Clinical Research Papers:
Actionable mutations in plasma cell-free DNA in patients with advanced cancers referred for experimental targeted therapies
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Filip Janku1, Philipp Angenendt2, Apostolia M. Tsimberidou1, Siqing Fu1 Aung Naing1, Gerald S. Falchook1, David S. Hong1, Veronica R. Holley1, Goran Cabrilo1, Jennifer J. Wheler1, Sarina A. Piha-Paul1, Ralph G. Zinner1, Agop Y. Bedikian3, Michael J. Overman4, Bryan K. Kee4, Kevin B. Kim3, E. Scott Kopetz4, Rajyalakshmi Luthra5, Frank Diehl2, Funda Meric-Bernstam1, Razelle Kurzrock1,6
1Department of Investigational Cancer Therapeutics (Phase I Clinical Trials Program), The University of Texas MD Anderson Cancer Center, Houston, TX, USA
2Sysmex Inostics GmbH, Hamburg, Germany
3Department of Melanoma Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
4Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
5Molecular Diagnostic Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
6Moores Cancer Center, The University of California San Diego, La Jolla, CA, USA
Filip Janku, e-mail: firstname.lastname@example.org
Keywords: EGFR, BRAF, KRAS, PIK3CA, cell-free DNA
Received: December 16, 2014 Accepted: February 11, 2015 Published: March 25, 2015
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.
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