{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,23]],"date-time":"2026-07-23T16:20:22Z","timestamp":1784823622586,"version":"3.55.0"},"reference-count":158,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T00:00:00Z","timestamp":1775520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>The emergence of novel cytotoxic agents, multikinase inhibitors, and various antibody-based therapies has significantly expanded salvage therapy options for metastatic colorectal cancer (mCRC). Consequently, establishing the optimal treatment sequence for patients has become a formidable clinical challenge. Emerging evidence highlights the value of comprehensive biomarker assessment, particularly longitudinal monitoring of circulating tumor DNA (ctDNA), to capture dynamic molecular changes during treatment. Liquid biopsy-based technologies now enable real-time tracking of molecular alterations, supporting truly personalized therapeutic decision-making. Furthermore, prior treatment exposure and residual toxicities must be carefully considered to balance efficacy, safety, and quality of life. This review provides a comprehensive overview of the current salvage-line landscape for mCRC, discusses the clinical utility of ctDNA as a predictive and prognostic tool, and proposes integrated strategies to optimize therapeutic outcomes in the evolving era of precision medicine.<\/jats:p>","DOI":"10.3390\/biom16040543","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T12:03:47Z","timestamp":1775563427000},"page":"543","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["A New Era of Salvage-Line Treatment for Metastatic Colorectal Cancer: The Role and Clinical Significance of Circulating Tumor DNA"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-8220-0282","authenticated-orcid":false,"given":"Eiichiro","family":"Toyokawa","sequence":"first","affiliation":[{"name":"Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akira","family":"Ooki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7448-5894","authenticated-orcid":false,"given":"Eiji","family":"Shinozaki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaoru","family":"Yoshikawa","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keito","family":"Suzuki","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manabu","family":"Shiozawa","sequence":"additional","affiliation":[{"name":"Department of Colorectal Surgery, Kanagawa Cancer Center, Yokohama 241-8515, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0246-1594","authenticated-orcid":false,"given":"Shin","family":"Maeda","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Yokohama City University, Yokohama 236-0004, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6887-5709","authenticated-orcid":false,"given":"Kensei","family":"Yamaguchi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4742-0446","authenticated-orcid":false,"given":"Hiroki","family":"Osumi","sequence":"additional","affiliation":[{"name":"Department of Gastroenterological Chemotherapy, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo 135-8550, Japan"},{"name":"Department of Gastroenterology, Kanagawa Cancer Center, Yokohama 241-8515, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"487","DOI":"10.1038\/nrc3298","article-title":"Evolutionary Dynamics of Carcinogenesis and Why Targeted Therapy Does Not Work","volume":"12","author":"Gillies","year":"2012","journal-title":"Nat. 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