Léo Mas

Background Combining high-dose stereotactic body radiation therapy (SBRT) with FOLFIRINOX (FFX) is promising as neoadjuvant strategy for pancreatic ductal adenocarcinoma (PDAC). This study provides an in-depth histo-molecular characterisation of resected PDAC samples from patients treated with FFX ± SBRT. Methods Residual tumour tissues from 56 non-metastatic PDAC patients were analysed: seventeen underwent upfront surgery, seventeen received neoadjuvant FFX alone and twenty-two FFX followed by radiotherapy (sixteen SBRT, six radiochemotherapy [RT-CT]). Samples were assessed using RNAseq and immunohistochemistry/fluorescence, including multiplex. Results Addition of SBRT to FFX favourably remodelled PDAC, influencing stromal, immune, metabolic and molecular features. Unlike RT-CT, SBRT counteracted several detrimental effects induced by FFX alone. Notably, FFX + SBRT enriched tumours with ‘Classical’ and ‘Inactive stroma’ signatures—linked to better prognosis - while reducing ‘Basal-like’ cell enrichment. SBRT promoted COL1A1-driven stromal remodelling while globally preserving T-lymphocyte infiltration, including cytotoxic T cells, which maintained close proximity to tumour cells despite increased desmoplasia. Key transcriptional alterations induced by SBRT were identified, offering targets for future combination therapies. Conclusions Highlighting a more favourable stromal and molecular profile after integration of high-dose SBRT to FFX, this study supports the development, rationale and validation in prospective trials of using this treatment combination in non-metastatic PDAC.

Deficiency in DNA mismatch repair (dMMR) is a common pathway of carcinogenesis across different tumor types and confers a characteristic microsatellite instability‐high (MSI‐H) molecular phenotype. The MSI‐H/dMMR phenotype may arise from an inherited pathogenic variant in the context of Lynch syndrome and is most frequently observed in endometrial, colorectal, and gastric cancers. MSI‐H/dMMR is a major predictive biomarker for the efficacy of immune‐checkpoint inhibitors (ICIs). Following the approval of ICIs for metastatic disease, these drugs are now being evaluated in localized disease settings. In this review, we provide an overview of current knowledge regarding the use of ICIs as neoadjuvant therapy and as a part of immuno‐ablative, surgery‐sparing strategies, with a focus on Lynch‐related cancers. Finally, we address the diagnosis, monitoring, and prevention challenges raised by these de‐escalation strategies.

Pancreatic cancer is a rising cause of cancer death. Therapeutic options are scarce and of limited efficacy. Up to 26% of patients with metastatic pancreatic cancer could benefit from targeted therapies. We report here for the first time the case of three patients with metastatic pancreatic ductal adenocarcinoma (PDAC) without KRAS alteration for whom an activating mutation in exon 19 of the epidermal growth factor receptor ( EGFR ) gene was found through mainstreaming NGS. The EGFR variant was confirmed on multiple tumor samples and by circulating tumor DNA (ctDNA) analysis in two patients. The three patients were treated with osimertinib with early molecular, biologic, and morpho-metabolic responses. At the last follow-up, one patient had an ongoing response after 17 months, and disease control had been maintained for 8 and 6 months in the other two. Known resistance mechanisms were observed on ctDNA analysis at progression. These observations demonstrate the benefit of osimertinib for treating EGFR -mutated PDAC and highlight the interest in investigating rare molecular alterations, especially in patients without KRAS alterations.

Background: Several studies reported improved outcomes with conventional treatments (CT, i.e., chemotherapy ± targeted therapy) administered after immune checkpoints inhibitors (ICI) in certain tumor types. No data are available concerning patients (pts) with metastatic colorectal cancer (mCRC) harboring mismatch repair deficiency/microsatellite instability (dMMR/MSI). We aimed to assess the outcomes of dMMR/MSI mCRC pts receiving CT after ICI failure. Methods: We conducted a retrospective multicenter study investigating the outcomes of all dMMR/MSI mCRC pts who received post-ICI CT between 2015 and 2020. Results: 31 pts (male 61%, median age 56 years) were included. ICI was an anti-PD(L)1 monotherapy in 71% of pts, and 61% received >2 lines before post-ICI CT. The overall response rate and disease control rate were 13% and 45%, with a median progression-free survival (PFS) and overall survival of 2.9 and 7.4 months, respectively. No association of the outcomes with either ICI efficacy or anti-angiogenic agents was observed. Prolonged PFS (range 16.1–21.3 months) was observed in 4 pts (13%). Conclusions: Although conducted on a limited number of patients, our results do not support an association of previous ICI treatment with an enhanced efficacy of CT in dMMR/MSI mCRC. However, prolonged disease control was observed in several cases, suggesting that some pts might derive an unexpected benefit from post-ICI treatments.

Intraductal papillary mucinous neoplasms (IPMN) are common and one of the main precursor lesions of pancreatic ductal adenocarcinoma (PDAC). PDAC derived from an IPMN is called intraductal papillary mucinous carcinoma (IPMC) and defines a subgroup of patients with ill-defined specificities. As compared to conventional PDAC, IPMCs have been associated to clinical particularities and favorable pathological features, as well as debated outcomes. However, IPMNs and IPMCs include distinct subtypes of precursor (gastric, pancreato-biliary, intestinal) and invasive (tubular, colloid) lesions, also associated to specific characteristics. Notably, consistent data have shown intestinal IPMNs and associated colloid carcinomas, defining the “intestinal pathway”, to be associated with less aggressive features. Genomic specificities have also been uncovered, such as mutations of the GNAS gene, and recent data provide more insights into the mechanisms involved in IPMCs carcinogenesis. This review synthetizes available data on clinical-pathological features and outcomes associated with IPMCs and their subtypes. We also describe known genomic hallmarks of these lesions and summarize the latest data about molecular processes involved in IPMNs initiation and progression to IPMCs. Finally, potential implications for clinical practice and future research strategies are discussed.