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"NeoRAS WT" refers to the loss of RAS mutations (MTs) following first-line treatment in metastatic colorectal cancer (mCRC). We evaluate the incidence and clinicopathological characteristics of NeoRAS WT mCRC using next-generation sequencing of plasma circulating tumor DNA. Patients with mCRC enrolled in the GOZILA study initially diagnosed with tissue RAS MT mCRC and received subsequent systemic therapy are eligible. NeoRAS WT is defined as the absence of detectable RAS MT in plasma and assessed in all eligible patients (Group A) and in a subgroup with at least one somatic alteration detected in plasma (Group B). Overall, 478 patients are included. NeoRAS WT prevalence is 19.0% (91/478) in Group A and 9.8% (42/429) in Group B. Absence of liver or lymph node metastasis and tissue RAS MTs other than KRAS exon 2 MTs are significantly associated with NeoRAS WT emergence. Overall, 1/6 and 2/6 patients with NeoRAS WT treated with anti-EGFR monoclonal antibodies (mAbs) show partial response and stable disease for ≥6 months, respectively. NeoRAS WT mCRC is observed at a meaningful prevalence, and anti-EGFR mAb-based therapy may be effective., (© 2024. The Author(s).)

Background: The phase 3 BEACON CRC study demonstrated the survival benefits of encorafenib and cetuximab, with or without binimetinib (the BEACON triplet or doublet regimen), for BRAF V600E -mutant metastatic colorectal cancer (mCRC). This expanded access program (EAP) and subsequent follow-up study assessed the efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAF V600E -mutant mCRC., Materials and Methods: The EAP was an open-label, single-arm study including Japanese patients with BRAF V600E -mutant mCRC whose disease progressed after 1 to 2 prior regimens. The patients received the BEACON triplet regimen with 28-day cycles. The subsequent follow-up study assessed the survival outcomes following EAP completion. Safety was assessed only during the EAP., Results: Among the 86 enrolled patients, 81 received the BEACON triplet regimen. The objective response rate and median progression-free survival were 27.6% (95% confidence interval [CI], 18.0%-39.1%) and 5.26 (95% CI, 4.14-5.52) months, respectively. Grade 3 to 4 adverse events and treatment-related adverse events occurred in 43.2% and 28.4% of patients, respectively. No new safety signals were observed during the EAP. Among 58 patients with confirmed survival at EAP completion, 57 were included in the follow-up study. With a median observation period of 9.17 months through the EAP and follow-up study, the median overall survival was 10.38 (95% CI, 9.00-16.16) months., Conclusion: The efficacy and safety of the BEACON triplet regimen in Japanese patients with BRAF V600E -mutant mCRC were consistent with those reported in the BEACON CRC trial, supporting its use as a standard treatment for pretreated patients with BRAF V600E -mutant mCRC., Competing Interests: Disclosure DK reports honoraria from Takeda, Chugai, Lilly, Merck Sharp and Dome (MSD), Ono, Taiho, Bristol-Myers Squibb (BMS), Daiichi Sankyo, Pfizer, Novartis, Eisai, Seagen, Merck Biopharma, and Sysmex; and research funding from Ono, MSD, Novartis, Servier, Janssen, IQVIA, Syneos Health, Cmic, and Cmic ShiftZero. AT reports grants from MSD, Amgen, BMS, AstraZeneca, Eisai, and Ono; and honoraria from Lilly, Taiho, Takeda, Ono, Chugai, and Merck Serono. TK reports honoraria from Chugai, Takeda, Eli Lilly, and Ono. TS reports grants from Ono, Chugai, and Yakult Honsha; and honoraria from Eli Lilly, Ono, BMS, and Daiichi Sankyo. TM reports grants from MSD, Daiichi Sankyo, Ono, Novartis, Amgen, Syneos Health Clinical, Boehringer Ingelheim, Pfizer, Cmic ShiftZero, and Eli Lilly; and honoraria from Takeda, Chugai, Merck Bio Pharma, Taiho, Bayer, Lilly Japan, Yakult Honsha, Sanofi, Daiichi Sankyo, Ono, BMS, and Nippon Kayaku. YK reports grants and scholarships funding from Ono, Taiho, Daiichi Sankyo, and Chugai; funding from IQVIA Services Japan, MSD, Astellas Pharma, Incyte Bioscience Japan, Eisai, National Cancer Center Hospital East, Syneos Health, Cmic Holdings, Parexel International, and National Cancer Center Japan; scholarships from Shionogi, Nippon Zoki, Nippon Kayaku, and Asahi Kasei; and honoraria from Ono, Chugai, Bayer Yakuhin, Astellas, Daiichi Sankyo, Taiho, Eli Lilly, MSD, Yakult, and Incyte Bioscience Japan. TE reports grants from MSD, Daiichi Sankyo, Pfizer, Astellas, Quintiles, Syneos Health, Chugai, Amgen, Ono, Novartis, Astellas Amgen Biopharma, Asahi Kasei, and IQVIA; and honoraria from Chugai, Daiichi Sankyo, Taiho, Eli Lilly, BMS, and MSD. NI reports a grant from Ono. ST reports honoraria from Chugai and Eli Lilly. HB reports honoraria from Ono, Eli Lilly Japan, and Taiho. SI reports grants from Ono and BMS; honoraria from Ono and BMS; and employment by Chugai. HT reports grants from Takeda, Ono, and Daiichi Sankyo; and honoraria from Ono, Merck Biopharma, Eli Lilly, Chugai, and Takeda. TYo reported grants from Amgen K.K., Chugai, Daiichi Sankyo, Eisai, FALCO Biosystems, Genomedia, Molecular Health GmbH, MSD K.K., Nippon Boehringer Ingelheim, Ono, Pfizer Japan, Roche Diagnostics K.K., Sanofi K.K., Sysmex, and Taiho; and consulting fees from Sumitomo Corporation; honoraria from Bayer Yakuhin, Chugai, Merck Biopharma, MSD K.K., Ono, and Takeda. YU, TO, and CI are employees of Ono. Other authors have declared no conflict of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: The significance of angiogenic factors as predictors of second-line (2L) chemotherapy efficacy when combined with angiogenesis inhibitors for metastatic colorectal cancer (mCRC) remains unestablished., Patients and Methods: In this multicenter prospective observational study, 17 angiogenic factors were analyzed in plasma samples collected at pretreatment and progression stages using a Luminex multiplex assay. Patients who received chemotherapy plus bevacizumab (BEV group), FOLFIRI plus ramucirumab (RAM group), or FOLFIRI plus aflibercept (AFL group) as the 2L treatment were included. Interactions between pretreatment and treatment groups for progression-free survival (PFS), overall survival (OS), and response rate (RR) were assessed using the propensity-score weighted Cox proportional hazards model., Results: From February 2018 to September 2020, 283 patients were analyzed in the 2L cohort. A strong interaction was observed for PFS between BEV and RAM with HGF, sNeuropilin-1, sVEGFR-1, and sVEGFR-3. Interactions for RR between the BEV and RAM groups were observed for sNeuropilin-1 and sVEGFR-1. Contrarily, OS, PlGF, sVEGFR-1, and sVEGFR-3 differentiated the treatment effect between BEV and AFL. Plasma samples were evaluable for dynamic analysis in 203 patients. At progression, VEGF-A levels significantly decreased in the BEV group and increased in the RAM and AFL groups., Conclusion: The pretreatment plasma sVEGFR-1 and sVEGFR-3 levels could be predictive biomarkers for distinguishing BEV and RAM when combined with chemotherapy in 2L mCRC treatment. Based on the VEGF-A dynamics at progression, selecting RAM or AFL for patients with significantly elevated VEGF-A levels may be a 2L treatment strategy, with BEV considered for the third-line treatment., Clinical Trial Number: UMIN000028616., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background/aim: Trifluridine/tipiracil (FTD/TPI) is used to treat metastatic colorectal cancer (mCRC). Since the standard regimen of FTD/TPI features a complex dosing schedule and frequently results in severe hematological toxicities, a simplified regimen has emerged, in which FTD/TPI is orally administered biweekly. However, the survival benefits and potential adverse events associated with the biweekly FTD/TPI regimen have not been fully evaluated in previous reports. Therefore, in this study, the differences in efficacy and safety between the standard and biweekly FTD/TPI regimens were retrospectively investigated in patients with mCRC., Patients and Methods: Data from 90 patients who received FTD/TPI for mCRC were extracted from the electronic medical records at the Osaka University Hospital. According to the inclusion and exclusion criteria, 85 of the 90 patients were enrolled in the study. We compared patient characteristics, overall survival (OS), progression-free survival (PFS), and adverse events between the standard (n=56) and biweekly groups (n=29)., Results: The biweekly group exhibited prolonged OS and PFS compared to patients in the standard group. Multivariate analysis for OS and PFS demonstrated that the biweekly regimen was the only significant factor that affected OS, and not PFS (HR=0.561, p=0.049). Kaplan-Meier analysis indicated that neutropenia (grade ≥3) in the biweekly group was significantly prolonged compared to the standard group (p=0.012). However, there were no significant differences in adverse events between the two groups (p>0.999)., Conclusion: The biweekly FTD/TPI regimen, compared to the standard regimen, should enhance both OS and PFS in patients with mCRC without escalating any adverse event., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: We previously reported the response rate of a phase II OGSG1602 study on panitumumab in chemotherapy-naive frail or elderly patients with RAS wild-type unresectable colorectal cancer (CRC) [Terazawa T, Kato T, Goto M, et al. Oncologist. 2021;26(1):17]. Herein, we report a survival analysis., Methods: Patients aged ≥65 years and considered unsuitable for intensive chemotherapy or aged ≥76 years were enrolled. Primary tumors located from the cecum to the transverse colon were considered right-sided tumors (RSTs); those located from the splenic flexure to the rectum were considered left-sided tumors (LSTs)., Results: Among the 36 enrolled patients, 34 were included in the efficacy analysis, with 26 and 8 having LSTs and RSTs, respectively. The median progression-free survival (PFS) and overall survival (OS) were 6.0 [95% CI, 5.4-10.0] and 17.5 months (95% CI, 13.8-24.3), respectively. Although no significant differences existed in PFS between patients with LST and RST {6.6 (95% CI, 5.4-11.5) vs. 4.9 months [95% CI, 1.9-not available (NA), P = .120]}, there were significant differences in OS [19.3 (95% CI, 14.2-NA) vs.12.3 months (95% CI, 9.9-NA), P = .043]., Conclusion: Panitumumab showed favorable OS in frail or elderly patients with RAS wild-type CRC and no prior exposure to chemotherapy. Panitumumab may be optimal for patients with LSTs (UMIN Clinical Trials Registry Number UMIN000024528)., (© The Author(s) 2022. Published by Oxford University Press.)

