{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T11:23:56Z","timestamp":1783596236483,"version":"3.55.0"},"reference-count":31,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"},{"start":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T00:00:00Z","timestamp":1783555200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springernature.com\/gp\/researchers\/text-and-data-mining"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Gastrointest Canc"],"DOI":"10.1007\/s12029-026-01524-9","type":"journal-article","created":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:48:08Z","timestamp":1783594088000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Treatment Selection Beyond Second Line in Metastatic Colorectal Cancer: Practical Sequencing of Cytotoxic Salvage Therapy, Anti-angiogenic Agents, Rechallenge Strategies, and Biomarker-Guided Treatments"],"prefix":"10.1007","volume":"57","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1994-4795","authenticated-orcid":false,"given":"Tamotsu","family":"Sagawa","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Nagashima","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Koshi","family":"Fujikawa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,7,9]]},"reference":[{"key":"1524_CR1","doi-asserted-by":"publisher","first-page":"303","DOI":"10.1016\/S0140-6736(12)61900-X","volume":"381","author":"A Grothey","year":"2013","unstructured":"Grothey A, Van Cutsem E, Sobrero A, et al. Regorafenib monotherapy for previously treated metastatic colorectal cancer: an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet. 2013;381:303\u201312. https:\/\/doi.org\/10.1016\/S0140-6736(12)61900-X.","journal-title":"Lancet"},{"key":"1524_CR2","doi-asserted-by":"publisher","first-page":"619","DOI":"10.1016\/S1470-2045(15)70156-7","volume":"16","author":"J Li","year":"2015","unstructured":"Li J, Qin S, Xu R, et al. Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer: the CONCUR randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2015;16:619\u201329. https:\/\/doi.org\/10.1016\/S1470-2045(15)70156-7.","journal-title":"Lancet Oncol"},{"key":"1524_CR3","doi-asserted-by":"publisher","first-page":"1070","DOI":"10.1016\/S1470-2045(19)30272-4","volume":"20","author":"TS Bekaii-Saab","year":"2019","unstructured":"Bekaii-Saab TS, Ou FS, Ahn DH, et al. Regorafenib dose-optimisation in patients with refractory metastatic colorectal cancer: ReDOS, a randomised, multicentre, open-label, phase 2 study. Lancet Oncol. 2019;20:1070\u201382. https:\/\/doi.org\/10.1016\/S1470-2045(19)30272-4.","journal-title":"Lancet Oncol"},{"key":"1524_CR4","doi-asserted-by":"publisher","first-page":"1909","DOI":"10.1056\/NEJMoa1414325","volume":"372","author":"RJ Mayer","year":"2015","unstructured":"Mayer RJ, Van Cutsem E, Falcone A, et al. Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med. 2015;372:1909\u201319. https:\/\/doi.org\/10.1056\/NEJMoa1414325.","journal-title":"N Engl J Med"},{"key":"1524_CR5","doi-asserted-by":"publisher","first-page":"1657","DOI":"10.1056\/NEJMoa2214963","volume":"388","author":"GW Prager","year":"2023","unstructured":"Prager GW, Taieb J, Fakih M, et al. Trifluridine-tipiracil and bevacizumab in refractory metastatic colorectal cancer. N Engl J Med. 2023;388:1657\u201367. https:\/\/doi.org\/10.1056\/NEJMoa2214963.","journal-title":"N Engl J Med"},{"key":"1524_CR6","doi-asserted-by":"publisher","first-page":"2486","DOI":"10.1001\/jama.2018.7855","volume":"319","author":"J Li","year":"2018","unstructured":"Li J, Qin S, Xu RH, et al. Effect of fruquintinib vs placebo on overall survival in patients with previously treated metastatic colorectal cancer: the FRESCO randomized clinical trial. JAMA. 2018;319:2486\u201396. https:\/\/doi.org\/10.1001\/jama.2018.7855.","journal-title":"JAMA"},{"key":"1524_CR7","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1016\/S0140-6736(23)00772-9","volume":"402","author":"A Dasari","year":"2023","unstructured":"Dasari A, Lonardi S, Garcia-Carbonero R, et al. Fruquintinib versus placebo in patients with refractory metastatic colorectal cancer: FRESCO-2, an international, multicentre, randomised, double-blind, phase 3 study. Lancet. 