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

Autores: Alegre Martínez, Estíbaliz; Fusco, Juan Pablo; Restituto Aranguibel, Patricia; Salas Benito, Diego; Rodríguez Ruiz, María Esperanza; Andueza Arrieta, María Pilar; Pajares Villandiego, María José; Patiño García, Ana; Pio Osés, Rubén; Lozano Escario, María Dolores; Gurpide Ayarra, Luis Alfonso; Lopez-Picazo, J. M.; Gil Bazo, Ignacio; Pérez Gracia, José Luis; González Hernández, Álvaro
Título de la revista: TUMOR BIOLOGY
ISSN: 1010-4283
Volumen: 37
Número: 10
Páginas: 13687 - 13694
Fecha de publicación: 2016
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.