Early changes in plasma levels of mutant KRAS DNA as a sensitive marker of response to chemotherapy in pancreatic cancer

Abstract

Background: Pancreatic cancer (PDAC) is still lacking of good markers to monitor tumor response and chemotherapy represents the gold standard to treat advanced disease. Ca19.9 is the only one approved, however, it has several limitations in sensitivity and specificity. Since mutations of KRAS occur in more than 90% of tumors, its detection and variations in circulating free tumor DNA (cftDNA) could represent a biomarker to monitor chemotherapy response. Material and Methods: Twenty-seven advanced PDAC patients given first-line 5-fluorouracil, irinotecan and oxaliplatin or gemcitabine and nab-paclitaxel were enrolled. Three ml of plasma were collected 1) before to start chemotherapy (baseline), 2) at day 15 of treatment and 3) at each clinical follow-up. CftDNA was extracted and analysed for KRAS mutations (mutKRAS) by digital droplet PCR to monitor its variation and to compare its predictive role respect to Ca19.9. Results: A total of 27 patients with locally advanced (n = 4) and metastatic (n = 23) PDAC were included in this prospective study. Median PFS and OS were 7.4 and 11.5 months, respectively. Nineteen patients displayed a mutKRAS in baseline plasma, and there were no significant statistically differences in median PFS and OS in patients with baseline positive or negative cftDNA mutKRAS (median PFS: 7.4 months vs. not reached, p = 0.24; median OS: 11.5 months vs. not reached, p = 0.16). Monitoring mutKRAS cftDNA during treatment and correlation with outcome were possible in 25 patients. There was a statistically significant difference in PFS and OS in patients with increase vs. stability/reduction of cftDNA in the sample collected at day 15 (median PFS 2.5 vs 7.5 months, p = 0.03; median OS 6.5 vs 11.5 months, p = 0.009). None of the other parameters (sex, age, stage, PS, primary tumor location, baseline CA19.9) was significantly correlated with PFS or OS. Moreover, mutKRAS cftDNA variations were deeper than those of Ca19.9, suggesting that mutKRAS cftDNA can be more accurate and sensible biomarker (Table 1).Table: D11Comparison of mutKRAS cftDNA and Ca19.9 is a patient undergoing progression of disease (PD).Baseline2 weeks8 weeks - PDmutKRAS cftDNA (copies/ml)2002902800Ca19.9 (U/ml)260020001500 Open table in a new tab Conclusions: The results of this study support the hypothesis that mutKRAS in plasma may be used as a new marker for monitoring treatment outcome and disease progression in PDAC, suggesting that cftDNA mutKRAS changes are associated with tumor response to chemotherapy.