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The interim analysis of the CIRCULATE-Japan GALAXY observational study demonstrated the association of circulating tumor DNA (ctDNA)-based molecular residual disease (MRD) detection with recurrence risk and benefit from adjuvant chemotherapy (ACT) in resectable colorectal cancer (CRC). This updated analysis with a 23-month median follow-up, including 2,240 patients with stage II-III colon cancer or stage IV CRC, reinforces the prognostic value of ctDNA positivity during the MRD window with significantly inferior disease-free survival (DFS; hazard ratio (HR): 11.99, P < 0.0001) and overall survival (OS; HR: 9.68, P < 0.0001). In patients who experienced recurrence, ctDNA positivity correlated with shorter OS (HR: 2.71, P < 0.0001). The significantly shorter DFS in MRD-positive patients was consistent across actionable biomarker subsets. Sustained ctDNA clearance in response to ACT was an indicator of favorable DFS and OS compared to transient clearance (24-month DFS: 89.0% versus 3.3%; 24-month OS: 100.0% versus 82.3%). True spontaneous clearance rate with no clinical recurrence was 1.9% (2/105). Overall, our findings provide evidence for the utility of ctDNA monitoring for post-resection recurrence and mortality risk stratification that could be used for guiding adjuvant therapy., Competing Interests: Competing interests Y.N. reports advisory roles with Guardant Health Pte Ltd., Natera, Inc., Roche Ltd., Seagen, Inc., Premo Partners, Inc., Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., Exact Sciences Corporation and Gilead Sciences, Inc.; speakers’ bureau from Guardant Health Pte Ltd., MSD K.K., Eisai Co., Ltd., Zeria Pharmaceutical Co., Ltd., Miyarisan Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., CareNet, Inc., Hisamitsu Pharmaceutical Co., Inc., Taiho Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Chugai Pharmaceutical Co., Ltd., Becton, Dickinson and Company and Guardant Health Japan Corp.; research funding from Seagen, Inc., Genomedia, Inc., Guardant Health AMEA, Inc., Guardant Health, Inc., Tempus Labs, Inc., Roche Diagnostics K.K., Daiichi Sankyo Co., Ltd. and Chugai Pharmaceutical Co., Ltd. J.W. reports receiving honoraria for lectures from Johnson & Johnson, Medtronic, Eli Lilly and Takeda Pharmaceuticals and receiving research funding from Medtronic, AMCO, TERUMO and Stryker Japan, all outside the submitted work. N.A. reports nothing to declare. K.H. reports nothing to declare. K. Kataoka reports speakers’ bureau from Merck Biopharma Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eli Lilly Japan Co., Ltd. and Guardant Health Japan Corp. and research funding from Sysmex. M.Y. reports receipt of personal fees and honoraria for lectures from Medtronic, Johnson & Johnson, INTUITIVE, Eli Lilly, Taiho, Merck KGaA, Takeda and Daiichi Sankyo. K. Kato reports nothing to declare. M.K. reports speakers’ bureau from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co., Ltd., Eli Lilly and Yakult Honsha. Y.K. reports speakers’ bureau from Guardant Health Pte Ltd., MSD K.K., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Takeda Pharmaceutical Co. and Ono Pharmaceutical Co., Ltd. K.H.Y. reports payment or honoraria for lectures, presentations and speakers’ bureaus from Takeda Pharmaceutical Co., Ltd., Ono Pharmaceutical Co., Ltd, TTY Biopharm Co. Ltd., OEP Group Co., Ltd., Bristol Myers Squibb, Amgen, Inc., Bayer Co., Ltd., Daiichi Sankyo Co., Ltd., Merck Biopharma Co., Ltd., Novartis Co., Ltd. and CStone Pharmaceuticals Co., Ltd. and advisory roles with Merck & Co., Inc, Pfizer Inc., Pierre Fabre, Ltd. and AstraZeneca. S.M. reports honoraria from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd. and Eli Lilly. H.Y. reports nothing to declare. K.A. reports nothing to declare. M. Miyo reports nothing to