2023;402:41\u201353. https:\/\/doi.org\/10.1016\/S0140-6736(23)00772-9.","journal-title":"Lancet"},{"key":"1524_CR8","doi-asserted-by":"publisher","first-page":"1632","DOI":"10.1056\/NEJMoa1908075","volume":"381","author":"S Kopetz","year":"2019","unstructured":"Kopetz S, Grothey A, Yaeger R, et al. Encorafenib, binimetinib, and cetuximab in BRAF V600E-mutated colorectal cancer. N Engl J Med. 2019;381:1632\u201343. https:\/\/doi.org\/10.1056\/NEJMoa1908075.","journal-title":"N Engl J Med"},{"key":"1524_CR9","doi-asserted-by":"publisher","first-page":"273","DOI":"10.1200\/JCO.20.02088","volume":"39","author":"J Tabernero","year":"2021","unstructured":"Tabernero J, Grothey A, Van Cutsem E, et al. Encorafenib plus cetuximab as a new standard of care for previously treated BRAF V600E-mutant metastatic colorectal cancer: updated survival results and subgroup analyses from the BEACON study. J Clin Oncol. 2021;39:273\u201384. https:\/\/doi.org\/10.1200\/JCO.20.02088.","journal-title":"J Clin Oncol"},{"key":"1524_CR10","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2501912","author":"E Elez","year":"2025","unstructured":"Elez E, Yoshino T, Sobrero AF, et al. Encorafenib, cetuximab, and mFOLFOX6 in BRAF-mutated metastatic colorectal cancer. N Engl J Med. 2025. https:\/\/doi.org\/10.1056\/NEJMoa2501912.","journal-title":"N Engl J Med"},{"key":"1524_CR11","doi-asserted-by":"publisher","first-page":"2125","DOI":"10.1056\/NEJMoa2308795","volume":"389","author":"MG Fakih","year":"2023","unstructured":"Fakih MG, Salvatore L, Esaki T, et al. Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. N Engl J Med. 2023;389:2125\u201339. https:\/\/doi.org\/10.1056\/NEJMoa2308795.","journal-title":"N Engl J Med"},{"key":"1524_CR12","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1056\/NEJMoa2212419","volume":"388","author":"R Yaeger","year":"2023","unstructured":"Yaeger R, Uboha NV, Pelster MS, et al. Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med. 2023;388:44\u201354. https:\/\/doi.org\/10.1056\/NEJMoa2212419.","journal-title":"N Engl J Med"},{"key":"1524_CR13","doi-asserted-by":"publisher","first-page":"982","DOI":"10.1158\/2159-8290.CD-23-1467","volume":"14","author":"R Yaeger","year":"2024","unstructured":"Yaeger R, Weiss J, Pelster MS, et al. Efficacy and safety of adagrasib plus cetuximab in patients with KRAS G12C-mutated metastatic colorectal cancer. Cancer Discov. 2024;14:982\u201393. https:\/\/doi.org\/10.1158\/2159-8290.CD-23-1467.","journal-title":"Cancer Discov"},{"key":"1524_CR14","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1016\/S1470-2045(16)00150-9","volume":"17","author":"A Sartore-Bianchi","year":"2016","unstructured":"Sartore-Bianchi A, Trusolino L, Martino C, et al. Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12\/13 wild-type, HER2-positive metastatic colorectal cancer: the HERACLES trial. Lancet Oncol. 2016;17:738\u201346. https:\/\/doi.org\/10.1016\/S1470-2045(16)00150-9.","journal-title":"Lancet Oncol"},{"key":"1524_CR15","doi-asserted-by":"publisher","first-page":"496","DOI":"10.1016\/S1470-2045(23)00150-X","volume":"24","author":"JH Strickler","year":"2023","unstructured":"Strickler JH, Cercek A, Siena S, et al. Tucatinib plus trastuzumab for chemotherapy-refractory, HER2-positive, RAS wild-type unresectable or metastatic colorectal cancer: MOUNTAINEER, a multicentre, open-label, phase 2b study. Lancet Oncol. 2023;24:496\u2013508. https:\/\/doi.org\/10.1016\/S1470-2045(23)00150-X.","journal-title":"Lancet Oncol"},{"key":"1524_CR16","doi-asserted-by":"publisher","first-page":"2207","DOI":"10.1056\/NEJMoa2017699","volume":"383","author":"T Andre","year":"2020","unstructured":"Andre T, Shiu KK, Kim TW, et al. Pembrolizumab in microsatellite-instability-high advanced colorectal cancer. N Engl J Med. 2020;383:2207\u201318. https:\/\/doi.org\/10.1056\/NEJMoa2017699.","journal-title":"N Engl J Med"},{"key":"1524_CR17","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1016\/S1470-2045(22)00197-8","volume":"23","author":"T Andre","year":"2022","unstructured":"Andre T, Shiu KK, Kim TW, et al. Pembrolizumab versus chemotherapy in microsatellite instability-high or mismatch repair-deficient metastatic colorectal cancer: final analysis of KEYNOTE-177. Lancet Oncol. 