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Background: Despite a reduction of both incidence and mortality from CRC, recent studies have shown an increase in the incidence of early-onset CRC (EO-CRC). Data on this setting are limited. The aim of our study was to evaluate the clinical and molecular profiles of metastatic EO-CRC patients in order to identify differences compared to a late-onset CRC (LO-CRC) control group., Methods: We retrospectively collected data from 1272 metastatic colorectal cancers from 5 different Italian Institutions. The main objective was to the evaluate clinical outcome for EO-CRC patients in comparison to patients included in the control group., Results: In the overall population, mOS was 34,7 in EO-CRC pts vs 43,0 months (mo) (p < 0,0001). In the RAS/BRAF mutated subgroup mOS in EO-CRC pts was 30,3 vs 34,0 mo (p = 0,0156). In RAS/BRAF wild-type EO-CRC mOS was 43,0 vs 50,0 mo (p = 0,0290). mPFS was 11,0 in EO-CRC pts vs 14,0 mo (p < 0,0001)., Conclusion: Findings indicate a general worse prognosis for patients with early-onset colorectal cancer compared to late-onset patients. Interestingly this seems to occur regardless of the molecular status. These observations might have a considerable impact on clinical practice and research., Competing Interests: Competing interests: The authors declare no competing interests. Ethics approval and consent to participate: Ethics Committee approval was obtained for the study (Protocol number 2020/10912 – code: EMIBIOCCOR) from Cagliari Indipendent Ethics Committee and written informed consent was obtained from all participants for their tissues to be utilized for this work. This study was performed in accordance with the study protocol, the ethical principles stated in the Declaration of Helsinki as well as those indicated in the International Conference on Harmonization (ICH) Note for Guidance on Good Clinical Practice (GCP; ICH E6, 1995), and all applicable regulatory requirements., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.)

Background: Ascites is common in advanced gastrointestinal cancers with peritoneal metastases (PM) and negatively impacts patient survival. No study to date has specifically evaluated the relationship between ascites, PM and survival outcomes in metastatic colorectal cancer (mCRC) and metastatic gastric cancer (mGC)., Objectives: This study aims to investigate and elucidate the relationship between malignant ascites, PM and survival outcomes in both mCRC and mGC patients., Design: This is a retrospective analysis of prospectively collected clinical trial data of mCRC and mGC patients with PM., Methods: We performed two pooled analyses, firstly of two Italian randomized trials enrolling patients with mCRC eligible for systemic therapy (TRIBE2; VALENTINO), and secondly of gastric cancer and peritoneal metastasis (GCPM) patients who underwent bi-directional therapeutic treatment comprising systemic and peritoneal-directed therapies., Results: Of 900 mCRC patients, 39 (4.3%) had PM with malignant ascites. Compared to the group without PM, median progression-free and overall survival were significantly inferior in the ascites group (hazard ratio (HR) for progression-free survival (PFS) 1.68, 95% confidence interval (CI): 1.21-2.35, p  = 0.007; HR for overall survival (OS) 2.14, 95% CI: 1.57-3.01, p  < 0.001), but not in the group of PM without ascites (HR for PFS 1.10, 95% CI: 0.91 - 1.34; HR for OS 1.04, 95% CI: 0.84 - 1.30). Of 170 patients with GCPM, those with ascites had higher median Peritoneal Cancer Index scores (23 vs 9, p  < 0.001). Median OS was significantly inferior among those with ascites compared to those without (13.0 vs 21.0 months, HR 1.71, 95% CI: 1.16-2.52, p  = 0.007)., Conclusion: Ascites identifies a subgroup of patients with