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Background: T-cell immune infiltrates are robust prognostic variables in localised colon cancer. Evaluation of prognosis using artificial intelligence is an emerging field. We evaluated whether machine learning analysis improved prediction of patient outcome in comparison with analysis of T cell infiltrate only or in association with clinical variables., Methods: We used data from two phase III clinical trials (Prodige-13 and PETACC08) and one retrospective Italian cohort (HARMONY). Cohorts were split into training (N = 692), internal validation (N = 297) and external validation (N = 672) sets. Tumour slides were stained with CD3mAb. CD3 Machine Learning (CD3ML) score was computed using graphical parameters within the tumour tiles obtained from CD3 slides. CD3 infiltrates in tumour core and invasive margin were automatically detected. Associations of CD3 infiltrates and CD3ML with 5-year Disease-Free Survival (DFS) were examined using univariate and multivariable survival models by Cox regression., Findings: CD3 density both in the invasive margin and the tumour core were significantly associated with DFS in the different sets. Similarly, CD3ML score was significantly associated with DFS in all sets. CD3 assessment did not provide added value on top of CD3ML assessment (Likelihood Ratio Test (LRT), p = 0.13). In contrast, CD3ML improved prediction of DFS when combined with a clinical risk stage (LRT, p = 0.001). Stratified by clinical risk score (High or Low), patients with low CD3ML score had better DFS., Interpretation: In all tested sets, machine learning analysis of tumour cells improved prediction of prognosis compared to clinical parameters. Adding tumour-infiltrating lymphocytes assessment did not improve prognostic determination., Funding: This research received no external funding., Competing Interests: Declaration of interests JT has received honoraria as a speaker and/or in an advisory role from AMGEN, Astellas, Astra Zeneca, BMS, Merck KGaA, MSD, Novartis, ONO pharmaceuticals, Pierre Fabre, Roche Genentech, Sanofi and Servier. CL has received honoraria as a speaker and/or in an advisory role from AMGEN, AAA-Novartis, Takeda, Deciphera, Pierre Fabre, Servier. FG's institution has received grants or contracts from Astra, consulting fees from Roche, AMGEN and MSD, honoraria as a speaker from Merck and support for attending meetings and/or travel from AMGEN. FB has received honoraria for lectures, speakers, presentations, manuscript writing or educational events from MSD, Pierre Fabre, Sanofi, BMS, Incyte, Servier and Astellas and support for attending meetings and/or travel from AMGEN, Pierre Fabre and MSD., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Immunotherapy demonstrated remarkable efficacy in metastatic colorectal cancers (mCRCs) with mismatch repair deficiency (MMRd)/microsatellite instability (MSI). However, data regarding efficacy and safety of immunotherapy in the routine clinical practice are scarce., Patients and Methods: This is a retrospective, multicenter study aiming to evaluate efficacy and safety of immunotherapy in routine clinical practice and to identify predictive markers for long-term benefit. Long-term benefit was defined as progression-free survival (PFS) exceeding 24 months. All patients who received immunotherapy for an MMRd/MSI mCRC were included. Patients who received immunotherapy in combination with another known effective therapeutic class agent (chemotherapy or tailored therapy) were excluded., Results: Overall, 284 patients across 19 tertiary cancer centers were included. After a median follow-up of 26.8 months, the median overall survival (mOS) was 65.4 months [95% confidence interval (CI) 53.8 months-not reached (NR)] and the median PFS (mPFS) was 37.9 months (95% CI 30.9 months-NR). There was no difference in terms of efficacy or toxicity between patients treated in the real-world or as part of a clinical trial. Overall, 46.6% of patients had long-term benefit. Independent markers associated with long-term benefit were Eastern Cooperative Oncology Group-performance status (ECOG-PS) 0 (P = 0.025) and absence of peritoneal metastases (P = 0.009)., Conclusions: Our study confirms the efficacy and safety of immunotherapy in patients with advanced MMRd/MSI CRC in the routine clinical practice. ECOG-PS score and absence of peritoneal metastases provide