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

Hedde D Biesma, Tanya T D Soeratram, Karolina Sikorska, Irene A Caspers, Hendrik F van Essen, Jacqueline M P Egthuijsen, Aart Mookhoek, Hanneke W M van Laarhoven, Mark I van Berge Henegouwen, Marianne Nordsmark, Donald L van der Peet, Fabienne A R M Warmerdam, Maud M Geenen, Olaf J L Loosveld, Johanneke E A Portielje, Maartje Los, Daniëlle A M Heideman, Elma Meershoek-Klein Kranenbarg, Henk H Hartgrink, Johanna van SandickMarcel Verheij, Cornelis J H van de Velde, Annemieke Cats, Bauke Ylstra, Nicole C T van Grieken

Research output: Contribution to journalArticleAcademicpeer-review

10 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)640-651
Number of pages12
JournalGastric cancer
Issue number3
Publication statusPublished - May 2022


  • Epstein–Barr virus (EBV)
  • Histopathological response
  • Microsatellite instability (MSI)
  • Mucinous differentiation
  • Stomach neoplasms

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