2022;23:659\u201370. https:\/\/doi.org\/10.1016\/S1470-2045(22)00197-8.","journal-title":"Lancet Oncol"},{"key":"1524_CR18","doi-asserted-by":"publisher","first-page":"773","DOI":"10.1200\/JCO.2017.76.9901","volume":"36","author":"MJ Overman","year":"2018","unstructured":"Overman MJ, Lonardi S, Wong KYM, et al. Durable clinical benefit with nivolumab plus ipilimumab in DNA mismatch repair-deficient\/microsatellite instability-high metastatic colorectal cancer. J Clin Oncol. 2018;36:773\u20139. https:\/\/doi.org\/10.1200\/JCO.2017.76.9901.","journal-title":"J Clin Oncol"},{"key":"1524_CR19","doi-asserted-by":"publisher","first-page":"161","DOI":"10.1200\/JCO.21.01015","volume":"40","author":"HJ Lenz","year":"2022","unstructured":"Lenz HJ, Van Cutsem E, Luisa Limon M, et al. First-line nivolumab plus low-dose ipilimumab for microsatellite instability-high\/mismatch repair-deficient metastatic colorectal cancer: the phase II CheckMate 142 study. J Clin Oncol. 2022;40:161\u201370. https:\/\/doi.org\/10.1200\/JCO.21.01015.","journal-title":"J Clin Oncol"},{"key":"1524_CR20","doi-asserted-by":"publisher","first-page":"588","DOI":"10.1016\/j.annonc.2024.04.005","volume":"35","author":"MF Mosele","year":"2024","unstructured":"Mosele MF, Remon J, Mateo J, et al. Recommendations for the use of next-generation sequencing for patients with advanced cancer in 2024: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2024;35:588\u2013606. https:\/\/doi.org\/10.1016\/j.annonc.2024.04.005.","journal-title":"Ann Oncol"},{"key":"1524_CR21","doi-asserted-by":"publisher","first-page":"1491","DOI":"10.1016\/j.annonc.2020.07.014","volume":"31","author":"F Mosele","year":"2020","unstructured":"Mosele F, Remon J, Mateo J, et al. Recommendations for the use of next-generation sequencing for patients with metastatic cancers: a report from the ESMO Precision Medicine Working Group. Ann Oncol. 2020;31:1491\u2013505. https:\/\/doi.org\/10.1016\/j.annonc.2020.07.014.","journal-title":"Ann Oncol"},{"key":"1524_CR22","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1001\/jamaoncol.2018.5080","volume":"5","author":"C Cremolini","year":"2019","unstructured":"Cremolini C, Rossini D, Dell\u2019Aquila E, et al. Rechallenge for patients with RAS and BRAF wild-type metastatic colorectal cancer with acquired resistance to first-line cetuximab and irinotecan: the phase 2 CRICKET study. JAMA Oncol. 2019;5:343\u201350. https:\/\/doi.org\/10.1001\/jamaoncol.2018.5080.","journal-title":"JAMA Oncol"},{"key":"1524_CR23","doi-asserted-by":"publisher","first-page":"1612","DOI":"10.1038\/s41591-022-01886-0","volume":"28","author":"A Sartore-Bianchi","year":"2022","unstructured":"Sartore-Bianchi A, Pietrantonio F, Lonardi S, et al. Circulating tumor DNA to guide rechallenge with panitumumab in metastatic colorectal cancer: the phase 2 CHRONOS trial. Nat Med. 2022;28:1612\u20138. https:\/\/doi.org\/10.1038\/s41591-022-01886-0.","journal-title":"Nat Med"},{"key":"1524_CR24","doi-asserted-by":"publisher","first-page":"e245635","DOI":"10.1001\/jamanetworkopen.2024.5635","volume":"7","author":"D Ciardiello","year":"2024","unstructured":"Ciardiello D, Martinelli E, Famiglietti V, et al. Anti-EGFR rechallenge in patients with refractory ctDNA RAS\/BRAF wild-type metastatic colorectal cancer: a nonrandomized controlled trial. JAMA Netw Open. 2024;7:e245635. https:\/\/doi.org\/10.1001\/jamanetworkopen.2024.5635.","journal-title":"JAMA Netw Open"},{"key":"1524_CR25","doi-asserted-by":"publisher","first-page":"1057","DOI":"10.1111\/cas.15252","volume":"113","author":"K Ouchi","year":"2022","unstructured":"Ouchi