simple markers that could help identify patients who benefit the most from this treatment., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Disclosure AC reports fees paid to his institution as an invited speaker from Amgen, Foundation Medicine, Merck Serono and Roche; fees paid to his institution for advisory board membership from Amgen, AnHeart Therapeutics, Merck Serono, Roche and Transgene; personal fees for editorial roles as Associate Editor for Annals of Oncology and ESMO Open and as Editor for Cancer Treatment Reviews; institutional funding as principal investigator (PI) from Actuate Therapeutic, Adaptimmune, Amcure, Amgen, Astellas, AstraZeneca, Bayer, BeiGene, Bristol Myers Squibb (BMS), FibroGen, Genentech, Lilly, MedImmune, Merck Serono, Merck Sharp & Dohme (MSD), Natera, Novartis, Servier, Sierra Oncology and Takeda; he reports a non-remunerated role as General and Scientific Director of INCLIVA Biomedical Research Institute. RA reports personal fees as an invited speaker from Merck Serono and Sanofi. SR reports personal fees as an invited speaker from Amgen, MSD and Servier; personal fees for advisory board membership from Amgen, Servier and Sirtex; institutional funding as a local PI from Ability Pharmaceuticals, Astellas, G1 Therapeutics, Hutchinson, Menarini, Mirati, Novartis, Pfizer, Pierre Fabre, Roche and Seagen. DA reports personal fees as an invited speaker from Amgen, AstraZeneca, Boston Scientific, BMS, Ipsen, Merck Serono, MSD, Pierre Fabre, Roche, Samsung Bioepis, Sanofi (Genzyme), Servier and Terumo; personal fees as an invited speaker and continued medical education (CME) provider from ACE Oncology, Aptitude Health, Art Tempi Media, Clinical Care Options, From Research to Practice, Imedex, MedAhead (Austria), PRMA Consulting, Streamitup (Germany), Tactic MD LLC, WebMD Health Corp; personal fees for advisory board membership from AstraZeneca, Boston Scientific, BMS, CRA International, Ketchum, MSD, Pierre Fabre, Samsung Bioepis, Sanofi (Genzyme) and Terumo; personal fees for advisory board membership, CME provider and App producer from onkowissen; personal fees for editorial roles as an Associate Editor for Annals of Oncology, ESMO Open and Clinical Colorectal Cancer; institutional funding from AbbVie and as a local PI from BMS and Pierre Fabre, as a coordinating PI from OncoLytics and as a Steering Committee member from Roche; he reports fees paid to his institution as Chair of the Data Safety Monitoring Board from Sanofi (Genzyme); non-remunerated activities as a project lead with OncoLytics, member of the American Society of Clinical Oncology (ASCO), the Deutsche Gesellschaft für Hämatologie und Medizinische Onkologie (DGHO), European School of Oncology (ESO) and a leadership role and Steering Committee membership with the Arbeitsgemeinschaft Internistische Onkologie in der Deutschen Krebsgesellschaft (AIO) and European Organisation for Research and Treatment of Cancer (EORTC) gastrointestinal group. NN reports personal fees as an invited speaker from Eli Lilly, Illumina, Merck, MSD and Thermo Fisher; personal fees for advisory board membership from Amgen, AstraZeneca, Bayer, Biocartis, Incyte, Novartis and Roche; institutional funding from AstraZeneca, Biocartis, Blueprint, Illumina, Incyte, Merck, Qiagen, Roche and Thermo Fisher; and non-remunerated activities as President of International Quality Network of Pathology (IQN Path) and President of the Società Italiana di Cancerologia (SIC). JT reports personal fees as an invited speaker and for advisory board membership from Amgen, BMS, Merck, MSD, Novartis, Pierre Fabre, Roche and Servier; non-remunerated activities as Chair of the Aide et Recherche en Cancérologie Digestive (ARCAD) Foundation pancreas research group, president of the scientific committee for the ARCAD foundation and as member of the administrative council, scientific committee, executive board responsible for international relationships/partnerships for the Federation Francophone de Cancerologie Digestive (FFCD) in the PRODIGE Intergroup for the FFCD. JS reports personal fees as an invited speaker from Merck Serono, Pierre Fabre and Servier; personal fees for advisory board membership from Pierre Fabre, Ventana and Zentalis; personal fees for consultancy and review of guidelines from Roche Diagnostics; personal fees for CME activities from GI Connect; personal fees for expert testimony from Seagen; personal