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

Abstract

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.

Circulating Tumor DNA as a Prognostic Biomarker in Localized Non-small Cell Lung Cancer

“…Therefore, our data cannot evaluate the impact of adjuvant chemotherapy on ctDNA. However, previous studies have confirmed the possible role of circulating DNA in judging the efficacy of chemotherapy (24,25). A well-designed clinical trial is needed to verify the role of ctDNA in evaluating the efficacy of neoadjuvant therapy for lung adenocarcinoma.…”

Circulating Tumor DNA Detection by Digital-Droplet PCR in Pancreatic Ductal Adenocarcinoma: A Systematic Review

“…Thus, progression free survival analysis revealed that ctDNA KRAS mutation patients undergoing first-line chemotherapy tended to have worse progression free survival than those without a KRAS mutation (median 308.5 vs. 168 days, p = 0.07). Interestingly, they showed that, in those cases with a KRAS mutation in ctDNA at the time of diagnosis, the KRAS mutation disappeared after the initial course of chemotherapy and reappeared concurrently with or earlier than progression of the disease, highlighting the predictive factor for disease progression of PDAC patients [ 59 ].…”

Maintenance therapies in metastatic pancreatic cancer: present and future with a focus on PARP inhibitors

“…In the near future, in addition to clinical followup, imaging assessment and measurement of conventional serum tumor markers such as CA 19.9, the monitoring of circulating tumor DNA, tumor cells or extra-cellular vesicles will help guide maintenance therapies in patients with PDAC. [41][42][43] This confirms the importance of carefully designing ancillary studies as well as those for treatment.…”