Response to neoadjuvant chemotherapy and survival in molecular subtypes of resectable gastric cancer: a post hoc analysis of the D1/D2 and CRITICS trials

Abstract

Background Epstein–Barr virus positivity (EBV+) and microsatellite instability (MSI-high) are positive prognostic factors for survival in resectable gastric cancer (GC). However, benefit of perioperative treatment in patients with MSI-high tumors remains topic of discussion. Here, we present the clinicopathological outcomes of patients with EBV+, MSI-high, and EBV−/MSS GCs who received either surgery only or perioperative treatment. Methods EBV and MSI status were determined on tumor samples collected from 447 patients treated with surgery only in the D1/D2 trial, and from 451 patients treated perioperatively in the CRITICS trial. Results were correlated to histopathological response, morphological tumor characteristics, and survival. Results In the D1/D2 trial, 5-year cancer-related survival was 65.2% in 47 patients with EBV+, 56.7% in 47 patients with MSI-high, and 47.6% in 353 patients with EBV−/MSS tumors. In the CRITICS trial, 5-year cancer-related survival was 69.8% in 25 patients with EBV+, 51.7% in 27 patients with MSI-high, and 38.6% in 402 patients with EBV−/MSS tumors. Interestingly, all three MSI-high tumors with moderate to complete histopathological response (3/27, 11.1%) had substantial mucinous differentiation. No EBV+ tumors had a mucinous phenotype. 115/402 (28.6%) of EBV−/MSS tumors had moderate to complete histopathological response, of which 23/115 (20.0%) had a mucinous phenotype. Conclusions In resectable GC, MSI-high had favorable outcome compared to EBV−/MSS, both in patients treated with surgery only, and in those treated with perioperative chemo(radio)therapy. Substantial histopathological response was restricted to mucinous MSI-high tumors. The mucinous phenotype might be a relevant parameter in future clinical trials for MSI-high patients.

Extended Lymphadenectomy for Gastric Cancer in the Neoadjuvant Era: Current Status, Clinical Implications and Contentious Issues

“…Although MSI was found to be a positive prognostic factor in the post hoc analysis of the MAGIC and the CLASSIC trials, the use of perioperative or adjuvant chemotherapy was not effective or even potentially detrimental. The same results were confirmed in the post hoc analysis of the CRITICS study and the ITACA-S trial [93,94]. Similarly, in 2019 a meta-analysis further demonstrated that MSS patients could benefit from adjuvant chemotherapy [95].…”

Microsatellite instability and sex differences in resectable gastric cancer – A pooled analysis of three European cohorts

“…Tumour samples from Cologne scored as MMR proficient (MMRP) were grouped together with MSS. MSI status of the tumour samples from the D1/D2 and CRITICS trials was published before [21]. A detailed description of the MSI analysis and MMR immunohistochemistry method for each of the three cohorts can be found in online supplementary materials.…”

Treatment Response Predictors of Neoadjuvant Therapy for Locally Advanced Gastric Cancer: Current Status and Future Perspectives

“…MSI expression has been reported as a predictor of chemotherapy efficacy and response to immune checkpoint inhibitors [ 48 ]. However, the benefit of perioperative chemotherapy in MSI-high (MSH-H) gastric cancer remains controversial, due to the limited number of these patients in various clinical studies [ 49 ].…”

“…However, data on response rates to NAC in EBV+ resectable gastric cancer are limited [ 57 ]. In the CRITICS trial, among the molecular subgroups of gastric cancer, EBV+ tumors had the highest histopathologic response rate and better outcomes than EBV-/MSS tumors [ 49 ].…”