Background: There is a paucity of effective systemic therapy options for patients with advanced, chemotherapy-refractory colorectal cancer. We aimed to evaluate the efficacy and safety of fruquintinib, a highly selective and potent oral inhibitor of vascular endothelial growth factor receptors (VEGFRs) 1, 2, and 3, in patients with heavily pretreated metastatic colorectal cancer., Methods: We conducted an international, randomised, double-blind, placebo-controlled, phase 3 study (FRESCO-2) at 124 hospitals and cancer centres across 14 countries. We included patients aged 18 years or older (≥20 years in Japan) with histologically or cytologically documented metastatic colorectal adenocarcinoma who had received all current standard approved cytotoxic and targeted therapies and progressed on or were intolerant to trifluridine-tipiracil or regorafenib, or both. Eligible patients were randomly assigned (2:1) to receive fruquintinib (5 mg capsule) or matched placebo orally once daily on days 1-21 in 28-day cycles, plus best supportive care. Stratification factors were previous trifluridine-tipiracil or regorafenib, or both, RAS mutation status, and duration of metastatic disease. Patients, investigators, study site personnel, and sponsors, except for selected sponsor pharmacovigilance personnel, were masked to study group assignments. The primary endpoint was overall survival, defined as the time from randomisation to death from any cause. A non-binding futility analysis was done when approximately one-third of the expected overall survival events had occurred. Final analysis occurred after 480 overall survival events. This study is registered with ClinicalTrials.gov, NCT04322539, and EudraCT, 2020-000158-88, and is ongoing but not recruiting., Findings: Between Aug 12, 2020, and Dec 2, 2021, 934 patients were assessed for eligibility and 691 were enrolled and randomly assigned to receive fruquintinib (n=461) or placebo (n=230). Patients had received a median of 4 lines (IQR 3-6) of previous systemic therapy for metastatic disease, and 502 (73%) of 691 patients had received more than 3 lines. Median overall survival was 7·4 months (95% CI 6·7-8·2) in the fruquintinib group versus 4·8 months (4·0-5·8) in the placebo group (hazard ratio 0·66, 95% CI 0·55-0·80; p<0·0001). Grade 3 or worse adverse events occurred in 286 (63%) of 456 patients who received fruquintinib and 116 (50%) of 230 who received placebo; the most common grade 3 or worse adverse events in the fruquintinib group included hypertension (n=62 [14%]), asthenia (n=35 [8%]), and hand-foot syndrome (n=29 [6%]). There was one treatment-related death in each group (intestinal perforation in the fruquintinib group and cardiac arrest in the placebo group)., Interpretation: Fruquintinib treatment resulted in a significant and clinically meaningful benefit in overall survival compared with placebo in patients with refractory metastatic colorectal cancer. These data support the use of fruquintinib as a global treatment option for patients with refractory metastatic colorectal cancer. Ongoing analysis of the quality of life data will further establish the clinical benefit of fruquintinib in this patient population., Funding: HUTCHMED., Competing Interests: Declaration of interests AD reports support for the present manuscript from HUTCHMED; grants or contracts from HUTCHMED, Guardant Health, Natera, AAA/Novartis, Eisai, and Crinetics; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from HUTCHMED, Personalis, AAA/Novartis, Crinetics, and Voluntis. SL reports support for the present manuscript from HUTCHMED; grants or contracts from Amgen, Merck Serono, Bayer, Roche, Lilly, AstraZeneca, and Bristol Myers Squibb; consulting or advisory fees from Amgen, Merck Serono, Lilly, AstraZeneca, Incyte, Daiichi Sankyo, Bristol Myers Squibb, Servier, and MSD; and speakers' bureau fees from Roche, Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen, and MSD. RG-C reports support for the present manuscript to their institution from HUTCHMED; grants for investigator-initiated clinical trials from Pfizer, Bristol Myers Squibb, and MSD; consulting fees from AAA/Novartis, Advanz Pharma, Amgen, Bayer, Bristol Myers Squibb, Boerhringer Ingelheim, Esteve, HUTCHMED, Ipsen, Merck, Midatech Pharma, MSD, Pierre Fabre, Roche, and Servier; and support for attending meetings or travel from AAA/Novartis, Esteve, Ipsen, Merck, MSD, and Roche. EE reports grants or contracts to their institution from Amgen, Array Biopharma, AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Debiopharm International, F Hoffmann-La Roche, Genentech, HalioDX SAS, HUTCHMED, Janssen-Cilag, MedImmune, Menarini, Merck Health, Merck Sharp & Dohme, Merus NV, Mirati, Novartis Farmacéutica, Pfizer, Pharma Mar, Sanofi Aventis Recherche & Développement, Servier, and Taiho Pharma USA; consulting fees and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, Bayer, Hoffmann-La Roche, Merck Serono, MSD, Novartis, Organon, Pierre Fabre, Sanofi, and Servier; support for attending meetings or travel from Amgen, Array BioPharma, Bristol Myers Squibb, Merck Serono, Roche, Sanofi, and Servier; participation on a data safety monitoring or advisory board for Amgen, Bayer, F Hoffmann-La Roche, Merck Serono, MSD, Novartis, Organon, Pierre Fabre, Sanofi, and Servier; and a paid or unpaid leadership or fiduciary role with the American Society of Clinical Oncology, European Society for Medical Oncology, and Sociedad Española de Oncología Médica. TY reports grants or contracts to their institution from Ono Pharmaceutical, Sanofi, Daiichi Sankyo, PAREXEL International, Pfizer Japan, Taiho Pharmaceutical, MSD, Amgen, Genomedia, Sysmex Corporation, Chugai Pharmaceutical, and Nippon Boehringer Ingelheim; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly Japan, Merck Biopharma, Bayer Yakuhin, Ono Pharmaceutical, and MSD. ASo reports consulting fees and attending meetings or travel support from HUTCHMED; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, Servier, MSD, Bristol Myers Squibb, Amgen, Merck, Bayer, Sanofi, and Pierre Fabre; and participation on a data safety monitoring or advisory board for Bristol Myers Squibb, Pierre Fabre, Amgen, HUTCHMED, MSD, and Servier. JY reports support for the present manuscript and consulting fees from HUTCHMED, Ipsen, Crinetics, Amgen, Chiasma, Advanced Accelerator Applications, and Novartis. PG-A reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events; and support for attending meetings or travel from and participation on a data safety monitoring or advisory board for Amgen, Merck, Roche, Sanofi, Servier, Lilly, and Pierre Fabre. AS-B reports lecture or educational event fees from Amgen, Bayer, Guardant Health, Merck, Sanofi, and Servier; and advisory board fees from Amgen, Bayer, Novartis, and Servier. TS reports grants or contracts from Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, Daiichi Sankyo, Chugai Pharmaceutical, and Yakult Honsha; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Ono Pharmaceutical, Eli Lilly, Bristol Myers Squibb, and Daiichi Sankyo. VR reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, Servier, and Pierre Fabre; and meetings or travel support from Merck, Bayer, Amgen, Vifor Pharma, and Accord Healthcare. JTo reports consulting fees and honoraria for lectures and presentations from Eisai, Roche, Merck, Servier, Amgen, Novartis, MSD, and Bristol Myers Squibb. GC reports consulting fees to their institution from and participation on a data safety monitoring or advisory board for Bristol Myers Squibb; support for attending meetings or travel from HUTCHMED; and research funding to their institution from HUTCHMED, Servier, Bayer, Isofol, Merck Serono, Bristol Myers Squibb, AstraZeneca, Pharmacyclics, Regeneron, Morphosys, and Incyte. ASP reports support for the present manuscript to the institution from HUTCHMED; grants or contracts for clinical trials to their institution from Ipsen, Bristol Myers Squibb, Exelixis, HUTCHMED, Taiho, Lilly, AstraZeneca, Incyte, Deciphers, G1 Therapeutics, Zentalkis, Tempus, Camurus, Relay Therapeutics, Nucana, Merck, Bayer, Sotio, and Innovations Cellular Therapeutics; educational event fees from Ideo Oncology, and MJH Life Sciences; travel support from Pfizer; participation on a data safety monitoring or advisory board for Amgen, Bristol Myers Squibb, Eisai, Ipsen, AAA, Exelixis, Pfizer, QED, Lilly, Mirati, HUTCHMED, Astellas, Incyte, AADi, Stromatis, EMD, and Serono; holding stock or stock options in Aptose, Actinium, and Alexion; and payment for medical writing services from Bayer, Ipsen, HUTCHMED, and Exelixis. TM reports grants or contracts to the institution from MSD, Daiichi Sankyo, Ono, Novartis, Amgen, Syneos Health Clinical, Boehringer Ingelheim, Pfizer, Cimic Shift Zero, and Eli Lilly; and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Takeda, Chugai, Merck Bio Pharma, Taiho, Bayer, Lilly Japan, Yakult Honsha, Sanofi, Daiichi Sankyo, Ono, and Bristol Myers Squibb. CC reports consulting fees from Merck, Pierre Fabre, Servier, Amgen, and Nordic Pharma; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bayer, Roche, Servier, MSD, Merck, and Pierre Fabre; payment for expert testimony from Bayer, Servier, Pierre Fabre, and Merck; support for attending meetings or travel from Amgen; and participation on a data safety monitoring or advisory board for Amgen and Mirati. FG reports payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events to their institution from AstraZeneca, Roche, and MSD; and support for attending meetings or travel from MSD. ASh reports grants or contracts to their institution from HUTCHMED, Merck, INHIBRx, Verastem Oncology, Turning Point Therapeutics, Gritstone, Bolt Therapeutics, Bristol Myers Squibb, Pfizer, Astellas, Oncologie, Macogenics, Seattle Genetics, Amgen, Daiichi Sankyo, Lilly, and Jacobio; advisory board fees from Regeneron/Sanofi, Pfizer, and Catalyst Pharmaceuticals; and speaker fees from OncLive, OSCO/ASCO Direct, ACPMP, Cholangiocarcinoma Summit, Cholangiocarcinoma Foundation, and ASCO Advantage. HSH reports consulting fees from Merck, Processa, and TRIGR; lecture fees from Natera; and participation on a data safety monitoring or advisory board for Genentech and Seattle Genetics. JKr reports support for the present manuscript to their institution from Syneos Health/HUTCHMED; grants or contracts to their institution from Genentech, Bristol Myers Squibb, Amgen, Isofol Medical, Novartis, Tempest Therapeutics, MedImmune/AstraZeneca, AbbVie, MedImmune, Icon, and Turning Point Therapeutics; and participation on a data safety monitoring board for Amgen (Codebreak 300 trial, NCT05198934). MD reports support for the present manuscript from HUTCHMED; research grants from Roche, Keocyt, and Bayer; advisory board consulting fees from Boehringer, Roche, Merck Serono, Daiichi Sankyo, Rafael, Bayer, Agenus, Terumo, Pierre Fabre, and Servier; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Roche, Merck Serono, Bayer, Amgen, Pierre Fabre, Servier, Roche, Merck Serono, and MSD; support for attending meetings from Servier, Pierre Fabre, and Roche; participation on a data safety monitoring or advisory board for Roche and Pancan; and a personal conflict of interest with Sandoz. AE reports payments for advisory boards from Amgen, Merck, and Ewopharma; and lectures or educational events from Amgen, Merck, Ipsen, and Ewopharma. SK reports personal and institutional grants or contracts from Bristol Myers Squibb, Lilly, and Roche; consulting fees and payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Bristol Myers Squibb, Amgen, Servier, Lilly, Merck Serono, Roche, MSD, and Pierre Fabre; consulting fees from Novartis and Incyte; support for attending meetings or travel from Pierre Fabre, Lilly, Amgen, Bristol Myers Squibb, Roche, and Merch Serono; and participation on a data safety monitoring board or advisory board for Novartis. EVC reports grants or contracts to their institution from Amgen, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Ipsen, Lilly, Merck Sharp & Dohme, Merck, Novartis, Roche, and Servier; and consulting fees from AbbVie, ALX, Array, Astellas, AstraZeneca, Bayer, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Incyte, Ipsen, Lilly, Merck Sharp & Dohme, Merck, Mirati, Novartis, Nordic, Pierre Fabre, Pfizer, Roche, Seattle Genetics, Servier, Takeda, Terumo, Taiho, and Zymeworks. DA reports support for the present manuscript from his institution; consulting fees from AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Eli Lilly, Merck Serono, Merck Sharp & Dohme, Roche, Sanofi, Servier, Sirtex, and Terumo; payment or honoraria for lectures, presentations, speakers' bureaus, manuscript writing, or educational events from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Boston Scientific, Roche, Sanofi, Servier, Sirtex, Terumo, and CME providers Art Tempi, PriME Oncology, Medscape, and TRM Oncology; congress travel support from AstraZeneca; remunerated advisory board fees from Sanofi; non-remunerated advisory board fees from Oncolytics; and a paid or unpaid role with the European Society for Medical Oncology, European Organisation for Research in Treatment of Cancer, and Arbeitsgemeinschaft Internistische Onkologie of the German Cancer Society. SN, ZY, WRS, and MK report employment and holding stock or stock options with HUTCHMED. JTa reports consulting fees from Array Biopharma, AstraZeneca, Bayer, Boehringer Ingelheim, Chugai, Daiichi Sankyo, F Hoffmann-La Roche, Genentech, HalioDX SAS, HUTCHMED, Ikena Oncology, Inspirna, 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, and TheraMyc; educational collaboration fees from Imedex/HMP, Medscape Education, MJH Life Sciences, and PeerView Institute for Medical Education and Physicians Education Resource; and holding stock or stock options in Oniria Therapeutics. CE reports support for the present manuscript from HUTCHMED; grants or contracts from Elevar, Merck, Pfizer, and Gritstone; and consulting fees from Bayer, GlaxoSmithKline, Halio Dx, and Boston Scientific. All other authors declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Purpose: Genomic profiling programs have been implemented to apply next-generation sequencing (NGS) for facilitating trial enrollment. SCRUM-Japan GI-SCREEN is a large-scale genomic profiling program in advanced gastrointestinal cancers using a validated genomic assay with the goal of facilitating enrollment in targeted clinical trials, generating real-world data, and performing clinicogenomic analysis for biomarker discovery., Patients and Methods: Genotyping of tumor tissue samples from 5,743 patients with advanced gastrointestinal cancers enrolled in GI-SCREEN was centrally performed with NGS. Patients were enrolled in matched trials of targeted agents affiliated with GI-SCREEN on the basis of genotyping results., Results: A total of 11 gastrointestinal cancers were included, with colorectal cancer being the most common. The median age ranged from 59 to 70.5 years across cancer types. Patients enrolled after initiation of first-line treatment had significantly longer overall survival (OS) than that before treatment initiation with a median survival time difference of 8.9 months and a hazard ratio (HR) ranging from 0.25 to 0.73 across cancer types, demonstrating an immortal time bias. One hundred and forty-nine patients received matched therapies in clinical trials on the basis of their identified alterations. Among patients with colorectal cancer harboring actionable alterations, the median OS was significantly longer in patients who received matched therapies in trials than in those who did not (HR, 0.52; 95% CI, 0.26 to 1.01; P = .049). Cancer-specific pathway alterations were significantly associated with shorter survival and related to primary resistance to matched trial therapies., Conclusion: Our genomic profiling program led to patient enrollment in targeted clinical trials and improved survival of patients with colorectal cancer who received matched therapies in clinical trials. To avoid immortal time bias, precautions are needed when using data from patients who have undergone NGS testing after initiation of the evaluated treatment line.

Regorafenib has shown significant survival benefit as a salvage therapy for colorectal cancer; however, its starting dose has been controversial in recent studies. Therefore, we conducted a prospective study on the efficacy and safety of the dose reduction of regorafenib to 120 mg. Patients received 120 mg regorafenib once per day for 3 weeks, followed by a 1-week off-treatment period. The primary endpoint was the investigator-assessed disease control rate (DCR). Sixty patients were registered, and the DCR was 38.3% with a median progression-free survival of 2.5 months (95% confidence interval [CI] 1.9-3.7) and median overall survival of 10.0 months (95% CI 6.9-15.2). Common grade 3-4 adverse events were hand-foot skin reaction and hypertension (20.0% each). The results of administration of 120 mg regorafenib as the starting dose are consistent with reports from prior phase III trials, which used starting doses of 160 mg. This lower initiating dose of regorafenib may be beneficial to certain patient populations. This clinical trial was registered in the UMIN Clinical Trials Registry (UMIN-CTR number UMIN000018968, registration date: 10/09/2015)., (© 2023. The Author(s).)

