Interplay between Tumor Mutational Burden and Mutational Profile and Its Effect on Overall Survival: A Pilot Study of Metastatic Patients Treated with Immune Checkpoint Inhibitors

Abstract

Purpose: Solid tumors harboring tumor mutational burden (TMB) ≥10 mutations per megabase (mut/Mb) received agnostic approval for pembrolizumab. This work aims to analyze the somatic mutational profile’s influence on the outcomes of patients with TMB-high tumors treated with immune checkpoint inhibitors (ICIs). Methods: This post-hoc analysis evaluated clinical and molecular features of patients with solid tumors treated with ICIs that could be either monoclonal antibody directed against programmed cell death protein-1 or monoclonal antibody directed against programmed cell death ligand 1 (anti-PD-1/anti-PD-L1), monoclonal antibody directed against cytotoxic T lymphocyte-associated antigen (anti-CTLA-4) or a combined treatment regimen including one anti-PD-1/anti-PD-L1 and one anti-CTLA-4 (ICIs combination). We performed OS analysis for TMB thresholds of ≥10, ≥20, and <10 mut/Mb. We assessed OS according to the mutational profile for a TMB ≥ 10 mut/Mb cutoff. For genes correlated with OS at the univariate assessment, we conducted a Cox multivariate analysis adjusted by median TMB, sex, age, microsatellite instability (MSI), and histology. Results: A total of 1661 patients were investigated; 488 with a TMB ≥10 mut/Mb (29.4%). The median OS was 42 months for TMB ≥10 or 20 mut/Mb, and 15 months for TMB <10 mut/Mb (p < 0.005). Among TMB ≥10 mut/Mb patients, mutations in E2F3 or STK11 correlated with worse OS, and mutations in NTRK3, PTPRD, RNF43, TENT5C, TET1, or ZFHX3 with better OS. These associations were confirmed with univariate and multivariate analyses (p < 0.05). Melanoma histology and TMB above the median endowed patients with better OS (p < 0.05), while MSI status, age, and gender did not have a statistically significant effect on OS. Conclusion: Combining TMB and mutation profiles in key cancer genes can better qualify patients for ICI treatment and predict their OS.

Dissecting the Puzzling Roles of FAM46C: A Multifaceted Pan-Cancer Tumour Suppressor with Increasing Clinical Relevance

“…The FAM46C gene was originally identified as mutated in 13% of the cases analysed by Chapman and colleagues in their 2011 parallel sequencing of 38 MM patient genomes/exomes [5]. Later, similar mutation frequencies were confirmed by others using techniques ranging from fluorescence in situ hybridization (FISH) approaches to genetargeted next generation sequencing (NGS) [45][46][47][48][49][50][51][52][53]. Mutation mapping revealed alterations throughout the entire ORF of FAM46C, with an exception in a small portion of the Nterminal region, with most mutations being either indels or missense single nucleotide variations predicted to have a deleterious effect on protein structure/functionality [54], suggesting that FAM46C behaves as a tumour suppressor gene.…”

Biomarkers in the Era of Precision Oncology

“…Although the ≥10 mutations/Mb cut-off (TMB-high) has been used for the FDA approval of pembrolizumab for patients’ treatment, still a sizeable proportion of patients with TMB-high tumors do not respond to this type of ICI, making it necessary to identify additional molecular alterations that influence the TMB, which could assist in a better patient selection for immunotherapy. In this respect, the study by Xavier et al [ 11 ] investigated the mutational profiles of patients from the study by Samstein et al [ 12 ], which examined the association between TMB-high and survival outcomes in patients receiving ICI across a wide variety of cancer types. The authors could identify mutations in 27 genes which, in univariate analyses, correlated significantly with OS upon treatment with immune checkpoint inhibitors when tumors with TMB ≥ 10 mut/Mb were assessed.…”

The Role of Human Endogenous Retroviruses in Cancer Immunotherapy of the Post-COVID-19 World

“…Higher TMB produces more neoantigens, thereby improving T-cell recognition and ICI outcomes. Solid tumors bearing a TMB with ≥10 mutations per megabase received agnostic approval for pembrolizumab [8]. However, inconsistencies between TMB and ICI patient response across all cancer types redefined a clinical need for complementary predictive markers [8][9][10][11].…”

“…Solid tumors bearing a TMB with ≥10 mutations per megabase received agnostic approval for pembrolizumab [8]. However, inconsistencies between TMB and ICI patient response across all cancer types redefined a clinical need for complementary predictive markers [8][9][10][11]. Recent re-evaluation of the IMpower133 study, a pivotal trial demonstrating the survival advantage of combining the checkpoint inhibitor atezolizumab with carboplatin and etoposide in first-line extensivestage small cell lung cancer patients, underscored that both blood-based TMB and PD-L1 status should not be relied upon for patient treatment decisions, as current evidence suggests neither biomarker is consistently predictive [12].…”