Circulating DNA in EGFR-mutated lung cancer

Abstract

Circulating tumor DNA (ctDNA) consists of short double stranded DNA fragments that are released by tumors including non-small cell lung cancer (NSCLC). With the identification of driver mutations in the epidermal growth factor receptor (EGFR) gene and development of targeted tyrosine kinase inhibitors (TKIs), the clinical outcome of NSCLC patients in this subgroup has improved tremendously.The gold standard to assess EGFR mutation is through tissue biopsy, which can be limited by difficulty in accessing the tumor, inability of patients to tolerate invasive procedures, insufficient sample for molecular testing and inability to capture intratumoral heterogeneity. The great need for rapid and accurate identification of activating EGFR mutations in NSCLC patients paves the road for ctDNA technology.Studies have demonstrated ctDNA to be a reliable complement to tumor genotyping. Platforms like digital polymerase chain reaction (PCR) and next-generation sequencing based analyses have made it possible to identify EGFR mutations in plasma with high sensitivity and specificity. This article will provide an overview on ctDNA in the context of EGFR mutated NSCLC, especially its emerging applications in diagnosis, disease surveillance, treatment monitoring and detection of resistance mechanisms.

Detection of plasma EGFR mutations for personalized treatment of lung cancer patients without pathologic diagnosis

“…Studies have shown that ctDNA analysis is able to detect driver EGFR mutations in patients' plasma with high sensitivity and specificity, correlating with clinical outcomes including ORR, PFS, and OS . In September 2014, the European Medicines Agency (EMA) recommended the use of plasma ctDNA for genotyping in cases where tissue sample was not available.…”

“…Studies have shown that ctDNA analysis is able to detect driver EGFR mutations in patients' plasma with high sensitivity and specificity, correlating with clinical outcomes including ORR, PFS, and OS. 4,10,11 In September 2014, the European Medicines Agency (EMA) recommended the use of plasma ctDNA for genotyping in cases where tissue sample was not available. The US Food and Drug Administration (FDA) approved the cobas ® EGFR Mutation Test v2 to detect the presence of specific NSCLC mutations (exon 19 deletion or exon 21 [L858R] substitution) in patients' blood to determine who would be candidates for treatment with erlotinib, as well as to detect patients with T790M mutations who would benefit from osimertinib.…”

“…Traditionally, molecular genotyping has been performed on tumor tissue. With advances in testing platforms, we can now detect these alterations in circulating tumor DNA (ctDNA) in patients' plasma with high accuracy, using next‐generation sequencing (NGS) or digital polymerase chain reaction (PCR) assays . Despite these advances, tissue biopsy and tumor genotyping remains the gold standard for initial diagnosis of patients with molecular genotyping conducted after histopathological diagnosis.…”

“…With advances in testing platforms, we can now detect these alterations in circulating tumor DNA (ctDNA) in patients' plasma with high accuracy, using next-generation sequencing (NGS) or digital polymerase chain reaction (PCR) assays. 4 Despite these advances, tissue biopsy and tumor genotyping remains the gold standard for initial diagnosis of patients with molecular genotyping conducted after histopathological diagnosis. This is done not only to delineate key pathologic features like histology and immune microenvironment, but also due to the approximately 30% false negative rate of detecting these mutations in ctDNA.…”

Emerging uses of biomarkers in lung cancer management

“…The last section focuses on the rapid introduction of blood-based biomarker testing into routine practice with Velcheti et al (8) providing a general review of the available and emerging technology for ctDNA and CTCbased approaches. Next, Singh et al (9) will review the already carefully validated use of ctDNA testing for upfront EGFR mutation and EGFR T790M detection. Lastly, Marmarelis et al (10) will explore the large diversity of up and coming opportunities for ctDNA utilization in the clinic to optimize patient care.…”