Largest Liquid Biopsy Study: Compares With Tissue Sampling

Kate Johnson

June 09, 2016

CHICAGO — An analysis of circulating tumor (ct)DNA in more than 17,000 liquid biopsies reveals genetic mutations similar to those found with traditional tissue biopsy.

The findings, presented here at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting, "provide important evidence on the road to demonstrating the clinical utility of liquid biopsies," Richard Schilsky, MD, ASCO chief medical officer, told Medscape Medical News.

Next-generation sequencing of ctDNA from blood widens options for oncologists in terms of personalizing cancer therapy and monitoring response to treatment, experts said.

"We're increasingly using genomic data from day to day in our clinics to guide therapy, and tests such as this provide a useful alternative to tissue-based testing," Sumanta Kumar Pal, MD, ASCO spokesperson, said during a press conference. He noted that ease of access and convenience for collecting serial samples are advantages of liquid over tissue biopsies.

Dr Sumanta Pal

"Many of our patients in the clinic have tumors that are challenging to access, such as in the bone or the brain; these are very precarious sites [for tissue biopsy]," he explained. "Having a blood-based test to assess genomic profile is key. It's a much easier way to continuously access genomic data during the course of treatment, and it is certainly much easier than subjecting a patient to repeated biopsies."

Other Similar Tests Available

The study, which used the Guardant360 liquid biopsy assay "represents the largest experience in this domain today," said Dr Pal, explaining why ASCO highlighted this particular study when there are several other commercially available liquid biopsy assays competing for a spot in this field of cancer diagnostics and management.

Dr Don Dizon

"There are multiple platforms available; it's not the only technology that's being evaluated. It's way too early to tell which one we should be using," said Don Dizon, MD, from the Massachusetts General Hospital Cancer Center in Boston, who is chair of the ASCO Cancer Communications Committee.

"Cynvenio and Foundation Medicine, among others, have liquid biopsy assays that use different techniques or gene profiles," Dr Pal told Medscape Medical News. "At some point, we're going to have to refine our approach and identify which assay is better than the others. I think some juxtaposition of these assays in a prospective clinical trial is warranted."

Study Details

The researchers used 17,628 liquid biopsies from 15,191 patients with more than 50 different types of advanced cancer, including lung (37%), breast (14%), and colorectal (10%).

The assay was used to profile major classes of gene alterations that drive tumor growth, including EGFR, BRAF, KRAS, ALK, RET, and ROS1.

Dr Philip Mack

When results were compared with mutation patterns seen in 9077 tissue biopsies in The Cancer Genome Atlas (TCGA), "the detection of key cancer mutations in plasma ctDNA occurred at expected frequencies and distribution," reported Philip Mack, PhD, professor and director of molecular pharmacology at the University of California, Davis Comprehensive Cancer Center.

In 49% of patients, these biomarkers were associated with targeted drugs approved by the US Food and Drug Administration (FDA), and in 27%, the liquid biopsy picked up "actionable resistance targets," meaning resistance mutations for which there are approved medications, he said.

One example is the EGFR gene, which is "critically important to lung cancer patients. If they harbor one of these mutations, they are likely to have an exquisite response to one of the FDA-approved EGFR tyrosine kinase inhibitors," said Dr Mack.

Although tissue and liquid biopsy identified similar EGFR mutations in this gene, there was one important exception — the liquid biopsy showed high levels of the T790M resistance mutation not seen in the tissue sample.

One important caveat about this comparison is that tissue samples from the TCGA were taken before treatment in patients with all stages of cancer, whereas liquid biopsies were obtained from treated patients (generally second-line or higher) a mean of 748 days after diagnosis.

T790M resistance mutations are typically not present at the time of initial biopsy, but emerge as patients progress on therapy, Dr Mack explained. In this context, liquid biopsy can guide the choice of new therapy, he added.