K, Takahashi S, Okita A, et al. A modified MethyLight assay predicts the clinical outcomes of anti-epidermal growth factor receptor treatment in metastatic colorectal cancer. Cancer Sci. 2022;113:1057\u201368. https:\/\/doi.org\/10.1111\/cas.15252.","journal-title":"Cancer Sci"},{"key":"1524_CR26","doi-asserted-by":"publisher","first-page":"1439","DOI":"10.1007\/s00384-022-04177-9","volume":"37","author":"H Osumi","year":"2022","unstructured":"Osumi H, Shinozaki E, Takeda Y, et al. Effect of DNA methylation status on first-line anti-epidermal growth factor receptor treatment in patients with metastatic colorectal cancer. Int J Colorectal Dis. 2022;37:1439\u201347. PMID:35612620.","journal-title":"Int J Colorectal Dis"},{"key":"1524_CR27","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1007\/s00384-024-04659-y","volume":"39","author":"K Ouchi","year":"2024","unstructured":"Ouchi K, Takahashi S, Okita A, et al. Genome-wide DNA methylation status is a predictor of the efficacy of anti-EGFR antibodies in the second-line treatment of metastatic colorectal cancer. Int J Colorectal Dis. 2024;39:88. https:\/\/doi.org\/10.1007\/s00384-024-04659-y.","journal-title":"Int J Colorectal Dis"},{"key":"1524_CR28","unstructured":"Tohoku University. DNA methylation detection kit. \u2018OncoGuide EpiLight Methylation Detection Kit\u2019 obtained regulatory approval in Japan. Published June 26, 2024. Accessed May 6, 2026. https:\/\/www.tohoku.ac.jp\/japanese\/2024\/06\/press20240626-01-DNA.html"},{"key":"1524_CR29","unstructured":"Tohoku University Graduate School of Medicine. DNA methylation detection kit. \u2018OncoGuide EpiLight Methylation Detection Kit\u2019 approved for insurance coverage in Japan. Published June 2, 2025. Accessed May 6, 2026. https:\/\/www.life.med.tohoku.ac.jp\/newsroom\/press\/34536\/"},{"key":"1524_CR30","doi-asserted-by":"publisher","first-page":"731","DOI":"10.1056\/NEJMoa1714448","volume":"378","author":"A Drilon","year":"2018","unstructured":"Drilon A, Laetsch TW, Kummar S, et al. Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children. N Engl J Med. 2018;378:731\u20139. https:\/\/doi.org\/10.1056\/NEJMoa1714448.","journal-title":"N Engl J Med"},{"key":"1524_CR31","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/S1470-2045(19)30691-6","volume":"21","author":"RC Doebele","year":"2020","unstructured":"Doebele RC, Drilon A, Paz-Ares L, et al. Entrectinib in patients with advanced or metastatic NTRK fusion-positive solid tumours: integrated analysis of three phase 1\u20132 trials. Lancet Oncol. 2020;21:271\u201382. https:\/\/doi.org\/10.1016\/S1470-2045(19)30691-6.","journal-title":"Lancet Oncol"}],"container-title":["Journal of Gastrointestinal Cancer"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12029-026-01524-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s12029-026-01524-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s12029-026-01524-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,9]],"date-time":"2026-07-09T10:48:10Z","timestamp":1783594090000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s12029-026-01524-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,9]]},"references-count":31,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1524"],"URL":"https:\/\/doi.org\/10.1007\/s12029-026-01524-9","relation":{},"ISSN":["1941-6636"],"issn-type":[{"value":"1941-6636","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,9]]},"assertion":[{"value":"6 May 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"1 July 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 July 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics approval"}},{"value":"Not applicable.","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent to participate"}},{"value":"Not applicable.","order":4,"name":"Ethics","group":{"name":"EthicsHeading","label":"Consent for Publication"}},{"value":"The authors declare no competing interests.","order":5,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"151"}}