Evaluation of circulating tumor DNA as a prognostic and predictive biomarker in BRAF V600E mutated colorectal cancer—results from the FIRE‐4.5 study
The randomized FIRE‐4.5 (AIO KRK0116) trial compared first‐line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B‐Raf proto‐oncogene, serine/threonine kinase (BRAF) V600E‐mutant metastatic colorectal cancer (mCRC) patients. Thi...
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Wiley
2025-02-01
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| Series: | Molecular Oncology |
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| Online Access: | https://doi.org/10.1002/1878-0261.13778 |
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| author | Susanne Klein‐Scory Alexander Baraniskin Wolff Schmiegel Thomas Mika Roland Schroers Swantje Held Kathrin Heinrich David Tougeron Dominik P. Modest Ingo Schwaner Jan Eucker Rudolf Pihusch Martina Stauch Florian Kaiser Christoph Kahl Meinolf Karthaus Christian Müller Christof Burkart Sebastian Stintzing Volker Heinemann |
| author_facet | Susanne Klein‐Scory Alexander Baraniskin Wolff Schmiegel Thomas Mika Roland Schroers Swantje Held Kathrin Heinrich David Tougeron Dominik P. Modest Ingo Schwaner Jan Eucker Rudolf Pihusch Martina Stauch Florian Kaiser Christoph Kahl Meinolf Karthaus Christian Müller Christof Burkart Sebastian Stintzing Volker Heinemann |
| author_sort | Susanne Klein‐Scory |
| collection | DOAJ |
| description | The randomized FIRE‐4.5 (AIO KRK0116) trial compared first‐line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B‐Raf proto‐oncogene, serine/threonine kinase (BRAF) V600E‐mutant metastatic colorectal cancer (mCRC) patients. This study was accompanied by a prospective translational project analyzing cell‐free circulating tumor DNA (ctDNA) in plasma to test whether ctDNA analysis may help to guide clinical treatment decision making. FIRE‐4.5 included mCRC patients with BRAF V600E mutation detected by tissue‐based analyses. Liquid biopsies (LBs) were collected at baseline (pre‐treatment) and during therapy. Digital droplet PCR (ddPCR) technology was applied for determination of BRAF mutations and the in vitro diagnostics (IVD)‐certified ONCOBEAM RAS procedure for analysis of RAS mutations. The BRAF V600E variants in ctDNA were analyzable in 66 patients at start of the therapy, at baseline. No BRAF V600E mutations were detected in 26% (17/66) of patients and was associated with a significantly longer progression‐free survival (PFS: 13.2 vs 6.5 months; HR 0.47; P = 0.014) and overall survival (OS: 36.8 vs 13.2 months; HR 0.35; P = 0.02) as compared to ctDNA mutant patients. Patients with detectable BRAF mutations showed a clear superiority of FOLFOXIRI plus bevacizumab with regard to PFS (10.4 vs 5.7 months; HR 0.4; P = 0.009) and OS (16.6 vs 11.6 months; HR 0.5; P = 0.15), while this was not the case for BRAF wild‐type patients. Follow‐up LBs were obtained from 51 patients. Patients converting from BRAF V600E mutant to a BRAF V600 wild‐type status (36%, N = 18) had a superior PFS (8.6 vs 2.3 months; P = 0.0002) and OS (17.4 vs 5.1 months; P < 0.0001) compared to patients with stable or increased mutational allele frequency (12%, N = 6). Those patients also achieved a significantly greater disease control rate (89% vs 20%; P = 0.008). In conclusion, LB evaluating ctDNA is informative and may help to guide treatment in patients with BRAF V600E‐mutated mCRC. |
| format | Article |
| id | doaj-art-361aa8379bc94d739a95b0c6e7f8b223 |
| institution | Kabale University |
| issn | 1574-7891 1878-0261 |
| language | English |
| publishDate | 2025-02-01 |
| publisher | Wiley |
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| series | Molecular Oncology |
| spelling | doaj-art-361aa8379bc94d739a95b0c6e7f8b2232025-02-04T17:30:20ZengWileyMolecular Oncology1574-78911878-02612025-02-0119234435610.1002/1878-0261.13778Evaluation of circulating tumor DNA as a prognostic and predictive biomarker in BRAF V600E mutated colorectal cancer—results from the FIRE‐4.5 studySusanne Klein‐Scory0Alexander Baraniskin1Wolff Schmiegel2Thomas Mika3Roland Schroers4Swantje Held5Kathrin Heinrich6David Tougeron7Dominik P. Modest8Ingo Schwaner9Jan Eucker10Rudolf Pihusch11Martina Stauch12Florian Kaiser13Christoph Kahl14Meinolf Karthaus15Christian Müller16Christof Burkart17Sebastian Stintzing18Volker Heinemann19Department of Internal Medicine, Universitaetsklinikum Knappschaftskrankenhaus Bochum GmbH Ruhr University Bochum GermanyDepartment of Internal Medicine, Universitaetsklinikum Knappschaftskrankenhaus Bochum GmbH Ruhr University Bochum GermanyDepartment of Internal Medicine, Universitaetsklinikum Knappschaftskrankenhaus Bochum GmbH Ruhr University Bochum GermanyDepartment of Internal Medicine, Universitaetsklinikum Knappschaftskrankenhaus Bochum GmbH Ruhr University Bochum GermanyDepartment of Internal Medicine, Universitaetsklinikum Knappschaftskrankenhaus Bochum GmbH Ruhr University Bochum GermanyClinAssess GmbH Leverkusen