Department of Medical Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Unit of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy.
Oncologist. 2020 Mar;25(3):e460-e468. doi: 10.1634/theoncologist.2019-0471. Epub 2019 Nov 25.
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.
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.
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).
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.
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 <1% was not, conditioning a statistically significant interaction between such biomarker and treatment arms. The meta-analysis of individual patients' data from available studies could yield data on the role of MSI status that could inform clinical decisions.
具有高微卫星不稳定性（MSI）的胃癌（GC）患者的生存得到改善，并且辅助和/或围手术期化疗对其没有益处或危害。免疫微环境在 GC 中的作用在很大程度上尚不清楚。
在本研究中，从参加 ITACA-S 的患者中集中收集了 256 个肿瘤组织块，这是一项比较 5-FU/LV 与序贯 FOLFIRI 和顺铂-多西他赛的辅助随机试验。通过多重 PCR 评估 MSI 状态，通过 H&E 形态评估评估炎症反应，通过免疫组化评估程序性死亡配体 1（PD-L1）表达。
总体而言，9%的患者存在 MSI 高肿瘤，23%的患者存在高炎症反应，11%的患者肿瘤 PD-L1≥1%，11%的患者存在间质 PD-L1≥1%。MSI 高（危险比[HR]，0.43；p=0.02；HR，0.40；p=0.02）和高炎症反应（HR，0.55；p=0.010；HR，0.53；p=0.008）与无病生存期（DFS）和总生存期（OS）显著相关，但 PD-L1 则不然。多变量分析显示，只有 MSI 与 DFS（p=0.02）和 OS（p=0.01）均具有独立相关性，而炎症反应仅与 OS 具有独立相关性（p=0.04）。肿瘤 PD-L1≥1%的患者在序贯化疗中的无进展生存期明显长于 5-FU/LV 组（交互 p=0.04），OS 也有趋势（交互 p=0.12）。
我们的数据表明，MSI 状态可能是根治性切除的 II-III 期 GC 患者的有用预后生物标志物，应作为未来试验的分层因素。肿瘤 PD-L1≥1%应进一步作为密集化疗获益的潜在预测因子进行研究。
在 ITACA-S 试验中，对接受根治性切除术的胃癌患者进行了随机分组，分别接受密集序贯化疗方案或 5-氟尿嘧啶加亚叶酸（5-FU/LV）单药辅助治疗。本研究为该试验的事后分析。MSI 高状态与无病生存和总生存（OS）的改善独立相关，炎症反应与 OS 的改善独立相关。此外，与 5-氟尿嘧啶加亚叶酸（5-FU/LV）相比，肿瘤 PD-L1 表达≥1%与密集序贯化疗的更大获益相关，而 PD-L1 表达<1%则没有，这与生物标志物和治疗组之间存在统计学显著的相互作用有关。对现有研究中个体患者数据的荟萃分析可能会提供有关 MSI 状态作用的信息，从而为临床决策提供信息。
