Saskia Hussung1,2, Dilara Akhoundova2, Julian Hipp3, Marie Follo1, Rhena F U Klar1, Ulrike Philipp1, Florian Scherer1, Nikolas von Bubnoff1, Justus Duyster1,4,5, Melanie Boerries4,5,6,7, Uwe Wittel3, Ralph M Fritsch8,9,10. 1. Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany. 2. Department of Medical Oncology and Hematology, Zurich University Hospital, Raemistrasse 100, 8091, Zürich, Switzerland. 3. Department of Surgery, Freiburg University Medical Center, Freiburg, Germany. 4. German Cancer Consortium (DKTK), partner site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany. 5. Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 6. Institute of Medical Bioinformatics and Systems Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. 7. German Cancer Research Center (DKFZ), Heidelberg, Germany. 8. Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany. ralph.fritsch@usz.ch. 9. Department of Medical Oncology and Hematology, Zurich University Hospital, Raemistrasse 100, 8091, Zürich, Switzerland. ralph.fritsch@usz.ch. 10. Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. ralph.fritsch@usz.ch.
Abstract
BACKGROUND: Novel biomarkers and molecular monitoring tools hold potential to improve outcome for patients following resection of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that the combined longitudinal analysis of mutated cell-free plasma KRAS (cfKRASmut) and CA 19-9 during adjuvant treatment and follow-up might more accurately predict disease course than hitherto available parameters. METHODS: Between 07/2015 and 10/2018, we collected 134 plasma samples from 25 patients after R0/R1-resection of PDAC during adjuvant chemotherapy and post-treatment surveillance at our institution. Highly sensitive discriminatory multi-target ddPCR assays were employed to screen plasma samples for cfKRASmut. cfKRASmut and CA 19-9 dynamics were correlated with recurrence-free survival (RFS) and overall survival (OS). Patients were followed-up until 01/2020. RESULTS: Out of 25 enrolled patients, 76% had undergone R0 resection and 48% of resected PDACs were pN0. 17/25 (68%) of patients underwent adjuvant chemotherapy. Median follow-up was 22.0 months, with 19 out of 25 (76%) patients relapsing during study period. Median RFS was 10.0 months, median OS was 22.0 months. Out of clinicopathologic variables, only postoperative CA 19-9 levels and administration of adjuvant chemotherapy correlated with survival endpoints. cfKRASmut. was detected in 12/25 (48%) of patients, and detection of high levels inversely correlated with survival endpoint. Integration of cfKRASmut and CA 19-9 levels outperformed either individual marker. cfKRASmut outperformed CA 19-9 as dynamic marker since increase during adjuvant chemotherapy and follow-up was highly predictive of early relapse and poor OS. CONCLUSIONS: Integrated analysis of cfKRASmut and CA 19-9 levels is a promising approach for molecular monitoring of patients following resection of PDAC. Larger prospective studies are needed to further develop this approach and dissect each marker's specific potential.
BACKGROUND: Novel biomarkers and molecular monitoring tools hold potential to improve outcome for patients following resection of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that the combined longitudinal analysis of mutated cell-free plasma KRAS (cfKRASmut) and CA 19-9 during adjuvant treatment and follow-up might more accurately predict disease course than hitherto available parameters. METHODS: Between 07/2015 and 10/2018, we collected 134 plasma samples from 25 patients after R0/R1-resection of PDAC during adjuvant chemotherapy and post-treatment surveillance at our institution. Highly sensitive discriminatory multi-target ddPCR assays were employed to screen plasma samples for cfKRASmut. cfKRASmut and CA 19-9 dynamics were correlated with recurrence-free survival (RFS) and overall survival (OS). Patients were followed-up until 01/2020. RESULTS: Out of 25 enrolled patients, 76% had undergone R0 resection and 48% of resected PDACs were pN0. 17/25 (68%) of patients underwent adjuvant chemotherapy. Median follow-up was 22.0 months, with 19 out of 25 (76%) patients relapsing during study period. Median RFS was 10.0 months, median OS was 22.0 months. Out of clinicopathologic variables, only postoperative CA 19-9 levels and administration of adjuvant chemotherapy correlated with survival endpoints. cfKRASmut. was detected in 12/25 (48%) of patients, and detection of high levels inversely correlated with survival endpoint. Integration of cfKRASmut and CA 19-9 levels outperformed either individual marker. cfKRASmut outperformed CA 19-9 as dynamic marker since increase during adjuvant chemotherapy and follow-up was highly predictive of early relapse and poor OS. CONCLUSIONS: Integrated analysis of cfKRASmut and CA 19-9 levels is a promising approach for molecular monitoring of patients following resection of PDAC. Larger prospective studies are needed to further develop this approach and dissect each marker's specific potential.
Entities:
Keywords:
Cell-free DNA (cfDNA); Circulating KRAS (cfKRAS mut); Droplet digital PCR (ddPCR); Liquid biopsy; Molecular monitoring; Pancreatic cancer; Prognostic biomarkers
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