GermanyDepartment of Oncology LMU University Hospital Munich GermanyDepartment of Hepato‐Gastroenterology Poitiers University Hospital and University of Poitiers FranceDepartment of Hematology, Oncology, and Cancer Immunology (CCM) Charité—Universitaetsmedizin Berlin GermanyOnkologische Schwerpunktpraxis Kurfürstendamm Berlin GermanyDepartment of Hematology, Oncology, and Cancer Immunology (CBF) Charité—Universitaetsmedizin Berlin GermanyMVZ Praxis Pihusch Rosenheim GermanyHematology, Oncology/Hemostaseology Kronach GermanyVK&K Studien GmbH Landshut GermanyKlinikum Magdeburg gGmbH, Department of Hematology Oncology and Palliative Care Magdeburg GermanyDepartment of Hematology, Oncology and Palliative Care München Klinik Harlaching and Neuperlach GermanyEvang. Kliniken Essen‐Mitte GermanySchwarzwald‐Baar Klinikum Villingen‐Schwenningen GermanyDepartment of Hematology, Oncology, and Cancer Immunology (CCM) Charité—Universitaetsmedizin Berlin GermanyDepartment of Medicine III, LMU Klinikum Comprehensive Cancer Center Munich GermanyThe randomized FIRE‐4.5 (AIO KRK0116) trial compared first‐line therapy with FOLFOXIRI (folinic acid, fluorouracil, oxaliplatin, and irinotecan) plus either cetuximab or bevacizumab in B‐Raf proto‐oncogene, serine/threonine kinase (BRAF) V600E‐mutant metastatic colorectal cancer (mCRC) patients. This study was accompanied by a prospective translational project analyzing cell‐free circulating tumor DNA (ctDNA) in plasma to test whether ctDNA analysis may help to guide clinical treatment decision making. FIRE‐4.5 included mCRC patients with BRAF V600E mutation detected by tissue‐based analyses. Liquid biopsies (LBs) were collected at baseline (pre‐treatment) and during therapy. Digital droplet PCR (ddPCR) technology was applied for determination of BRAF mutations and the in vitro diagnostics (IVD)‐certified ONCOBEAM RAS procedure for analysis of RAS mutations. The BRAF V600E variants in ctDNA were analyzable in 66 patients at start of the therapy, at baseline. No BRAF V600E mutations were detected in 26% (17/66) of patients and was associated with a significantly longer progression‐free survival (PFS: 13.2 vs 6.5 months; HR 0.47; P = 0.014) and overall survival (OS: 36.8 vs 13.2 months; HR 0.35; P = 0.02) as compared to ctDNA mutant patients. Patients with detectable BRAF mutations showed a clear superiority of FOLFOXIRI plus bevacizumab with regard to PFS (10.4 vs 5.7 months; HR 0.4; P = 0.009) and OS (16.6 vs 11.6 months; HR 0.5; P = 0.15), while this was not the case for BRAF wild‐type patients. Follow‐up LBs were obtained from 51 patients. Patients converting from BRAF V600E mutant to a BRAF V600 wild‐type status (36%, N = 18) had a superior PFS (8.6 vs 2.3 months; P = 0.0002) and OS (17.4 vs 5.1 months; P < 0.0001) compared to patients with stable or increased mutational allele frequency (12%, N = 6). Those patients also achieved a significantly greater disease control rate (89% vs 20%; P = 0.008). In conclusion, LB evaluating ctDNA is informative and may help to guide treatment in patients with BRAF V600E‐mutated mCRC.https://doi.org/10.1002/1878-0261.13778bevacizumabcetuximabcirculating tumor DNAFOLFOXIRIliquid biopsymutational load |
| spellingShingle | Susanne Klein‐Scory Alexander Baraniskin Wolff Schmiegel Thomas Mika Roland Schroers Swantje Held Kathrin Heinrich David Tougeron Dominik P. Modest Ingo Schwaner Jan Eucker Rudolf Pihusch Martina Stauch Florian Kaiser Christoph Kahl Meinolf Karthaus Christian Müller Christof Burkart Sebastian Stintzing Volker Heinemann Evaluation of circulating tumor DNA as a prognostic and predictive biomarker in BRAF V600E mutated colorectal cancer—results from the FIRE‐4.5 study Molecular Oncology bevacizumab cetuximab circulating tumor DNA FOLFOXIRI liquid biopsy mutational load |
| title | Evaluation of circulating tumor DNA as a prognostic and predictive biomarker in BRAF V600E mutated colorectal cancer—results from the FIRE‐4.5 study |
| title_full | Evaluation of circulating tumor DNA as a prognostic and predictive biomarker in BRAF V600E mutated colorectal cancer—results from the FIRE‐4.5 study |
| title_fullStr | Evaluation of circulating tumor DNA as a prognostic and predictive biomarker in BRAF V600E mutated colorectal cancer—results from the FIRE‐4.5 study |
| title_full_unstemmed | Evaluation of circulating tumor DNA as a prognostic and predictive biomarker in BRAF V600E mutated colorectal cancer—results from the FIRE‐4.5 study |
| title_short | Evaluation of circulating tumor DNA as a prognostic and predictive biomarker in BRAF V600E mutated colorectal cancer—results from the FIRE‐4.5 study |
| title_sort | evaluation of circulating tumor dna as a prognostic and predictive biomarker in braf v600e mutated colorectal cancer results from the fire 4 5 study |
| topic | bevacizumab cetuximab circulating tumor DNA FOLFOXIRI liquid biopsy mutational load |
| url | https://doi.org/10.1002/1878-0261.13778 |
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