First-line Nivolumab plus FOLFOXIRI/Bevacizumab in advanced RAS/BRAF-mutated colorectal cancer: efficacy, safety and biomarker discovery from the phase II NIVACOR trial Angela Damato, Riziero Esposito Abate, Simona Tessitore, Daniela Frezzetti, Monica Rosaria Maiello, et al. Nature Communications, 2026 Immunotherapy achieved remarkable results in patients with deficient mismatch repair (dMMR)/microsatellite instable (MSI) metastatic colorectal carcinoma (mCRC). However, its efficacy in proficient MMR (pMMR)/microsatellite stable (MSS) mCRC remains limited. In the phase II NIVACOR trial, we evaluated the activity and safety of FOLFOXIRI/bevacizumab plus nivolumab as first-line therapy in patients with RAS/BRAF-mutated mCRC (NCT04072198). The primary endpoint of the trial was the Objective Response Rate (ORR) whereas secondary endpoints were safety profile, overall survival (OS), progression free survival (PFS), duration of response (DoR) and quality of life. The primary endpoint was met. Among the 73 enrolled patients, 76.7% achieved an objective response (95% CI, 65.4 to 85.8%), while the disease control rate was 97.3% (95% CI, 90.5 to 99.7%). The median progression-free survival (mPFS) was 10.1 months (95% CI, 9.0 to 14.3 months), and the median overall survival (mOS) was not reached. Treatment-related adverse events of grade 3 or higher occurred in 48 patients out 73 enrolled patients (65.8%). Comprehensive genomic profiling and RNA sequencing analysis revealed genomic and transcriptomic profiles associated with treatment response in pMMR/MSS patients. Alterations in pathways such as PI3K/AKT, chemokine signaling and DNA repair showed correlation with treatment activity. These findings highlight the potential synergy between immune checkpoint inhibitors and cytotoxic chemotherapy in selected patients with pMMR/MSS mCRC.
Liquid Biopsy Frontiers in Pancreatic Cancer: Insights from Circulating Cell-Free Nucleic Acids Maria Latiano, Maria De Angelis, Anna Latiano, Orazio Palmieri, Tiziana Pia Latiano, et al. Cells, 2026 Pancreatic cancer (PC) remains one of the most aggressive and lethal malignancies worldwide, largely due to late diagnosis, aggressive biology, limited therapeutic options and responsiveness. Conventional diagnostic and monitoring strategies, including imaging and serum biomarkers such as CA 19-9, provide limited sensitivity for early detection and suboptimal accuracy for the dynamic assessment of treatment response and disease evolution. These limitations highlight the urgent need for innovative, minimally invasive approaches capable of improving patient stratification and guiding personalized management. In this context, liquid biopsy has emerged as a promising, minimally invasive approach able to capture tumor-derived molecular information through the analysis of circulating cell-free nucleic acids, including circulating cell-free DNA (cfDNA) and circulating cell-free RNA (cfRNA). Released into the bloodstream by tumor cells, these analytes offer a real-time and comprehensive snapshot of tumor biology, capturing genetic, epigenetic, and transcriptional alterations through a simple blood draw. Liquid biopsy-based analyses hold significant potential for early detection, prognostic assessment, therapeutic decision-making, monitoring of minimal residual disease, and identification of resistance mechanisms. This review discusses the current state of research on circulating cell-free nucleic acids in PC, highlighting their biological basis, methodological approaches, clinical potential, and the challenges limiting their widespread implementation. By underscoring their translational relevance, we aim to outline how integrated liquid biopsy strategies, alongside the need for standardization and cross-study harmonization, may contribute to a more precise and dynamic approach to PC management.