PM and poor outcomes, for whom tailored research are needed., Competing Interests: F.P. reported receiving institutional research grants from BMS, Incyte, Agenus, Amgen, Lilly and AstraZeneca, and personal fees from BMS, MSD, Amgen, Merck-Serono, Pierre-Fabre, Servier, Bayer, Takeda, Astellas, Johnson&Johnson, Rottapharm, Ipsen, AstraZeneca, GSK, Daiichi-Sankyo, Seagen outside the submitted work. C.C. received honoraria from Amgen, Bayer, Merck, Roche and Servier; has consulting or advisory role at Amgen, Bayer, MSD and Roche; was a speakers bureau member at Servier; received research funding from Bayer, Merck and Servier; and received travel and accommodation expenses from Roche and Servier outside the submitted work. S.L. reports research funding from Amgen,Merck Serono, Bayer, Roche, Eli Lilly, AstraZeneca, Bristol Myers Squibb; honoraria from Roche, Eli Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen; participation in advisory board for Amgen, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, Bristol Myers Squibb, Servier, Merck Sharp & Dohme. M.G. reports honoraria from Roche, Amgen. W.P.Y. has consulting or advisory role at AbbVie/Genentech, Amgen, Bristol Myers Squibb, Ipsen, Novartis, AstraZeneca; is a speakers’ bureau member at Lilly, Sanofi/Aventis, Taiho Pharmaceutical, Eisai, Bayer, MSD Oncology; received travel and accommodations expenses from Pfizer. P.T. has stocks in Tempus Healthcare, Auristone Pte Ltd. R.S. reports grants from National Medical Research Council (NMRC/CIRG23Jul-0035 and NMRC/MOH-000627) during the conduct of the study, as well as other support from Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, Eli Lilly, Roche, AstraZeneca, DKSH, MSD, Paxman Coolers, Natera, Astellas, GSK, Ipsen, Pierre-Fabre, Tavotek, Sanofi, Daichii Sankyo, Beigene, CytoMed and Auristone outside the submitted work., (© The Author(s), 2024.)

Background: The decision to resect or not the primary tumor in asymptomatic patients with synchronous metastatic colorectal cancer (mCRC) is a complex and challenging issue for oncologists, especially when an antiangiogenic-based therapy is planned., Methods: Patients enrolled in the phase III TRIBE and TRIBE2 studies that compared upfront FOLFOXIRI + bevacizumab to FOLFIRI or FOLFOX + bevacizumab, respectively, were included. We assessed the association of primary tumor resection (PTR) with progression-free survival (PFS), overall survival (OS), response rate (ORR), rate of grade > 2 adverse events (AEs), and serious gastrointestinal and surgical AEs in the overall population and according to the treatment arm., Results: Of the 999 patients included, 513 (51%) underwent PTR at baseline. Longer PFS and OS were observed in resected patients compared to those with unresected primary tumors: 11.2 vs. 10.0 months ( p < 0.001) and 26.6 vs. 22.5 ( p < 0.001), respectively. In multivariate models, PTR was confirmed as an independent prognostic factor for better PFS ( p = 0.032) and OS ( p = 0.018). Patients with PTR experienced a higher incidence of grade 3 or 4 diarrhea ( p = 0.055) and lower incidence of anemia ( p = 0.053), perforation ( p = 0.015), and serious gastrointestinal and surgical AEs ( p < 0.001). No statistically significant differences were noted in incidence of bleeding ( p = 0.39). The benefit of FOLFOXIRI + bevacizumab in terms of PFS ( p for interaction: 0.46), OS ( p for interaction: 0.80), ORR ( p for interaction: 0.36), and incidence of grade 3 or 4 AEs was independent of PTR., Conclusions: PTR at baseline was independently associated with good prognosis in synchronous mCRC patients and with lower incidence of serious gastrointestinal and surgical AEs during upfront chemotherapy plus bevacizumab. The benefit and toxicity profile of FOLFOXIRI plus bevacizumab was independent of PTR.

