Quantitative monitoring of circulating tumor DNA in patients with advanced pancreatic cancer undergoing chemotherapy

摘要

According to cancer genome sequences, more than 90% of cases of pancreatic ductal adenocarcinoma (PDAC) harbor active KRAS mutations. Digital PCR (dPCR) enables accurate detection and quantification of rare mutations. We assessed the dynamics of circulating tumor DNA (ct‐DNA) in patients with advanced PDAC undergoing chemotherapy using dPCR. KRAS G12/13 mutation was assayed by dPCR in 47 paired tissue‐ and ct‐DNA samples. The 21 patients were subjected to quantitative ct‐DNA monitoring at 4 to 8‐week intervals during chemotherapy. KRAS mutation was detected in 45 of those 47 patients using tissue DNA. In the KRAS mutation‐negative cases, next‐generation sequencing revealed KRAS Q61K and NRAS Q61R mutations. KRAS mutation was detected in 23/45 cases using ct‐DNA (liver or lung metastasis, 18/19; mutation allele frequency [MAF], 0.1%‐31.7%; peritoneal metastasis, 3/9 [0.1%], locally advanced, 2/17 [0.1%‐0.2%]). In the ct‐DNA monitoring, the MAF value changed in concordance with the disease state. In the 6 locally advanced cases, KRAS mutation appeared concurrently with liver metastasis. Among the 6 cases with liver metastasis, KRAS mutation disappeared during the duration of stable disease or a partial response, and reappeared at the time of progressive disease. The median progression‐free survival was longer in cases in which KRAS mutation disappeared after an initial course of chemotherapy than in those in which it was continuously detected (248.5 vs 50?days, P ?.001). Therefore, ct‐DNA monitoring enables continuous assessment of disease state and could have prognostic utility during chemotherapy.