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EGFR L858R mutation in circulating free DNA linked to NSCLC outcomes
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A liquid biopsy approach efficiently assessed EGFR mutations in the circulating free DNA of blood samples from patients with non–small cell lung cancer, according to study results.
Patients who harbored EGFR L858R mutations in their circulating free DNA demonstrated shorter OS, results also showed.
Rafael Rosell, MD, of the Cancer Biology and Precision Medicine Program at Catalan Institute of Oncology in Barcelona, and colleagues evaluated data from 97 patients with advanced NSCLC enrolled on the EURTAC trial, which demonstrated superior outcomes with first-line erlotinib (Tarceva; Genentech, Astellas Oncology) vs. chemotherapy. All patients harbored oncogenic EGFR mutations in their tumor tissue.
Researchers used a novel peptide nucleic acid-mediated 5’ nuclease real-time polymerase chain reaction assay (TaqMan) to evaluate patients’ baseline blood samples. Overall, 76 (78%) of the patients had EGFR mutations in their circulating free DNA.
Median follow-up was 49.4 months.
EGFR exon 19 deletions were associated with prolonged median OS compared with EGFR L858R mutations in tumor tissue (24.9 months vs. 17.7 months; P = .006) and circulating free DNA (30 months vs. 13.7 months; P ˂ .001). The difference in OS with exon 19 deletions vs. L858R mutations also was apparent in patients treated with erlotinib (34.4 months vs. 13.7 months; P = .001).
Among 41 patients who harbored EGFR L858R mutations in their tissue, those who also had the L858R mutation in their circulating free DNA demonstrated significantly shorter OS (13.7 months vs. 27.7 months; HR = 2.2; 95% CI, 1.09-4.52). However, patients with the exon 19 deletion in both their tissue and blood samples demonstrated prolonged OS compared with patients who only had exon 19 deletion in their tissue (30 months vs. 14.2 months; HR = 0.39; 95% CI, 0.17-0.89).
Results of univariate analyses indicated patients with EGFR mutations in their circulating free DNA who had the L858R mutation in their tissue or blood samples demonstrated significantly shorter OS (HR = 2.7; 95% CI, 1.6-4.56) and PFS (HR = 2.04; 95% CI, 1.2-3.48). Multivariate analyses indicated only treatment with erlotinib was associated with prolonged PFS (HR = 0.41; 95% CI, 0.23-0.74).
“Using the … TaqMan assay, we have shown that the EGFR L858R mutation in circulating free DNA is a negative prognostic biomarker,” Rosell and colleagues concluded. “Although EGFR tyrosine kinase inhibitor therapy improved PFS over chemotherapy and still remains the standard of care for patients with L858R mutations, our results indicate the need for new combination therapies in this subgroup of patients.”
These data demonstrate the potential for liquid biopsies to help inform treatment decisions, Daniel Morgensztern, MD, of Washington University School of Medicine, and Katerina Politi, PhD, and Roy S. Herbst, MD, PhD, both of Yale Medical School, wrote in an invited commentary.
“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,” Morgensztern, Politi and Herbst wrote. “The presence of specific mutations in circulating free DNA may help identify populations of patients who are likely to have worse (or better) outcomes and who may require alternative treatments.” – by Alexandra Todak
Disclosure: The researchers report consultant/advisory roles with AstraZeneca, Boehringer Ingelheim, Lilly, Novartis, Pfizer and Roche. Morgensztern, Politi and Herbst report speaker/advisory roles with, research funding from and equity ownership in AstraZeneca, Boehringer Ingelheim, Celgene, Genentech, MolecularMD and Takeda.
Perspective
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Geoffrey R. Oxnard, MD
Today, oncologists broadly accept that EGFR genotyping is a fundamental biomarker in lung cancer care, and yet not all patients with lung adenocarcinoma receive tumor genotyping. This is in part due to the logistical challenges of identifying an adequate tumor specimen to genotype, which sometimes requires a patient to undergo a new biopsy. This manuscript by Karachaliou and colleagues highlights an emerging option for such patients. Rather than tumor genotyping, these patients can receive genotyping of their cell-free plasma DNA. Although cell-free plasma DNA genotyping assays are not as sensitive as tumor genotyping (78% sensitivity in this report), we see here that patients who are EGFR positive in plasma gain the same dramatic PFS benefit from erlotinib (Tarceva; Genentech, Astellas Oncology) vs. chemotherapy. Already, it is permissible in Europe to prescribe gefitinib (Iressa, AstraZeneca) for a patient with lung cancer based on positive plasma genotyping if tumor genotyping is not feasible. Plasma genotyping assays also are emerging for use in the United States. In the near future, I anticipate that genotyping of cell-free plasma DNA will become a standard method used to screen patients with lung cancer for presence of a targetable genotype, potentially reserving a biopsy for those with negative plasma genotyping. In the meantime, further research into how to optimally use these new plasma genotyping assays is needed.
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