Background: Subgroup analyses of randomized trials suggest the superiority of immune checkpoint inhibitor-based therapy over chemotherapy in patients with mismatch-repair deficient (dMMR) and/or microsatellite instability-high (MSI-high) advanced gastric or gastroesophageal junction adenocarcinoma. However, these subgroups are small and studies examining prognostic features within dMMR/MSI-high patients are lacking., Methods: We conducted an international cohort study at tertiary cancer centers and collected baseline clinicopathologic features of patients with dMMR/MSI-high metastatic or unresectable gastric cancer treated with anti-programmed cell death protein-1 (PD-1)-based therapies. The adjusted HRs of variables significantly associated with overall survival (OS) were used to develop a prognostic score., Results: One hundred and thirty patients were included. At a median follow-up of 25.1 months, the median progression-free survival (PFS) was 30.3 months (95% CI: 20.4 to NA) and 2-year PFS rate was 56% (95% CI: 48% to 66%). Median OS was of 62.5 months (95% CI: 28.4 to NA) and 2-year OS rate was 63% (95% CI: 55% to 73%). Among the 103 Response Evaluation Criteria in Solid Tumors-evaluable patients, objective response rate was 66% and disease control rate 87% across lines of therapy. In the multivariable models, Eastern Cooperative Oncology Group Performance Status of 1 or 2, non-resected primary tumor, presence of bone metastases and malignant ascites were independently associated with poorer PFS and OS. These four clinical variables were used to build a three-category (ie, good, intermediate, and poor risk) prognostic score. Compared with patients with good risk, patients with intermediate risk score had numerically inferior PFS and OS (2-year PFS rate: 54.3% versus 74.5%, HR 1.90, 95% CI: 0.99 to 3.66; 2-year OS rate: 66.8% versus 81.2%, HR 1.86, 95% CI: 0.87 to 3.98), whereas patients with poor risk score had significantly inferior PFS and OS (2-year PFS rate: 10.6%, HR 9.65, 95% CI: 4.67 to 19.92; 2-year OS rate: 13.3%, HR 11.93, 95% CI: 5.42 to 26.23)., Conclusions: Overall outcomes with anti-PD-1-based therapies are favorable in MSI-high gastroesophageal adenocarcinomas. However, within this overall favorable subgroup a more accurate prognostication using baseline clinical characteristics might identify patients at higher risk of rapid disease progression who may deserve intensified immunotherapy combination strategies., Competing Interests: Competing interests: RC has received personal fees from AstraZeneca, Bristol-Myers Squibb, Exeliom Biosciences, Enterome Bioscience, MSD Oncology, Mylan Medical, Pierre Fabre, Servier and non-financial support from Amgen, Bristol-Myers Squibb, Mylan Medical and Servier outside the submitted work. SJK reports consulting/advisory role with Astellas, Merck, BMS, Servier, Sanofi-Aventis, Novartis, Mersana, Exact Sciences, Natera, Coherus Biosciences, Daiichi-Sankyo, AstraZeneca, Pfizer, and Eli Lilly. SJK reports equity in Turning Point Therapeutics, and Nuvalent Therapeutics. SBM received consulting fees from Natera, Bicara, Novartis, Basilea, Elevation Oncology, and Daiichi Sankyo. LF reported receiving personal honoraria as invited speaker from Incyte, BMS, Lilly; research funding (to Institution) from MSD, BMS, AstraZeneca, Incyte, BeiGene, Astellas, Daiichi Sankyo, Roche; participation in advisory board for MSD, AstraZeneca, Incyte, Taiho, Servier, Daiichi Sankyo, Lilly. AK reports receiving honoraria (lecture fee) from Lilly, Bristol-Myers Squibb, Ono Pharmaceutical, Merck Pharmaceutical, Taiho Pharmaceutical, Daiichi Sankyo; receiving personal fees for advisory roles from Merck Pharmaceutical, Zymeworks; and receiving research funding from AstraZeneca, outside the submitted work. SL reports roles as consultant or advisor for Amgen, AstraZeneca, Bristol-Myers Squibb, Daiichi-Sankyo, Incyte, Lilly, Merck Serono, MSD, Servier, and reports research funding from