Comparative Analysis of Fecal Microbiota in Healthy Controls and Pancreatic Cancer Patients: A Focus on Tumor Localization Differences in Pancreatic Head and Body–Tail Annacandida Villani, Gandino Mencarelli, Giovanna Cocomazzi, Elena Binda, Edy Virgili, et al. Cancer Medicine, 2025 Background Pancreatic cancer (PC) remains one of the most lethal malignancies worldwide, characterized by late‐stage diagnosis and a poor prognosis. This study explores the clinical, biochemical, and gut microbiota differences between PC patients and healthy controls (CTRL), as well as between subgroups of PC patients with pancreatic head cancer (PHC) and pancreatic body‐tail cancer (PBTC). Methods A total of 72 PC patients and 37 CTRL subjects were included, with further stratification of PC patients into 45 PHC and 27 PBTC cases. Clinical and biochemical data were collected. Gut microbiota was analyzed by 16S rRNA gene sequencing. Alpha‐diversity indices, Firmicutes/Bacteroidetes ratio and taxonomic composition were evaluated and compared in all the experimental group. Correlation analyses were performed between specific bacterial taxa and biochemical markers and a Random Forest algorithm was applied to identify taxa discriminating PC from CTRL and PHC from PBTC. Results Clinical and biochemical data revealed significant heterogeneity between groups, with PHC patients exhibiting higher markers of inflammation and liver dysfunction, while PBTC patients showed relatively preserved physiological status. Gut microbiota analysis revealed significant dysbiosis in PC patients compared to CTRL. Alpha‐diversity indices demonstrated reduced species evenness in PC patients, while the Firmicutes/Bacteroidetes ratio was significantly lower. Taxonomic composition analysis indicated enrichment of pro‐inflammatory taxa and depletion of beneficial SCFA‐producing genera. However, subgroup comparisons revealed distinct microbial profiles, with PHC patients enriched in taxa associated with localized inflammation and PBTCs showing higher levels of anti‐inflammatory and SCFA‐producing bacteria. A correlation analysis linked specific bacteria to markers of liver dysfunction and systemic inflammation, such as GGT, ALP, and ESR, while SCFA‐producing taxa correlated negatively with inflammatory markers. A Random Forest algorithm identified key microbial taxa discriminating PC patients from CTRL and PHC from PBTC. Conclusions These findings highlight the interplay between microbiota composition, tumor localization, and systemic inflammation, showing a potential for microbiota‐based diagnostics and interventions in PC.
Germline Findings From Tumor-Only Comprehensive Genomic Profiling in the RATIONAL Study: A Missed Opportunity? Riziero Esposito Abate, Alessandro Morabito, Michele Milella, Fabrizio Tabbò, Valentina Guarneri, et al. JCO Precision Oncology, 2025 PURPOSE Tumor comprehensive genomic profiling (CGP) may detect potential germline pathogenic/likely pathogenic (P/LP) alterations as secondary findings. We analyzed the frequency of potentially germline variants and large rearrangements (LRs) in the RATIONAL study, an Italian multicenter, observational clinical trial that collects next-generation sequencing–based tumor profiling data, and evaluated how these findings were managed by the enrolling centers. PATIENTS AND METHODS Patients prospectively enrolled in the pathway-B of the RATIONAL study and undergoing CGP with the FoundationOne CDx assays were included in the analysis. Potentially germline variants detected in 40 cancer susceptibility genes (CSGs) were classified in three classes with different actionability, most (MA), high (HA), and standard (SA), on the basis of penetrance, mutational spectrum, and intervention for prevention/early detection. RESULTS On the basis of the European Society of Medical Oncology recommendations, we identified 225 potentially germline P/LP variants in 193/1,339 (14.4%) enrolled patients. In particular, 62/225 (27.5%) variants were detected in genes classified as MA-CSG class, 53/225 (23.6%) in genes belonging to the HA-CSG class, and 110/225 (48.9%) in the SA-CSG class. In addition, we detected 58 LRs in the 16/40 CSGs in 53/1,339 (3.95%) patients. Information about germline-focused analysis and follow-up was available for 99 patients with potentially germline variants. Surprisingly, 95/99 (96%) patients were not referred to oncogenetic consultation and follow-up, including 30/32 (93.75%) patients with variants in the MA-CSG class. CONCLUSION Our data confirm the utility of CGP for the identification of potentially germline variants in CSGs, highlighting the importance of reporting LRs in addition to single-nucleotide variants and insertions/deletions. However, our findings also demonstrate a relative lack of knowledge of the implications of germline findings detected on tumor-only sequencing among oncologists and underline the need for specific training in this area.