In the clinic, the finding of a T790M mutation would mean that the lung cancer patient is eligible for treatment with a third-generation EGFR inhibitor, such as osimertinib (Tagrisso, AstraZeneca). This drug was launched with a companion diagnostic test (cobas EGFR Mutation Test v2) to detect the T790M mutation, but the test is carried out on tumor tissue samples. Liquid biopsies offer that information from blood, but they also offer information about many other mutations, which, at this point, might not be clinically useful.

Another advantage of liquid biopsy is that it can overcome the problems faced with insufficient tissue, said Dr Mack. In some cases, once a tissue biopsy is used for diagnosis and initial testing, there is very little left for further analysis, but being able to serially sample with liquid biopsy can overcome this.

Although many experts believe there will be a strong role for liquid biopsy, it will likely serve to complement rather than replace tissue biopsy, said Dr Mack.

"There's always going to be a role for tissue-based biopsies, or pathologic assessment of morphology. It's still considered the gold standard for mutation testing," Dr Dizon said. "However, in many cases, the tissue sample may be insufficient in quality or quantity to allow a broad array of testing, and situation plasma analysis can represent a very good complementary source of information."

Great Potential, But Issues Around Utility

 
Just because a test can be done doesn't mean it should be done.
 

"The big issue for all of us is going to be around the issue of utility," said Dr Dizon. "Before we even choose a liquid biopsy, we need to ask ourselves what we're going to do with that information."

"Just because a test can be done doesn't mean it should be done, doesn't mean it's informative for it to be done. The burden is on all of us to demonstrate the true utility of doing this testing," said Dr Schilsky. "This is a rapidly evolving field; we need a lot of data to guide the clinical usefulness of these kinds of test. This is an important study with a lot of important new information being presented that leads us down that path, but we continue to need to develop new data."

"Surveillance of mutations that might lead to resistance using genetic analyses of ctDNA has become mandatory in the management of patients with EGFR-mutant NSCLC, and is a rapidly advancing area of interest in melanoma, CRC, and other types of tumors," Rafael Rosell, MD, director of the cancer biology and precision medicine program at the Catalan Institute of Oncology, and Niki Karachaliou, MD, PhD, director of the Rosell Medical Oncology Service at University Hospital Sagrat Cor, in Barcelona, Spain, write in a recent report (Nat Rev Clin Oncol. Published online June 1, 2016).

"Oncologists are excited about ctDNA analysis, although further refinement of these techniques is required," the pair adds.

 
By finding actionable mutations within the blood, we hopefully have a tool that can increase the number of patients eligible for personalized therapies.
 

"By finding actionable mutations within the blood, we hopefully have a tool that can increase the number of patients eligible for personalized therapies and for clinical trials who may not have had the opportunity before due to the issues associated with tumor biopsies, such as risk, cost, and heterogeneity," they write.

There is a "near-perfect specificity and high sensitivity" of liquid biopsy, compared with the tissue sampling in the study, Drs Rosell and Karachaliou told Medscape Medical News.

"Blood genotyping has great potential as a rapid, noninvasive way of screening a cancer for common genetic fingerprints, while avoiding the challenges of traditional invasive biopsies. This is even more important for tumors like lung cancer, where in almost 25% of the cases, the tissue from small biopsies is insufficient to execute the growing list of genotyping reactions recommended for optimal care of lung cancer patients," said Dr Karachaliou.

Dr Schilsky, Dr Rosell, and Dr Karachaliou have disclosed no relevant financial relationships. Dr Pal reports financial relationships with Astellas Pharma, Medivation, Novartis, Aveo, Bristol-Myers Squibb, Exelixis, Genentech, Myriad Pharmaceuticals, and Pfizer. Dr Dizon reports receiving research funding from Aeterna Zentaris. Dr Mack reports financial relationships with Guardant Health, MolecularMD, Apton Biosystems, AstraZeneca, and Novartis, and Boehringer Ingelheim.

American Society of Clinical Oncology (ASCO) 2016 Annual Meeting: Abstract LBA11501. Presented June 7, 2016.

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