Amgen, Astellas, AstraZeneca, Bayer, BMS Daichii Sankyo, Hutchinson, Incyte, Merck Serono, Mirati, MSD, Pfizer, Roche. She is part of speakers’ bureau of Amgen, Bristol-Myers Squibb, GlaxoSmithKline, Lilly, Merck Serono, Pierre Fabre, Roche, Servier. KS reports receiving personal fees for advisory roles from Lilly, Bristol-Myers Squibb, Takeda, Pfizer, Ono Pharmaceutical, Merck Pharmaceutical, Taiho Pharmaceutical,Astellas, Novartis, AbbVie, GlaxoSmithKline, Daiichi Sankyo, Amgen, Boehringer Ingelheim, Guardant Health Japan,and Janssen; receiving honoraria (lecture fee) from Takeda, Bristol-Myers Squibb and Janssen; and receiving research funding from Astellas, Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, Chugai, Merck Pharmaceutical, Medi Science, Eisai and Amgen, outside the submitted work. TA reports attending advisory board meetings and receiving consulting fees from Aptitude Health, AstraZeneca, Astellas, Bristol-Myers Squibb, Gritstone Oncology, GamaMabs Pharma Sa, Gilead, GlaxoSmithKline, Merck & Co. Inc., Nordic Oncology, Pierre Fabre, Seagen, Servier and Transgène; honoraria from AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Merck & Co. Inc., Pierre Fabre, Roche, Sanofi Seagen and Servier; and support for meetings from Merck & Co. Inc. and Servier. FP reported receiving grants from BMS, Incyte, and AstraZeneca and personal fees from BMS, MSD, AstraZeneca, Amgen, Merck Serono, Eli Lilly & Company, Pierre Fabre, Servier, Bayer, and Organon outside the submitted work. JC received grants or contracts from Merck and Brooklyn Immunotherapeutics; consulting fees from Lilly, Merck, AstraZeneca, Foundation Medicine, Daiichi Sankyo, Amgen, Bristol-Myers Squibb, Astellas, Turning Point Therapeutics, Silverback Therapeutics, Novartis, Coherus Biosciences, Geneos, Roche, Guardant Health; payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Merck, Bristol-Myers Squibb and disclose Participation on a Data Safety Monitoring Board or Advisory Board of Yiviva and Daiichi-Sankyo; disclose other financial or non-financial interests (employment) from Amgen. No other competing interests to disclose., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Immune checkpoint inhibitors (ICIs) show a tremendous activity in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC), but a consistent fraction of patients does not respond. Prognostic/predictive markers are needed. Despite previous investigations in other tumor types, immune-related adverse events (irAEs) have not been well evaluated in patients with MSI-H cancers treated with ICIs., Methods: We conducted an international cohort study at tertiary cancer centers collecting clinic-pathological features from 331 patients with MSI-H mCRC treated with ICIs. Of note, the irAEs were summarized using a 'burden score' constructed in a way that the same score value could be obtained by cumulating many low-grade irAEs or few high-grade irAEs; as a result, the lower the burden the better. Clearly, the irAE burden is not a baseline information, thus it was modeled as a time-dependent variable in univariable and multivariable Cox models., Results: Among 331 patients, irAEs were reported in 144 (43.5%) patients. After a median follow-up time of 29.7 months, patients with higher burden of skin, endocrine and musculoskeletal irAEs (the latter two's effect was confirmed at multivariable analysis) had longer overall survival (OS), as opposed to gastrointestinal, pneumonitis, neurological, liver, renal and other irAEs, which showed an harmful effect. Similar results were observed for progression-free survival (PFS). Based on the results retrieved from organ-specific irAEs, 'aggregated' burden scores were developed to distinguish 'protective' (endocrine and musculoskeletal) and 'harmful' (gastrointestinal, pneumonitis, neurological, hepatic) irAEs showing prognostic effects on OS and PFS., Conclusions: Our results demonstrate that not all irAEs could exert a protective effect on oncologic