Julian Hamfjord, Tormod Kyrre Guren, Bengt Glimelius, Halfdan Sorbye, Per Pfeiffer, Olav Dajani, Ole Christian Lingjærde, Kjell Magne Tveit, Karen-Lise Garm Spindler, Niels Pallisgaard, Elin H Kure
{"title":"探讨RAS-/ braf突变的转移性结直肠癌患者CEA、ctDNA和cfDNA的早期动力学特征","authors":"Julian Hamfjord, Tormod Kyrre Guren, Bengt Glimelius, Halfdan Sorbye, Per Pfeiffer, Olav Dajani, Ole Christian Lingjærde, Kjell Magne Tveit, Karen-Lise Garm Spindler, Niels Pallisgaard, Elin H Kure","doi":"10.1016/j.clcc.2024.11.004","DOIUrl":null,"url":null,"abstract":"<p><strong>Introduction: </strong>Patients with metastatic colorectal cancer (mCRC) respond differently to first-line chemotherapy. Early identification of patients with limited or no clinical benefit could prompt a timelier introduction of second-line therapy and potentially lead to improved overall outcomes. Carcinoembryonic antigen (CEA) is currently the only blood-based marker in clinical use for disease control monitoring in mCRC. Circulating cell-free DNA (cfDNA), including circulating tumor DNA (ctDNA) could become a useful surrogate for oncological outcomes.</p><p><strong>Materials and methods: </strong>Forty patients with RAS-/BRAF-mutated mCRC from the prospective NORDIC-VII trial (NCT00145314) were included. An exploratory model system was made to describe the early on-treatment kinetics of CEA, cfDNA and ctDNA during first-line oxaliplatin-based chemotherapy, and investigate the associations with radiological response, progression-free survival (PFS) and overall survival (OS).</p><p><strong>Results: </strong>Summary metrics were made, representing percentage change from treatment start to time-grid day 7 (P<sub>7</sub>), day 14 (P<sub>14</sub>), and day 49 (P<sub>49</sub>); slope from time-grid day 0 to 7 (S<sub>7</sub>), day 8 to 14 (S<sub>14</sub>), and day 15 to 49 (S<sub>49</sub>); and area under the curve from time-grid day 0 to 49 (AUC). Notably P<sub>49</sub> and S<sub>49</sub> for ctDNA and CEA were associated with radiological response and/or PFS. The early dynamics of the two markers differed substantially, with faster and more marked changes in ctDNA compared with CEA. Nine patients did not reach complete/near complete molecular ctDNA response close to first evaluation (∼week 8), a state associated with a short PFS (HR 2.72; 95% CI, 1.22-6.06; P = .01) and OS (HR 3.12; 95% CI, 1.35-7.23; P < .01). Contrary, twenty-two patients did not reach radiological response (i.e., complete or partial response) at first evaluation, but this was not associated with PFS (HR 1.21; 95% CI, 0.64-2.30; P = .55) nor OS (HR 1.37; 95% CI, 0.70-2.68; P = .37).</p><p><strong>Conclusion: </strong>Early dynamics of ctDNA during first-line oxaliplatin-based chemotherapy hold prognostic value, supporting the idea of prospectively validating a ctDNA-RECIST framework in the early care pathway of mCRC patients.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT00145314.</p>","PeriodicalId":93939,"journal":{"name":"Clinical colorectal cancer","volume":" ","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-12-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Exploring Early Kinetic Profiles of CEA, ctDNA and cfDNA in Patients With RAS-/BRAF-Mutated Metastatic Colorectal Cancer.\",\"authors\":\"Julian Hamfjord, Tormod Kyrre Guren, Bengt Glimelius, Halfdan Sorbye, Per Pfeiffer, Olav Dajani, Ole Christian Lingjærde, Kjell Magne Tveit, Karen-Lise Garm Spindler, Niels Pallisgaard, Elin H Kure\",\"doi\":\"10.1016/j.clcc.2024.11.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Introduction: </strong>Patients with metastatic colorectal cancer (mCRC) respond differently to first-line chemotherapy. Early identification of patients with limited or no clinical benefit could prompt a timelier introduction of second-line therapy and potentially lead to improved overall outcomes. Carcinoembryonic antigen (CEA) is currently the only blood-based marker in clinical use for disease control monitoring in mCRC. Circulating cell-free DNA (cfDNA), including circulating tumor DNA (ctDNA) could become a useful surrogate for oncological outcomes.</p><p><strong>Materials and methods: </strong>Forty patients with RAS-/BRAF-mutated mCRC from the prospective NORDIC-VII trial (NCT00145314) were included. An exploratory model system was made to describe the early on-treatment kinetics of CEA, cfDNA and ctDNA during first-line oxaliplatin-based chemotherapy, and investigate the associations with radiological response, progression-free survival (PFS) and overall survival (OS).