Despite progresses in prevention and screening, gastric adenocarcinoma (GA) remains the third cause of cancer-related mortality worldwide (1). Immune checkpoint inhibitors (ICI) have been developed and evaluated in several settings in GA. The benefit of nivolumab and pembrolizumab, two PD-1 inhibitors, was first shown over placebo in pretreated patients in the ATTRACTION-2 and KEYNOTE-061 trials (2, 3). In the first-line metastatic setting, addition of nivolumab to chemotherapy recently improved overall survival (14.4 versus 11.1 months) for PD-L1-positive [combined positive score (CPS) ≥ 5] advanced gastric and esophageal adenocarcinomas (4).

Somatic genomic analysis of large series of gastric cancers identified distinct molecular subtypes with their own prognosis and therapeutic targets. The Cancer Genome Atlas classified 22% of gastric cancers as microsatellite instability-high (MSI-H) tumors, with deficient mismatch repair (dMMR) and high mutational burden (TMB) (5). As for colorectal adenocarcinoma, MSI-H tumors seem to have a good prognosis, and are more frequent in localized gastric cancers (6 to 20%) (6–10) than in advanced disease (2.5-3%) (10, 11).

The benefit of ICI for MSI-H tumors was first provided by a small phase 2 trial evaluating pembrolizumab in refractory tumors with or without MMR deficiency (12). Efficacy was shown in both colorectal and non-colorectal MSI-H/dMMR tumors including one MSI-H gastric cancer. The KEYNOTE-158 study further confirmed the benefit of pembrolizumab for various non-colorectal MSI-H/dMMR tumors, with a 46% response rate and a 11 months median progression-free survival for the gastric adenocarcinoma subgroup (13). Later, an exploratory analysis of the KEYNOTE-062 study showed that pembrolizumab improved overall survival compared to first-line chemotherapy in the small MSI-H subgroup (50/763 patients) whereas it was only non-inferior for the overall population of PD-L1-positive (CPS ≥ 1) gastric adenocarcinomas (14, 15). A recently published meta-analysis of randomized clinical trials confirmed the predictive role of microsatellite instability for PD-1 blockade efficacy (16). However, the number of MSI-H GA treated with ICI is currently low (all available data in MSI-H GA are summarized in Table 1 ).

Patterns of response and progression during immunotherapy may differ from what is observed with chemotherapy (17). A dramatic worsening of disease progression, known as hyperprogressive disease (HPD) has been described in a subset of patients treated with immunotherapy, especially for head and neck squamous cell (18) and non-small cell lung cancers (19), but data are lacking about HPD in MSI-H tumors for which only a few cases have been reported (20, 21).

We described the case of a MSI-H/dMMR gastric adenocarcinoma patient with HPD while receiving ICI, and reviewed the potential causes and predictive factors of hyperprogression.

We report the case of a 68-year old Caucasian patient with a metastatic MSI-H/dMMR gastric adenocarcinoma. This patient with no significant past medical history was treated four years ago for localized antral gastric cancer. He benefited from a subtotal gastrectomy with perioperative FOLFOX chemotherapy (5 cycles received). Pathological examination of surgical specimen revealed poorly differentiated GA, classified ypT3N1 (2N+/23), HER2-negative [immunohistochemistry (IHC) 2+, fluorescence in-situ hybridization (FISH) negative], Epstein-Barr Virus ambiguous status (positive on the first sample but not confirmed on the second sample), Helicobacter pylori-negative, with MMR-deficiency and microsatellite-instability (loss of expression of MLH1 and PMS2, caused by MLH1 promoter hypermethylation).

The patient experienced early recurrence in retroperitoneal and intraperitoneal lymph nodes after ending the perioperative chemotherapy. He received paclitaxel and ramucirumab as second-line chemotherapy, with a near-complete tumor response, followed by radiochemotherapy on residual disease.

After two years of follow-up, he presented another locoregional lymph node recurrence and was treated again with paclitaxel and ramucirumab until progression (apparition of hepatic lesions and increase of lymph nodes) occurring 7 months later.