declare. T.M. reports advisory role with Anaut, Inc. and Fujifilm Corporation and speakers’ bureau from AstraZeneca K.K., Chugai Pharmaceutical Co., Ltd. and Miyarisan Pharmaceutical Co., Ltd. K.Y. reports speakers’ bureau from Chugai Pharmaceutical Co., Ltd., Daiichi Sankyo Co., Ltd., Yakult Honsha Co., Ltd., Takeda Pharmaceutical Co., Ltd., Merck Biopharma Co., Ltd., Taiho Pharmaceutical Co., Ltd., Eli Lilly Japan K.K., Ono Pharmaceutical Co., Ltd., MSD Co., Ltd. and Bristol Myers Squibb and research funding from Taiho Pharmaceutical Co., Ltd. H.E. reports honoraria from Amgen, Chugai Pharmaceutical Co., Ltd., Guardant Health Japan Corp., Incyte Japan Co., Ltd., Merck Serono Co., Ltd., Ono Pharmaceutical Co., Ltd. and Konica Minolta Co, Ltd. and research funding from Astellas Pharmaceutical Co., Ltd. K.O. reports speakers’ bureau from Taiho Pharmaceutical Co., Ltd. A.H. reports receiving honoraria for lectures from Medtronic, Johnson & Johnson, Merck Biopharma Co., Ltd., Eli Lilly and Fujifilm Corporation. H.S. reports nothing to declare. S.K. is a full-time employee of EPS Corporation. G.L., V.N.A., S.S. and A.J. are employees of Natera, Inc., with stock or options to own stock. M.C.L. is an employee of Natera, Inc., with stock or options to own stock, and further reports grants/contracts (funding to institution: Mayo Clinic) from Eisai, Exact Sciences Corporation, Genentech, Genomic Health, GRAIL, Menarini Silicon Biosystems, Merck, Novartis, Seattle Genetics and Tesaro; travel support reimbursement from AstraZeneca, Genomic Health and Ionis; and ad hoc advisory board meetings (all funds to Mayo Clinic; no personal compensation) from AstraZeneca, Celgene, Roche/Genentech, Genomic Health, GRAIL, Ionis, Merck, Pfizer, Seattle Genetics and Syndax. A.A. is an employee of Natera, Inc., with a leadership position and stock or options to own stock. M.R. reports employment, leadership position, stock and other ownership interests and consulting and advisory role at Natera, Inc., MyOme and Marble Therapeutics and research funding, patents/royalties/other intellectual property and travel/accommodations/expenses from Natera, Inc. and MyOme. H.B. reports research funding from Ono Pharmaceutical and honoraria from Ono Pharmaceutical, Eli Lilly Japan and Taiho Pharmaceutical. H.T. reports speakers’ bureau from MSD K.K, Merck Biopharma Co., Ltd., Takeda, Taiho, Eli Lilly Japan, Bristol Myers Squibb Japan, Chugai Pharmaceutical, Ono Yakuhin and Amgen and research funding from Takeda and Daiichi Sankyo. I.T. reports speakers’ bureau from Medtronic, Johnson & Johnson, Intuitive, Medicaroid and Eli Lilly and research funding from Medtronic and Sysmex. T.K. reports nothing to declare. D.K. reports honoraria from Takeda, Chugai, Eli Lilly, MSD, Ono Pharmaceutical, Seagen, Guardant Health, Eisai, Taiho, Bristol Myers Squibb, Daiichi Sankyo, Pfizer, Merck Biopharma Co., Ltd. and Sysmex and research funding from Ono Pharmaceutical, MSD, Novartis, Servier, Janssen, IQVIA, Syneoshealth, CIMIC and Cimicshiftzero. M. Mori reports nothing to declare. T.Y. reports honoraria from Chugai Pharmaceutical, Takeda Pharmaceutical, Merck Biopharma Co., Ltd., Bayer Yakuhin, Ono Pharmaceutical and MSD K.K; consulting fee from Sumitomo Corp.; and research funding from Amgen, Bristol Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia, Medical & Biological Laboratories, Merus N.V., Molecular Health GmbH, MSD, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer Japan, Roche Diagnostics, Sanofi, Sysmex, Taiho Pharmaceutical and Takeda Pharmaceutical. E.O. reports speakers’ bureau from Chugai Pharmaceutical Co., Ltd., Bristol Meyers Squibb, Ono Pharmaceutical Co., Ltd., Eli Lilly and Takeda Pharmaceutical Co., Ltd.; research funding from Guardant Health, Inc.; and an advisory role with GlaxoSmithKline., (© 2024. The Author(s).)