fees for travel expenses from BMS and Servier; institutional funding from Pierre Fabre. TDB reports personal fees as an invited speaker from Boston Scientific and GE Healthcare; personal fees for advisory board membership from Guerbet, Quantum Surgical and Terumo; institutional funding from Quantum Surgical and Terumo. PO reports personal fees as an invited speaker from BMS Eisai, Fresenius Kabi, Nordic Drugs, Novartis, Nutricia, Roche and Servier; personal feels for advisory board membership from Amgen, AstraZeneca, Bayer, Daiichi Sankyo (in collaboration with AstraZeneca), Eisai, Incyte, Merck, MSD, Pierre Fabre, Roche, Sanofi and Sobi; and personal fees for expert testimony for the Finnish Medicines Agency from BMS; she reports institutional funding for research grants from Amgen and Servier; as a local PI from Incyte and as a coordinating PI from Pfizer and Roche; she reports non-remunerated activities as a member of the Colores patient advocacy group and as a Board Member of the Finnish Cancer Society. TY reports personal fees as an invited speaker from Bayer, Chugai, Merck Biopharma, MSD and Ono; institutional funding from Amgen, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Genomedia, MSD, Ono, Sysmex and Taiho and as a local PI from Chugai, Daiichi Sankyo, Ono, Pfizer and Sanofi. EM reports personal fees as an invited speaker from Bayer, ESMO, Incyte, Merck S.p.A., Merck Serono, Pierre Fabre, Roche and Servier; personal fees for writing engagements from AstraZeneca, Incyte, MSD, Pierre Fabre, Roche and Servier; personal fees for advisory board membership from Amgen, Incyte, MSD, Pierre Fabre, Roche and Servier.

The pre-operative work-up for non-metastatic colon cancer includes colonoscopy and thoraco-abdomino-pelvic computed tomography (CT) with intravenous (IV) contrast. Colonoscopic determination of the anatomical location of the tumor may be erroneous, particularly with a long redundant colon (dolichocolon), and the search for synchronous colon neoplasms is limited when the endoscope cannot traverse the tumor-bearing segment. While computed tomography colonography angiography (CTC-A) makes it possible to assess distant tumor metastasis, it remains limited for the assessment of loco-regional extension. CTC-A requires specific colonic preparation, controlled colonic insufflation with CO 2 , and an injection of IV contrast. CTC-A provides a 3-D view of the overall morphology of the colon and precisely localizes the site of the colonic tumor. Merging the images of the colon with those of mesenteric and colonic vessels provides a representation of anatomical vascular variations. This information could help the surgeon to better plan the colectomy. The use of two-dimensional images of CTC-A with sections perpendicular to the major axis of the tumor-bearing colonic segment can provide precise information on the degree of parietal extension and be useful in evaluating the value of neo-adjuvant chemotherapy., (Copyright © 2021 Elsevier Masson SAS. All rights reserved.)

Background: Adjuvant treatment for stage II colon cancer remains debated. Finding a tool to select patients at risk for disease recurrence may help the clinical decision. Circulating tumor DNA (ctDNA) has been reported recently as a potential predictive marker for disease recurrence. We thus aim to test its ability to better select stage II colon cancer patients for adjuvant therapy., Methods: This national, phase III trial (NCT00002019-000935-15) conducted in more than 100 centers in France, plans to screen around 2640 patients in order to randomize (2:1; minimization method) 198 ctDNA positive patients. Patients aged 18 to 75 years with ECOG performance status ≤1 with R0 surgical resection of a pT3-T4aN0 colon or high rectum adenocarcinoma will be randomized within 63 days after curative-intent surgery, to adjuvant mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², and 5-FU bolus 400 mg/m2 then 5FU Continuous infusion 2.4 g/m²) every two weeks for 12 cycles or observation. Patients will be followed for maximum 7 years. A gain of 17.5% in 3-yr disease free survival (DFS) is expected (42.5% in the experimental arm vs. 25% in the control arm; HR:0.62; α, 5% [two-sided log-rank test]; 1-β, 80%). Secondary endpoints include 2-yr DFS, overall survival, and toxicity. Recruitement began End of January 2020., (Copyright © 2020 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.)

