Originally published February 26, 2020
Benjamin P. Levy, MD
During the past decade, unprecedented scientific advances in non–small cell lung cancer (NSCLC) have translated into meaningful improvements in patient outcomes. Many of these gains have been predicated on better characterization of tumor biology, including the identification of relevant, actionable mutations, which enables patients to receive genotype-directed therapies. Although tissue biopsies historically have been the reference standard for the diagnosis and genetic interrogation of patients with advanced-stage cancer, many real-world clinical challenges with biopsies remain, such as procedural complications, tissue heterogeneity (both spatial and temporal), tumor specimen inadequacy, and prolonged turnaround times.
The recent advent of cell-free DNA (cfDNA) or circulating-tumor DNA (ctDNA) platforms to genotype lung cancer has drastically altered the diagnostic paradigm in NSCLC. These platforms have a number of advantages: They are minimally invasive, have a rapid turnaround time, and can be performed serially. In addition, molecular alterations identified in ctDNA seem to be as predictive of response to targeted therapies as those identified in tissue. Recent data suggest that ctDNA may be more likely to reveal molecular alterations when compared with paired tissue from the same patient.
Brief Primer on ctDNA
First discovered in 1948 by Mandel and Metais, fragmented DNA or cfDNA has been associated with a number of conditions, including end-stage renal disease, myocardial infarction, stroke, and trauma. Multiple studies have shown a correlation between cfDNA levels and cellular injury and necrosis, processes relevant in cancer cell survival and propagation. As tumors increase in volume, the capacity of phagocytes to eliminate and clear apoptotic and necrotic fragments can be exceeded, leading to passive release of ctDNA, a source of cfDNA, into the bloodstream. Alternatively, in vitro studies have shown that DNA can be released by an active mechanism in which cancer cells spontaneously release DNA fragments into circulation. Depending on the tumor size and vascularity, the amount of ctDNA released into circulation can vary from 0.01% to 90% of all DNA present in plasma. Importantly, not all malignancies shed ctDNA, and release can depend both on tumor size and site (number and location) of metastases.