was 83·2% (95% CI 75·2-92·0), 74·8% (69·9-80·1), and 66·0% (60·1-72·4), respectively (p=0·012). The predictive single patient classifier (based on the expression of GZMB, WARS, and CDX1) assigned 281 (45%) of 625 patients in the validation cohort to the chemotherapy-benefit group and 344 (55%) to the no-benefit group. In the predicted chemotherapy-benefit group, 5-year overall survival was significantly improved in those patients who had received adjuvant chemotherapy after surgery compared with those who received surgery only (80% [95% CI 73·5-87·1] vs 64·5% [56·8-73·3]; univariate hazard ratio 0·47 [95% CI 0·30-0·75], p=0·0015), whereas no such improvement in 5-year overall survival was observed in the no-benefit group (72·9% [66·5-79·9] in patients who received chemotherapy plus surgery vs 72·5% [65·8-79·9] in patients who only had surgery; 0·93 [0·62-1·38], p=0·71). The predictive single patient classifier groups (chemotherapy benefit vs no-benefit) could predict adjuvant chemotherapy benefit in terms of 5-year overall survival in the validation cohort (p=0·036 in univariate analysis). Similar results were obtained in the internal evaluation cohort.
The single patient classifiers validated in this study provide clinically important prognostic information independent of standard risk-stratification methods and predicted chemotherapy response after surgery in two independent cohorts of patients with resectable, stage II-III gastric cancer. The single patient classifiers could complement TNM staging to optimise decision making in patients with resectable gastric cancer who are eligible for adjuvant chemotherapy after surgery. Further validation of these results in prospective studies is warranted.
Ministry of ICT and Future Planning; Ministry of Trade, Industry, and Energy; and Ministry of Health and Welfare.
手术后辅助化疗可改善 II-III 期可切除胃癌患者的生存。然而，观察到的辅助化疗的整体生存获益是适度的，这表明并非所有接受辅助化疗的可切除胃癌患者都从中获益。我们旨在开发和验证一种可预测 II-III 期可切除胃癌患者辅助化疗反应的检测方法。
在这项多队列、回顾性研究中，我们通过多步策略开发了一种由两个基于规则的分类器算法组成的预测性测试，这些算法对辅助化疗反应和预后具有预测价值。探索性生物信息学分析确定了胃癌转录组数据集中与生物学相关的候选基因。在发现分析中，开发了一种实时 RT-PCR 检测方法，并在 307 名接受 D2 胃癌切除术加氟尿嘧啶为基础的辅助化疗（n=193）或单纯手术（n=114）的 II-III 期胃癌患者的内部队列的 FFPE 肿瘤组织中进行了分析验证。使用与 5 年总生存率的关联，对相同的内部队列进行了单个患者分类器基因的预后和化疗反应预测价值评估。使用 CLASSIC 试验（NCT00411229）中接受 D2 胃癌切除术加卡培他滨和奥沙利铂化疗（n=323）或单纯手术（n=302）的 FFPE 肿瘤样本的一个子集（n=625）进行了验证。主要终点是 5 年总生存率。
我们确定了四个与相关胃癌特征相关的分类器基因（GZMB、WARS、SFRP4 和 CDX1），它们构成了单个患者分类器检测方法。在验证队列中，基于 GZMB、WARS 和 SFRP4 表达的预后单个患者分类器确定了 625 名患者中的 79 名（13%）为低风险，296 名（47%）为中风险，250 名（40%）为高风险，这些患者的 5 年总生存率分别为 83.2%（95%CI 75.2-92.0）、74.8%（69.9-80.1）和 66.0%（60.1-72.4）（p=0.012）。基于 GZMB、WARS 和 CDX1 表达的预测性单个患者分类器将验证队列中的 625 名患者中的 281 名（45%）分配到化疗获益组，344 名（55%）分配到无获益组。在预测的化疗获益组中，与仅接受手术的患者相比，接受手术后辅助化疗的患者 5 年总生存率显著提高（80%[95%CI 73.5-87.1]vs 64.5%[56.8-73.3]；单因素风险比 0.47[95%CI 0.30-0.75]，p=0.0015），而在无获益组中，5 年总生存率没有改善（接受化疗加手术的患者为 72.9%[66.5-79.9]，仅接受手术的患者为 72.5%[65.8-79.9]；0.93[0.62-1.38]，p=0.71）。在验证队列中，预测性单个患者分类器组（化疗获益与无获益）可以根据 5 年总生存率预测辅助化疗的获益（单因素分析中 p=0.036）。在内部评估队列中也得到了类似的结果。
本研究中验证的单个患者分类器提供了与标准风险分层方法独立的重要临床预后信息，并预测了两个可切除 II-III 期胃癌患者独立队列的手术后辅助化疗反应。单个患者分类器可以补充 TNM 分期，以优化适合辅助化疗的可切除胃癌患者的决策。需要在前瞻性研究中进一步验证这些结果。
韩国信息通信技术和未来规划部；韩国贸易、工业和能源部；以及韩国卫生和福利部。
Zotero 插件