Abstract
BackgroundNovel 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.MethodsBetween 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.ResultsOut 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.ConclusionsIntegrated 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.
Highlights
Novel biomarkers and molecular monitoring tools hold potential to improve outcome for patients following resection of pancreatic ductal adenocarcinoma (PDAC)
Despite significant progress in understanding tumor genetics and the molecular mechanisms driving tumor development and resistance to therapy, only minor improvements have been achieved to date in the treatment of patients with pancreatic ductal adenocarcinoma (PDAC)
Patient cohort 25 patients with non-metastatic, R0/R1-resected adenocarcinoma of the pancreas were included in the study
Summary
Novel biomarkers and molecular monitoring tools hold potential to improve outcome for patients following resection of pancreatic ductal adenocarcinoma (PDAC). The development and validation of novel biomarkers and molecular monitoring tools to predict disease course and assess efficacy of adjuvant chemotherapy are urgently needed. We recently described the development and validation of highly sensitive single-target and discriminatory multi-target KRAS ddPCR assays for the analysis of cfDNA [30]. These assays allow identification and quantification of mutated KRAS directly from circulation without previous knowledge of tumor KRAS mutational status, which is not routinely tested for resectable PDACs
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