Background: The QUATTRO-II trial examined the efficacy and safety of capecitabine+oxaliplatin+irinotecan (CAPOXIRI)+bevacizumab (BEV) vs. 5-fluorouracil+folinic acid+oxaliplatin+irinotecan (FOLFOXIRI)+BEV in metastatic colorectal cancer (mCRC)., Methods: In this phase II study (ClinicalTrials.gov: NCT04097444; jRCTs041190072), patients were randomized (1:1) to FOLFOXIRI+BEV or CAPOXIRI+BEV. The induction treatment in the FOLFOXIRI+BEV/CAPOXIRI+BEV arms was continued for 8/6 cycles (maximum 12/8 cycles if feasible), and the maintenance treatment was 5-fluorouracil/leucovorin+BEV or capecitabine+BEV at the investigators' discretion. The primary endpoint was progression-free survival (PFS), with the two arms deemed equivalent if the hazard ratio (HR) of the point estimate was 0.80 < HR < 1.25. Secondary endpoints were overall response rate (ORR), overall survival (OS), incidence of adverse events (AEs), and patient-reported outcomes., Findings: Overall, 51 and 52 patients were randomized to FOLFOXIRI+BEV and CAPOXIRI+BEV, respectively. The study met its primary endpoint; PFS at median follow-up of 23.7 months was 10.6 months (95% confidence interval [CI], 7.7-13.3) in the FOLFOXIRI+BEV arm vs. 10.9 months (95% CI, 9.3-14.3) in the CAPOXIRI+BEV arm (HR 1.114 [0.80 < HR < 1.25], p = 0.654). In the FOLFOXIRI+BEV vs. CAPOXIRI+BEV arms, the 2-year OS rate (95% CI) was 65.5% (49.5%-77.6%) vs. 74.3% (59.8%-84.2%), and the ORR (95% CI) was 76.5% (62.5%-87.2%) vs. 84.6% (71.9%-93.1%). Major (grade ≥3) AEs in the FOLFOXIRI+BEV vs. CAPOXIRI+BEV arms were neutropenia (68.6% vs. 40.4%), febrile neutropenia (9.8% vs. 11.5%), diarrhea (7.8% vs. 17.3%), and appetite loss (7.8% vs. 17.3%)., Conclusion: CAPOXIRI+BEV was well tolerated with reduced hematological toxicity and efficacy comparable to those of FOLFOXIRI+BEV, providing a potentially convenient first-line treatment alternative to FOLFOXIRI+BEV in patients with mCRC., Funding: Chugai Pharmaceutical Co., Ltd., Competing Interests: Declaration of interests H.B. received grants from Ono Pharmaceutical. H.B. also reports honoraria for lectures from Ono Pharmaceutical, Eli Lilly Japan, and Taiho Pharmaceutical. D.K. reports honoraria from Takeda Pharmaceutical, Chugai Pharmaceutical, Novartis, Eli Lilly, Seagen, MSD, Ono Pharmaceutical, Eisai, Taiho Pharmaceutical, Bristol Myers Squibb, Daiichi-Sankyo, Pfizer, Merck Biopharma, and Sysmex and research funding from Ono Pharmaceutical, MSD, Novartis, Servier, Janssen, IQVIA, Syneoshealth, CIMIC, and Cimic Shift Zero. H.S. received grants from Ono Pharmaceutical, Daiichi Sankyo, Taiho Pharmaceutical, and Sanofi and reports honoraria from Bayer, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly Japan, Merck Bio Pharma, MSD, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha. T.H. reports honoraria for lectures from Chugai Pharmaceutical. M.S. is on the speakers’ bureau at Johnson & Johnson, Kaken Pharmaceutical, Eli Lilly Japan, Merck Serono, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha. M.K. reports honoraria for lectures from Chugai Pharmaceutical, Takeda Pharmaceutical, Eli Lilly, Yakult Honsha, and Taiho Pharmaceutical. T. Masuishi reports honoraria from Bayer Yakuhin, Bristol-Myers Squibb, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly, Merck Serono, Ono Pharmaceutical, Sanofi, Taiho Pharmaceutical, Takeda Pharmaceutical, and Yakult Honsha and reports research funding from Amgen (Inst), Boehringer Ingelheim (Inst), CMIC (Inst), Daiichi Sankyo (Inst), Eli Lilly Japan (Inst), MSD (Inst), Novartis (Inst), Ono Pharmaceutical (Inst), Pfizer (Inst), and Syneos Health (Inst). H.Y. reports honoraria from Chugai Pharmaceutical and Yakult Honsha. Y. Kagawa reports honoraria from Chugai Pharmaceutical and Yakult Honsha. Y. Komatsu received grants from Ono Pharmaceutical, Chugai Pharmaceutical, Taiho Pharmaceutical, Shionogi, Nippon Zoki Pharmaceutical, Asahi Kasei Pharma Corporation, Nippon Kayaku, Daichi Sankyo, IQVIA Services Japan, MSD, Astellas Pharma, Incyte Corporation, Eisai, National Cancer Center Japan, Syneos Health Clinical, Shift Zero, PARAXEL International, Japan Clinical Cancer Research Organization, EPS Holdings, SYSMEX Corporation, Public Health Research Foundation, Aichi Cancer Center, and the Kyushu Study group of Clinical Cancer and reports honoraria for lectures from Ono Pharmaceutical, Taiho Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Eli Lilly and Company, Alfresa Pharma Corporation, Astellas Pharma, EA Pharma, Nippon Kayaku, Pfizer, Nippon Zoki Pharmaceutical, Sanofi, NIPRO, MOROO, Boehringer lngelheim, Hakodate National