Philip C. Mack, PhD
The optimal use of emerging assays that characterize molecular abnormalities from plasma in late-stage non–small cell lung cancer (NSCLC) will be to augment tissue biopsies at initial diagnosis and to evaluate patients for second- and third-line therapies, according to Philip C. Mack, PhD.
And, although these so-called “liquid biopsies” are not expected to supplant tissue-based testing for diagnosis and first-line analysis, the growing list of actionable targets in NSCLC make it imperative that molecular testing cover a broad range of genes no matter what technology is used, Mack noted.
Mack, director of Molecular Pharmacology at the UC Davis Comprehensive Cancer Center, discussed liquid biopsies in the context of NSCLC genomics in an interview with OncLive in advance of his presentation about developments in the field during the 2016 International Lung Cancer Congress.
There are several roles that liquid biopsies, defined as tests that detect the presence of somatic mutations or alterations in circulating tumor DNA (ctDNA), can fulfill in managing patients with advanced or metastatic NSCLC, Mack noted.
At initial diagnosis, there might not be enough tissue left after the pathological examination to conduct the more extensive molecular testing that would help inform therapy selection, he said. Then, as patients progress or develop resistance to a first-line targeted therapy, liquid biopsies provide a noninvasive means of detecting mutations that can be attacked with drugs in later lines of therapy.
“I don’t think that a liquid biopsy will replace an initial diagnostic biopsy. You still need that actual specimen for a pathologist to review,” said Mack. “However, it can provide a wealth of information that can complement and expand the information that we have on those tumors from the get-go, particularly in terms of mutations that are potentially actionable, and may indicate appropriate assignment to a targeted therapy.
“One of the major advantages of liquid biopsies is their ability to detect emergent resistance mutations when patients begin to progress on an otherwise effective therapy,” Mack noted. “And you can do this without having to form a secondary biopsy, which is, of course, an arduous procedure with myriad safety risks that often yields uninformative results.”
Mack, however, has several caveats about the promising new technology. Importantly, a positive mutational finding on a liquid biopsy should be used to recommend a targeted therapy, but a negative finding should not exempt a patient from receiving a matching drug, Mack said.
“My cardinal rule for liquid biopsies—assuming you’re using a validated assay and a certified laboratory—is that a positive result is actionable, but a negative result should be considered neither positive nor negative. It is uninterpretable for the factor of interest,” Mack said.
“In many cases, the tumor just may not be shedding enough DNA for detection,” he continued. “The tumor might be positive for your factor of interest, for example, the EGFR
T790M resistance mutation. But that tumor that is growing is not yet shedding enough DNA in circulation for it to be detected. So it can be tumor-positive, but plasma-negative.”
Mack said some lung cancer specialists are now recommending that when the need for a second biopsy arises, clinicians start with a liquid biopsy. “If you get information from that liquid biopsy, then you can proceed with your treatment course,” he said. “If you do not get any information, you make no assumptions about it, and you proceed with a second biopsy.”
The ability to evaluate driver mutations in NSCLC will become increasingly important as the number of actionable mutations increases, researchers have noted. There are approximately 12 molecular markers now that “could be very informative,” Mack said.
The National Comprehensive Cancer Network recommends broad molecular profiling for patients with metastatic NSCLC.1 Although currently approved therapies are aimed at EGFR mutations and ALK rearrangements, emerging new targets include BRAF
V600E mutations, MET
amplification or MET
exon 14 skipping mutations, RET
rearrangements, and HER2
mutations, according to the guidelines.1
“It’s really essential in the modern era to be doing a comprehensive biomarker assessment in lung adenocarcinoma,” Mack said. “Whether it’s by tissue or plasma, the physicians owe it to their patients to perform these tests.”
Evidence Builds for Assays
The liquid biopsy field has drawn intense interest from biopharmaceutical companies in recent years, and new developments are unfolding rapidly.