The BRAF V600E mutation accounts for approximately 5% of colorectal cancer (CRC) cases and is an extremely poor prognostic factor. However, there are no clear recommendations regarding first-line therapy for patients with early recurrent BRAF V600E-mutated CRC, during or after adjuvant chemotherapy. Recently, a novel combination of encorafenib, binimetinib and cetuximab, showed a higher response rate than standard chemotherapy in patients with BRAF V600E-mutated CRC. Here we describe our plan for the TRESBIEN study (OGSG 2101), which is an open-label, multicenter, single-arm, phase II study designed to evaluate whether encorafenib, binimetinib and cetuximab are effective for patients with early recurrent BRAF V600E-mutated colorectal cancer, during or after adjuvant chemotherapy. The planned number of subjects is 25.

Purpose: Activated Notch receptor signaling has been implicated in tumor growth and progression in colorectal cancer (CRC). However, the pathogenic relevance of NOTCH gene alterations remains unclear. The aim of this study was to clarify mutational landscapes and assess their clinical significance in patients with metastatic CRC., Methods: Pre-chemotherapy tumor tissues obtained from 1154 metastatic CRC patients in the Nationwide Cancer Genome Screening Project in Japan between April 2017 and March 2019 were studied using the Oncomine Comprehensive Assay., Results: The frequencies of NOTCH1, NOTCH2, and NOTCH3 nonsynonymous sequence variants were 11.5%, 4.4%, and 10.4%, respectively. The majority of variants were missense of unknown significance that were distributed across all domains of all three NOTCH genes. The gain-of-function mutations in NOTCH reported in multiple malignancies were not identified. The NOTCH amplification rate was less than 1%. No NOTCH fusions were detected. In patients who were registered before, or within 1 year of, first-line chemotherapy, overall survival for 51 patients with only NOTCH3 variants was significantly longer than for 540 patients with no NOTCH variants (median, 40.2 months vs 27.7 months; P = 0.04). Multivariate analysis revealed that variant NOTCH3 was an independent prognostic factor for increased survival (hazard ratio 0.61, 95% confidence interval, 0.39-0.94; P = 0.03) besides poor prognostic factors associated with mutant TP53, KRAS, and BRAF, as well as amplified MYC., Conclusion: NOTCH genes are unlikely to harbor driver mutations and amplifications in patients with metastatic CRC. NOTCH3 variant should be further investigated as a favorable prognostic marker., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background/aim: This phase II study (MCSGO-1202) aimed to evaluate the initial dose reduction of oxaliplatin in XELOX plus bevacizumab therapy., Patients and Methods: This was a phase II, multicenter, open-label, single-arm, prospective, study conducted at 14 Japanese institutions. The study included patients with metastatic colorectal cancer (mCRC) with performance status (PS) of 1 or 2 who had not undergone chemotherapy. Patients received oxaliplatin (100 mg/m 2 ) plus bevacizumab (7.5 mg/kg) on day 1 and capecitabine (2,000 mg/m2/day) on days 1-14 of a 21-day cycle. The primary endpoint was the objective response rate. The secondary endpoints were progression-free and overall survival, 1-year survival rate, disease control rate, dose intensity, and adverse events., Results: Between April 2012 and March 2016, 56 patients were enrolled. The median age was 71 years (range=44-85 years), and the majority (90.6%) had a PS of 1. A complete response was observed in three patients (5.7%), partial response in 24 (45.3%), stable disease in 22 (43.4%), and progressive disease in one (1.9%). The median progression-free survival and overall survival were 11.4 and 26.5 months, respectively. The most common grade 3-4 adverse events were leucopenia (15.1%), neutropenia (9.4%), neuropathy (9.4%)., Conclusion: The dose-reduction strategy of oxaliplatin was effective for elderly or vulnerable patients with mCRC., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Low concordance between plasma-based and tissue-based tests for determining the RAS mutational status have been reported in some but not all patients with limited-extent metastatic colorectal cancer (mCRC). In this study, we investigated the relationship between metastatic site and circulating tumor DNA (ctDNA) detection using ctDNA genotyping, an alternative to tissue genotyping for precision oncology., Materials and Methods: We investigated the relationship between metastatic site and ctDNA detection using Guardant360, a next-generation sequencing ctDNA assay, in mCRC patients with single-organ metastasis in the SCRUM-Japan GOZILA study (UMIN000029315)., Results: Of 1,187 patients with mCRC enrolled in GOZILA, 138 were eligible (49 with liver-only, 15 with lymph node-only, 27 with peritoneum-only, and 47 with lung-only metastases). The concordance of RAS / BRAF status between Guaradant360 and tissue in vitro diagnostic tests was 95.9% in patients with liver-only, 80.0% in lymph node-only, 56.0% in peritoneum-only, and 65.9% in lung-only metastases. ctDNA fraction, as measured by the median maximum variant allelic fraction (max VAF), and median number of detected variants were 23.1% and five in liver-only, 6.0% and five in lymph node-only, 0.4% and three in peritoneum-only, and 0.4% and three in lung-only metastases, respectively (all P < .001, Kruskal-Wallis test). Few patients with liver-only (2.0%) and lymph node-only metastasis (13.3%) had a max VAF < 0.2%, which is required to ensure a detection limit of 95%, but max VAF was more frequently < 0.2% in patients with lung-only (27.7%) or peritoneum-only metastasis (29.6%)., Conclusion: Patients with lung-only and peritoneum-only metastatic disease have significantly lower levels of ctDNA, suggesting decreased clinical sensitivity for subclonal variants. This observation suggests that such patients may benefit from concurrent tissue and plasma testing to provide optimal genotyping for subsequent therapy selection., Competing Interests: Hideaki BandoHonoraria: Taiho Pharmaceutical, Takeda, Chugai Pharma, Sanofi, Yakult Honsha, Merck Serono, Lilly Japan, Ono Pharmaceutical, Bristol Myers Squibb JapanResearch Funding: Ono Pharmaceutical Yoshiaki NakamuraHonoraria: Chugai Pharma, Guardant Health AMEA, MerckResearch Funding: Taiho Pharmaceutical (Inst), Guardant Health (Inst), Genomedia (Inst), Chugai Pharma (Inst), Seattle Genetics (Inst), Roche (Inst) Hiroya TaniguchiHonoraria: Bayer, Sanofi, Takeda, Chugai Pharma, Taiho Pharmaceutical, Lilly Japan, Merck Serono, Yakult Honsha, Medical & Biological Laboratories Co, Ltd, Bristol Myers Squibb Japan, MSD K.K, Novartis, Daiichi Sankyo, Mitsubishi Tanabe Pharma, Nippon Kayaku, Ono YakuhinResearch Funding: Dainippon Sumitomo Pharma (Inst), Array BioPharma (Inst), MSD Oncology (Inst), Ono Pharmaceutical (Inst), Daiichi Sankyo (Inst), Sysmex (Inst), Novartis (Inst), Takeda (Inst) Hisateru YasuiHonoraria: Taiho Pharmaceutical, Chugai Pharma, Bristol Myers Squibb Japan, Daiichi Sankyo, Lilly Japan, Yakult Honsha, Bayer Yakuhin, Takeda, Ono PharmaceuticalConsulting or Advisory Role: Ono PharmaceuticalResearch Funding: MSD (Inst), Daiichi Sankyo (Inst), Ono Pharmaceutical (Inst), Astellas Pharma (Inst) Taito EsakiHonoraria: Lilly, Taiho Pharmaceutical, Daiichi Sankyo, Chugai Pharma, Ono Pharmaceutical, Sanofi, MSDResearch Funding: Daiichi Sankyo (Inst), MSD (Inst), Novartis (Inst), Ono Pharmaceutical (Inst), Astellas Pharma (Inst), Lilly (Inst), Bayer (Inst), Nihonkayaku (Inst), Amgen Astellas BioPharma (Inst), Parexel (Inst), IQVIA (Inst), Quintiles (Inst), Eisai (Inst), Sumitomo Dainippon Pharma (Inst), Taiho Pharmaceutical (Inst), Pfizer (Inst), Chugai Pharma (Inst), Syneos Health (Inst) Yoshinori KagawaSpeakers' Bureau: Lilly, Sanofi, Takeda, Merck, Taiho Pharmaceutical, MSD, Chugai Pharma, Yakult Pharmaceutical, Bayer Tadamichi DendaHonoraria: Ono PharmaceuticalSpeakers' Bureau: Daiichi-Sankyo, Ono PharmaceuticalResearch Funding: Ono Pharmaceutical (Inst) Taroh SatohHonoraria: Chugai Pharma, Merck Serono, Bristol Myers Squibb, Takeda, Yakult Honsha, Lilly, Bayer Yakuhin, Ono Pharmaceutical, Merck, Astellas Pharma, Taiho Pharmaceutical, Nihonkayaku, Daiihi-SankyoConsulting or Advisory Role: Bayer Yakuhin, Lilly, Ono Pharmaceutical, Takara Bio, Merck Serono, NihonkayakuResearch Funding: Yakult Honsha (Inst), Chugai Pharma (Inst), Ono Pharmaceutical (Inst), Sanofi (Inst), Lilly (Inst), Daiichi Sankyo (Inst), Merck (Inst), Merck Serono (Inst), Gilead Sciences (Inst), Dainippon Sumitomo Pharma (Inst), IQVIA (Inst) Kentaro YamazakiHonoraria: Chugai Pharma, Daiichi Sankyo, Yakult Honsha, Takeda, Bayer, Merck Serono, Taiho Pharmaceutical, Lilly, Sanofi, Ono Pharmaceutical, MSD, Bristol Myers SquibbResearch Funding: Taiho Pharmaceutical (Inst) Yu SunakawaHonoraria: Taiho Pharmaceutical, Chugai Pharma, Takeda, Bayer Yakuhin, Bristol Myers Squibb Japan, Lilly Japan, Merck, Sysmex, MSD K.K, Ono Pharmaceutical, Daiichi Sankyo, Guardant Health, IncyteConsulting or Advisory Role: Bristol Myers Squibb Japan, MSD K.K, Daiichi SankyoResearch Funding: Taiho Pharmaceutical, Takeda, Chugai Pharma, Lilly Japan, Sanofi, Otsuka Takeshi KatoHonoraria: Chugai Pharma, Ono Pharmaceutical, Takeda, Lilly Japan, Asahi KaseiResearch Funding: Chugai Pharma Masahiro GotoHonoraria: Daiichi Sankyo Company, Ltd, Ono Pharmaceutical, Taiho Pharmaceutical, MSD K.K, Takeda, Sumitomo Dainippon Pharma Co, Ltd, Yakult Pharmaceutical, Eli Lilly Japan K.KResearch Funding: Chugai Pharma, Taiho Pharmaceutical, Nippon Kayaku Satoshi YukiHonoraria: Chugai Pharma, Takeda, Lilly Japan, Bayer Yakuhin, Taiho Pharmaceutical, Sanofi, Yakult Honsha, Bristol Myers Squibb Japan, Ono Pharmaceutical, Merck, MSD K.K Tomohiro NishinaHonoraria: Taiho Pharmaceutical, Chugai Pharma, Lilly, Merck Serono, Takeda, Bristol Myers Squibb, Ono PharmaceuticalResearch Funding: Taiho Pharmaceutical (Inst), Chugai Pharma (Inst), Dainippon Sumitomo Pharma (Inst), Lilly Japan (Inst), Merck Serono (Inst), MSD (Inst), Daiichi Sankyo (Inst), Ono Pharmaceutical (Inst), Eisai (Inst) Eiji OkiSpeakers' Bureau: Chugai Pharma, Lilly Japan, Takeda, Ono Pharmaceutical, Bristol Myers Squibb Japan Eiji ShinozakiHonoraria: Yakult Honsha, Merck Serono, Chugai Pharma, Takeda, Sanofi, Lilly, Taiho Pharmaceutical, Daiichi Sankyo/UCB Japan Naoki TakahashiHonoraria: Ono Pharmaceutical, Bristol Myers Squibb, Taiho Pharmaceutical Akihito TsujiSpeakers' Bureau: Chugai Pharma, Taiho Pharmaceutical, Merck Serono, Takeda Pharmaceutical Company Limited, Lilly Japan, Bristol Myers Squibb Corporation, SanofiResearch Funding: Taiho Pharmaceutical Co, Ltd (Inst), Sanofi (Inst), Ono Pharmaceutical (Inst) Justin I. OdegaardEmployment: Guardant HealthStock and Other Ownership Interests: Guardant Health Takayuki YoshinoHonoraria: Chugai Pharma, Merck, Bayer Yakuhin, Ono Pharmaceutical, MSD K.KResearch Funding: MSD (Inst), Daiichi Sankyo Company, Ltd (Inst), Ono Pharmaceutical (Inst), Taiho Pharmaceutical (Inst), Amgen (Inst), Sanofi (Inst), Pfizer (Inst), Genomedia (Inst), Sysmex (Inst), Nippon Boehringer Ingelheim (Inst), Chugai Pharma (Inst)No other potential conflicts of interest were reported.

Background: Microsatellite instability (MSI) is a key marker for predicting the response of immune checkpoint inhibitors (ICIs) and for screening Lynch syndrome (LS)., Aim: This study aimed to see the characteristics of cancers with high level of MSI (MSI-H) in genetic medicine and precision medicine., Methods: This study analyzed the incidence of MSI-H in 1000 cancers and compared according to several clinical and demographic factors., Results: The incidence of MSI-H was highest in endometrial cancers (26.7%, 20/75), followed by small intestine (20%, 3/15) and colorectal cancers (CRCs)(13.7%, 64/466); the sum of these three cancers (15.6%) was significantly higher than that of other types (2.5%)(P < 0.0001). MSI-H was associated with LS-related cancers (P < 0.0001), younger age (P = 0.009), and family history, but not with smoking, drinking, or serum hepatitis virus markers. In CRC cases, MSI-H was significantly associated with a family history of LS-related cancer (P < 0.0001), Amsterdam II criteria [odds ratio (OR): 5.96], right side CRCs (OR: 4.89), and multiplicity (OR: 3.31). However, MSI-H was very rare in pancreatic (0.6%, 1/162) and biliary cancers (1.6%, 1/64) and was null in 25 familial pancreatic cancers. MSI-H was more recognized in cancers analyzed for genetic counseling (33.3%) than in those for ICI companion diagnostics (3.1%)(P < 0.0001). Even in CRCs, MSI-H was limited to 3.3% when analyzed for drug use., Conclusions: MSI-H was predominantly recognized in LS-related cancer cases with specific family histories and younger age. MSI-H was limited to a small proportion in precision medicine especially for non-LS-related cancer cases., (© 2022. The Author(s).)