Hospital, Asahi Kasei Pharma Corporation, MSD, Zeria Pharmaceutical, Bayer Yakuhin, Yakult Honsha, Sumitomo Dainippon Pharma, Incyte Corporation, Merck Biopharma, The Japanese Gastroenterological Association, Sapporo Minami Tokushukai Hospital, and Pancan Japan. E.O. is on the speakers’ bureau at Bristol-Myers Squibb Japan, Chugai Pharmaceutical, Eli Lilly Japan, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical and received research funding from Guardant Health. Y.Y. reports honoraria for lectures from Ono Pharmaceutical, Bristol Myers Squibb, Yakult, Chugai Pharmaceutical, Eli Lily, Bayer, Taiho Pharmaceutical, Servier, Takeda Pharmaceutical, Daiichi Sankyo, Teijin, and Insight. H.K. received grants or contracts from Chugai Pharmaceutical, Taiho Pharmaceutical, and Eisai and received consulting fees from BMS, Eli Lilly Japan, Ono Pharmaceutical, Daiichi Sankyo, and Taiho Pharmaceutical; and has received honoraria from BMS, Bayer Yakuhin, Eli Lilly Japan, MSD, Ono Pharmaceutical, Chugai Pharmaceutical, Daiichi Sankyo, Takeda Pharmaceutical, and Taiho Pharmaceutical. T. Misumi reports honoraria from Chugai Pharmaceutical, AstraZeneca, and Miyarisan. H.T. received lecture fees from Takeda Pharmaceutical, Ono Pharmaceutical, Eli Lilly, Merck Biopharma, and Chugai Pharmaceutical and received research funds from Takeda Pharmaceutical, Daiichi Sankyo, and Ono Pharmaceutical. K.Y. reports honoraria for lectures from Chugai Pharmaceutical, Yakult, Daiichi Sankyo, Merk Serono, Sanofi, MSD, Takeda Pharmaceutical, Taiho Pharmaceutical, Bayer, Eli Lily, Ono Pharmaceutical, and Bristol-Myers Squibb. K.M. reports honoraria from Bristol-Myers Squibb, Daiichi Sankyo, MSD, Eli Lilly, Ono Pharmaceutical, Taiho Pharmaceutical, and Takeda Pharmaceutical; reports a consulting or advisory role at Amgen, Astellas Pharma, AstraZeneca, Chugai Pharmaceutical, and Ono Pharmaceutical; and received research funding from Amgen (Inst), Astellas Pharma (Inst), Chugai Pharmaceutical (Inst), Eisai (Inst), MSD (Inst), Novartis (Inst), Ono Pharmaceutical (Inst), Sanofi (Inst), and Taiho Pharmaceutical (Inst). T.Y. received consulting fees Sumitomo Corporation; received grants from Amgen, Chugai Pharmaceutical, Daiichi Sankyo, Eisai, FALCO biosystems, Genomedia, Molecular Health GmbH, MSD, Nippon Boehringer Ingelheim, Ono Pharmaceutical, Pfizer Japan, Roche Diagnostics, Sanofi, Sysmex, and Taiho Pharmaceutical; and reports honoraria for presentations from Bayer Yakuhin, Chugai Pharmaceutical, Merck Biopharma, MSD, Ono Pharmaceutical, and Takeda Pharmaceutical. T.K. reports honoraria for lectures from Chugai Pharmaceutical, Ono Pharmaceutical, Taiho Pharmaceutical, Takeda Pharmaceutical, and Eli Lilly and Company. A.T. is on the speakers' bureau at Bristol-Myers Squibb, Chugai Pharmaceutical, Eli Lilly Japan, Merck Serono, Sanofi, Taiho Pharmaceutical, and Takeda Pharmaceutical and reports research funding from Ono Pharmaceutical (Inst), Sanofi (Inst), and Taiho Pharmaceutical (Inst)., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Certain genetic alterations and right-sided primary tumor location are associated with resistance to anti-epidermal growth factor (EGFR) treatment in metastatic colorectal cancer (mCRC). The phase 3 PARADIGM trial (n = 802) demonstrated longer overall survival with first-line anti-EGFR (panitumumab) versus antivascular endothelial growth factor (bevacizumab) plus modified FOLFOX6 in patients with RAS wild-type mCRC with left-sided primary tumors. This prespecified exploratory biomarker analysis of PARADIGM (n = 733) evaluated the association between circulating tumor DNA (ctDNA) gene alterations and efficacy outcomes, focusing on a broad panel of gene alterations associated with resistance to EGFR inhibition, including KRAS, NRAS, PTEN and extracellular domain EGFR mutations, HER2 and MET amplifications, and ALK, RET and NTRK1 fusions. Overall survival was prolonged with panitumumab plus modified FOLFOX6 versus bevacizumab plus modified FOLFOX6 in patients with ctDNA that lacked gene alterations in the panel (that is, negative hyperselected; median in the overall population: 40.7 versus 34.4 months; hazard ratio, 0.76; 95% confidence interval, 0.62-0.92) but was similar or inferior with panitumumab in patients with ctDNA that contained any gene alteration in the panel (19.2 versus 22.2 months; hazard ratio, 1.13; 95% confidence interval, 0.83-1.53), regardless of tumor sidedness. Negative hyperselection using ctDNA may guide optimal treatment selection in patients with mCRC. ClinicalTrials.gov registrations: NCT02394834 and NCT02394795 ., (© 2024. The Author(s).)

