Tustumi, Francisco

Background: Tumor mutational burden (TMB) is an FDA-approved biomarker for immune checkpoint inhibitor (ICI) therapy. However, its predictive value varies among tumor types and molecular contexts. We investigated whether a very high TMB identifies a biologically distinct subset and whether a higher cutoff provides additional clinical insights beyond the conventional high TMB threshold. Methods: We analyzed 133 patients with advanced solid tumors and TMB ≥ 10 mutations/Mb (mut/Mb) who underwent tumor genomic profiling using a 523-gene DNA/RNA next-generation sequencing panel. Tumors were stratified into prespecified TMB categories: 10–20 mut/Mb (TMB-H) and >20 mut/Mb (TMB-VH). The clinical characteristics, ICI outcomes (in the treated subset), and pathway-level genomic features were compared between groups. Results: TMB-VH was observed in 42/133 (31.6%) patients and spanned more than 20 tumor types. MSI was markedly more prevalent in TMB-VH than in TMB-H tumors (38.1% vs. 2.2%; Fisher’s exact p = 8.9 × 10−8). Pathway-level comparisons did not identify statistically significant differences after false discovery rate correction (all q > 0.05), and the observed patterns were descriptive in nature. In the ICI-treated subset with complete follow-up, objective response did not differ according to the TMB group. Overall survival (OS) was also similar between groups, whether measured from metastatic diagnosis (log-rank p = 0.937) or from ICI initiation (log-rank p = 0.814), although OS was numerically longer in the TMB-VH group in both analyses without reaching statistical significance. Conclusions: In this cohort study, TMB-VH was strongly associated with MSI but not independently associated with improved ICI outcomes. Larger multicenter cohorts are needed to validate pathway-oriented patterns and clarify the clinical utility of extreme TMB thresholds across various histologies. Integrating the functional context (e.g., MSI status, gene-level context, and pathway-level features) with TMB magnitude may enable more robust, tumor-aware biomarker models for immunotherapy selection.

This cross-sectional study examines the lawsuits that followed national and international policies for pembrolizumab approval.

ABSTRACT Background: Esophageal cancer remains one of the most aggressive malignancies of the gastrointestinal tract, with high rates of recurrence and mortality despite curative-intent surgery and adjuvant therapies. Identifying factors associated with recurrence is crucial for improving outcomes and guiding personalized treatment. Aims: The aim of this study was to evaluate pretreatment and treatment-related variables associated with recurrence in patients with esophageal cancer undergoing surgical resection. Methods: This retrospective study analyzed data from patients with stage I–III esophageal carcinoma who underwent esophagectomy between 2000 and 2025, using the Fundação Oncocentro de São Paulo (FOSP) database. Clinical, histological, and treatment-related variables were evaluated. Disease-free survival and recurrence patterns were assessed using Cox proportional hazards models and Fine–Gray subdistribution hazard models. Results: A total of 2,057 patients were included, with a mean follow-up of 36.5 months (±44.8). In the multivariate analysis, advanced tumor stage (stage II: HR 1.68, 95%CI 1.21–2.33; stage III: HR 3.23, 95%CI 2.29–4.56; both p<0.01), location (middle esophagus: HR 1.31, 95%CI 1.11–1.54; p=0.001; upper esophagus: HR 1.54, 95%CI 1.21–1.96; p<0.001), and histological subtype (rare histologies: HR 2.17, 95%CI 1.35–3.49; p=0.001) were associated with worse disease-free survival. Multimodal therapy improved disease-free survival (HR 0.40, 95%CI 0.24–0.66) in stage III tumors. Squamous cell carcinoma was independently associated with locoregional recurrence (SHR 1.52, 95%CI 1.05–2.20; p=0.027). For distant recurrence, squamous cell carcinoma showed a protective effect (SHR 0.52, 95%CI 0.31–0.88; p=0.015), while high tumor grade (grade II: SHR 3.65, 95%CI 1.98–6.72; p<0.001) was associated with an increased risk. Multimodal treatments influenced recurrence patterns but did not independently predict outcomes after adjustment. Conclusions: Tumor stage, location, and histology were strong predictors of disease-free survival after surgery for esophageal cancer. Histological subtypes significantly influenced recurrence patterns. Squamous cell carcinoma was associated with a higher risk of locoregional recurrence but a lower risk of distant metastasis compared to adenocarcinoma. Multimodal therapy demonstrated a protective effect in stage III disease.