A recent study showed that plasma-based genotyping of circulating tumor DNA from patients with metastatic non–small cell lung cancer detected clinically relevant targetable driver and resistance mutations in roughly one third of cases, whether used alone or in combination with sequencing data from tumor tissue. This means that liquid biopsies are a valid clinical option for many patients. In addition, more than 85% of patients who received targeted treatment based on the liquid biopsy findings experienced a complete or partial response or stable disease.

National Comprehensive Cancer Network guidelines recommend that patients with advanced or metastatic non–small cell lung cancer (NSCLC) be screened for tumor mutations to help identify treatments most likely to be effective. Typically, this is done by genotyping biopsied tumor samples, but tissue isn't always available or easy to obtain, prompting researchers to investigate the value of plasma-based next-generation sequencing (NGS), or so-called liquid biopsies.

In a recent study conducted in patients with metastatic NSCLC, investigators showed that by performing NGS on circulating tumor DNA in plasma, they could detect “targetable” mutations—those for which a targeted therapy exists—in one third of patients. This number increased only slightly in patients for whom both liquid and tissue biopsy were ordered.

Erica Carpenter, PhD, of the University of Pennsylvania in Philadelphia, the study's senior investigator, says that these results “demonstrate strong clinical utility for the use of liquid biopsy in metastatic NSCLC.”

The study analyzed NGS data from 323 patients with metastatic NSCLC, focusing on clinically relevant, therapeutically targetable mutations in EGFR, ALK, MET, BRCA1, ROS1, RET, ERBB2/HER2, and BRAF. Ninety-four patients’ physicians ordered a liquid biopsy; targeted mutations were identified in 31 (33%) of them. Concurrent liquid and tissue biopsies were ordered for the 229 remaining patients. Although tissue testing could not be completed for 101 of them, tissue testing for the rest identified targetable mutations in 47 (20.5%). Considering their liquid biopsy sequencing data as well increased the number of patients with targetable mutations to 82 (35.8%), little more than in the group for whom only liquid biopsy had been ordered.

Strikingly, of the 42 patients who received personalized therapy based on liquid biopsy data alone, 36 (85.7%) achieved either a complete or partial response or experienced stable disease.

“The response rates to treatment were remarkable,” says Alberto Bardelli, PhD, of the University of Torino in Italy, who was not involved in the study.

Carpenter's team now wants to determine the sensitivity of liquid biopsy in various scenarios, based on the study's preliminary findings. For example, liquid biopsy was equivalent to tissue biopsy at uncovering targetable mutations among the 13 patients whose cancer had metastasized to the liver. However, it found no targetable mutations among the 13 patients whose tumors were confined to the thoracic cavity, whereas tissue biopsy detected mutations in seven patients.

“If we can better define the clinical settings in which liquid biopsy can be used as a first diagnostic step to identify mutations, that may help avoid additional invasive procedures and hasten delivery of personalized therapy,” says Charu Aggarwal, MD, of the University of Pennsylvania, lead author of the study.

Liquid biopsies are already routine for patients with NSCLC at some institutions, including Carpenter's. However, Bardelli says their use remains mostly confined to clinical trials, though that could soon change. He expects that in the next 5 years liquid biopsies will be used to determine which patients who have had surgery should receive chemotherapy. “This will be a huge milestone in the field,” he says.

Timothy Craig Allen, MD, of the University of Mississippi in Jackson, believes that prospective studies like this one are “moving liquid biopsy closer and closer to becoming the standard of care.” However, he notes that to change clinical practice, standardizing plasma-based genotyping methods so that physicians do not have to choose from among a bewildering number of test options—and educating physicians about the benefits of liquid biopsy—will be key. –Kristin Harper