Purpose: Immune checkpoint inhibitors (ICIs) appeared active in single-arm trials for patients with chemoresistant metastatic colorectal cancer (mCRC) harboring microsatellite instability (MSI). Given the paucity of randomised controlled trials (RCTs) in this setting, we evaluated the effect size of ICIs using intra-patients comparison and ARCAD database as historical controls., Patients and Methods: Individual-patient data from NIPICOL and CheckMate 142 phase II trials that evaluated a combination of ICIs for MSI mCRC patients (N = 176) and from five non-ICI mCRC historical RCTs in second-line or latter (N = 4026) were analyzed. Firstly, promising of ICIs was identified using intra-patient comparison based on growth modulation index (GMI) defined the ratio of progression-free survivals (PFS) on ICIs and previous line of therapy. Survival outcomes of ICIs-treated patients were then compared with those matched non-ICIs treated from ARCAD database historical RCTs., Results: Among ICIs-treated patients, median PFS on ICIs was 32.66 (range 0.10-74.25) versus 4.07 months (range 0.7-49.87) on prior therapy, resulting on median GMI of 4.97 (range 0.07-59.51; hazard-ratio (HR)= 0.16 (95 %CI=0.11-0.22, P < 0.001)). Compared to matched non-ICI patients, in third-line, median overall survival (OS) was not reached with ICIs versus 3.52 months with placebo (HR=0.20, 95 %CI=0.10-0.41, P < 0.001), and 6.51 months with active drugs (HR=0.30, 95 %CI=0.15-0.60, P = 0.001). In second-line, median OS was not reached with ICIs versus 11.7 months with chemotherapy+placebo (HR=0.12, 95 %CI=0.07-0.22, P < 0.001), and 16.3 months with chemotherapy+targeted therapy (HR=0.10, 95 %CI=0.05-0.19, P < 0.001)., Conclusion: ICIs demonstrates high effect size for MSI mCRC patients in second-line and later. This work might be useful as an example of methodology to avoid RCTs when benefit from experimental therapy is likely to be high., Competing Interests: Declaration of Competing Interest Romain Cohen reports honoraria from Astra-Zeneca, 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. Benoist Chibaudel reports consulting and advisory role from Amgen, Bayer, Beigine, Biocartis, Lilly, Merck, MSD, Pfizer, Pierre Fabre, Revolution Medicines, Roche, SeqOne, Sanofi, Servier, Takeda. Josep Tabernero reports personal financial interest in form of scientific consultancy role for Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Cardiff Oncology, Chugai, Daiichi Sankyo, F. Hoffmann-La Roche Ltd, Genentech Inc, HalioDX SAS, Hutchison MediPharma International, Ikena Oncology, Inspirna Inc, IQVIA, Lilly, Menarini, Merck Serono, Merus, MSD, Mirati, Neophore, Novartis, Ona Therapeutics, Orion Biotechnology, Peptomyc, Pfizer, Pierre Fabre, Samsung Bioepis, Sanofi, Scandion Oncology, Scorpion Therapeutics, Seattle Genetics, Servier, Sotio Biotech, Taiho, Tessa Therapeutics, TheraMyc and Tolremo Therapeutics. Stocks: Oniria Therapeutics and also educational collaboration with Imedex/HMP, Medscape Education, MJH Life Sciences, PeerView Institute for Medical Education and Physicians Education Resource (PER). Qian Shi reports consulting/advisory role from Yiviva Inc, Boehringer Ingelheim Pharmaceuticals, Inc, Regeneron Pharmaceuticals, Inc., Hoosier Cancer Research Network, Kronos Bio, and Mirati Therapeutics Inc; Honorarium/speaker role from Chugai Pharmaceutical Co., Ltd (to myself), research funds from Celgene/BMS, Roche/Genentech, Janssen, Novartis (to institution). Thierry Andre reports attending advisory board meetings and receiving consulting fees from Abbvie, Astellas, Aptitude Health, Bristol Myers Squibb, Gritstone Oncology, Gilead, GlaxoSmithKline, Merck & Co. Inc., Nordic Oncology, Seagen, Servier, Takeda and Transgène and honoraria from Bristol Myers Squibb, GlaxoSmithKline, Merck & Co. Inc., Merck Serono, Pierre Fabre, Roche, Sanofi, Seagen and Servier; and support for meetings from Merck & Co. Inc. and Servier. Hideaki Bando reports research fund from Ono pharmaceutical, and honoraria from Ono pharmaceutical, Taiho pharmaceutical, Eli Lilly Japan. Michael J. Overman reports Consulting: Merck, Pfizer, Array, Gritstone, 3DMed, Nouscom, Atreca, Bayer, Simcere and Research Funding: Takeda, Roche, Lilly, Merck, Medimmune, BMS, Nouscom, Phanes. John Zalcberg reports leadership from ICON Group, Lipotek, PRAXIS; Stock from Biomarin, Ophthea, Amarin, Concert Pharmaceuticals, Frequency Therapeutics, Gilead, Madrigal Pharmaceuticals, UniQure, Zogenix, Orphazyme, Moderna