Scientific publications

Total and mutated EGFR quantification in cell-free DNA from non-small cell lung cancer patients detects tumor heterogeneity and presents prognostic value

Alegre E [SP] (1,2,3), Fusco JP (4), Restituto P (1,3), Salas-Benito D (3,4), Rodríguez-Ruiz ME (3,4), Andueza MP (4), Pajares MJ (3,5,6), Patiño-García A [SP] (3,7), Pio R (2,3,5), Lozano MD [SP] (3,8), Gúrpide A [SP] (3,4), Lopez-Picazo JM [SP] (3,4), Gil-Bazo I (3,4), Perez-Gracia JL [SP] (3,4), Gonzalez A [SP] (9,10,11).
(1) Clinical Chemistry Department, Clínica Universidad de Navarra, Av Pio XII 36, 31008, Pamplona, Spain.
(2) Department of Biochemistry and Genetics, Universidad de Navarra, Irunlarrea 1, 31008, Pamplona, Spain.
(3) IdiSNA, Navarra Institute for Health Research, Irunlarrea 3, 31008, Pamplona, Spain.
(4) Department of Oncology, Clínica Universidad de Navarra, Av Pio XII 36, 31008, Pamplona, Spain.
(5) Program in Solid Tumors and Biomarkers|, Centro de Investigación Médica Aplicada (CIMA), Av Pio XII, 55 31008, Pamplona, Spain.
(6) Department of Histology, Universidad de Navarra, Irunlarrea 1, 31008, Pamplona, Spain.
(7) Department of Pediatrics and CIMA LAB Diagnostics, Clínica Universidad de Navarra, Av Pio XII 36, 31008, Pamplona, Spain.
(8) Department of Pathology, Clínica Universidad de Navarra, Av Pio XII 36, 31008, Pamplona, Spain.
(9) Clinical Chemistry Department, Clínica Universidad de Navarra, Av Pio XII 36, 31008, Pamplona, Spain. agonzaleh@unav.es.
(10) Department of Biochemistry and Genetics, Universidad de Navarra, Irunlarrea 1, 31008, Pamplona, Spain. agonzaleh@unav.es.
(11) IdiSNA, Navarra Institute for Health Research, Irunlarrea 3, 31008, Pamplona, Spain 

Magazine: Tumour Biology

Date: Jul 29, 2016

Clinical Genetics Unit [SP] Pathological Anatomy [SP] Biochemistry [SP] Medical Oncology

ABSTRACT

Mutation analysis of epidermal growth factor receptor (EGFR) gene is essential for treatment selection in non-small cell lung cancer (NSCLC). Analysis is usually performed in tumor samples. We evaluated the clinical utility of EGFR analysis in plasma cell-free DNA (cfDNA) from patients under treatment with EGFR inhibitors.

We selected 36 patients with NSCLC and EGFR-activating mutations. Blood samples were collected at baseline and during treatment with EGFR inhibitors. Wild-type EGFR, L858R, delE746-A750, and T790M mutations were quantified in cfDNA by droplet digital PCR.

Stage IV patients had higher total circulating EGFR copy levels than stage I (3523 vs. 1003 copies/mL; p < 0.01). There was high agreement for activating mutations between baseline cfDNA and tumor samples, especially for L858R mutation (kappa index = 0.679; p = 0.001). In 34 % of advanced NSCLC patients, we detected mutations in cfDNA not previously detected in tumor samples and double mutations in 17 %.

Patients with baseline total EGFR copy levels above the median presented decreased overall survival (OS) (341 vs. 870 days, p < 0.05) and progression-free survival (PFS) (238 vs. 783 days; p < 0.05) compared with those with total EGFR copy levels below the median.

Patients with baseline concentrations of activating mutations above the median (94 copies/mL) had lower OS (317 vs. 805 days; p < 0.05) and PFS (195 vs. 724 days; p < 0.05). During follow-up, T790M resistance mutation was detected in 53 % of patients. Total and mutated EGFR analysis in cfDNA seems a relevant tool to characterize the molecular profile and prognosis of NSCLC patients harboring EGFR mutations.

CITATION  Tumour Biol. 2016 Jul 29

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