New Evidence Supports Use of Liquid Biopsies in Lung Cancer

Liquid biopsies were able to detect mutations in patients with non-small cell lung cancer (NSCLC) that closely paralleled mutations identified from tissue biopsies.

Furthermore, in several cases, liquid biopsies were able to capture clinically-relevant mutations that tissue biopsies did not identify, a study published in Clinical Cancer Research found.

“This represents a bit of a paradigm shift,” said senior study author Erica L. Carpenter, PhD, MBA. “The tissue biopsy sequencing result has been considered the gold standard against which one compares the ctDNA result. Our work suggests that one can act on a ctDNA result, even in the absence of so-called gold standard, and get a clinical response in these patients. It also offers the advantage of testing without discomfort to patients and possible risks associated with invasive biopsies.”

For the study, researchers enrolled 102 consecutive patients with advanced NSCLC who were treated between February 2015 and March 2016. The participants had their blood samples sent for ctDNA testing as part of their routine clinical care.

Sixty-eight percent of participants were women with adenocarcinoma (81%) and stage IV cancer (96%), and each had different courses of treatment for their disease.

In each of the patients, liquid biopsy samples were collected, and sent to Guardant Health for genomic analysis, utilizing the 70 gene Guardant360 panel. For the tissue samples, researchers were only able to collect them in 50 patients, and subsequently analyze them at Penn’s Center for Personalized Diagnostics with 47-gene panel.

Out of the 50 patients, 41 mutations were detected with both methods. There were 24 therapeutically targetable driver EGFR mutations detected in the tissue samples and 19 in the ctDNA samples.

When the samples were obtained concurrently, there was nearly 100% concordance between the 2 tests. The discordance increased when the blood samples were collected at longer intervals after the tissue sample, according to the study.

Authors noted a potential explanation could be that the blood test is able to detect new mutations that evolved to resist treatment and might not be detectable at the time of the initial tissue test. The EGFR T790M resistance mutation was identified in 8 liquid biopsy samples, and 4 tissue samples.

Researchers also conducted serial liquid biopsies on 6 patients as part of disease surveillance for the study. They found that in all 6 of the cases, the results helped guide clinical decision-making by identifying a driver or resistance mutation amenable to targeted therapy, or by confirming that chemotherapy was most likely the best course of treatment when a tissue sample was not possible.

In an additional part of the study, researchers described the clinical history of 3 participants who had ctDNA detect the emergence of therapeutically-targetable variants over the course of their therapy. In one patient, metastatic disease was present at diagnosis, with a tissue biopsy detecting no variants in EGFR, ROS1, or ALK. After the patient was referred to Penn, the ctDNA testing showed an EML4-ALF translocation and a TP53 mutation.

The patient was started on crizotinib monotherapy, and saw a significant improvement in symptoms. Two months after therapy, another ctDNA test showed a decrease in EML4-ALK while the TP53 was undetectable.

This correlated with symptomatic and radiographic improvement. The other 2 patients saw similar success. As each mutation was detected with ctDNA next generation sequencing, they were cross-referenced with available FDA-approved, off-label, or investigational therapies.

Seventy percent of participants were determined to have a relevant clinical trial available, with 55% of patients who had an off-label targeted therapy that could potentially be used, and 31% who had an FDA-approved therapy available to target the detected mutation.

According to researchers, when taken together, these data suggest that liquid biopsies for NSCLC patients can yield results with high clinical relevance, which includes the detection of targetable mutations in ALK, EGFR, and other genes.

“The ever-expanding number of targeted therapies for lung cancer patients has been accompanied by a need for diagnostics with real-time detection of therapeutically targetable mutations,” said study co-author Corey J. Langer, MD. “More and more, liquid biopsies are proving to help fill this need. While tissue samples will likely remain a major part of the initial diagnostic process, this non-invasive approach appears to be another powerful tool in our toolbox to help determine the best course of treatment for lung cancer patients.”

Authors noted that the next step is to evaluate the utility of the liquid biopsy at diagnosis as a complement to tissue testing, and in the context of genetically heterogeneous metastatic disease. Although researchers were able to report on serial ctDNA testing for 6 of the participants, larger scale studies are needed to further evaluate ctDNA monitoring for treatment selecting, including patients who have no detectable targetable mutations, and may be candidates for checkpoint inhibitors.

The study is the largest of its kind to use clinical assay to monitor NSCLC patients.

“Being able to accurately predict when a patient may develop drug resistance could have profound implications for selecting appropriate cancer therapies for individual patients,” the authors wrote in a recent correlating article.