Therapeutics, TWST, Novavax, Teladoc; Honoraria from Gilead Sciences, MSD Oncology, Viatris; Consulting & Advisory Role from Merck Sharp & Dohme, Specialized Therapeutics, CEND, Deciphera, REVOLUTION MEDICINE, FivePHusion, Genorbio, 1Global, Novatech, Alloplex Biotherapeutics Inc, Oncology Republic; Research Funding from BMS, AstraZeneca, Pfizer, IQvia, Mylan, Ipsen, Eisai, Medtronic, MSD Oncology, Servier; Travel from MSD Oncology, ICON Group, PRAXIS. Eric Van Cutsem repors participation to advisory boards for Abbvie, ALX, Amgen, Array, Astellas, Astrazeneca, Bayer, Beigene, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi, GSK, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, Zymeworks; research grants from Amgen, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck KGaA, Novartis, Roche, Servier paid to his institution. Takayuki Yoshino reports honoraria from Chugai Pharma, Takeda Pharma, Merck, Bayer Yakuhin, Ono Pharmaceutical and MSD K.K; consulting fee from Sumitomo Corp.; research grant from Amgen, Chugai, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia Inc., Molecular Health, MSD, Nippon Boehringer Ingelheim, Ono, Pfizer, Roche Diagnostics, Sanofi, Sysmex and Taiho. Richard Adams reports Speaker fees/travel from Servier, Takeda, Amgen; Consultancy from Takeda, Seagen, Bayer; Institutional research funding from AZ, Jazz Pharma, MSD. Toshihiro Misumi reports Honoraria from Chugai, AstraZeneca, and Miyarisan. All remaining authors have declared no conflicts of interest., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

In Europe and the United States, the Foundation Aide et Recherche en Cancérologie Digestive(ARCAD)database project was initiated in 2006 and 43,488 patient data(IPD)for metastatic colorectal cancer from 59 trials have been collected and constructed as the integrated database. The ARCAD-Asia was launched in 2021 and has been actively collecting Asian clinical trials and converted IPD are stored into the integrated database. In addition, the ARCAD-Asian data are transferred to ARCAD and IPD are integrated to ARCAD global database. All the data are shared with 3 data centers of ARCAD-Asia and ARCAD, located in France, the United States and Japan. In the ARCAD database, there are 1,673 IPD treated with placebo in a salvage line setting. We are now planning to utilize placebo IPD as the synthetic control arms(SCAs)to compare the efficacies of active agents. Furthermore, we will continue to collect the Asian IPD and will expand the cancer type, leading to more comprehensive global database.

Importance: For patients with RAS wild-type metastatic colorectal cancer, adding anti-epidermal growth factor receptor (anti-EGFR) or anti-vascular endothelial growth factor (anti-VEGF) monoclonal antibodies to first-line doublet chemotherapy is routine, but the optimal targeted therapy has not been defined., Objective: To evaluate the effect of adding panitumumab (an anti-EGFR monoclonal antibody) vs bevacizumab (an anti-VEGF monoclonal antibody) to standard first-line chemotherapy for treatment of RAS wild-type, left-sided, metastatic colorectal cancer., Design, Setting, and Participants: Randomized, open-label, phase 3 clinical trial at 197 sites in Japan in May 2015-January 2022 among 823 patients with chemotherapy-naive RAS wild-type, unresectable metastatic colorectal cancer (final follow-up, January 14, 2022)., Interventions: Panitumumab (n = 411) or bevacizumab (n = 412) plus modified fluorouracil, l-leucovorin, and oxaliplatin (mFOLFOX6) every 14 days., Main Outcomes and Measures: The primary end point, overall survival, was tested first in participants with left-sided tumors, then in the overall population. Secondary end points were progression-free survival, response rate, duration of response, and curative (defined as R0 status) resection rate., Results: In the as-treated population (n = 802; median age, 66 years; 282 [35.2%] women), 604 (75.3%) had left-sided tumors. Median follow-up was 61 months. Median overall survival was 37.9 months with panitumumab vs 34.3 months with bevacizumab in participants with left-sided tumors (hazard ratio [HR] for death, 0.82; 95.798% CI, 0.68-0.99; P = .03) and 36.2 vs 31.3 months, respectively, in the overall population (HR, 0.84; 95% CI, 0.72-0.98; P = .03). Median progression-free survival for panitumumab vs bevacizumab was 13.1 vs 11.9 months, respectively, for those with left-sided tumors (HR, 1.00; 95% CI, 0.83-1.20) and 