Background: According to the IDEA trial, 6-month adjuvant chemotherapy should remain the treatment standard in stage III T4 or N2 colon cancer. The relatively poor survival in this high-risk subgroup-a 3-year disease-free survival (DFS) rate of 65%-and the potential synergistic efficacy of 5-fluorouracil (5-FU), oxaliplatin, and irinotecan suggest that FOLFIRINOX may be a regimen of particular interest in this setting., Patients and Methods: This multicenter international phase 3 trial (ClinicalTrials.gov NCT02967289) being conducted in 49 centers in France and Canada plans to randomize (1:1; minimization method) 640 patients aged 18 to 70 years with Eastern Cooperative Oncology Group performance status ≤ 1. Randomization occurs within 42 days (with treatment initiated within 56 days) after curative-intent R0 surgical resection of a pT4N1 or pT1-4N2 colon adenocarcinoma. Patients will be randomized to receive adjuvant modified FOLFIRINOX (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , irinotecan 180 mg/m 2 , and 5-FU 2.4 g/m 2 over 46 hours) or modified FOLFOX6 (oxaliplatin 85 mg/m 2 , leucovorin 400 mg/m 2 , 5-FU bolus 400 mg/m 2 , then 2.4 g/m 2 over 46 hours) every 2 weeks for 24 weeks (12 cycles). Patients will be followed for 5 years after the end of adjuvant chemotherapy. A gain of 9% in 3-year DFS (primary end point) is expected (74% in the experimental arm vs. 65% in the control arm; α, 5% [2-sided log-rank test]; 1-β, 80%). Secondary end points of this study include 2-year DFS, overall survival, and toxicity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Deficient mismatch repair (dMMR) colon cancer (CC) is reportedly resistant to 5-fluorouracil (5FU) adjuvant chemotherapy while preliminary data suggest chemosensitivity to oxaliplatin. We assessed the efficacy of fluoropyrimidine with and without oxaliplatin in a large cohort of dMMR CC patients., Methods: This retrospective multicenter study included all consecutive patients who underwent curative surgical resection for stage II or III dMMR CC between 2000 and 2011. Prognostic factors were analyzed using Cox models, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. All statistical tests were two-sided., Results: A total of 433 dMMR CC patients were included (56.8% stage II, 43.2% stage III). Mean follow-up was 47.0 months. The patients received surgery alone (n = 263) or surgery plus adjuvant chemotherapy consisting of fluoropyrimidine with (n = 119) or without (n = 51) oxaliplatin. Adjuvant chemotherapy was administered to 16.7% of stage II and 69.0% of stage III CC patients. As compared with surgery alone, adjuvant oxaliplatin-based chemotherapy improved disease-free survival (DFS) in multivariable analysis (HR = 0.35, 95% CI = 0.19 to 0.65, P < .001), contrary to adjuvant fluoropyrimidine alone (HR = 0.73, 95% CI = 0.36 to 1.49, P = .38). In the subgroup analysis, the DFS benefit of oxaliplatin-based chemotherapy was statistically significant in multivariable analysis only in stage III (HR = 0.41, 95% CI = 0.19 to 0.87, P = .02)., Conclusion: This study supports the use of adjuvant chemotherapy with fluoropyrimidine plus oxaliplatin in stage III dMMR CC., (© The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Purpose: Adding oxaliplatin to adjuvant 5-fluorouracil (5-FU) chemotherapy improves 3-year disease-free survival (DFS) after resection of stage III colon cancer. Several studies suggest that patients with tumors exhibiting defective mismatch repair (MMR) do not benefit from adjuvant 5-FU chemotherapy, but there are few data on 5-FU-oxaliplatin (FOLFOX) adjuvant chemotherapy in this setting. The aim of this study was to evaluate the prognostic value of MMR status for DFS in patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy., Experimental Design: MMR status was determined by microsatellite instability testing or immunohistochemistry in 303 unselected patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy in 9 centers. Cox proportional hazards models were used to examine the association between MMR status and 3-year DFS., Results: The 3-year DFS rate was significantly higher in the 34 patients (11.2% of the study population) with defective MMR tumors (90.5%) than in patients with proficient MMR tumors (73.8%; log-rank test; HR = 2.16; 95% CI, 1.09-4.27; P = 0.027). In multivariate analysis, MMR status remained an independent significant prognostic factor for DFS (HR = 4.48; 95% CI, 1.34-14.99; P = 0.015)., Conclusion: MMR status is an independent prognostic biomarker for DFS in patients with stage III colon cancer receiving adjuvant FOLFOX chemotherapy., (©2011 AACR.)