title: Actionable mutations in plasma cell-free DNA in patients with advanced cancers referred for experimental targeted therapies.
abstract: Cell-free (cf) DNA in the plasma of cancer patients offers an easily obtainable source of biologic material for mutation analysis. Plasma samples from 157 patients with advanced cancers who progressed on systemic therapy were tested for 21 mutations in BRAF, EGFR, KRAS, and PIK3CA using the BEAMing method and results were compared to mutation analysis of archival tumor tissue from a CLIA-certified laboratory obtained as standard of care from diagnostic or therapeutic procedures. Results were concordant for archival tissue and plasma cfDNA in 91% cases for BRAF mutations (kappa = 0.75, 95% confidence interval [CI] 0.63 - 0.88), in 99% cases for EGFR mutations (kappa = 0.90, 95% CI 0.71- 1.00), in 83% cases for KRAS mutations (kappa = 0.67, 95% CI 0.54 - 0.80) and in 91% cases for PIK3CA mutations (kappa = 0.65, 95% CI 0.46 - 0.85). Patients (n = 41) with > 1% of KRAS mutant cfDNA had a shorter median survival compared to 20 patients with </= 1% of KRAS mutant DNA (4.8 vs. 7.3 months, p=0.008). Similarly, 67 patients with >1% of mutant cfDNA (BRAF, EGFR, KRAS, or PIK3CA) had a shorter median survival compared to 33 patients with </= 1% of mutant cfDNA (5.5 vs. 9.8 months, p = 0.001), which was confirmed in multivariable analysis. [Corrected]
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Filip
authors.initials: F
authors.lastname: Janku
authors.affiliation: Sysmex Inostics GmbH, Hamburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Angenendt
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Apostolia M
authors.initials: AM
authors.lastname: Tsimberidou
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Siqing
authors.initials: S
authors.lastname: Fu
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Aung
authors.initials: A
authors.lastname: Naing
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Gerald S
authors.initials: GS
authors.lastname: Falchook
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Hong
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Veronica R
authors.initials: VR
authors.lastname: Holley
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Goran
authors.initials: G
authors.lastname: Cabrilo
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Wheler
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Sarina A
authors.initials: SA
authors.lastname: Piha-Paul
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Ralph G
authors.initials: RG
authors.lastname: Zinner
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Agop Y
authors.initials: AY
authors.lastname: Bedikian
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Overman
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Bryan K
authors.initials: BK
authors.lastname: Kee
authors.affiliation: Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Kevin B
authors.initials: KB
authors.lastname: Kim
authors.affiliation: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Kopetz
authors.affiliation: Molecular Diagnostic Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Rajyalakshmi
authors.initials: R
authors.lastname: Luthra
authors.affiliation: Sysmex Inostics GmbH, Hamburg, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Diehl
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: Funda
authors.initials: F
authors.lastname: Meric-Bernstam
authors.affiliation: Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA.|Moores Cancer Center, The University of California San Diego, La Jolla, CA, USA.
authors.forename: Razelle
authors.initials: R
authors.lastname: Kurzrock
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000097:blood / Q000235:genetics; D058534:Class I Phosphatidylinositol 3-Kinases; D004252:DNA Mutational Analysis; D004273:DNA, Neoplasm / Q000097:blood* / Q000235:genetics*; D005260:Female; D018773:Genes, erbB-1 / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009369:Neoplasms / Q000235:genetics* / Q000401:mortality; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D004273:DNA, Neoplasm; C117307:KRAS protein, human; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras)
keywords: BRAF; EGFR; KRAS; PIK3CA; cell-free DNA