12.2 vs 11.4 months overall (HR, 1.05; 95% CI, 0.90-1.24). Response rates with panitumumab vs bevacizumab were 80.2% vs 68.6%, respectively, for left-sided tumors (difference, 11.2%; 95% CI, 4.4%-17.9%) and 74.9% vs 67.3% overall (difference, 7.7%; 95% CI, 1.5%-13.8%). Median duration of response with panitumumab vs bevacizumab was 13.1 vs 11.2 months for left-sided tumors (HR, 0.86; 95% CI, 0.70-1.10) and 11.9 vs 10.7 months overall (HR, 0.89; 95% CI, 0.74-1.06). Curative resection rates with panitumumab vs bevacizumab were 18.3% vs 11.6% for left-sided tumors; (difference, 6.6%; 95% CI, 1.0%-12.3%) and 16.5% vs 10.9% overall (difference, 5.6%; 95% CI, 1.0%-10.3%). Common treatment-emergent adverse events were acneiform rash (panitumumab: 74.8%; bevacizumab: 3.2%), peripheral sensory neuropathy (panitumumab: 70.8%; bevacizumab: 73.7%), and stomatitis (panitumumab: 61.6%; bevacizumab: 40.5%)., Conclusions and Relevance: Among patients with RAS wild-type metastatic colorectal cancer, adding panitumumab, compared with bevacizumab, to standard first-line chemotherapy significantly improved overall survival in those with left-sided tumors and in the overall population., Trial Registration: ClinicalTrials.gov Identifier: NCT02394795.

Despite standard-of-care treatment, more than 30% of patients with resectable colorectal cancer (CRC) relapse. Circulating tumor DNA (ctDNA) analysis may enable postsurgical risk stratification and adjuvant chemotherapy (ACT) treatment decision-making. We report results from GALAXY, which is an observational arm of the ongoing CIRCULATE-Japan study (UMIN000039205) that analyzed presurgical and postsurgical ctDNA in patients with stage II-IV resectable CRC (n = 1,039). In this cohort, with a median follow-up of 16.74 months (range 0.49-24.83 months), postsurgical ctDNA positivity (at 4 weeks after surgery) was associated with higher recurrence risk (hazard ratio (HR) 10.0, P < 0.0001) and was the most significant prognostic factor associated with recurrence risk in patients with stage II or III CRC (HR 10.82, P < 0.001). Furthermore, postsurgical ctDNA positivity identified patients with stage II or III CRC who derived benefit from ACT (HR 6.59, P < 0.0001). The results of our study, a large and comprehensive prospective analysis of ctDNA in resectable CRC, support the use of ctDNA testing to identify patients who are at increased risk of recurrence and are likely to benefit from ACT., (© 2023. The Author(s).)

Background: The purpose of this prospective study was to assess the ability of plasma vascular endothelial growth factor-A short isoforms (pVEGF-Asi) to predict bevacizumab (BV) efficacy and to explore other circulating biomarkers in metastatic colorectal cancer (mCRC) patients treated with modified FOLFOX6/XELOX plus BV (mFOLFOX6/XELOX + BV)., Patients and Methods: Pre-treatment plasma samples were collected from 100 mCRC patients receiving first-line chemotherapy with mFOLFOX6/XELOX + BV. The plasma levels of 11 angiogenesis-associated molecules, including pVEGF-Asi and 22 cancer-associated gene mutations in circulating tumor DNA, were analyzed. For the primary endpoint, we assumed that the hazard ratio (HR) for progression-free survival (PFS) calculated using a Cox proportional hazards model was <1.15, comparing patients with a high versus those with a low pVEGF-Asi level divided according to the median pVEGF-Asi value., Results: The median value of pVEGF-Asi was 37 (range 6.5-262) pg/ml. The HR for PFS between the high and low pVEGF-Asi patient groups was 1.3 [95% confidence interval (CI) 0.8-2.1; log rank, P = 0.25], which was larger than the predefined threshold of 1.15. The multivariate analysis demonstrated that PFS was significantly associated with plasma intercellular adhesion molecule-1 (pICAM-1) (≥190.0 versus <190.0 ng/ml; HR 2.1; 95% CI 1.3-3.5), RAS (mutant versus wild; HR 2.5; 95% CI 1.5-4.3), and FBXW7 (mutant versus wild; HR 2.8; 95% CI 1.2-6.8), whereas overall survival was significantly associated with pICAM-1 (HR 2.0; 95% CI 1.1-3.7) and RAS (HR 2.6; 95% CI 1.5-4.6)., Conclusions: The addition of BV was unable to compensate for the poor PFS associated with a high pVEGF-Asi level, suggesting that pVEGF-Asi is unlikely to be a good predictive biomarker of the efficacy of mFOLFOX6/XELOX + BV therapy. The clinical significance of circulating ICAM-1, mutant RAS, and mutant FBXW7 levels should be studied further., (Copyright © 2022. Published by Elsevier Ltd.)

