Dynamic assessment of circulating tumor DNA in prediction of response to nab-paclitaxel-based first-line chemotherapy in metastatic pancreatic cancer.

Abstract

e15769 Background: Emerging evidence showed circulating tumor DNA (ctDNA) may be used as biomarker for monitoring tumor response to chemotherapy in pancreatic cancer. This pilot study was to evaluate the clinical application of dynamic assessment ctDNA in MPC. Methods: From December 2016 to June 2018 in our center, 29 MPC patients treated with nab-paclitaxel based first-line chemotherapy (NS or N plus Gemcitabine, NG) had at least 2 ctDNA tests were included for analysis. Plasma samples were prospectively collected at baseline and periodical follow-ups until progression, death, or withdrawal of consent. Next-generation sequencing for a panel of 425 genes covering a wide range of cancer-related loci was performed to profile ctDNA. Progression of ctDNA was defined as increased mutation allelic frequency (MAF) of common mutant gene from baseline or nadir, or the presence of new gene alternations. The clinical relevance of the common alteration, and its dynamic changes in ctDNA were analyzed, and compared to conventional imaging response and survival. Results: In our patient cohort, the best overall response of partial response (PR) was 48.3% (14/29). By February 2019, 18 patients passed away with median follow-up of 9.7 months. At baseline, 22 patients (75.9%, N = 29) had at least one common driver gene alterations ( KRAS, TP53, CDKN2A, SMAD4) detected in ctDNA. Mutant KRAS and TP53 were identified in 72.4% and 62.1% patients with a median MAF of 5.8% and 4.7%, respectively. Of 14 patients achieved PR on image, MAF of the mutant driver genes found declined significantly or mutant gene disappeared. At the time of clinical progressive disease (PD), 24 patients had evaluable image and ctDNA results whereas both demonstrated PD in 23 (95.8%), including 9 found earlier progression of ctDNA with median time of 1.93 months compared to image findings. Among 22 patients with any of the above 4 mutant driver genes in ctDNA at baseline, 13 patients demonstrated significant reduction of MAF (reduction to < 1% or undetectable) within 6 weeks, who had a longer progression free survival (PFS, reduction 6.6m vs no reduction 3.4m, P = 0.001) and overall survival (OS, reduction 12.6m vs no reduction 5.4m, P = 0.001), compared to those who had an increased or stable MAF. Conclusions: Our initial findings demonstrated the changes in MAF of 4 common driver genes in ctDNA was well correlated with treatment response to chemotherapy, PFS and OS in MPC. Peripheral ctDNA was a potential reliable alternative biomarker for efficacy and progression prediction in MPC.