outcome. An easy-to-use model for ICIs toxicity (burden score of protective and harmful irAEs) may be used as surrogate marker of response., Competing Interests: Competing interests: LS: Speakers’ and consultant’s fees from MSD, Astra-Zeneca, Servier, Bayer, Merck, Amgen, Pierre-FabreMJO: Consulting fees from Pfizer, Merck, Glaxosmithkline, 3D Medicine, Nouscom, Roche. Research fees from Roche, Takeda, Merck, BMS, Astra-Zeneca, Nouscom. FP: Honoraria: Servier, Bayer, AstraZeneca/MedImmune, Lilly, MSD Oncology, Amgen, Pierre-Fabre, Merck-Serono, BMS. Consulting or Advisory Role: Merck-Serono, Amgen, Servier, MSD Oncology, Organon. Research Funding: Bristol Myers Squibb (Inst), AstraZeneca (Inst), Incyte. All other authors declare no specific conflicts of interest(s)., (© Author(s) (or their employer(s)) 2023. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Complex tumor and immune microenvironment render pancreatic ductal adenocarcinoma (PDAC) resistant to immune checkpoint inhibitors (ICIs). Therefore, a strategy to convert the immune hostile into an immunopermissive tumor is required. Recent studies showed that intratumoral injection of Toll-like receptor 9 agonist IMO-2125 primes the adaptive immune response. Phase I and II trials with intratumoral IMO-2125 demonstrated its safety and antitumoral activity., Methods: We generated an array of preclinical models by orthotopically engrafting PDAC-derived cell lines in syngeneic mice and categorized them as high, low and no immunogenic potential, based on the ability of tumor to evoke T lymphocyte or NK cell response. To test the antitumor efficacy of IMO-2125 on locally treated and distant sites, we engrafted cancer cells on both flanks of syngeneic mice and treated them with intratumoral IMO-2125 or vehicle, alone or in combination with anti-PD1 ICI. Tumor tissues and systemic immunity were analyzed by transcriptomic, cytofluorimetric and immunohistochemistry analysis., Results: We demonstrated that intratumoral IMO-2125 as single agent triggers immune system response to kill local and distant tumors in a selected high immunogenic subtype affecting tumor growth and mice survival. Remarkably, intratumoral IMO-2125 in combination with systemic anti-PD1 causes a potent antitumor effect on primary injected and distant sites also in pancreatic cancer models with low immunogenic potential, preceded by a transition toward an immunopermissive microenvironment, with increase in tumor-infiltrating dendritic and T cells in tumor and lymph nodes., Conclusion: We demonstrated a potent antitumor activity of IMO-2125 and anti-PD1 combination in immunotherapy-resistant PDAC models through the modulation of immune microenvironment, providing the rationale to translate this strategy into a clinical setting., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Pancreatic ductal adenocarcinoma is one of the most lethal human cancers. Its precursor lesions include pancreatic intra-epithelial neoplasia, mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm (IPMN). IPMNs usually present as an incidental finding at imaging in 2.6% of the population and, according to the degree of dysplasia, they are classified as low- or high-grade lesions. Since the risk of malignant transformation is not accurately predictable, the management of these lesions is based on morphological and clinical parameters, such as presence of mural nodule, main pancreatic duct dilation, presence of symptoms, or high-grade dysplasia. Although the main genetic alterations associated to IPMNs have been elucidated, they are still not helpful for disease risk stratification. The growing body of genomic and epigenomic studies along with the more recent development of organotypic cultures provide the opportunity to improve our understanding of the malignant transformation process, which will likely deliver biomarkers to help discriminate between low- and high-risk lesions. Recent insights on the topic are herein summarized.