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Clinical Trial
. 2021 Jan 11;21(1):49.
doi: 10.1186/s12885-020-07736-x.

Longitudinal analysis of cell-free mutated KRAS and CA 19-9 predicts survival following curative resection of pancreatic cancer

Saskia Hussung  1   2 , Dilara Akhoundova  2 , Julian Hipp  3 , Marie Follo  1 , Rhena F U Klar  1 , Ulrike Philipp  1 , Florian Scherer  1 , Nikolas von Bubnoff  1 , Justus Duyster  1   4   5 , Melanie Boerries  4   5   6   7 , Uwe Wittel  3 , Ralph M Fritsch  8   9   10
Affiliations
Clinical Trial

Longitudinal analysis of cell-free mutated KRAS and CA 19-9 predicts survival following curative resection of pancreatic cancer

Saskia Hussung et al. BMC Cancer. .

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.

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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Conflict of interest statement

The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
Association of cfKRASmut detection and elevated CA 19–9 levels with survival endpoints. a, b Kaplan-Meier estimates of RFS (a) and OS (b) for patients following curative resection of PDAC with versus without detectable cfKRASmut at any time point during study period. c, d. A more stringent cfKRASmut cut-off level of > 15 copies/mL plasma was chosen. e, f Kaplan-Meier estimates of RFS (e) and OS (f) for resected PDAC patients with elevated (> 36 U/mL) versus normal (≤ 36 U/mL) CA 19–9 levels at any time point during observation period. g, h Kaplan-Meier estimates of RFS (g) and OS (h) for resected PDAC patients with either CA 19–9 positivity or cfKRASmut levels > 15 copies/mL cfKRAS during study course. OS, overall survival; RFS, recurrence-free survival; PDAC, pancreatic ductal adenocarcinoma
Fig. 2
Fig. 2
Association of cfKRASmut and CA 19–9 dynamic changes with survival endpoints. a, b Kaplan-Meier estimates of OS for resected PDAC patients with increase of cfKRASmut (a) or CA 19–9 (b) during observation period. c, d Kaplan-Meier estimates of OS for resected PDAC patients with early increase of cfKRASmut (a) or CA 19–9 (b) during observation period. Increase of cfKRASmut or CA 19–9 during observation period was defined as numerical increase of the respective parameter in initially positive patients or rise above threshold in initially negative patients. Early increase was defined as increase within 6 months after surgery. e Kaplan-Meier estimates of OS for resected PDAC patients with combined early increase of cfKRASmut or CA 19–9. f Kaplan-Meier estimates of OS for resected PDAC patients with combined early increase of cfKRASmut and CA 19–9. OS, overall survival; RFS, recurrence-free survival; PDAC, pancreatic ductal adenocarcinoma
Fig. 3
Fig. 3
Longitudinal cfKRASmut and CA 19–9 monitoring. a Top left: Absolut levels of cfKRASmut during observation period. Patients with relapse during study period are marked red. Black arrow mark the time of disease recurrence. Top right: Relapse versus non-relapse patients with increase in cfKRASmut during observation period. Fisher’s exact test was used to test for statistical significance between the two groups. P values < 0.05 were considered significant. Bottom left: Absolut levels of CA 19–9 during observation period. Patients with relapse are marked red. Black arrows mark the time of disease recurrence. Bottom right: Relapse versus non-relapse patients with increase in cfKRASmut during observation period. Fisher’s exact test was used to test for statistical significance between the two groups. P values < 0.05 were considered significant. b Swimmers plot of disease course of resected PDAC patients. cfKRASmut and CA 19–9 analysis in blood were compared to clinical course of disease before and during adjuvant chemotherapy. CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease
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