Search

Understanding progression mechanisms and developing new targeted therapies is imperative in pancreatic ductal adenocarcinoma (PDAC). In this study, 80 metastatic PDAC patients were prospectively recruited and divided into discovery (n=37) and validation (n=43) cohorts. Tumor and plasma samples taken at diagnosis were pair analyzed using whole exome sequencing (WES) in patients belonging to the discovery cohort alone. The variant allele frequency (VAF) of KRAS mutations was measured by ddPCR in plasma at baseline and response assessment in all patients. Plasma WES identified at least one pathogenic variant across the cohort, uncovering oncogenic mechanisms, DNA repair, microsatellite instability, and alterations in the TGFb pathway. Interestingly, actionable mutations were mostly found in plasma rather than tissue. Patients with shorter survival showed enrichment in cellular organization regulatory pathways. Through WES we could identify a specific molecular profile of patients with liver metastasis, which exhibited exclusive mutations in genes related to the adaptive immune response pathway, highlighting the importance of the immune system in liver metastasis development. Moreover, KRAS mutations in plasma (both at diagnosis and persistent at follow-up) correlated with shorter progression free survival (PFS). Patients presenting a reduction of over 84.75 % in KRAS VAF at response assessment had similar PFS to KRAS-negative patients. Overall, plasma WES reveals molecular profiles indicative of rapid progression, potentially actionable targets, and associations between adaptive immune response pathway alterations and liver tropism., Competing Interests: Declaration of competing interest AC declares institutional research funding from Genentech, Merck Serono, BMS, MSD, Roche, Beigene, Bayer, Servier, Lilly, Natera, Novartis, Takeda, Astellas and Fibrogen and advisory board or speaker fees from Merck Serono, Roche, Servier, Takeda and Astellas. NT declares advisory board or speaker fees from Merck Serono, Servier, Pfizer, Natera and Guardant Health. MH declares advisory board and speaker fees from Servier. TF declares institutional research funding from Genentech, Adapt immune, Roche, Beigene, Astelas, BMS, Daichii Sanyo, Amgen and speaker fees from Astrazeneca, Amgen, Bayer, BMS, Lilly, MSD and Servier. VG declares advisory board fees from Boehringer Ingelheim and institutional research funding from Bayer, Boehringer, Roche, Genentech, Merck Serono, Beigene, Servier, Lilly, Novartis, Takeda, Astelas, Fibrogen, Amcure, Natera, Sierra Oncology, AstraZeneca, Medimmune, BMS, MSD. SR declares personal fees as an invited speaker from Amgen, MSD and Servier. Advisory board fees from Amgen, Servier and Sirtex and institutional funding from Ability Pharmaceuticals, Astellas, G1 Therapeutics, Hutchinson, Menarini, Mirati, Novartis, Pfizer, Pierre Fabre, Roche and Seagen. LS declares advisory board or speaker fees from Johnson and Johnson, Medtronic, Baxter, Cella Medical Solutions. The remaining authors declare no competing interests. All authors have read the journal's policy on disclosure of potential conflicts of interest., (Copyright © 2024. Published by Elsevier Inc.)

Cancer has become a global health issue and liquid biopsy has emerged as a non-invasive tool for various applications. In cancer, circulating tumor DNA (ctDNA) can be detected from cell-free DNA (cfDNA) obtained from plasma and has potential for early diagnosis, treatment, resistance, minimal residual disease detection, and tumoral heterogeneity identification. However, the low frequency of ctDNA requires techniques for accurate analysis. Multitarget assay such as Next Generation Sequencing (NGS) need improvement to achieve limits of detection that can identify the low frequency variants present in the cfDNA. In this review, we provide a general overview of the use of cfDNA and ctDNA in cancer, and discuss techniques developed to optimize NGS as a tool for ctDNA detection. We also summarize the results obtained using NGS strategies in both investigational and clinical contexts., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Molecular-matched therapies have revolutionized cancer treatment. We evaluated the improvement in clinical outcomes of applying an in-house customized Next Generation Sequencing panel in a single institution., Methods: Patients with advanced solid tumors were molecularly selected to receive a molecular-matched treatment into early phase clinical trials versus best investigators choice, according to the evaluation of a multidisciplinary molecular tumor board. The primary endpoint was progression-free survival (PFS) assessed by the ratio of patients presenting 1.3-fold longer PFS on matched therapy (PFS2) than with prior therapy (PFS1)., Results: Of a total of 231 molecularly screened patients, 87 were eligible for analysis. Patients who received matched therapy had a higher median PFS2 (6.47 months; 95% CI, 2.24-14.43) compared to those who received standard therapy (2.76 months; 95% CI, 2.14-3.91, Log-rank p = 0.022). The proportion of patients with a PFS2/PFS1 ratio over 1.3 was significantly higher in the experimental arm (0.33 vs 0.08; p = 0.008)., Discussion: We demonstrate the pivotal role of the institutional molecular tumor board in evaluating the results of a customized NGS panel. This process optimizes the selection of available therapies, improving disease control. Prospective randomized trials are needed to confirm this approach and open the door to expanded drug access., (© 2021. The Author(s).)