Purpose: Chemotherapy with panitumumab is expected to be well tolerated and improve survival in patients with metastatic colorectal cancer (mCRC). However, skin toxicities are its most common adverse events. The aim of this trial was to evaluate the efficacy and safety of pre-emptive antibiotic treatment with clarithromycin (CAM) to prevent panitumumab skin toxicities., Methods: We conducted a phase lll, multicenter, open-label, randomized clinical trial on mCRC patients treated with panitumumab. Eligible patients were randomly assigned 1:1 to pre-emptive antibiotic and control groups. In the pre-emptive group, CAM administration (200 mg twice per day) continued daily through the panitumumab treatment period. The control regimen consisted of skin care only. The primary end point was the incidence of grade ≥ 2 skin toxicities during the 6-week skin treatment period., Results: Of 156 enrolled patients, 78 received pre-emptive antibiotic treatment, and 78 received reactive treatment. The number and incidence of grade ≥ 2 skin toxicities during the 6-week skin treatment period were 16 (21.3%) and 41 (54.7%) for the pre-emptive and control groups, respectively (HR, 0.32; 95% CI, 0.17-0.56). There was almost no difference in the rate of other adverse events between the two groups, but the incidence of grade ≥ 3 diarrhea in the pre-emptive group was high, at 8% vs. 1.3% in the control group. There were no treatment-related deaths., Conclusion: Prophylactic oral CAM together with relatively simple skin care was found to be effective in suppressing the development of grade ≥ 2 skin toxicities induced by panitumumab., Clinical Trial Registration: UMIN000011485 DATE OF REGISTRATION: Sep 1st, 2013., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Among patients with colorectal cancer (CRC) treated with oxaliplatin (L-OHP)-based chemotherapy, delayed chemotherapy-induced nausea and vomiting (CINV) have not been well controlled., Methods: We pooled data from two prospective observational studies in Japan and one phase III clinical trial to assess whether delayed CINV could be controlled with a combination of three antiemetics adding a neurokinin-1 receptor antagonist and identified individual risk factors, using an inverse probability treatment-weighted analysis., Results: A total of 661 patients were evaluable in this study (median age: 64 years; 391 male, and 270 female). 3 antiemetics controlled delayed nausea (33.18% vs. 42.25%; p = 0.0510) and vomiting (4.15% vs. 16.08%; p < 0.0001) better than with 2 antiemetics. Female and 2 antiemetics were risk factors for both delayed nausea (female-odds ratio [OR]: 1.918; 95% confidence interval [CI]: 1.292-2.848; p = 0.0012; 2 antiemetics-OR: 1.485; 95% CI: 1.000-2.204; p = 0.0498) and delayed vomiting (female-OR: 2.735; 95% CI: 1.410-5.304; p = 0.0029; 2 antiemetics-OR: 4.551; 95% CI: 2.116-9.785; p = 0.0001)., Conclusions: Identifying individual risk factors can facilitate personalized treatments for delayed CINV. We recommend a 3-antiemetic combination prophylaxis for CRC patients treated with L-OHP-based chemotherapy, especially for female patients., (© 2021. The Author(s).)

Background: Regorafenib(Rego)is the salvage line standard treatment for metastatic colorectal cancer(mCRC), which often causes severe toxicities, such as hand-foot syndrome. Previously, we reported that in phase Ⅱ study, S-1 plus bevacizumab( Bev)(SB)showed favorable anticancer activity and feasibility as a salvage line. The aim of this study was to evaluate 2 treatments for mCRC as salvage line., Patients and Methods: In this multicenter phase Ⅱ study, the patients were randomly assigned(1:1)to the Rego or SB group. In the Rego group, Rego 160 mg/kg body weight was orally administered every 28 days for 21 days. In the SB group, S-1 was orally administered every 42 days for 28 days, according to body surface area, and Bev 5 mg/kg was administered by intravenous infusion on days 1, 15, and 29. Administration of S-1 every 21 days for 14 days and Bev 7.5 mg/kg on day 1 was also permitted. The primary endpoint was overall survival(OS), and the planned sample size was 86., Results: This study was ended prematurely due to poor accrual. Overall, 8 patients were enrolled from 6 institutions between Oct 2013 and May 2015. Although 4 patients were assigned to each group, one patient in the Rego group was excluded after enrollment. The median OS in the Rego and SB groups was 30.2 months and 6.6 months, respectively(hazard ratio: 0.205, p=0.123). The median progression-free survival in the Rego and SB groups was 3.7 months and 1.6 months, respectively. The disease control rate in the Rego and SB groups was 100% and 75%, respectively. The Grade 3 or 4 adverse events were increased, including AST/ALT(n=1, 25%), hyponatremia(n=1, 25%), hand-foot syndrome(n=1, 25%), hypertension(n=1, 25%), and proteinuria(n=1, 25%)in the Rego group and colitis( n=1, 25%)in the SB group; the treatment was discontinued., Conclusion: Despite the fact that data could only be collected from a small number of patients, SB is not recommended as salvage line for mCRC.

Background: Although chemotherapy for metastatic colorectal cancer (mCRC) has improved, the standard chemotherapy regimens for patients with RAS wild-type mCRC remain debated. This study aimed to compare S-1 and oxaliplatin (SOX) + bevacizumab (B-mab) with SOX + cetuximab (C-mab) in patients with previously untreated recurrent advanced CRC with wild-type KRAS., Methods: This randomized phase II, open-label, multicenter study compared the efficacy and safety of SOX+B-mab with SOX+C-mab in patients with previously untreated advanced CRC with wild-type KRAS. Between February 2012 and October 2016, 45 patients were enrolled., Results: Overall response rates were 59.1 and 43.5% (p = 0.29) and disease control rates were 90.9 and 91.3% (p = 0.96) in the SOX+B-mab and SOX+C-mab groups, respectively. Median overall survival (OS) was 25.3 and 15.5 months (HR = 0.607, p = 0.167) and median progression-free survival (PFS) were 11.7 and 5.5 months (HR = 0.558, p = 0.077) in the SOX+B-mab and SOX+C-mab groups, respectively. The OS and PFS of patients with early tumor shrinkage (ETS) were not significantly different in the SOX+B-mab group. However, they were significantly better when ETS was ≥20 in the SOX+C-mab group (p = 0.032 and p = 0.003, respectively)., Conclusions: The efficacy and safety of SOX+B-mab and SOX+C-mab for wild-type KRAS recurrent advanced CRC as first-line chemotherapy were almost the same. Consideration of the treatment strategy based on ETS may improve patient prognosis, especially in patients receiving the SOX+C-mab regimen., Trial Registration: UMIN Clinical Trials Registry ( UMIN000006706 ). Date of registration: NOV/11/2011. URL of trial registry record: https://upload.umin.ac.jp/cgi-open-bin/ctr&#95;e/ctr&#95;view.cgi?recptno=R000007920., (© 2021. The Author(s).)

The BRAF V600E mutation occurs in approximately 10% of patients with metastatic colorectal cancer (CRC) and constitutes a distinct subtype of the disease with extremely poor prognosis. To address this refractory disease, we investigated the unique metabolic gene profile of BRAF V600E-mutated tumors via in silico analysis using a large-scale clinical database. We found that BRAF V600E-mutated tumors exhibited a specific metabolic gene expression signature, including some genes that are associated with poor prognosis in CRC. We discovered that BRAF V600E-mutated tumors expressed high levels of glycolytic enzyme enolase 2 (ENO2), which is mainly expressed in neuronal tissues under physiological conditions. In vitro experiments using CRC cells demonstrated that BRAF V600E-mutated cells exhibited enhanced dependency on ENO2 compared to BRAF wild-type cancer cells and that knockdown of ENO2 led to the inhibition of proliferation and migration of BRAF V600E-mutated cancer cells. Moreover, inhibition of ENO2 resulted in enhanced sensitivity to vemurafenib, a selective inhibitor of BRAF V600E. We identified AP-1 transcription factor subunit (FOSL1) as being involved in the transcription of ENO2 in CRC cells. In addition, both MAPK and PI3K/Akt signaling were suppressed upon inhibition of ENO2, implying an additional oncogenic role of ENO2. These results suggest the crucial role of ENO2 in the progression of BRAF V600E-mutated CRC and indicate the therapeutic implications of targeting this gene., (© 2021 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Epithelial-mesenchymal transition (EMT) is a drastic phenotypic change during cancer metastasis and is one of the most important hallmarks of aggressive cancer. Although the overexpression of some specific transcription factors explains the functional alteration of EMT-induced cells, a complete picture of this biological process is yet to be elucidated. To comprehensively profile EMT-related genes in colorectal cancer, we quantified the EMT induction ability of each gene according to its similarity to the cancer stromal gene signature and termed it "mesenchymal score." This bioinformatic approach successfully identified 90 candidate EMT mediators, which are strongly predictive of survival in clinical samples. Among these candidates, we discovered that the neuronal gene ARC, possibly originating from the retrotransposon, unexpectedly plays a crucial role in EMT induction. Profiling of novel EMT mediators we demonstrated here may help understand the complexity of the EMT program and open up new avenues for therapeutic intervention in colorectal cancer.

Background: Regorafenib is a key agent for patients with advanced or recurrent colorectal cancer. Sarcopenia represented by skeletal muscle depletion is closely related to frailty and predicts oncological prognoses. We hypothesized that sarcopenia negatively affects the time to treatment failure (TTF) or overall survival (OS) of patients treated with regorafenib., Methods: We retrospectively reviewed the medical records of all patients treated with regorafenib between May 2013 and April 2019 at our institution. The cross-sectional area of the psoas muscle at the level of the third lumbar vertebra on baseline computed tomography (CT) was assessed to calculate the psoas muscle index (PMI). Sarcopenia was defined based on PMI cut-off values for Asian adults (6.36 cm 2 /m 2 for males and 3.92 cm 2 /m 2 for females)., Results: Thirty-four patients were analyzed. The prevalence of sarcopenia was 44.1%. Sarcopenia was significantly associated with poorer OS (median 3.2 vs. 5.3 months, p = 0.031). Less 75% 1-Month Relative Dose Intensity patients experienced significantly shorter TTF and OS than the rest, as did patients receiving total regorafenib dose of < 3360 mg (median 3.1 and 9.4 months, p < 0.001). Multivariate analysis showed that sarcopenia was a significant predictor of prognosis., Conclusion: Sarcopenia was a predictive marker of negative outcome for patients with advanced or recurrent colorectal cancer treated with regorafenib. Screening for sarcopenia can be used to identify patients more likely to benefit from regorafenib in routine clinical practice.

Lessons Learned: Panitumumab monotherapy showed favorable efficacy and feasibility in the treatment of frail or elderly patients with RAS wild-type unresectable colorectal cancer. It is especially effective for left-sided tumors; therefore, panitumumab as first-line treatment could be an additional therapeutic option for frail elderly patients, particularly in those who are unsuitable for upfront oxaliplatin-based or irinotecan-based combination regimens., Background: First-line panitumumab monotherapy is expected to be well tolerated and improve survival in patients ineligible for intensive chemotherapy. However, its safety and efficacy in chemotherapy-naïve frail or elderly patients with unresectable RAS wild-type (WT) colorectal cancer (CRC) have not been studied. The aim of this phase II trial was to evaluate the efficacy and safety of panitumumab as first-line treatment., Methods: We conducted a multicenter phase II study on patients aged ≥76 years or ≥65 years considered unsuitable for intensive chemotherapy. Panitumumab 6 mg/kg of intravenous infusion was administered every 2 weeks. The primary endpoint was disease control rate (DCR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), response rate (RR), time to treatment failure (TTF), and incidence of grade 3 or 4 toxicities., Results: Thirty-six patients (median age: 81 [range, 67-88] years) were enrolled between February 2017 and August 2018. Two patients were excluded from the analysis of efficacy: one from lack of image examination at baseline and the other from lack of a measurable lesion. Thirty-three (91.6%) patients had a performance status (PS) of 0 or 1, whereas two (5.6%) patients and one (2.8%) patient had a PS of 2 and 3, respectively. Twenty-eight patients (77.8%) had left-sided CRC, whereas eight (22.2%) had right-sided CRC. The RR was 50.0% (95% confidence interval [CI], 32.4-67.6), including three patients (8.8%) who had complete responses. A total of 26.5% had stable diseases, resulting in a DCR of 76.5% (90% CI, 61.5-87.7). The RR of patients with left- and right-sided tumors was 65.4% (95% CI, 44.3-82.8) and 0.0% (95% CI, 0.0-36.9), respectively. Major grade 3 or 4 nonhematologic toxicities were rash (n = 6, 16.7%), hypomagnesemia (n = 4, 11.1%), fatigue (n = 3, 8.3%), paronychia (n = 2, 5.6%), and hyponatremia (n = 2, 5.6%). The only grade 3 hematologic toxicity was neutropenia (n = 1, 2.8%)., Conclusion: Panitumumab monotherapy showed favorable efficacy and feasibility in frail or elderly patients with RAS WT unresectable CRC. Survival analysis including OS, PFS, and TTF is currently in progress., (© AlphaMed Press; the data published online to support this summary are the property of the authors.)

