NCCN Recommends Universal Testing for Microsatellite Instability by PCR/NGS or Mismatch Repair by IHC for All Newly Diagnosed Gastric Cancer Patients

By Lakshmi N. Rajdev, MD, MS

Microsatellite instability (MSI) status is assessed by polymerase chain reaction (PCR) to measure gene expression levels of microsatellite markers (i.e., BAT25, BAT26, MONO27, NR21, NR24).¹ Mismatch repair (MMR) deficiency is evaluated by immunohistochemistry (IHC) to assess nuclear expression of proteins involved in DNA mismatch repair (i.e., MLH1, MSH2, MSH6, PMS2).²

PCR/next generation sequencing (NGS) for MSI and IHC for MMR proteins measure different biological effects caused by deficient MMR function. Testing is performed on formalin-fixed, paraffin-embedded (FFPE) tissue and results are interpreted as MSI-high (MSI-H) or MMR-deficient (dMMR), in accordance with College of American Pathologists (CAP) DNA Mismatch Repair Biomarker Reporting Guidelines.³ Testing should be performed only in CLIA-approved laboratories. 

For us to improve the standard of care, all patients with gastric and esophageal cancers should have biomarker testing done as early as possible for MSI and MMR. The National Comprehensive Cancer Network’s Clinical Practice Guidelines in Oncology (NCCN Guidelines^®) include this recommendation.

Currently, the most common treatment approach for patients with operable MSI-H/dMMR gastric or gastroesophageal junction (GEJ) cancer is perioperative immunotherapy (IO) followed by surgery and then adjuvant IO. In these patients, IO leads to higher pathologic complete response rates and more durable outcomes than chemotherapy. However, about one-third of patients do not see impressive results with this approach. Chemotherapy has activity in MSI-H gastric cancer as reported in an analysis of MSI-H patients from CheckMate 649⁴ and the DANTE Trial.⁵

The EA2212 study is designed to establish whether combining chemotherapy and immunotherapy is superior to immunotherapy alone for patients with operable MSI-H/dMMR gastric or GEJ cancer. Patients will be randomized into one of two groups. The first group will receive chemotherapy and atezolizumab, an immune checkpoint inhibitor, for three to four cycles, followed by surgery. After surgery, they will again have chemotherapy and atezolizumab for three to four cycles, followed by atezolizumab alone for six cycles. The second group of patients will have atezolizumab alone for three cycles, followed by surgery, and then atezolizumab alone for another nine cycles.

The study’s primary objective is to compare three-year event-free survival (EFS) between the two groups. Secondary objectives are to assess tumor regression grade (TRG) rates, overall survival (OS) rates, and toxicity between the two groups, as well as to correlate circulating tumor DNA clearance with TRG, EFS, and OS.

To be eligible for this study, patients must have a histologically or cytologically confirmed diagnosis of gastric or GEJ adenocarcinoma that is MSI-H/dMMR. The cancer must be localized (without evidence of metastatic disease) and able to be removed by surgery. Patients must not have received any prior treatment for the cancer.

Learn more about EA2212 at ecog-acrin.org.

Dr. Rajdev (Mount Sinai Health System/The Tisch Cancer Institute) is the study chair for this trial. The study co-chair is Natalia V. Uboha, MD, PhD (University of Wisconsin/Carbone Cancer Center).

^{1Murphy KM, Zhang S, Geiger T, et al. Comparison of the microsatellite instability analysis system and the Bethesda panel for the determination of microsatellite instability in colorectal cancers. J Mol Diagn 2006;8:305-311. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16825502} 

²Le DT, Durham JN, Smith KN, et al. Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade. Science 2017;357:409-413. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28596308 

^{3Bartley AN, Fitzgibbons PL, Broaddus RR, Shi C. Template for reporting results of DNA mismatch repair testing in patients being considered for checkpoint inhibitor immunotherapy. College of American Pathologists 2018. Available at: https://documents.cap.org/protocols/cpgeneral-dnamismatchrepair-18biomarker-1001.pdf} 

^{4 Shitara K, Ajani JA, Moehler M, et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022 Mar;603(7903):942-948. doi: 10.1038/s41586-022-04508-4. Epub 2022 Mar 23. PMID: 35322232; PMCID: PMC8967713}  

^{5 Al-Batran S-E, et al. Surgical and pathological outcome, and pathological regression, in patients receiving perioperative atezolizumab in combination with FLOT chemotherapy versus FLOT alone for resectable esophagogastric adenocarcinoma: Interim results from DANTE, a randomized, multicenter, phase IIb trial of the FLOT-AIO German Gastric Cancer Group and Swiss SAKK. J Clin Oncol. 2022;40(16_suppl):4003–4003}