Prognostic and Predictive Value of Microsatellite Instability, Inflammatory Reaction and PD-L1 in Gastric Cancer Patients Treated with Either Adjuvant 5-FU/LV or Sequential FOLFIRI Followed by Cisplatin and Docetaxel: A Translational Analysis from the ITACA-S Trial
Prognostic and Predictive Value of Microsatellite Instability, Inflammatory Reaction and PD-L1 in Gastric Cancer Patients Treated with Either Adjuvant 5-FU/LV or Sequential FOLFIRI Followed by Cisplatin and Docetaxel: A Translational Analysis from the ITACA-S Trial
复制标题
DOI：
10.1634/theoncologist.2019-0471
复制
发表时间：
2019-11-25
期刊：
影响因子：
5.8
通讯作者：
Cavanna, Luigi
中科院分区：
文献类型：
--
作者：
Di Bartolomeo, Maria;Morano, Federica;Cavanna, Luigi
背景：高微卫星不稳定性（MSI）胃癌（GC）患者的生存率提高，辅助和/或围手术期化疗无益处或危害。免疫微环境在GC中的作用在很大程度上是未知的。材料与方法在本研究中，集中收集了256例来自ITACA-S的患者的肿瘤组织块，ITACA-S是一项5-FU/LV与序贯FOLFIRI和顺铂-多西他赛的随机辅助试验。MSI状态通过多重PCR评估，炎症反应通过H&E形态学评估，程序性死亡配体1（PD-L1）表达通过免疫组织化学评估。总体而言，9%的患者有MSI高肿瘤，23%有高炎症反应，11%有肿瘤PD-L1 >= 1%，11%有间质PD-L1 >= 1%。发现MSI高（风险比[HR]，0.43; p = .02; HR，0.40; p =.02）和炎症反应高（HR，0.55; p = .010; HR，0.53; p = .008）与无病生存期（DFS）和总生存期（OS）显著相关，但与PD-L1无关。在多变量分析中，只有MSI显示与DFS（p = .02）和OS（p = .01）独立相关，而炎症反应仅与OS（p = .04）独立相关。肿瘤PD-L1 >= 1%的患者在序贯化疗中的DFS显著长于5-FU/LV组（相互作用p = 0.04），OS趋势（相互作用p = 0.12）。结论MSI状态可能是II ~ III期胃癌根治性切除患者的一个有用的预后指标，在未来的研究中应作为分层因素。肿瘤PD-L1 >= 1%应作为强化化疗获益的潜在预测因素进行进一步研究。实践意义在ITACA-S试验中，对胃癌根治术患者随机接受强化序贯化疗方案与5-FU/LV单药辅助治疗的事后分析中，MSI高状态与更好的无病生存期和总生存期（OS）独立相关，炎症反应与更好的OS独立相关。与5-氟尿嘧啶加亚叶酸（5-FU/LV）相比，PD-L1表达>= 1%的肿瘤患者从强化序贯化疗中获益更大，而PD-L1表达
Background Patients with high microsatellite instability (MSI) gastric cancer (GC) show improved survival and no benefit or harm from adjuvant and/or perioperative chemotherapy. The role of immune microenvironment in GC is largely unknown. Materials and Methods In the present study, 256 tumor tissue blocks were centrally collected from patients enrolled in ITACA-S, a randomized adjuvant trial of 5-FU/LV versus sequential FOLFIRI and cisplatin-docetaxel. MSI status was assessed by multiplex PCR, inflammatory reaction by H&E morphological assessment, and programmed death-ligand 1 (PD-L1) expression by immunohistochemistry. Results Overall, 9% patients had MSI-high tumors, 23% had high inflammatory reaction, 11% had tumor PD-L1 >= 1%, and 11% had stromal PD-L1 >= 1%. A significant association with disease-free survival (DFS) and overall survival (OS) was found for MSI-high (hazard ratio [HR], 0.43; p = .02; HR, 0.40; p = .02) and high inflammatory reaction (HR, 0.55; p = .010; HR, 0.53; p = .008) but not for PD-L1. At multivariable analysis, only MSI showed an independent association with both DFS (p = .02) and OS (p = .01), whereas inflammatory reaction showed an independent association only with OS (p = .04). Patients with tumor PD-L1 >= 1% had a significantly longer DFS in sequential chemotherapy than in than 5-FU/LV arm (interaction p = .04) and a trend for OS (interaction p = .12). Conclusion Our data suggest that MSI status could be a useful prognostic biomarker in patients with radically resected stage II-III GC and should be used as stratification factor in future trials. Tumor PD-L1 >= 1% should be further investigated as a potential predictor of benefit from intensive chemotherapy. Implications for Practice In this post hoc analysis of patients with radically resected gastric cancer randomized to an intensive sequential chemotherapy regimen versus 5-FU/LV monotherapy as adjuvant treatment in the ITACA-S trial, MSI-high status was independently associated with better disease-free survival and overall survival (OS) and inflammatory reaction was independently associated with better OS. Moreover, tumor PD-L1 expression >= 1% was associated with greater benefit from intensive sequential chemotherapy compared with 5-fluorouracil plus leucovorin (5-FU/LV), whereas PD-L1 expression