Background: Cetuximab has been shown to be clinically active when given in combination with irinotecan in patients with irinotecan-refractory metastatic colorectal cancer (mCRC). However, it has remained unclear whether panitumumab is effective when combined with irinotecan. We compared efficacies of both regimens in this randomised phase II study., Patients and Methods: Patients with wild-type KRAS exon 2 mCRC previously treated with fluorouracil-, oxaliplatin- and irinotecan-based chemotherapies were randomised (1:1) to either panitumumab plus irinotecan (panitumumab arm) or cetuximab plus irinotecan (cetuximab arm). The primary end-point was progression-free survival (PFS). The planned sample size was 120, expecting a hazard ratio (HR) of 1.0 with non-inferiority margin of 1.3 (one-sided alpha error 0.2 and power 0.7). Major secondary end-points were overall survival (OS), response rate and safety., Results: From December 2011 to September 2014, 121 patients were enrolled, and 61 and 59 patients were randomised to the panitumumab and cetuximab arms, respectively (1 patient excluded). Most patients (97%) had received prior chemotherapies containing bevacizumab. The median PFS was 5.42 months in the panitumumab arm and 4.27 months in the cetuximab arm (HR = 0.64, 95% confidence interval [CI] = 0.44-0.94, P < 0.001 for non-inferiority, P = 0.058 for superiority), and median OS was 14.85 and 11.53 months (HR = 0.66, 95% CI = 0.44-1.00, P = 0.050 for superiority), respectively. The incidence of grade 3 or 4 hypomagnesaemia was higher in the panitumumab arm than that in the cetuximab arm (17% vs. 7%)., Conclusion: Panitumumab may be non-inferior to cetuximab in combination with irinotecan in survival of patients with irinotecan-refractory mCRC., Competing Interests: Conflict of interest statement DS reports grants from Yakult Honsha, Chugai, Ono, Eli Lilly, Daiichi Sankyo, Incyte and Taiho, and personal fee from Chugai, outside the submitted work. T.T. reports receiving personal fees from Merck Serono Co., Ltd, and Takeda Pharmaceutical Co., Ltd., during the conduct of the study, and receiving grants from Ono Pharmaceutical, Bristol-Myers Squibb and Japan AMED, outside the submitted work. N.S. reports receiving personal fees from Merck-Biopharm and Takeda Pharmaceutical Co.Ltd. , and ONO Pharmaceutical Co.,Ltd., MSD, Sanofi, Daiichi Sankyo, Parexel International, Sumitomo Dainippon Pharma, Bristol-Myers Squibb, Solasia Pharma, Chugai Parmaceutical, Taiho Pharmaceutical and Eli Lilly, outside the submitted work. T.N. reports grants and personal fees from Taiho pharma, grants and personal fees from Chugai pharma, grants from Daiichi sankyo pharma, grants from MSD, grants and personal fees from Ono pharma, grants and personal fees from Bristol myers squibb, grants and personal fees from Lilly pharma, grants from Dainippon sumitomo pharma, outside the submitted work. H.H. reports paid consulting or advisory roles for MSD and Ono; honoraria from Bayer, Bristol-Myers Squibb, Chugai, Daiichi Sankyo, Kyowa Hakko Kirin, Lilly, Merck Biopharma, MSD, Ono, Sanofi, Taiho, Takeda and Yakult; and research funding from Astellas, AstraZeneca, BeiGene, Boehringer Ingelheim, Chugai, Daiichi Sankyo, Dainippon Sumitomo, Eisai, Incyte, LSK BioPharma, Merck Biopharma, MSD, Ono, Pfizer, and Taiho, outside the submitted work. T.E. reports research funding from Taiho, MSD, Eli Lilly, Daiichi Sankyo, Ono, Bayer, Novartis, Astellas, Astellas Amgen Biopharma, BeiGene, Pierre Fabre Medicament, Ignyta, Array BioPharma, Dainippon Sumitomo, and honoraria from Taiho, MSD, Eli Lilly, Daiichi Sankyo, Ono, Bayer, Chugai, Nihon Kayaku, Sanofi, Takeda, Merck Serono, Bristol, Eisai. T.D. reports personal fees from SAWAI Pharmaceutical Co, personal fees from Sysmex, grants from MSD, grants from ONO Pharmaceutical, outside the submitted work. T.S. reports receiving personal fees from Merck-BioPharm and Takeda Pharmaceutical and grants and personal fees from Yakult Honsha and Daiichi-Sankyo, outside the submitted work. A.M. reports receiving personal fees from Lily, Chugai and Takeda, outside the submitted work. A.H. reports receiving personal fees from Taiho Pharmaceutical, Takeda Pharmaceutical, Ono Pharmaceutical, Novartis, Eisai, Chugai Pharmaceutical, Eli Lilly, Daiichi Sankyo, Teijin Pharma, Sanofi and Merck Biopharma and grants from Chugai Pharmaceutical, Taiho Pharmaceutical, Ono Pharmaceutical, Eisai and Yakult Honsha, outside the submitted work.T.M. reports receiving grants and personal fees from Taiho Pharmaceutical, Yakult Honsha and Takeda Pharmaceutical; receiving personal fees from Chugai Pharmaceutical, Novelpharma, Merck Serono and Sanofi and receiving grants from Boehringer Ingelheim and Eisai, outside the submitted work. H.Y. reports research funding from MSD, Daiichi Sankyo, and Ono Pharmaceutical, personal fees from Taiho Pharmaceutical, honoraria from Chugai Pharma, Bristol-Myers Squibb Japan, Daiichi Sankyo, TERUMO, Eli Lilly Japan, Merk Biopharma, and Yakult Honsha, outside the submitted work. A.T. reports receiving personal fees from Daiichi Sankyo Co., Ltd., Takeda Pharmaceutical Co., Ltd., and Merck Serono Co., Ltd. E.B. reports receiving grants and personal fees from Ono, Merck-Serono, Taiho, Chugai and Daiichi-Sankyo and personal fees from BMS, Takeda, Eli lilly, Tsumura, Kyowa-Kirin and Yakult, outside the submitted work. K.S. reports personal fees from SHIONOGI & CO., LTD., personal fees from Takeda Pharmaceutical Company Limited, personal fees from Taiho Pharmaceutical Co Ltd, personal fees from ONO PHARMACEUTICAL CO., LTD., personal fees from Merck Biopharma Co., Ltd, personal fees from NIPPON KAYAKU Co., Ltd., personal fees from Asahi Kasei Pharma, from Eisai Co., Ltd., personal fees from Bayer Yakuhin, Ltd., personal fees from Kyowa Hakko Kirin Co., Ltd., personal fees from CHUGAI PHARMACEUTICAL CO., LTD., personal fees from MOCHIDA PHARMACEUTICAL CO.,LTD., personal fees from Eli Lilly Japan K.K., personal fees from DAIICHI SANKYO COMPANY, LIMITED, outside the submitted work. M.G. reports receiving grants, personal fees and non-financial support from Taiho Pharmaceutical Co., Ltd., Yakult Honsha Co., Ltd., Kyowa Hakko Kirin Co., Ltd., Ono Pharmaceutical Co., Ltd., Mochida Pharmaceutical Co., Ltd., and Chugai Pharmaceutical Co., Ltd., during the conduct of the study and personal fees and non-financial support from Takeda Pharmaceutical Co., Ltd., Novartis Pharmaceuticals and Bayer Yakuhin, Ltd., outside the submitted work. S.K. reports receiving grants and personal fees from Eli Lilly, Taiho Pharmaceutical, Ono Pharmaceutical and Bristol-Myers Squibb and personal fees from Chugai Pharma, Merck Serono, Bayer, Eisai and Yakult Honsha, outside the submitted work. Y.K. reports receiving research grants and personal fees from AstraZeneca, Chugai Pharmaceutical, Boehringer Ingelheim Japan, Ono Pharmaceutical, Bristol-Myers Squibb, and Tosoh Corp., research grants from MSD, Toppan Printing, Terumo and On-chip Biotechnologies, and personal fees from Thermo Fisher, and Lilly outside the submitted work. K.Y. reports receiving personal fees and other fees from Chugai, Bayer and MSD; personal fees from Takeda, Taiho, Yakult, Daiichi Sankyo, Merck Serono, Sanofi, Lily and other fees from Boehringer Ingelheim, outside the submitted work. S.H. reports receiving personal fees from Ono Pharm, Bristol-Myers Squibb, Taiho Pharm, Yakult Honsha, Daiichi Sankyo, Lilly, Chugai Pharm, Nihonkayaku and Tsumura & Co., outside the submitted work. N.B. reports receiving research grant from Ono, Bristol-Myers Squibb and Taiho and honorarium from Ono, Bristol-Myers Squibb, Taiho, Eli-Lilly and Chugai. I.H. reports receiving grants and personal fees from Chugai, Taiho, Takeda, Ono, Daiichi-Sankyo and Yakult-Honsha and personal fees from Merck-Serono, outside the submitted work. K.M. reports receiving grants and personal fees from ONO Pharmaceutical CO.,LTD. and Sanofi, and grants from Daiichi Sankyo, Parexel International, Shionogi Pharmaceutical, Sumitomo Dainippon Pharma, MSD, Pfizer, Mediscience Planning, Solasia Pharma, and Merck Serono. He also reports receiving personal fees from Eli Lilly, Chugai Pharmaceutical, Takeda Pharmaceutical, Taiho Pharmaceutical, Bristol-Myers Squibb, and Bayer; outside the submitted work. The other authors declare no conflicts of interest., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Chemotherapy in relapsed colorectal cancer patients treated with oxaliplatin as adjuvant chemotherapy is under debate. REACT study aimed to investigate the efficacy of reintroducing modified FOLFOX6 (mFOLFOX6) or CAPOX with or without bevacizumab in recurrent colorectal cancer patients after oxaliplatin adjuvant chemotherapy., Methods: Patients that participated in this trial had a medical history of adjuvant chemotherapy, including oxaliplatin with a cumulative dose greater than 400 mg/m 2 , and recurrence that was diagnosed more six months post adjuvant chemotherapy. Primary endpoints were response rate (RR) and disease control rate (DCR), while key secondary endpoints were time to treatment failure (TTF), progression-free survival (PFS), overall survival (OS), and safety., Results: A total of 31 patients were enrolled between October 2012 and October 2016. Of the 29 eligible patients, 7 received mFOLFOX6 and 22 received CAPOX. The RR was 62.1% (95% confidence interval 42.3-79.3) and the DCR was 82.8% (95% confidence interval 64.2-94.2). The RR for oxaliplatin-free interval was 100.0% in months 6-12 and 56.0% after 12 months. Median TTF, PFS, and OS were 6.3, 10.8, and 28.7 months, respectively. Grade 3 or worse peripheral sensory neuropathy developed in 6.5%. Allergic reactions occurred in 12.9% of the patients, with one (3.2%) grade 3 episode. There were no other severe treatment-related adverse events., Conclusion: Reintroduction of oxaliplatin was feasible and achieved high RR or DCR in patients after more than 6 months post oxaliplatin adjuvant chemotherapy.

Background: Older or frail patients are often underrepresented in clinical trials for metastatic colorectal cancer (mCRC). We here assessed the efficacy and safety of 5-fluorouracil (5-FU)-leucovorin plus bevacizumab in such patients., Methods: The study (OGSG 0802) was designed as a single-arm, open-label, multicenter phase II trial. Eligible patients had mCRC and at least one of the following: an age of ≥ 65 years, an Eastern Cooperative Oncology Group performance status of 1 or 2, a serum albumin level of ≤ 3.5 g/dL, incompatibility with oxaliplatin or irinotecan, and a history of abdominal or pelvic radiotherapy. Patients received 5-FU (600 mg/m 2 ) and l-leucovorin (200 mg/m 2 ) on days 1, 8, and 15 together with bevacizumab (5 mg/kg) on days 1 and 15 every 4 weeks. The primary end point was objective response rate (ORR), and secondary end points were progression-free survival (PFS), overall survival (OS), and safety., Results: Forty-one patients were enrolled and eligible. Median age was 76 years (range 56-90 years), and 51% of patients had a performance status of 0. The ORR was 36.6% [95% confidence interval (CI) 22.1-53.1%], median PFS was 9.4 months (95% CI 7.4-17.7 months), and median OS was 24.0 months (95% CI 19.9 months-not reached). The most common treatment-related adverse events of grade ≥ 3 were neutropenia (24%), anorexia (10%), leukopenia (7%), and mucositis/stomatitis (7%). There were no treatment-related deaths., Conclusion: Weekly 5-FU-leucovorin with biweekly bevacizumab may be a tolerable and effective treatment option for older or frail patients with mCRC.

