A Kurreck1, M Geissler2, U M Martens3, J Riera-Knorrenschild4, J Greeve5, A Florschütz6, S Wessendorf2, T Ettrich7, S Kanzler8, D Nörenberg9, M Seidensticker10, S Held11, P Buechner-Steudel12, J Atzpodien13, V Heinemann14,15, S Stintzing1, T Seufferlein7, A Tannapfel16, A C Reinacher-Schick17, D P Modest18. 1. Department of Hematology, Oncology, and Tumor Immunology (CVK/CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. 2. Klinikum Esslingen, Esslingen, Germany. 3. Klinik für Innere Medizin III, SLK-Kliniken Heilbronn, Heilbronn, Germany. 4. Universitätsklinik Marburg, Marburg, Germany. 5. St. Vincenz-Krankenhaus Paderborn, Paderborn, Germany. 6. Stadtisches Klinikum Dessau, Dessau, Germany. 7. Universitätsklinikum Ulm, Ulm, Germany. 8. Leopoldina Krankenhaus, Schweinfurt, Germany. 9. Medical Faculty Mannheim, Institute of Clinical Radiology and Nuclear Medicine, University Medical Center Mannheim, Heidelberg University, Mannheim, Germany. 10. Klinik Und Poliklinik für Radiologie, LMU Klinikum, München, Germany. 11. ClinAssess, Leverkusen, Germany. 12. Universitätsklinikum Halle (Saale), Halle, Germany. 13. Franziskus-Hospital Harderberg, Georgsmarienhütte, Germany. 14. Department of Medicine III and Comprehensive Cancer Center, University Hospital Munich (LMU), Munich, Germany. 15. German Cancer Consortium (DKTK), German Cancer Research Center, Heidelberg, Germany. 16. Institute of Pathology, Ruhr-University Bochum, Bochum, Germany. 17. Department of Hematology, Oncology and Palliative Care, St. Josef Hospital, Ruhr-University Bochum, Bochum, Germany. 18. Department of Hematology, Oncology, and Tumor Immunology (CVK/CCM), Charité University Medicine Berlin, Augustenburger Platz 1, 13353, Berlin, Germany. dominik.modest@charite.de.
Abstract
PURPOSE: In mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints. METHODS: We analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively. RESULTS: BRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (- 57.6% vs. - 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1-4.4) vs. 3.9 (95% CI 2.5-5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9-8.0) versus 2.6 (95% CI 1.2-4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11-0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0-41.3) vs. 5.4 (95% CI 5.0-5.9) months; HR 0.27 (95% CI 0.13-0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site. CONCLUSIONS: BRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR.
PURPOSE: In mCRC, disease dynamics may play a critical role in the understanding of long-term outcome. We evaluated depth of response (DpR), time to DpR, and post-DpR survival as relevant endpoints. METHODS: We analyzed DpR by central review of computer tomography images (change from baseline to smallest tumor diameter), early tumor shrinkage (≥ 20% reduction in tumor diameter at first reassessment), time to DpR (study randomization to DpR-image), post-DpR progression-free survival (pPFS = DpR-image to tumor progression or death), and post-DpR overall survival (pOS = DpR-image to death) with special focus on BRAF status in 66 patients and primary tumor site in 86 patients treated within the VOLFI-trial, respectively. RESULTS:BRAF wild-type (BRAF-WT) compared to BRAF mutant (BRAF-MT) patients had greater DpR (- 57.6% vs. - 40.8%, p = 0.013) with a comparable time to DpR [4.0 (95% CI 3.1-4.4) vs. 3.9 (95% CI 2.5-5.5) months; p = 0.8852]. pPFS was 6.5 (95% CI 4.9-8.0) versus 2.6 (95% CI 1.2-4.0) months in favor of BRAF-WT patients (HR 0.24 (95% CI 0.11-0.53); p < 0.001). This transferred into a significant difference in pOS [33.6 (95% CI 26.0-41.3) vs. 5.4 (95% CI 5.0-5.9) months; HR 0.27 (95% CI 0.13-0.55); p < 0.001]. Similar observations were made for patients stratified for primary tumor site. CONCLUSIONS:BRAF-MT patients derive a less profound treatment response compared to BRAF-WT patients. The difference in outcome according to BRAF status is evident after achievement of DpR with BRAF-MT patients hardly deriving any further disease control beyond DpR. Our observations hint towards an aggressive tumor evolution in BRAF-MT tumors, which may already be molecularly detectable at the time of DpR.
Entities:
Keywords:
BRAF; Combination chemotherapy; Depth of response; Disease dynamics; Early tumor shrinkage; Metastatic colorectal cancer; Primary tumor site
Authors: Dominik Paul Modest; Meinolf Karthaus; Stefan Fruehauf; Ullrich Graeven; Lothar Müller; Alexander Otto König; Ludwig Fischer von Weikersthal; Karel Caca; Albrecht Kretzschmar; Eray Goekkurt; Siegfried Haas; Annika Kurreck; Arndt Stahler; Swantje Held; Armin Jarosch; David Horst; Anke Reinacher-Schick; Stefan Kasper; Volker Heinemann; Sebastian Stintzing; Tanja Trarbach Journal: J Clin Oncol Date: 2021-09-17 Impact factor: 44.544
Authors: Rodrigo Motta; Santiago Cabezas-Camarero; Cesar Torres-Mattos; Alejandro Riquelme; Ana Calle; Paola Montenegro; Miguel J Sotelo Journal: J Clin Transl Res Date: 2021-11-29
Authors: Annika Kurreck; Volker Heinemann; Ludwig Fischer von Weikersthal; Thomas Decker; Florian Kaiser; Jens Uhlig; Michael Schenk; Jens Freiberg-Richter; Bettina Peuser; Claudio Denzlinger; Ullrich Graeven; Kathrin Heinrich; Swantje Held; Arndt Stahler; Annabel Helga Sophie Alig; Ivan Jelas; Jobst C von Einem; Sebastian Stintzing; Clemens Giessen-Jung; Dominik P Modest Journal: Front Oncol Date: 2022-02-18 Impact factor: 6.244