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

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.

• Authors: E Alegre, J P Fusco, P Restituto, D Salas-Benito, M E Rodríguez-Ruiz, M P Andueza, M J Pajares, A Patiño-García, R Pio, M D Lozano, A Gúrpide, J M Lopez-Picazo, I Gil-Bazo, J L Perez-Gracia, A Gonzalez
• Journal: Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine (Tumour Biol) Vol. 37 Issue 10 Pg. 13687-13694 (Oct 2016) ISSN: 1423-0380 [Electronic] Netherlands
• PMID: 27473086 (Publication Type: Journal Article)

Chemical References

• Biomarkers, Tumor
• Protein Kinase Inhibitors
• EGFR protein, human
• ErbB Receptors

Topics

• Biomarkers, Tumor (genetics)
• Carcinoma, Non-Small-Cell Lung (classification, drug therapy, genetics, pathology)
• DNA Mutational Analysis (methods)
• Drug Resistance, Neoplasm (genetics)
• ErbB Receptors (genetics)
• Female
• Follow-Up Studies
• Humans
• Lung Neoplasms (classification, drug therapy, genetics, pathology)
• Male
• Middle Aged
• Mutation (genetics)
• Neoplasm Staging
• Prognosis
• Protein Kinase Inhibitors (therapeutic use)
• Real-Time Polymerase Chain Reaction
• Retrospective Studies
• Survival Rate