Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis
Predictive test for chemotherapy response in resectable gastric cancer: a multi-cohort, retrospective analysis
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DOI：
10.1016/s1470-2045(18)30108-6
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发表时间：
2018-05-01
期刊：
影响因子：
51.1
通讯作者：
Noh, Sung Hoon
中科院分区：
文献类型：
--
作者：
Cheong, Jae-Ho;Yang, Han-Kwang;Noh, Sung Hoon
背景：手术后辅助化疗可提高II-III期可切除胃癌患者的生存率。然而，辅助化疗后观察到的总体生存获益是中等的，这表明并非所有接受辅助化疗的可切除胃癌患者都能从中获益。我们的目的是开发和验证可切除的II-III期胃癌患者辅助化疗反应的预测性试验。我们通过多步骤策略开发了一种预测性测试，其由两个基于规则的分类器算法组成，具有辅助化疗反应和预后的预测值。探索性生物信息学分析确定了胃癌转录组数据集中的生物学相关候选基因。在发现分析中，开发了一种四基因实时RT-PCR检测方法，并在福尔马林固定、石蜡包埋（FFPE）的肿瘤组织中进行了分析验证，该组织来自在延世癌症中心接受D2胃切除术加辅助氟尿嘧啶化疗（n=193）或单纯手术（n=114）治疗的307例II-III期胃癌患者的内部队列。使用相同的内部队列来评估单个患者分类器基因的预后和化疗反应预测值，其使用与5年总生存期的关联。使用来自CLASSIC试验（NCT 00411229）中接受治疗的独立患者队列的FFPE肿瘤样本子集（n=625）验证了结果，这些患者接受了D2胃切除术加卡培他滨和奥沙利铂化疗（n=323）或单纯手术（n=302）。主要终点是5年的总survival.Findings我们确定了四个相关的胃癌功能（GZMB，WARS，SFRP 4和CDX 1），形成了单一的患者分类器检测相关的分类器基因。在验证队列中，预后单个患者分类器根据GZMB、WARS和SFRP 4的表达，625例患者中有79例（13%）为低风险，296例（47%）为中等风险，250例（40%）为高风险，这些组的5年总生存率为83.2%。（95% CI 75.2-92.0）、74.8%（69.9-80.1）和66.0%（60.1-72.4）（p=0.012）。预测性单个患者分类器（基于GZMB、WARS和CDX 1的表达）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。在预测化疗获益组中，与仅接受手术的患者相比，术后接受辅助化疗的患者的5年总生存率显著提高（80% [95% CI 73.5-87.1] vs 64.5% [56.8-73.3];单变量风险比0.47 [95% CI 0.30-0.75]，p=0.0015），而在无获益组中，5年总生存率没有观察到这种改善（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）。预测性单个患者分类器组（化疗获益vs无获益）可以预测验证队列中5年总生存期方面的辅助化疗获益（单变量分析中P-相互作用=0.036）。在内部评估cohol.Interpretation中获得了类似的结果。在本研究中验证的单个患者分类器提供了独立于标准风险分层方法的临床重要预后信息，并在两个独立的可切除的II-III期胃癌患者队列中预测了手术后的化疗反应。单个患者分类器可以补充TNM分期，以优化手术后有资格接受辅助化疗的可切除胃癌患者的决策。在前瞻性研究中进一步验证这些结果是必要的。
Background 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.Methods 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.Findings 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-interaction =0.036 in univariate analysis). Similar results were obtained in the internal evaluation cohort.Interpretation 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.