Due to the dMMR/MSI-H status and lack of immunotherapy approval in France for non-colorectal MSI-H cancers, he was referred to our comprehensive cancer center. His general condition was good (ECOG-PS 1) but he presented a 11% weight loss during the previous 6 months. Blood analysis showed mild perturbations of hepatic function, twofold elevation of LDH and elevated neutrophil-to-lymphocyte ratio (5.7) ( Table 2 ). After discussion in multidisciplinary tumor board and written consent, the patient was enrolled in the immunotherapy cohort of the “MOST plus” phase II trial (NCT02029001) evaluating the benefit of the PD-L1 inhibitor durvalumab (1500 mg flat dose every 4 weeks until disease progression) combined with the CTLA4 inhibitor tremelimumab (1 mg/kg every 4 weeks for 4 cycles) in immunogenic tumors such as MSI-H or high mutational board tumors after failure of standard of care.

The patient was hospitalized in emergency eighteen days after the first injection because of intestinal obstruction and impaired general condition. The CT-scan showed significant disease progression of lymph nodes and hepatic lesions, compressing the gastric stump ( Figure 1 ). Laboratories exams showed grade 3 cytolysis, anicteric cholestasis, rising of neutrophil-to-lymphocyte ratio (to 10.1) and LDH and elevation of tumor marker ACE to 20.9 ng/mL (normal before treatment) ( Table 2 ). The situation worsened rapidly with liver impairment evolving to hepatic encephalopathy and death twelve days later.

Hyperprogression was confirmed by an external review of an expert radiologist calculating the Tumor Growth Kinetics ratio (TGKR) to 7 ( Figure 1 ).

After this unexpected outcome, we decided to repeat molecular analyses on a liver metastasis biopsy performed a few days before starting immunotherapy. The expert pathologist confirmed the lack of expression of MLH1 and PMS2 proteins with IHC [antibodies anti-MSH2 (clone FE11, Dako), anti-MSH6 (clone EP49, Dako), anti-MLH1 (clone ES05, Dako) and anti-PMS2 (clone EP51, Dako) on Benchmark Ultra; detection kit Ultraview Universal DAB ref: 760-500, Amplification kit Ref 760-080, with positive internal controls] and evaluated the PD-L1 expression in tumor cells as negative (< 1% of membrane expression; clone SP263, Kit Ventana Ref 790-4905 on Benchmark Ultra; detection kit Ultraview Universal DAB ref: 760-500, Amplification kit Ref 760-080, with positive external controls). RNAseq analysis identified a deleterious mutation in TP53 gene (FusionPlex RNA CTL_V6, Archerdx; list of covered genes in Supplementary Table 1 ). No other significant molecular alteration was identified and FISH confirmed the lack of MDM2 amplification (ZytoVision ZytoLight SPEC MDM2/CEN 12 Dual Color Probe).

Microsatellite instability is a strong predictive factor for tumor response, regardless of tumor site of origin. However, this case reminds us that MSI-H status does not guarantee a response to ICI: even in this highly-selected population, disease progression and even hyperprogression can be observed. Despite recent efforts, the prevalence, mechanisms, and predictive factors for HPD remain unclear.

We report here the first case of HPD in a PD-L1-negative MSI-H gastric cancer patient treated with an ICI combination and describe in detail its clinical, biological and molecular characteristics. Combining MMR status with TMB and PD-L1 analyses may be of great interest to identify ICI-responders. Validation of a combined score or other predictive factors is needed to avoid such dramatic evolutions with ICI.

The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found below: https://www.ncbi.nlm.nih.gov/bioproject/PRJNA755252.

Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.

RV and AF collected data. TG and CM reviewed CT scans and calculated the TGK ratio. AB performed the molecular analyzes. RV and CF wrote the initial manuscript. All authors contributed to the article and approved the submitted version.

LYRICAN (INCA-DGOS-INSERM 12563), LabEx DEvweCAN (ANR-10-LABX-0061), Institut Convergence PLASCAN (17-CONV-0002), RHU4 DEPGYN (ANR-18-RHUS-0009), Association DAM’s, NetSARC+ (INCA & DGOS), EURACAN (EC 739521), la Fondation ARC (PGA 1° 2016 02 03 721), La Ligue contre le Cancer, funded this study.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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