</p><p><strong>Results: </strong>Summary metrics were made, representing percentage change from treatment start to time-grid day 7 (P<sub>7</sub>), day 14 (P<sub>14</sub>), and day 49 (P<sub>49</sub>); slope from time-grid day 0 to 7 (S<sub>7</sub>), day 8 to 14 (S<sub>14</sub>), and day 15 to 49 (S<sub>49</sub>); and area under the curve from time-grid day 0 to 49 (AUC). Notably P<sub>49</sub> and S<sub>49</sub> for ctDNA and CEA were associated with radiological response and/or PFS. The early dynamics of the two markers differed substantially, with faster and more marked changes in ctDNA compared with CEA. Nine patients did not reach complete/near complete molecular ctDNA response close to first evaluation (∼week 8), a state associated with a short PFS (HR 2.72; 95% CI, 1.22-6.06; P = .01) and OS (HR 3.12; 95% CI, 1.35-7.23; P < .01). Contrary, twenty-two patients did not reach radiological response (i.e., complete or partial response) at first evaluation, but this was not associated with PFS (HR 1.21; 95% CI, 0.64-2.30; P = .55) nor OS (HR 1.37; 95% CI, 0.70-2.68; P = .37).</p><p><strong>Conclusion: </strong>Early dynamics of ctDNA during first-line oxaliplatin-based chemotherapy hold prognostic value, supporting the idea of prospectively validating a ctDNA-RECIST framework in the early care pathway of mCRC patients.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT00145314.</p>\",\"PeriodicalId\":93939,\"journal\":{\"name\":\"Clinical colorectal cancer\",\"volume\":\" \",\"pages\":\"\"},\"PeriodicalIF\":0.0000,\"publicationDate\":\"2024-12-03\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Clinical colorectal cancer\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.clcc.2024.11.004\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"\",\"JCRName\":\"\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Clinical colorectal cancer","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.clcc.2024.11.004","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
Exploring Early Kinetic Profiles of CEA, ctDNA and cfDNA in Patients With RAS-/BRAF-Mutated Metastatic Colorectal Cancer.
Introduction: Patients with metastatic colorectal cancer (mCRC) respond differently to first-line chemotherapy. Early identification of patients with limited or no clinical benefit could prompt a timelier introduction of second-line therapy and potentially lead to improved overall outcomes. Carcinoembryonic antigen (CEA) is currently the only blood-based marker in clinical use for disease control monitoring in mCRC. Circulating cell-free DNA (cfDNA), including circulating tumor DNA (ctDNA) could become a useful surrogate for oncological outcomes.
Materials and methods: Forty patients with RAS-/BRAF-mutated mCRC from the prospective NORDIC-VII trial (NCT00145314) were included. An exploratory model system was made to describe the early on-treatment kinetics of CEA, cfDNA and ctDNA during first-line oxaliplatin-based chemotherapy, and investigate the associations with radiological response, progression-free survival (PFS) and overall survival (OS).
Results: Summary metrics were made, representing percentage change from treatment start to time-grid day 7 (P7), day 14 (P14), and day 49 (P49); slope from time-grid day 0 to 7 (S7), day 8 to 14 (S14), and day 15 to 49 (S49); and area under the curve from time-grid day 0 to 49 (AUC). Notably P49 and S49 for ctDNA and CEA were associated with radiological response and/or PFS. The early dynamics of the two markers differed substantially, with faster and more marked changes in ctDNA compared with CEA. Nine patients did not reach complete/near complete molecular ctDNA response close to first evaluation (∼week 8), a state associated with a short PFS (HR 2.72; 95% CI, 1.22-6.06; P = .01) and OS (HR 3.12; 95% CI, 1.35-7.23; P < .01). Contrary, twenty-two patients did not reach radiological response (i.e., complete or partial response) at first evaluation, but this was not associated with PFS (HR 1.21; 95% CI, 0.64-2.30; P = .55) nor OS (HR 1.37; 95% CI, 0.70-2.68; P = .37).
Conclusion: Early dynamics of ctDNA during first-line oxaliplatin-based chemotherapy hold prognostic value, supporting the idea of prospectively validating a ctDNA-RECIST framework in the early care pathway of mCRC patients.
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