title: Clinical relevance of circulating KRAS mutated DNA in plasma from patients with advanced pancreatic cancer.
abstract: We 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 Peptide-nucleic acid-clamp 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 0.6-12.9 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 ctDNA-positive before chemotherapy, nine (90%) experienced disease progression during follow-up, compared to one (25%) of four ctDNA-negative patients (P = 0.01). The pre-therapy ctDNA level was a statistically significant predictor of both progression-free and overall survival (P = 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. This pilot study supports the hypothesis that ctDNA may be used as a marker for monitoring treatment efficacy and disease progression in pancreatic cancer patients. Recruitment of more patients is ongoing to corroborate these findings.
authors.affiliation: Department of Haematology and Oncology, Stavanger University Hospital, N-4068 Stavanger, Norway; Laboratory for Molecular Biology, Stavanger University Hospital, N-4068 Stavanger, Norway. Electronic address: ktje@sus.no.
authors.forename: Kjersti
authors.initials: K
authors.lastname: Tjensvoll
authors.affiliation: Laboratory for Molecular Biology, Stavanger University Hospital, N-4068 Stavanger, Norway.
authors.forename: Morten
authors.initials: M
authors.lastname: Lapin
authors.affiliation: Department of Haematology and Oncology, Stavanger University Hospital, N-4068 Stavanger, Norway.
authors.forename: Tove
authors.initials: T
authors.lastname: Buhl
authors.affiliation: Department of Haematology and Oncology, Stavanger University Hospital, N-4068 Stavanger, Norway; Laboratory for Molecular Biology, Stavanger University Hospital, N-4068 Stavanger, Norway.
authors.forename: Satu
authors.initials: S
authors.lastname: Oltedal
authors.affiliation: Laboratory for Molecular Biology, Stavanger University Hospital, N-4068 Stavanger, Norway.
authors.forename: Katrine
authors.initials: K
authors.lastname: Steen-Ottosen Berry
authors.affiliation: Department of Haematology and Oncology, Stavanger University Hospital, N-4068 Stavanger, Norway.
authors.forename: Bjørnar
authors.initials: B
authors.lastname: Gilje
authors.affiliation: Department of Gastrointestinal Surgery, Stavanger University Hospital, N-4068 Stavanger, Norway; Department of Clinical Medicine, University of Bergen, N-5021 Bergen, Norway.
authors.forename: Jon Arne
authors.initials: JA
authors.lastname: Søreide
authors.affiliation: Department of Gastrointestinal (GI) Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Millind
authors.initials: M
authors.lastname: Javle
authors.affiliation: Department of Haematology and Oncology, Stavanger University Hospital, N-4068 Stavanger, Norway; Laboratory for Molecular Biology, Stavanger University Hospital, N-4068 Stavanger, Norway.
authors.forename: Oddmund
authors.initials: O
authors.lastname: Nordgård
authors.affiliation: Department of Haematology and Oncology, Stavanger University Hospital, N-4068 Stavanger, Norway.
authors.forename: Rune
authors.initials: R
authors.lastname: Smaaland
mesh_terms: D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D004273:DNA, Neoplasm / Q000097:blood / Q000235:genetics; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000097:blood / Q000188:drug therapy / Q000235:genetics / Q000401:mortality; D010865:Pilot Projects; D016283:Proto-Oncogene Proteins p21(ras) / Q000097:blood / Q000235:genetics; D015996:Survival Rate
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)
keywords: Cell-free DNA; Circulating tumor DNA; KRAS; Liquid biopsy; Pancreatic cancer; cfDNA; ctDNA