Clinical relevance of circulating KRAS mutated DNA in plasma from patients with advanced pancreatic cancer

Abstract

Cell-free DNA cfDNA KRAS Pancreatic cancer Liquid biopsy A B S T R A C TWe used KRAS mutations to investigate the clinical relevance of circulating tumor DNA (ctDNA) measurements in patients with advanced pancreatic cancer. Fifty-three blood samples were collected from 14 prospectively recruited patients prior to chemotherapy (gemcitabine or FOLFIRINOX) and subsequently every month during treatment. Samples were processed by density centrifugation and plasma DNA isolation. A Peptideenucleic acideclamp PCR was then used to detect KRAS mutations (present in >90% of pancreatic cancers) as a surrogate marker for ctDNA. Plasma samples from 29 healthy individuals were analyzed as a reference group. Results were compared to conventional monitoring measures and survival data. Median follow-up time was 3.7 months (range 0.6e12.9 months).Ten (71%) patients had a positive KRAS status in the plasma samples obtained prior to chemotherapy, indicating the presence of ctDNA. Among the patients who were ctDNApositive before chemotherapy, nine (90%) experienced disease progression during followup, compared to one (25%) of four ctDNA-negative patients (P ¼ 0.01). The pre-therapy ctDNA level was a statistically significant predictor of both progression-free and overall survival (P ¼ 0.014 and 0.010, respectively). Of the 14 patients, ten had !2 follow-up samples; in several of these patients, the ctDNA level changed substantially during the course of chemotherapy. Changes in ctDNA levels corresponded both with radiological follow-up data and CA19-9 levels for several patients.

KRAS mutations in the circulating free DNA (cfDNA) of non-small cell lung cancer (NSCLC) patients

“…EGFR mutations have also been shown to be of prognostic and predictive value, and patients with an activating mutation in EGFR in cfDNA have been reported to respond significantly better to TKIs (27). KRAS gene alterations detected in cfDNA have also been used as prognostic biomarkers, mainly in colorectal and pancreatic cancer (28,29). However, their predictive and prognostic value in NSCLC remains undefined, and to an extent controversial, due to the relatively few studies performed.…”

Circulating tumor DNA quantity is related to tumor volume and both predict survival in metastatic pancreatic ductal adenocarcinoma

“…In addition, ctDNA detection appears to have a strong prognostic value in patients with PDAC, but validation of this finding is required . Lastly, it has been suggested that ctDNA is a surrogate marker for tumor burden, but very few studies have formally assessed the relationship between ctDNA quantity and 3D tumor volumes, and never in PDAC . As PDAC is comprised of dense desmoplastic stroma with comparatively few tumor cells, the relationship between tumor volume and ctDNA quantity is difficult to predict.…”

Liquid biopsy in pancreatic ductal adenocarcinoma: current status of circulating tumor cells and circulating tumor DNA

“…10.2 months, P < 0.001) (Chen et al ., ). Furthermore, it has been reported that high amount of cfDNA is a relevant prognostic marker for pancreatic cancer patients (Singh et al ., ; Tjensvoll et al ., ). A recent meta‐analysis by Creemers et al .…”