Circulating tumor DNA as a prognostic biomarker in early stage pancreatic cancer.

Abstract

Background: While adjuvant therapy provides a survival benefit for patients (pts) with early-stage pancreatic cancer there are currently no biomarkers that define pts that are more or less likely to benefit from such treatment. This prospective study investigated the use of circulating tumour DNA (ctDNA) as a marker of residual disease, where detection could predict recurrence. Method(s): Patients newly diagnosed with operable pancreatic adenocarcinoma were enrolled. PCR-based-SafeSeqS assays were used to identify mutations at codons 12, 13 and 61 of KRAS in the primary tumor and to detect ctDNA in plasma samples. Patient management was as per standard of care, blinded to ctDNA data. Result(s): From January 2015 to June 2017, 42 pts with matched plasma samples, collected pre- and post-operatively, and tumor tissue available were evaluated. The median time between surgery and post-op blood collection was 6.3 (range:4-8) weeks. RAS mutations were identified in 38 (90.5%) tumor samples. ctDNA was detected in 23/37 (62.2%) pre-op and 13/35 (37.1%) post-op plasma samples. In multivariate analysis including stage, and resection margin, ctDNA status was the only statistically significant variable. Pre-op ctDNA detection was associated with worse median recurrence free survival (RFS), 10.3 months versus not reached, (Hazard Ratio (HR),3.4; 95% confidence interval (CI), 1.5- 7.6; P = 0.005) and 5.4 months versus 17.1 months, (HR, 5.4; 95% CI, 4.7-37.3; P < 0.0001) post-operatively. Similarly, the presence of ctDNA was associated with worse median overall survival (OS), 13.8 months versus not reached pre-operatively, (HR,3.4; 95% CI 1.1 to 8.3; P = 0.04) and 10.6 months versus not reached (HR,4.5; 95% CI 2.4-28.6; P = 0.001) post-operatively. Notably, recurrence occurred in 13 of 13 pts with detectable post-op ctDNA, despite more than half receiving standard adjuvant chemotherapy. Conclusion(s): ctDNA analysis is a promising prognostic marker in early-stage pancreatic cancer that could be used to stratify recurrence risk and guide risk-adaptive treatment strategies. ctDNA detection postoperatively may also define a pt subset destined to progress despite standard adjuvant chemotherapy, where novel approaches need to be explored.