Background: While the BRAF V600E mutation occurs in 5%-15% of metastatic colorectal cancer (mCRC), BRAF non-V600E mutations were recently reported to range from 1.6% to 5.1%. We have previously reported that BRAF non-V600E mutations could have a negative impact on efficacy outcomes as well as BRAF V600E mutation for antiepidermal growth factor receptor (EGFR) antibody treatment for pretreated patients with mCRC. Recently, simultaneous inhibitions of mitogen-activated protein kinase kinase (MEK), BRAF and EGFR exhibited relevant antitumour activities in patients with BRAF V600E mutant and also in BRAF non-V600E mutant but only in the preclinical model., Trial Design: The BIG BANG (study is a multicentre, phase II study to assess the efficacy, safety and proof of concept of the combinations of binimetinib+encorafenib+cetuximab in patients with BRAF non-V600E mutated mCRC, identified by either tumour tissue (tumour tissue group) or blood samples (liquid biopsy group). Key eligibility criteria include Eastern Cooperative Oncology Group Performance Status of ≤1, mCRC with BRAF non-V600E mutant and RAS wild type, refractory or intolerant to at least one fluoropyrimidine-based regimen and no prior history of regorafenib, and no prior history of anti-EGFR antibody treatment (primary analysis cohort and liquid biopsy cohort) or refractory to prior anti-EGFR antibody treatment in patients with class 3 BRAF mutations (anti-EGFR antibody refractory class three cohort). Enrolled patients receive binimetinib (45 mg, two times per day), encorafenib (300 mg, once a day) and cetuximab (initially 400 mg/m 2 and subsequently 250 mg/m 2 , once per week). The primary endpoint is the confirmed objective response rate in the primary analysis cohort., Trial Registration Numbers: UMIN000031857 and 000031860., (© 2020 THE AUTHORS. Published by Elsevier Limited on behalf of European Society for Medical Oncology.)

Background: BRAF V600E mutations are associated with aggressive biology and limited response to standard chemotherapy, especially during second-line and beyond therapies. BRAF V600E mutant and wild-type colorectal cancers (CRCs) differ in their expression profiles, and preclinical evidence suggests that microtubule inhibitors have an antitumour effect on xenograft models of BRAF V600E mutant CRCs. Eribulin has the best growth inhibitory activity in vitro of the microtubule inhibitors. Also, we have evidenced a hint of activity for patients with BRAF V600E mutant metastatic CRC (mCRC) with tumour shrinkage following eribulin treatment., Trial Design: The BRAVERY study is a multicentre phase II study to evaluate the efficacy and safety of eribulin in patients with BRAF V600E mutant mCRC detected in either tumour tissues (primary analysis part) or circulating tumour DNA assays (liquid biopsy part). Key eligibility criteria are refractoriness and intolerance to at least one regimen (including irinotecan or oxaliplatin) containing fluoropyrimidine and Eastern Cooperative Oncology Group performance status of 0-1. Eribulin is to be administered intravenously at a dose of 1.4 mg/m 2 on days 1 and 8 and repeated every 21 days. The primary endpoint is the confirmed objective response rate (ORR) by investigator's assessment. We calculated the sample size of the primary analysis part at 27 patients using a two-stage design with 25% ORR deemed promising and 5% unacceptable (one-sided α, 0.05; β, 0.1). Secondary endpoints include disease control rate, progression-free survival, overall survival and adverse events. Moreover, we will collect pretreated tissue and serial blood samples for biomarker analyses, focusing on gene expression associated with BRAF mutant-like CRC to find predictive markers and acquired gene alterations to detect resistance mechanisms to eribulin. We initiated patient enrolment in March 2018, completed the primary analysis on May 2019, and are currently continuing with the liquid biopsy part., Trial Registration Number: UMIN000031221 and 000031552., Competing Interests: Competing interests: TM has received honoraria from Takeda, Chugai, Merck Serono, Taiho, Bayer, Lilly Japan, Yakult Honsha, and Sanofi and has received research funding from Yakult Honsha, MSD, Daiichi Sankyo, and Ono; HT has received honoraria from Takeda, Chugai, Merck Serono, Taiho, Bayer, Lilly Japan, and Yakult Honsha, Sanofi; DK has received honoraria from Takeda, Chugai, Lilly and Merck Serono; HB has received honoraria from Taiho and Eli Lilly Japan and has received research funding from Taiho, Astrazeneca and Sysmex; YK has received honoraria Takeda, Chugai, Bristol-Myers Squibb, Ono, Merck Biopharma, Taiho, Bayer, Lilly, Yakult Honsha, Sanofi, Nipro, Moroo, Asahi Kasei, Mitsubishi Tanabe, Otsuka, Medical Review, and Shiseido and has received research funding from MSD, Daiichi Sankyo, NanoCarrier, Eisai, Sysmex, Shionogi, IQVIA, Parexel International, Astellas, Mediscience, Sumitomo Dainippon, A2 Healthcare, Ono, Taiho, Bayer, Yakult Honsha, and Sanofi, ES has received honoraria from Taiho, Yakult, Chugai, Lilly, Sanofi, Merck bioparm, and Takeda; TEN has received honoraria from Takeda, Chugai, Merck Serono, Taiho, Bayer, Lilly Japan, Sanofi, Kyowa Hakko Kirin, Sawai, Bristol-Myers Squibb Japan, Ono, Dainippon Sumitomo Pharma, MSD, Nippon Kayaku, Celltrion Healthcare Japan, and Teijin and has received research funding from Takeda, Chugai, Merck Serono, Taiho, Lilly Japan, Sanofi, Ono, Dainippon Sumitomo Pharma, MSD, Nippon Kayaku, Eisai, Daiichi Sankyo, A2 Healthcare and Solasia Pharma; TS has received honoraria from Chugai, Merck Serono, Bristol-Myers Squibb, Takeda, Yakult Honsha, Lilly, Bayer Yakuhin, Ono, Merck, Astellas Pharma, Taiho and Nihonkayaku, has received consulting or advisory role from Bayer, Lilly, Ono, Takara Bio, Merck Serono, and Nihonkayaku, and has received research funding from Yakult Honsha, Chugai, Ono, Sanofi, Lilly, Daiichi Sankyo, Merck Serono, Gilead Sciences, and Dainippon Sumitomo; TE has received honoraria from Lilly, Taiho, Bristol-Myers Squibb Japan, Eisai, Daiichi Sankyo, Merck Serono, Chugai, Ono, Takeda, Bayer, and Sanofi and has received research funding from Daiichi Sankyo, Merck Serono, MSD, Novartis, Dainippon Sumitomo, Ono, Astellas Pharma, Lilly, Bayer, Nihonkayaku, Pfizer, and Bristol-Myers Squibb Japan; MW has received honoraria from Chugai and Johnson and Johnson; SN has received honoraria from Taiho and Astrazeneca, AS has received research funding from MSD, Eisai, Ono, Taiho, Takeda, and Bayer, Atsushi Ohtsu has received honoraria from Ono, BMS, Chugai, Taiho, Eisai, and Amgen and has received research funding from Bristol-Myers Squibb and immediate family member of Atsushi Ohtsu have been employed by Celgene, and Takayuki Yoshino has received research funding from Novartis, MSD, Sumitomo Dainippon, Chugai, Sanofi, Daiichi Sankyo, Parexel, Ono, GlaxoSmithKline and Boehringer Ingelheim., (© Author (s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. Published by BMJ on behalf of the European Society for Medical Oncology.)

Background: Regorafenib improved the overall survival (OS) of patients with metastatic colorectal cancer (mCRC) who progress after standard therapies in two phase III trials. The present large-scale prospective observational study evaluated the safety and effectiveness of regorafenib administered to Japanese patients with mCRC in real-life setting., Materials and Methods: Patients with mCRC were prospectively registered and initially received ≤160 mg oral regorafenib daily, at the investigator's discretion, for weeks 1-3 of each 4-week cycle. The study's primary aim was to assess safety, particularly unexpected clinically significant adverse drug reactions (ADRs). A Cox's proportional hazards model was used to evaluate the association between OS, hand-foot skin reaction (HFSR), and baseline characteristics., Results: We evaluated 1,227 of 1,301 patients (enrolled from March 2013 to May 2015). ADRs occurred in 89.3% of patients (mostly within the first 4 weeks) and were a major reason for discontinuing treatment. The most frequent ADRs were HFSR, liver injury, and hypertension. The cumulative incidence of HFSR and liver injury was higher in patients who initially received 160 mg than in those who received ≤120 mg. The incidence of hypertension and fatigue was similar between groups. Median OS was 6.9 months (95% confidential interval, 6.4-7.4). OS was associated with early onset of HFSR and good performance status (PS) but not with the initial dose., Conclusion: The outcomes of this study were consistent with those of clinical trials. There were no new safety concerns. Regorafenib treatment would not be recommended for patients with higher PS., Implications for Practice: Previous clinical trials demonstrated regorafenib improved overall survival in patients with metastatic colorectal cancer who progress after standard chemotherapies. Because the eligibility criteria of the trials were restricted compared with a real-world setting, the data from the trials may not fully represent the profiles of regorafenib in clinical practice. This large-scale observational study showed that the safety and effectiveness of regorafenib in clinical practice were generally consistent with previous trials. The majority of patients reported adverse drug reactions within the first 4 weeks, most commonly hand-foot skin reaction. Regorafenib treatment would not be recommended for patients with higher performance status., Competing Interests: Disclosures of potential conflicts of interest may be found at the end of this article., (© AlphaMed Press 2019.)

Background: A cytotoxic chemotherapeutic regimen is not routinely recommended for frail elderly patients with unresectable colorectal cancer (CRC) because of susceptibility to treatment. Panitumumab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). Use of panitumumab as first-line therapy is expected to be well tolerated and to improve survival rates, even in patients who are not eligible for intensive chemotherapy. However, the efficacy and safety of panitumumab as the first-line therapy for the frail elderly patients with unresectable CRC have not been yet studied., Methods: We plan to conduct a prospective multi-center phase II study. Patients with wild-type RAS unresectable CRC aged ≥76 years or ≥ 65 who are not considered eligible for intensive chemotherapy will be included in the study. A total of 36 patients will be enrolled from Osaka Gastrointestinal Cancer Chemotherapy Study Group for over 2 years. Panitumumab 6 mg/kg IV infusion will be administered every 2 weeks. The purpose of this trial is to assess the efficacy of panitumumab as first-line therapy for patients with unresectable CRC. The primary endpoint is to determine the disease control rate. Secondary endpoints include progression-free survival, overall survival, response rate, time to treatment failure, and the incidence of grade 3/4 toxicities., Discussion: This is a prospective phase II trial assessing the efficacy of panitumumab monotherapy in the elderly patients with wild-type RAS unresectable CRC., Trial Registration: The ethics committee of the Osaka Medical College approved this study on November 7, 2016. The trial registration number of the government was UMIN000024528 on December 1, 2016. It was registered prospectively (the day of enrollment of the first participant was February 9, 2017).

Detection of RAS and BRAF mutations is essential to determine the optimal treatment strategy for metastatic colorectal cancer (CRC). We prospectively evaluated the MEBGEN RASKET-B KIT (RASKET-B), a novel multiplex kit, simultaneously detecting 48 types of RAS mutations and the BRAF V600E mutation using Luminex xMAP technology. The aim was to obtain market approval for RASKET-B as an in vitro diagnostic (IVD) option in Japan. Genomic DNA was extracted from 302 formalin-fixed paraffin-embedded tissues obtained from CRC patients. The primary endpoints were the concordance rate (CR) between the results from RASKET-B and the previously approved IVD kit (RASKET) for RAS mutations, and CR between the results from RASKET-B and direct sequencing (DS) for BRAF mutations. The secondary endpoints included the CR between RASKET-B and DS for RAS mutations and between RASKET-B and the pyrosequencing (PYRO) for the BRAF V600E mutation. Among the 302 samples, 142 RAS mutations (47%) and 18 BRAF V600E mutations (6.0%) were detected by RASKET-B. All mutations detected in the recruited patients were mutually exclusive. Both RAS and BRAF mutation rates were statistically higher in right-sided than left-sided CRC. The CR between RASKET-B and RASKET for RAS gene and RASKET-B and DS for BRAF V600E mutation was 100% for both (95% CI: 99%-100%). The results from RASKET-B were also highly concordant with DS for RAS (97.4%) and with PYRO for the BRAF (V600E) gene (99.7%). RASKET-B thus provides rapid, precise, and simultaneous detection of RAS and BRAF mutations in CRC., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Recent studies have indicated that long noncoding RNAs (lncRNAs) play a pivotal role in almost all physiological cellular processes, including every stage of cancer development. Given that hypoxia in the tumor microenvironment is involved in the malignant behavior of tumors, such as invasion and metastasis, we investigated the cytoplasmic and nuclear localization of lncRNAs in colorectal cancer cells. A cell culture under hypoxic conditions revealed several lncRNAs, such as LINC00152, whose levels were increased in the cytoplasm of colorectal cancer cells. A database study indicated that LINC00152 shares microRNA-binding sites, such as miR-138 and miR-193, with the hypoxia-inducible factor 1 (HIF1), thus suggesting that LINC00152 could possibly function as a competing endogenous RNA that can augment Hif1 translation in the cytoplasm of hypoxic colorectal cancer cells. Moreover, the data presented in the studies of surgically resected samples showed that patients with colorectal cancer exhibiting high LINC00152 expression were associated with a worsened survival rate; this supports the suggested oncogenic function of LINC00152 in the cytoplasm under hypoxic conditions. The present study demonstrated that lncRNA networks could provide diagnostic tools and novel therapeutic targets against colorectal cancer cells.

Background: Targeting epigenetic regulators is a promising therapeutic strategy against cancer. However, because of the broad spectrum of targets, selective inhibition of cancer-associated genes remains a major challenge. To address this issue, we focused on the oncogene-regulated histone demethylase, nucleolar protein 66 (NO66 [C14orf169/MAPJD]), which is known to work coordinately with the well-characterized oncogene, c-MYC., Methods: To investigate expression patterns and clinical significance of NO66 in colorectal cancer (CRC), we performed immunohistochemical staining in 114 CRC cases. We performed functional analysis of NO66 to evaluate its contribution to proliferation and migration ability in CRC cells in vitro., Results: NO66 was selectively expressed in CRC tissues. Furthermore, high expression levels of NO66 were associated with cancer metastatic potential, including lymphatic duct invasion (p = 0.047), venous invasion (p = 0.033), and lymph node metastasis (p = 0.015). Multivariate analysis indicated that NO66 was an independent prognostic factor for overall survival. In vitro assays revealed that NO66 expression is closely associated with malignant potential, including proliferation, migration and anti-apoptotic activity., Conclusions: NO66 is an independent prognostic factor in CRC. The cancer-selective expression patterns and its involvement in metastatic phenotypes suggest that NO66 is not only a crucial biomarker but is also a promising therapeutic target in CRC.

