{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T04:58:56Z","timestamp":1781240336925,"version":"3.54.1"},"reference-count":34,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T00:00:00Z","timestamp":1781222400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Treatment options for refractory metastatic colorectal cancer remain limited, and no biomarkers predict fruquintinib benefit before imaging. This study evaluated whether early dynamics of circulating tumor DNA predict efficacy and prognosis during fruquintinib treatment.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This single-center prospective cohort study enrolled patients with refractory metastatic colorectal cancer receiving fruquintinib 5 mg daily. Blood was collected at baseline, day 14, and day 28 for circulating tumor DNA testing using high-depth panel sequencing with clonal hematopoiesis filtering. Based on the day-28 maximum variant allele frequency change from baseline, patients were categorized as clearance, decrease, stable, or increase. Progression-free and overall survival were evaluated using day-28 landmark analysis. Multivariable regression models adjusted for nine clinical covariates assessed disease control rate and progression-free survival. Model performance was evaluated using Harrell's C-index, time-dependent receiver operating characteristic (ROC), bootstrap validation, and sensitivity analyses.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Among 120 enrolled patients, 107 completed day-28 circulating tumor DNA testing. Day-28 dynamics showed clearance in 17.8% and a decrease in 43.9%. Compared with stable\/increase, the clearance and decrease groups had higher disease control rates (adjusted odds ratios, 6.92 and 3.45; both\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.01) and lower progression risk (adjusted hazard ratios, 0.41 and 0.62; both\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.05). Adding circulating tumor DNA stratification improved model discrimination for progression-free survival (\u0394C-index = 0.07) and overall survival (\u0394C-index = 0.06). Areas under the curve for 3-month and 6-month progression-free survival were 0.73 and 0.68. Sensitivity analyses confirmed robustness across alternative thresholds (hazard ratio range, 0.49\u20130.61; all\n                      <jats:italic>P<\/jats:italic>\n                      &amp;lt; 0.01). Common adverse events included hypertension (46.7%), hand-foot skin reaction (40.8%), and fatigue (36.7%), with acceptable tolerability.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Day-28 circulating tumor DNA dynamics predict efficacy and survival during fruquintinib treatment and enhance clinical model performance. However, the modest discriminative performance (C-index 0.69) indicates that prospective validation is required before clinical implementation. These findings support further investigation of ctDNA-guided risk stratification in refractory metastatic colorectal cancer.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fmed.2026.1833355","type":"journal-article","created":{"date-parts":[[2026,6,12]],"date-time":"2026-06-12T04:41:45Z","timestamp":1781239305000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Early circulating tumor DNA dynamics predict fruquintinib efficacy in refractory metastatic colorectal cancer before imaging"],"prefix":"10.3389","volume":"13","author":[{"given":"Hebin","family":"Hou","sequence":"first","affiliation":[{"name":"Department of Gastroenterology, Tengzhou Central People's Hospital, Tengzhou","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pingping","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Tengzhou Central People's Hospital, Tengzhou","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohuan","family":"Dong","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Tengzhou Central People's Hospital, Tengzhou","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Gai","sequence":"additional","affiliation":[{"name":"Department of Gastroenterology, Tengzhou Central People's Hospital, Tengzhou","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peng","family":"Jiang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Tengzhou Central People's Hospital, Tengzhou","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[{"name":"Department of Oncology, Tengzhou Central People's Hospital, Tengzhou","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chongli","family":"Hao","sequence":"additional","affiliation":[{"name":"Department of Oncology, Tengzhou Central People's Hospital, Tengzhou","place":["Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,6,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"62","DOI":"10.1055\/s-0043-1761420","article-title":"Effectiveness of standard treatment for stage 4 colorectal cancer: traditional management with surgery, radiation, and chemotherapy","volume":"37","author":"Feria","year":"2023","journal-title":"Clin Colon Rectal Surg."},{"key":"B2","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.annonc.2022.10.003","article-title":"Metastatic colorectal cancer: ESMO clinical practice guideline for diagnosis, treatment and follow-up","volume":"34","author":"Cremolini","year":"2023","journal-title":"Ann Oncol."},{"key":"B3","doi-asserted-by":"publisher","first-page":"165","DOI":"10.1016\/j.clcc.2020.04.003","article-title":"Current options for third-line and beyond treatment of metastatic colorectal cancer. 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