PREDICTIVE ROLE OF EGFR MUTATIONS FOR NSCLC

Using a novel polymerase chain reaction assay “to efficiently assess” epidermal growth factor receptor (EGFR) mutations in circulating free DNA (cfDNA) from blood samples of patients with advanced non–small cell lung cancer (NSCLC), the Spanish Lung Cancer Group has “shown that the EGFR L858R mutation in cfDNA is a negative prognostic biomarker.”

The group reached this conclusion after conducting a prespecified analysis of a secondary objective of the European Tarceva vs Chemotherapy (EURTAC) trial. That trial demonstrated greater efficacy of erlotinib compared with chemotherapy for the first-line treatment of European patients with advanced NSCLC and the L858R mutation in exon 21 or a deletion in exon 19. In the recently reported analysis by Karachaliou et al, published in JAMA Oncology, median overall survival was shorter in patients with the L848R mutation in cfDNA than in patients with the exon 19 deletion.

In an accompanying editorial, corresponding author Roy S. Herbst, MD, PhD, of the Yale School of Medicine, New Haven, Connecticut, and coauthors stated, “The updated EURTAC study demonstrates that mutations detected in cfDNA are prognostic and consistent with data obtained from tumor biopsies.” The editorialists noted that “the potential benefits of liquid biopsies include a better evaluation of the tumor genome landscape with the identification of a comprehensive set of targetable mutations and the serial noninvasive monitoring, which may allow the detection of additional mutations from emerging subclones, including those involved in the development of acquired resistance. Finally, the presence of specific mutations in cfDNA may help identify populations of patients who are likely to have worse (or better) outcomes and who may require alternative treatments.”

Assay Yields High Sensitivity, Specificity

Using the peptide nucleic acid–mediated 5´ nuclease real-time polymerase chain reaction (TaqMan) assay, the Spanish Lung Cancer Group examined EGFR mutations in cfDNA isolated from 97 baseline blood samples from patients in the EURTAC trial from 2007 to 2011. These patients had advanced NSCLC, oncogenic EGFR mutations in the tumor, no prior chemotherapy for metastatic disease, and were treated in the trial with erlotinib or chemotherapy. The authors noted that the “rate of detection of EGFR mutations in cfDNA varies according to the method used” and that the TaqMan assay they developed “yields 78% sensitivity and 100% specificity.”

EGFR mutations in cfDNA were detected in 76 of 97 (78%) patients with usable blood samples. Median overall survival was 13.7 months in patients with the L858R mutation in cfDNA vs 30.0 months in those with the exon 19 deletion (P < .001).

Marker of Shorter Survival 

“Univariate analyses of patients with EGFR mutations in cfDNA identified the L858R mutation in tumor tissue or in cfDNA as a marker of shorter [overall survival] (hazard ratio [HR], 2.70 [95% CI, 1.60-4.56]; P < .001) and [progression-free survival] (HR, 2.04 [95% CI, 1.20–3.48]; P = .008). For patients with the L858R mutation in tissue, median [overall survival] was 13.7 (95% CI, 7.1–17.7) months for patients with the L858R mutation in cfDNA and 27.7 (95% CI, 16.1–46.2) months for those in whom the mutation was not detected in cfDNA (HR, 2.22 [95% CI, 1.09–4.52]; P = .03),” the researchers added.

“In the multivariate analysis of the 76 patients with EGFR mutations in cfDNA, only erlotinib treatment remained an independent predictor of longer [progression-free survival] (HR, 0.41 [95% CI, 0.23-0.74]; P = .003).”

The authors noted that the “finding that the L858R mutation detected in cfDNA exerts a negative influence on survival indicates that a prospective study is warranted to examine the use of EGFRmutations in cfDNA as a viable surrogate biomarker. The Spanish Lung Cancer Group is participating in two ongoing clinical trials in patients with advanced-stage EGFR-mutant NSCLC, in which plasma and serum are being collected for EGFR mutation testing in cfDNA at baseline, at response, and at progression: the European phase II BELIEF trial (NCT01562028) of erlotinib plus bevacizumab [Avastin] and the Spanish Lung Cancer Group phase II GOAL trial (NCT01513174) comparing gefitinib [Iressa] plus olaparib [Lynparza] vs gefitinib alone. These trials will shed additional light on EGFRmutation assessment in cfDNA and pave the way for its implementation in clinical care.”

Rafael Rossell, MD, of Catalan Institute of Oncology, is the corresponding author for the JAMA Oncology article.

Work in Dr. Rossell’s laboratory if partially supported by grants from La Caixa Foundation and the Red Tematica de Investigacion Cooperativa en Cancer. For full disclosures of the study authors, visit oncology.jamanetwork.com.