Background: We previously reported in the SENRI trial on the usefulness of aprepitant for the prevention of chemotherapy-induced nausea and vomiting (CINV) in colorectal cancer patients receiving an oxaliplatin-based regimen which is classified as moderately emetogenic cancer chemotherapy. In the present subgroup analysis of the SENRI trial, we assessed the risk factors for CINV in colorectal cancer patients who received oxaliplatin-based chemotherapy., Methods: Multivariate logistic regression models were used to assess the impact of aprepitant use and patient characteristics on vomiting and nausea. We also assessed the proportion of CINV in patients by gender., Results: Female gender and aprepitant use were associated with the incidence of vomiting and no significant nausea. Significantly more men achieved no vomiting than women (92.9 vs 84.5 % in men and women, respectively; P = 0.0001). The rate of no nausea, complete response, complete protection, and total control was also higher in men. The rate rescue therapy use was significantly higher in women than men. We compared the rate of CINV between aprepitant and control groups and found a significant difference in male patients who achieved no vomiting and complete protection in the overall phase. In women, the rate of no nausea, no vomiting, and total control was higher in the aprepitant group than in the control group., Conclusions: Gender and aprepitant use were risk factors for CINV in colorectal patients who received oxaliplatin-based chemotherapy. Aprepitant therapy was more effective for women than for men in the prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen.

Background: Capecitabine and irinotecan combination therapy (XELIRI) has been examined at various dose levels to treat metastatic colorectal cancer (mCRC). Recently, in the Association of Medical Oncology of the German Cancer Society (AIO) 0604 trial, tri-weekly XELIRI plus bevacizumab, with reduced doses of irinotecan (200 mg/m 2 on day 1) and capecitabine (1600 mg/m 2 on days 1-14), repeated every 3 weeks, has shown favorable tolerability and efficacy which were comparable to those of capecitabine and oxaliplatin (XELOX) plus bevacizumab. The doses of capecitabine and irinotecan in the AIO trial are considered optimal. In a phase I/II study, XELIRI plus bevacizumab (BIX) as second-line chemotherapy was well tolerated and had promising efficacy in Japanese patients., Methods: The Asian XELIRI ProjecT (AXEPT) is an East Asian collaborative, open-labelled, randomized, phase III clinical trial which was designed to demonstrate the non-inferiority of XELIRI with or without bevacizumab versus standard FOLFIRI (5-fluorouracil, leucovorin, and irinotecan combination) with or without bevacizumab as second-line chemotherapy for patients with mCRC. Patients with 20 years of age or older, histologically confirmed mCRC, Eastern Cooperative Oncology Group performance status 0-2, adequate organ function, and disease progression or intolerance of the first-line regimen will be eligible. Patients will be randomized (1:1) to receive standard FOLFIRI with or without bevacizumab (5 mg/kg on day 1), repeated every 2 weeks (FOLIRI arm) or XELIRI with or without bevacizumab (7.5 mg/kg on day 1), repeated every 3 weeks (XELIRI arm). A total of 464 events were estimated as necessary to show non-inferiority with a power of 80% at a one-sided α of 0.025, requiring a target sample size of 600 patients. The 95% confidence interval (CI) upper limit of the hazard ratio was pre-specified as less than 1.3., Conclusion: The Asian XELIRI ProjecT is a multinational phase III trial being conducted to provide evidence for XELIRI with or without bevacizumab as a second-line treatment option of mCRC. Trial registration ClinicalTrials.gov NCT01996306. UMIN000012263.

Tumor cells respond to their microenvironment, which can include hypoxia and malnutrition, and adapt their metabolism to survive and grow. Some oncogenes are associated with cancer metabolism via regulation of the related enzymes or transporters. However, the importance of metabolism and precise metabolic effects of oncogenes in colorectal cancer remain unclear. We found that colorectal cancer cells survived under the condition of glucose depletion, and their resistance to such conditions depended on genomic alterations rather than on KRAS mutation alone. Metabolomic analysis demonstrated that those cells maintained tricarboxylic acid cycle activity and ATP production under such conditions. Furthermore, we identified pivotal roles of GLUD1 and SLC25A13 in nutritional stress. GLUD1 and SLC25A13 were associated with tumor aggressiveness and poorer prognosis of colorectal cancer. In conclusion, GLUD1 and SLC25A13 may serve as new targets in treating refractory colorectal cancer which survive in malnutritional microenvironments., Competing Interests: Institutional endowments were partly received from Taiho Pharmaceutical Co., Ltd. (http://www.taiho.co.jp/english/), the Evidence Based Medical (EBM) Research Center (http://ebmrce.co.jp/index.html), Chugai Co., Ltd. (http://www.chugai-pharm.co.jp/english/index.html), Yakult Honsha Co., Ltd. (http://www.yakult.co.jp/english/index.html), and Merck Co., Ltd. (http://www.merck.co.jp/en/index.html). Those funders had no role in the main experimental equipment, supply expenses, study design, data collection and analysis, decision to publish, or preparation of the manuscript for this work.

Deranged metabolism is a hallmark of cancer, playing a significant role in driving the disease process. One such example is the induction of carcinogenesis by the oncometabolite D-2 hydroxyglutarate (D-2HG), which is produced by the mutated enzyme isocitrate dehydrogenase (IDH) occurring in subsets of leukaemias and brain tumours. The oncogenic property of D-2HG appears to stem from its ability to interfere with the activities of α-ketoglutarate-dependent dioxygenases, including the Jumonji family histone demethylases. Here, we find in colorectal cancer cells that even in the absence of IDH mutation, the levels of D-2HG and its enantiomer L-2HG were elevated through glutamine anaplerosis. D-2HG, but not L-2HG, increased the trimethylation of histone H3 lysine 4 of the promoter region of ZEB1, a master regulator of epithelial-mesenchymal transition (EMT), and increased the expression of the ZEB1 gene to directly induce EMT in colorectal cancer cells. EMT promotes the ability of cancer cells to invade the local tissue and enter into the bloodstream, leading to distant organ metastasis. D-2HG levels were elevated in colorectal cancer specimens, particularly in those associated with distant metastasis, supporting the observations in vitro and implicating the contribution of D-2HG in metastasis, the major cause of death in this disease.

Background: Regorafenib and TAS-102 are novel antitumor agents for patients with metastatic colorectal cancer (mCRC) whose disease has progressed after standard therapies. In randomized trials, regorafenib and TAS-102 prolonged survival in patients with mCRC. However, the appropriate selection of regorafenib or TAS-102 in treatment strategy has not yet been established., Patients and Methods: We performed a retrospective analysis, between March 2013 and July 2015, on the efficacy and safety of regorafenib or TAS-102., Results: Thirty-seven patients with mCRC treated with regorafenib or TAS-102 were included. Of these 37 patients, 23 first received regorafenib and 14 received TAS-102. The median progression-free survival and overall survival were 3.0 and 5.8 months, respectively, in the regorafenib group and 2.1 and 6.3 months, respectively, in the TAS-102 group. Drug-related adverse events (AEs) and grade ≥3 AEs were 23 (100%) and 10 (43.5%), respectively, in the regorafenib group and 13 (92.9%) and 2 (14.3%), respectively, in the TAS-102 group. The most frequent grade ≥3 AEs were hepatotoxicity (17.4%) and hand-foot syndrome (13.0%) in the regorafenib group, and neutropenia (14.3%) in the TAS-102 group. In subgroup analysis, the median overall survival was 11.5 months in patients receiving crossover treatment with regorafenib to TAS-102, and 7.6 months in those receiving crossover treatment with TAS-102 to regorafenib., Conclusion: Our results showed that regorafenib and TAS-102 have comparable efficacy but different toxicity profiles in patients with mCRC. Both are considered new salvage treatment options. Differences in the toxicity profiles between the two treatments will help in choosing regorafenib or TAS-102., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: Patients with metastatic colorectal cancer (mCRC) harboring wild-type KRAS benefit from epidermal growth factor receptor (EGFR)-targeted therapy. However, patients who are treated with anti-EGFR antibodies will eventually develop the resistance to those agents. HER2 amplification is one of the mechanisms conferring resistance to anti-EGFR antibody therapy and could therefore be a potential therapeutic target. The aim of this study was to detect HER2 amplification in circulating tumor DNA (ctDNA) from patients with CRC and acquired resistance to anti-EGFR antibody therapy., Results: Our data showed that 22% (4/18) of patients in the cohort exhibited HER2 amplification. One of these patients was found to be positive for HER2 amplification in matched tumor specimens collected after cetuximab therapy, at which point the patient had acquired cetuximab resistance, despite being negative for HER2 amplification prior to therapy., Methods: We analyzed plasma ctDNA using digital polymerase chain reaction (PCR) from 18 patients with CRC, who had been treated with anti-EGFR antibody-based therapy (cetuximab) and subsequently acquired resistant cetuximab. HER2 gene copy number was analyzed using fluorescence in situ hybridization in tumor samples before and after acquisition of resistance to cetuximab-based therapy., Conclusions: Analysis of plasma ctDNA by digital PCR could be useful for detecting HER2 amplification in patients with CRC who were resistant to anti-EGFR antibody therapy.

Although BRAF(V600E) mutation is associated with adverse clinical outcomes in patients with colorectal cancer (CRC), response and resistance mechanisms for therapeutic BRAF(V600E) inhibitors remains poorly understood. In the present study, we demonstrate that selective BRAF(V600E) inhibition activates AMP-activated protein kinase (AMPK), which induces autophagy as a mechanism of therapeutic resistance in human cancers. The present data show AMPK-dependent cytoprotective roles of autophagy under conditions of therapeutic BRAF(V600E) inhibition, and AMPK was negatively correlated with BRAF(V600E)-dependent activation of MEK-ERK-RSK signaling and positively correlated with unc-51-like kinase 1 (ULK1), a key initiator of autophagy. Furthermore, selective BRAF(V600E) inhibition and concomitant suppression of autophagy led to the induction of apoptosis. Taken together, present experiments indicate that AMPK plays a role in the survival of BRAF(V600E) CRC cells by selective inhibition and suggest that the control of autophagy contributes to overcome the chemoresistance of BRAF(V600E) CRC cells.

Background: Amphiregulin, a ligand of the epidermal growth factor receptor (EGFR), is associated with the efficacy of cetuximab, an antibody against EGFR, as treatment for colorectal cancer (CRC). In contrast, the HER3 ligand heregulin correlates with cetuximab resistance. In this study, we evaluated how the combined levels of circulating amphiregulin and heregulin affect clinical outcomes in patients who receive cetuximab as therapy against advanced CRC., Methods: Plasma levels of amphiregulin and heregulin were measured by enzyme-linked immunosorbent assay in 50 patients with CRC in a training cohort, and in 10 patients in a validation cohort. The combined expression was then assessed with clinical outcome after receiver operating characteristics analysis., Results: Overall response rate was 26%, and median progression-free survival was 110 days in the training cohort. Patients with high amphiregulin and low heregulin had significantly higher objective response rate at 58% and significantly longer progression-free survival of 216 days. This result was confirmed in the validation cohort., Conclusion: A subgroup of CRC patients with high amphiregulin and low heregulin respond to cetuximab therapy better than other patients.