Background/aim: Routine use of adjuvant chemotherapy (AC) following hepatectomy for colorectal liver metastases (CRLM) is not universally practiced because of the lack of supporting evidence. Therefore, we investigated the efficacy of AC following curative CRLM resection., Patients and Methods: Among the 742 patients who underwent their first hepatectomy for CRLM at our institution, 335 were stratified into surgery alone (SA; n=162) and AC (n=173) groups. Poor prognostic factors for SA were identified using multivariate logistic regression analysis. Propensity score matching was used to compare the clinical outcomes between SA and AC groups according to the number of prognostic factors., Results: Multivariate analysis showed that preoperative carcinoembryonic antigen (CEA) levels (≥10 ng/ml; p=0.01), primary lymph node metastases (≥1; p=0.0001), and the number (n≥4; p=0.01) and maximum diameter (≥5 cm; p=0.00001) of CRLM tumours were independent poor prognostic factors for overall survival (OS) in the SA group. Patients with ≥3 risk factors were categorized as being high risk. After propensity score matching, the 5-year OS rate was significantly higher in the AC group (n=13) than that in the SA group (n=15; 47.9% vs. 7.3%; p=0.03) among high-risk patients., Conclusion: Adjuvant chemotherapy after curative CRLM resection may improve the prognosis of patients with three or more risk factors including preoperative CEA levels ≥10 g/ml, primary lymph node metastases ≥1, number (≥4) and maximum diameter (≥5 cm) of CRLM tumours., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Lynch syndrome (LS), which is known as a hereditary cancer syndrome, is distinguished by microsatellite instability, represented by the altered number of repetitive sequences in the coding and/or non-coding region. Immunohistochemical staining (IHC) of DNA mismatch repair (MMR) proteins (e.g., MLH1, MSH2, MSH6, and PMS2) has been recognized as an useful technique for screening of LS. Previous study has shown that the assessment of IHC, however, requires specific caution due to variable staining patterns even without germline mutations in MMR genes., Case Presentation: A 48-year-old man, who had been treated for anaplastic astrocytoma, was referred to our department for the precise examination of progressing anemia. Whole-body examination revealed two advanced carcinomas in descending colon and stomach. A hypo-vascular mass lesion was detected in liver as well. Pathological diagnosis (on surgical specimens) was poorly differentiated adenocarcinoma in descending colon, moderately differentiated tubular adenocarcinoma in stomach, and liver metastasis, which is possibly from colon. It was suspected that this case would be Turcot's syndrome-type-1 due to its specific family history having two cases of colon cancer within the second relatives. Pathogenic frameshift mutations in codon 618 of MLH1 gene was identified. Immunohistochemical analyses (IHC) demonstrated complete loss of MLH1 immuno-expression as well as of PMS2 except for those in brain tumor. Although frameshift mutation was not found in MSH6 gene, histological expression of MSH6 was patchy in primary colon carcinoma and was completely lost in the metastatic site in liver. MSH6 expression in gastric carcinoma, a coincidental cancer in this case, was intact. An abnormal (C)8 region was identified by the cloned PCR of colon and liver tumors but not from gastric cancer. Frameshift mutation in a (C)8 tract in exon 5 of the MSH6 gene was also detected in liver metastasis., Conclusion: This case supports a plausible mechanism, proposed by a previous literature, for the reduced expression of MSH6 in a somatic mutation manner, which might preferentially happen in colon cancer rather than in stomach carcinoma in MLH1/PMS2-deficient type of Turcot's syndrome type 1.

We encountered 2 cases of colorectal liver metastasis with biliarydilatation mimicking cholangiocarcinoma. Case 1: A 70- year-old male patient, who was diagnosed with colorectal cancer and underwent transverse colectomy3 years prior, was preoperativelydiagnosed with cholangiocarcinoma with biliarydilatation of the medial and lateral segments. He underwent left hemi-hepatectomy. The pathological diagnosis was colorectal liver metastasis with intra-biliarytumor thrombosis. Case 2: A 67-year-old male patient was diagnosed with descending colon cancer and cholangiocarcinoma with biliarydilatation of the medial segment. He underwent left hemi-colectomyand left hemi-hepatectomy. The pathological diagnosis was descending colon cancer and colorectal liver metastasis with biliaryinfiltration. The immunopathological findings showed double positivityfor CK20 and CDX2 antibodies and negativityfor CK7 antibodyin these cancer lesions.