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

Abstract

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 <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.

Microsatellite instability in Gastric Cancer: Between lights and shadows

“…A growing body of evidence has revealed that the MSI status in GC is positively correlated with a better survival compared with the MSS counterpart [3,6]. Additionally, due to their intrinsic mutational burden, increased inflammation and expression of immune checkpoints, such as the programmed death-ligand 1 (PD-L1), MSI tumors exhibit promising molecular hallmarks of potential sensitivity to cancer immunotherapy [7,8].…”

The Prognostic Importance of Microsatellite Instability Status in Turkish Stage II and III Gastric Cancer Patients who Received Adjuvant Chemotherapy

“…In comparison, the post hoc analysis of the ITA-CA-S trial, which included 256 patients, showed that MSI-H status was an independent favorable factor for both DFS and OS in stage II and III GC patients who had received adjuvant or perioperative CT. 24 In the post hoc analysis of the CLAS-SIC trial, which included patients who had been treated with D2 gastrectomy alone or adjuvant CT after D2 gastrectomy, 19 (6.2%) MSI-H patients had received adjuvant CT; 21 had received surgery alone. Disease-free survival was evaluated in groups, and MSI-H was an independent factor for DFS.…”

Review: Gastric cancer: Basic aspects

“…In a study aiming at determining the predictive value of MLH1 and PD‐L1 expression for prognosis and response to preoperative chemotherapy in gastric cancer, Hashimoto et al 26 demonstrated that patients with resectable MSI GC, due to loss of mutL homolog 1 (MHL1), exhibit a good prognosis and negative response to fluorouracil‐based chemotherapy. In a similar study, Di Bartolomeo et al 27 showed that MSI status was independently associated with increased disease‐free survival and overall survival in GC patients randomised for an intensive sequential chemotherapy regimen vs fluorouracil/leucovorin monotherapy as adjuvant treatment. It is noteworthy that MSI tumours are also the ones with a better response to current immunotherapies 28 .…”