Introduction: The oral neurokinin-1 antagonist aprepitant is recommended in several guidelines for preventing chemotherapy-induced nausea & vomiting (CINV) due to highly emetogenic cancer chemotherapy. Little is known about the feasibility and safety of aprepitant in patients treated with oxaliplatin., Methods: In this multicentre, open label, randomised, phase 3 trial, we recruited patients with colorectal cancer who underwent an oxaliplatin-based chemotherapy. Patients were centrally randomised in a 1:1 ratio to the control group (5-HT3-receptor antagonist+dexamethasone) or aprepitant group (5-HT3-receptor antagonist+dexamethasone+aprepitant or fosaprepitant) in the first course. All patients were treated with aprepitant/fosaprepitant therapy in the second course. The primary end-point was the proportion of patients with no emesis., Results: A total of 413 patients entered this clinical trial from 25 centres in Japan. Significantly more patients in the aprepitant group achieved no vomiting overall and delayed phase than those in the control group (95.7% versus 83.6%, and 95.7% versus 84.7%, respectively). The aprepitant group also had statistically significantly higher percentages of no significant nausea, complete response and complete protection than the control group overall. In the control group, the percentages of no vomiting were higher in the second cycle than in the first cycle. The incidence of vomiting occurred day 7 or later was significantly higher in the control group compared with the aprepitant group. Other adverse events were not significant between the groups., Conclusion: The aprepitant therapy was more effective than the control therapy for prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Background/aim: The epidermal growth factor family (EGF) has been suggested to influence the sensitivity to anti-epidermal growth factor receptor therapy. We examined the correlation between circulating levels of the epidermal growth factors amphiregulin and transforming growth factor-α (TGF-α) and the MET ligand hepatocyte growth factor and sensitivity to the anti-epidermal growth factor receptor antibody in colorectal cancer (CRC) patients., Materials and Methods: Plasma levels of each ligand were measured by enzyme-linked immunosorbent assay in 51 patients with wild-type KRAS CRC., Results: Patients with high hepatocyte growth factor (HGF) levels had a significantly lower disease control rate (DCR) and shorter median progression-free survival (PFS) and overall survival (OS) than those with low expression levels. Amphiregulin was correlated with objective response rate (ORR) but not with PFS or OS. Cetuximab response and survival were not associated with TGF-α., Conclusion: Circulating HGF may help identify CRC patients most likely to benefit from anti-epidermal growth factor receptor antibody therapy., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: RAS (KRAS and NRAS) testing is required to predict anti-epidermal growth factor receptor (EGFR) treatment efficacy in metastatic colorectal cancer (CRC). Although direct sequencing (DS) with manual microdissection (MMD) is widely used, a diagnostic kit providing rapid detections of RAS mutations would be clinically beneficial. We evaluated the MEBGEN(TM) RASKET KIT (RASKET KIT), a multiplex assay using PCR-reverse sequence specific oligonucleotide and xMAP(®) technology to concurrently detect exon 2, 3, and 4 RAS mutations in a short turnaround time (4.5 h/96-specimens)., Methods: Formalin-fixed paraffin-embedded (FFPE) tissues were obtained from 308 consenting patients with histologically-confirmed CRC at six hospitals in Japan. For the RASKET KIT, we used only 50-100 ng DNA from each FFPE specimen not processed by MMD. The primary endpoint was the concordance rate between RAS mutations identified with the RASKET KIT and two reference assays (DS with MMD and TheraScreen(®) K-RAS Mutation Kit). As the secondary endpoints, we evaluated the concordance rate between DS and the RASKET KIT for RAS mutations in the wild-type KRAS exon 2 population and the genotyping performance of the RASKET KIT compared with DS., Findings: Among 307 analyzable specimens, the reference assays detected 140 (45.6%, 140/307) RAS mutations: 111 KRAS exon 2 and 29 other (minor) RAS mutations. The RASKET KIT detected 143 (46.6%, 143/307) mutations: 114 KRAS exon 2 and 29 minor RAS mutations. The between-method concordance rate was 96.7% (297/307) (95% CI: 94.1-98.4%). Minor RAS mutations were detected in 15.7% (30/191) of the wild-type KRAS exon 2 population (n = 191); the concordance rate was 98.4% (188/191) (95% CI: 95.5-99.7%). The concordance rate of RAS genotyping was 100% (139/139) (95% CI: 97-100%)., Interpretation: The RASKET KIT provides rapid and precise detections of RAS mutations and consequently, quicker and more effective anti-EGFR therapy for CRC (Study ID: UMIN000011784)., Funding: Medical & Biological Laboratories Co., Ltd. (MBL). MBL had roles in study design, data collection, data analysis, and writing of the report for the study.

A combination of oxaliplatin, leucovorin and 5-fluorouracil (FOLFOX) plus bevacizumab has been widely used for the first-line chemotherapy of metastatic colorectal cancer (mCRC). S-1 is an oral fluoropyrimidine preparation that combines tegafur, a prodrug of 5-fluorouracil, with two modulators. Several studies of combination chemotherapy with oxaliplatin plus S-1 (SOX) conducted in Asia have reported promising efficacy and safety in patients with mCRC, suggesting the potential to replace mFOLFOX6. The SOFT trial (JapicCTI-090699) was a randomized Phase III trial designed to evaluate the noninferiority of SOX plus bevacizumab to mFOLFOX6 plus bevacizumab in patients with mCRC. This review summarizes the drug concept of S-1 and the results of clinical trials of S-1 and SOX in CRC and presents an overview of the SOFT trial.

Purpose: The FIRIS study previously demonstrated non-inferiority of IRIS (irinotecan plus S-1) to FOLFIRI (5-fluorouracil/leucovorin with irinotecan) for progression-free survival as the second-line chemotherapy for metastatic colorectal cancer (mCRC) as the primary endpoint. The overall survival (OS) data were immature at the time of the primary analysis., Methods: Between 30 January 2006 and 29 January 2008, 426 patients with mCRC who failed in first-line chemotherapy were randomly assigned to receive either FOLFIRI or IRIS. After the primary analysis, the follow-up survey was cut off on 29 July 2010, and the final OS data were analysed., Results: With a median follow-up of 39.2 months, the median OS was 17.4 months in the FOLFIRI group and 17.8 months in the IRIS group [hazard ratio (HR) 0.900; 95% confidence interval (CI) 0.728-1.112]. In the pre-planned subgroup of patients who received prior chemotherapy containing oxaliplatin, the median OS was 12.7 months in the FOLFIRI group and 15.3 months in the IRIS group (HR 0.755; 95% CI 0.580-0.983)., Conclusions: IRIS is non-inferior to FOLFIRI for OS as second-line chemotherapy for mCRC. IRIS can be an option for second-line chemotherapy of mCRC. (ClinicalTrials.gov Number: NCT00284258).

Objective: We investigated the incidence and clinical features of drug-induced lung injury during cetuximab therapy in Japanese patients with colorectal cancer in a prospective multicenter registry based on a central registration system., Methods: We investigated and followed up patients with or suspected of having drug-induced lung injury among 2006 patients with cetuximab-treated colorectal cancer. A subcommittee of medical oncologists, pulmonologists and a radiologist evaluated and discussed each case of drug-induced lung injury that occurred during cetuximab therapy., Results: Sixty-six patients were identified and further examinations of drug-induced lung injury were conducted during the registration period. We analyzed time to onset, patient characteristics and factors associated with mortality. Cetuximab-related drug-induced lung injury occurred in 24 (1.2%) patients, and was rated as Grade 3 or worse in 15 (0.7%) patients. Fourteen patients received steroid pulse therapy. Ten patients with drug-induced lung injury died, of whom eight received steroid pulse therapy. The incidence of drug-induced lung injury was significantly higher in elderly patients, and in patients with prior interstitial lung disease. There was no particular trend in the time to onset. Patients with early onset of drug-induced lung injury (within 90 days) after starting cetuximab therapy had higher mortality than patients with later onset (over 90 days)., Conclusions: The incidence of drug-induced lung injury in cetuximab-treated patients was 1.2%. Because drug-induced lung injury is potentially serious, it is important to promptly initiate appropriate treatments. Considering that early onset drug-induced lung injury during cetuximab therapy is associated with a poor prognosis, close monitoring is mandatory for these patients., (© The Author 2014. Published by Oxford University Press.)

Purpose: This study evaluated the feasibility and safety of laparoscopic colorectal surgery for cancer in obese patients based on the short-term outcomes., Methods: We conducted a retrospective analysis of 561 patients with colorectal cancer treated from April 2007 to October 2010. The surgical outcomes were compared between non-obese (BMI <25 kg/m(2)) and obese (BMI ≥ 25 kg/m(2)) patients., Results: All of the enrolled patients were classified as non-obese (n = 421) or obese (n = 140). The obese group had a significantly higher proportion of male patients (72.1 vs. 57.0 %; P = 0.002), a higher incidence of left colon cancer (49.3 vs. 36.8 %; P = 0.033), and more systematic comorbidities (P < 0.001) than did the non-obese group. The length of the surgery was significantly longer in obese than in non-obese patients (221 vs. 207 min; P = 0.025). There was no significant difference in the overall incidence of postoperative complications between the two groups; however, surgical wound infections were more common in obese patients (12.1 vs. 5.2 %; P = 0.005). Obesity was not a significant-independent risk factor for total postoperative complications (odds ratio 1.330; P = 0.289)., Conclusion: Laparoscopic colorectal surgery is technically feasible and safe for obese patients and provides all the benefits of a minimally invasive approach.

Objective: Infusion reactions are common adverse reactions associated with antibody preparations. However, no studies have examined the time to onset of serious infusion reactions after administering cetuximab. We aimed to investigate the timing and severity of IRs affecting Japanese patients after administration of cetuximab., Methods: Study subjects were identified from a nationwide prospective registry of 2126 metastatic colorectal cancer patients scheduled to receive cetuximab. Infusion reactions were examined in 2006 patients with adequate safety data., Results: Infusion reactions of any grade occurred in 114 patients (5.7%), including Grade 3-4 infusion reactions in 22 patients (1.1%). Premedications were antihistamine plus corticosteroid (88.9% of patients with infusion reactions), antihistamine alone (9.2%) or corticosteroid alone (1.1%). In 95 patients (83.3%), infusion reactions occurred after the first dose. Twenty of the 22 Grade 3-4 infusion reactions occurred within 1 h of the first dose (the timing of the infusion reaction was unknown in one patient while another infusion reaction occurred after the fourth dose). Infusion reactions resolved in 111/114 patients (97.4%) while one patient recovered with sequelae, one patient died and one patient failed to recover within the follow-up period. Thirteen patients (15.7% of patients with infusion reactions) with Grade 1-2 infusion reactions showed recurrence after readministration of cetuximab; the recurrent infusion reactions were less severe than the initial reactions., Conclusions: Grade 3-4 infusion reactions occurred in 1.1% of colorectal cancer patients, and most occurred within 1 h of receiving the first dose of cetuximab. Therefore, patients should be carefully observed following cetuximab infusion, especially during the first hour after the first infusion., (© The Author 2014. Published by Oxford University Press.)

Background: Studies done in Asia have shown that a regimen of S-1 plus oxaliplatin (SOX) has promising efficacy and safety in patients with metastatic colorectal cancer. We aimed to establish whether SOX plus bevacizumab is non-inferior to mFOLFOX6 (modified regimen of leucovorin, fluorouracil, and oxaliplatin) plus bevacizumab as first-line chemotherapy for metastatic colorectal cancer., Methods: We undertook an open-label, non-inferiority, randomised phase 3 trial in 82 sites in Japan. We enrolled individuals aged 20-80 years who had metastatic colorectal cancer, had an Eastern Cooperative Oncology Group performance status of 0 or 1, had assessable lesions, had received no previous chemotherapy or radiotherapy, could take drugs orally, and had adequate organ function. Eligible patients were randomly assigned (1:1) to receive either mFOLFOX6 plus bevacizumab (on day 1 of each 2-week cycle, 5 mg/kg intravenous infusion of bevacizumab and a simultaneous intravenous infusion of 85 mg/m(2) oxaliplatin, 200 mg/m(2)l-leucovorin, 400 mg/m(2) bolus fluorouracil, and 2400 mg/m(2) infusional fluorouracil) or SOX plus bevacizumab (on day 1 of each 3-week cycle, 7·5 mg/kg intravenous infusion of bevacizumab and 130 mg/m(2) intravenous infusion of oxaliplatin; assigned dose of S-1 twice a day from after dinner on day 1 to after breakfast on day 15, followed by 7-day break). Randomisation was done centrally with the minimisation method, with stratification by institution and whether postoperative adjuvant chemotherapy had been given. Participants, investigators, and data analysts were not masked to treatment assignment. The primary endpoint was progression-free survival (PFS), which was defined as the interval between enrolment and progressive disease (≥20% increase in sum of longest dimensions of target lesions from baseline, or appearance of new lesions) or death, whichever came first. The primary analysis was done by modified intention to treat. This trial is registered with the Japan Pharmaceutical Information Center, number JapicCTI-090699., Findings: Between Feb 1, 2009, and March 31, 2011, 512 patients underwent randomisation. 256 patients assigned to receive SOX plus bevacizumab and 255 assigned to receive mFOLFOX6 plus bevacizumab were included in the primary analysis. Median PFS was 11·5 months (95% CI 10·7-13·2) in the group assigned to mFOLFOX6 plus bevacizumab and 11·7 months (10·7-12·9) in the group assigned to SOX plus bevacizumab (HR 1·04, 95% CI 0·86-1·27; less than non-inferiority margin of 1·33, pnon-inferiority=0·014). The most common haematological adverse events of grade 3 or higher were leucopenia (21 [8%] of 249 patients given mFOLFOX6 plus bevacizumab included in safety analysis vs six [2%] of 250 given SOX plus bevacizumab; p=0·0029) and neutropenia (84 [34%] vs 22 [9%]; p<0·0001). Grade 3 or higher anorexia (13 [5%] vs three [1%]; p=0·019) and diarrhoea (23 [9%] vs seven [3%]; p=0·0040) were significantly more common in patients given SOX plus bevacizumab than in those given mFOLFOX6 plus bevacizumab. We recorded seven treatment-related deaths (three in the group given mFOLFOX6 plus bevacizumab; four in that given SOX plus bevacizumab)., Interpretation: SOX plus bevacizumab is non-inferior to mFOLFOX6 plus bevacizumab with respect to PFS as first-line treatment for metastatic colorectal cancer, and could become standard treatment in Asian populations., Funding: Taiho., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

The global incidence of colorectal cancer (CRC) is increasing. Although there are emerging epigenetic factors that contribute to the occurrence, development and metastasis of CRC, the biological significance of epigenetic molecular regulation in different subpopulations such as cancer stem cells remains to be elucidated. In this study, we investigated the functional roles of the H3K4 demethylase, jumonji, AT rich interactive domain 1B (JARID1B), an epigenetic factor required for the continuous cell growth of melanomas, in CRC. We found that CD44(+)/aldehyde dehydrogenase (ALDH)(+) slowly proliferating immature CRC stem cell populations expressed relatively low levels of JARID1B and the differentiation marker, CD20, as well as relatively high levels of the tumor suppressor, p16/INK4A. Of note, lentiviral‑mediated continuous JARID1B depletion resulted in the loss of epithelial differentiation and suppressed CRC cell growth, which was associated with the induction of phosphorylation by the c‑Jun N‑terminal kinase (Jnk/Sapk) and senescence‑associated β‑galactosidase activity. Moreover, green fluorescent‑labeled cell tracking indicated that JARID1B‑positive CRC cells had greater tumorigenicity than JARID1B‑negative CRC cells after their subcutaneous inoculation into immunodeficient mice, although JARID1B‑negative CRC cells resumed normal growth after a month, suggesting that continuous JARID1B inhibition is necessary for tumor eradication. Thus, JARID1B plays a role in CRC maintenance. JARID1B may be a novel molecular target for therapy‑resistant cancer cells by the induction of cellular senescence.