In a study reported in The Lancet Oncology, Wang et al identified mutations linked to high tumor mutation burden in microsatellite-stable (MSS) gastrointestinal cancers that may be associated with efficacy of immune checkpoint inhibitor therapy.
Study Details
Molecular alterations in 48,606 gastrointestinal tumors from Caris Life Sciences (CARIS) were identified through next-generation sequencing. Antitumor immune response within the tumor environment associated with molecular alterations was predicted by analyzing infiltration of immune cells and immune signatures using The Cancer Genome Atlas database. The potential impact of mutations associated with high tumor mutation burden in MSS tumors on efficacy of immune checkpoint inhibition was examined.
Key Findings
Among the 48,606 tumors, 1,600 (3.29%) were MSS–high tumor mutation burden; 2,272 (4.67%) were mismatch repair–deficient (dMMR) or microsatellite instability–high (dMMR/MSI-H); and 44,734 (92.03%) were MSS–low tumor mutation burden.
Antitumor immune response analysis indicated that mutations in SMAD2, MTOR, NFE2L2, RB1, KEAP1, TERT, and RASA1 might impair response, despite association with high tumor mutation burden.
In contrast, mutations in 16 other genes—CDC73, CTNNA1, ERBB4, EZH2, JAK2, MAP2K1, MAP2K4, PIK3R1, POLE, PPP2R1A, PPP2R2A, PTPN11, RAF1, RUNX1, STAG2, and XPO1—were related to high tumor mutation burden with enhanced antitumor immune response, independent of dMMR/MSI-H status. These findings allowed construction of a gene signature—modified tumor mutation burden (mTMB)—for potential prediction of immune checkpoint inhibitor efficacy.
Among patients in the CARIS cohort with MSS tumors who received immune checkpoint inhibitor therapy, those with any mutation in the mTMB gene signature had improved overall survival vs those with mTMB wild-type tumors (median = 18.8 months, 95% confidence interval [CI] = 17.3–20.2 months, vs 7.03 months, 95% CI = 5.73–8.34 months; hazard ratio = 0.55, 95% CI = 0.31–0.99, P = .044).
In addition, it was found that copy number amplification in chromosome 11q13—eg, in the CCND1 (cyclin D1) and FGF genes—was more common in MSS–high tumor mutation burden tumors than in dMMR/MSI-H or MSS–low tumor mutation burden tumors.
The investigators concluded, “Not all mutations related to high tumor mutation burden can enhance antitumor immune response. More composite biomarkers should be investigated (eg, mTMB signature) to tailor treatment with immune checkpoint inhibitors. Our data also provide novel insights for the combination of immune checkpoint inhibitors and drugs targeting cyclin D1 or FGFs.”
Heinz-Josef Lenz, MD, of Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, is the corresponding author for The Lancet Oncology article.
Disclosure: The study was funded by the National Cancer Institute, Gloria Borges WunderGlo Foundation, Dhont Family Foundation, National Natural Science Foundation of China, and others. For full disclosures of the study authors, visit thelancet.com.
