{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,14]],"date-time":"2026-10-14T04:47:55Z","timestamp":1791953275399,"version":"4.3.4"},"reference-count":108,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T00:00:00Z","timestamp":1790812800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Background: The therapeutic landscape of refractory metastatic colorectal cancer (mCRC) has expanded with antiangiogenic agents, cytotoxic therapies, immunotherapy, and biomarker-driven treatments. Randomized clinical trials (RCTs) establish efficacy and safety, while real-world evidence (RWE) can complement them by addressing generalizability, treatment delivery, safety, and outcomes in populations underrepresented in prospective studies. This narrative review examines the contribution and limitations of RWE in precision oncology and later-line therapeutic sequencing in mCRC. Methods: We reviewed evidence from randomized trials, observational studies, real-world registries, translational research, and contemporary international guidance, focusing on later-line antiangiogenic strategies, trifluridine\/tipiracil-based treatment, fruquintinib, anti-EGFR rechallenge, immunotherapy in MSI-H\/dMMR disease, and targeted therapies for actionable molecular alterations. Particular attention was given to RWE methodology and interpretation. Results: RWE complements randomized evidence by characterizing effectiveness and toxicity in heterogeneous populations, treatment delivery and dose modification, and implementation of biomarker-guided strategies in routine practice. Observational studies may also inform therapeutic sequencing and identify prognostic or pharmacodynamic correlates, although causal interpretation is limited by selection bias, treatment attrition, time-dependent and residual confounding. Longitudinal circulating tumor DNA (ctDNA) assessment is particularly relevant to molecular reassessment and anti-EGFR rechallenge, while broader ctDNA-guided adaptive treatment strategies remain investigational. Conclusions: Later-line mCRC management increasingly integrates molecular profiling, treatment history, patient fitness, toxicity, and therapeutic sequencing. High-quality RWE provides complementary evidence on how these strategies perform and are implemented in routine practice but should be interpreted according to study design and susceptibility to bias. Integration of rigorous RWE with randomized and prospective molecular evidence may help bridge the gap between trial efficacy and real-world effectiveness and support individualized later-line care.<\/jats:p>","DOI":"10.3390\/cancers18193174","type":"journal-article","created":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T18:43:24Z","timestamp":1790880204000},"page":"3174","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Real-World Evidence as a Driver of Precision Oncology and Personalized Therapeutic Sequencing in Later-Line Metastatic Colorectal Cancer"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9710-4962","authenticated-orcid":false,"given":"Carlo","family":"Signorelli","sequence":"first","affiliation":[{"name":"Medical Oncology Unit, Santa Rosa Hospital, Azienda Sanitaria Locale Viterbo, 01100 Viterbo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,10,1]]},"reference":[{"key":"ref_1","first-page":"229","article-title":"Global cancer statistics 2022: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries","volume":"74","author":"Bray","year":"2024","journal-title":"CA Cancer J. 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