Large Study Gives Boost to Liquid Biopsy Testing for Mutations

Anita T. Shaffer @Shaffer1
Published: Saturday, Jun 04, 2016

Philip Mack, PhD

Philip Mack, PhD

A genomic analysis of circulating tumor DNA (ctDNA) in blood samples from more than 15,000 patients representing multiple cancer types demonstrated that the liquid biopsy testing method correlated closely with mutations described in databases and in some cases from tumor biopsies, according to research presented at the 2016 ASCO Annual Meeting.

ASCO experts said the research, described as the largest-ever liquid biopsy study, marks an important step forward for the field but more research is needed to establish the clinical utility of assays being developed throughout the testing industry.

The liquid biopsy sector has been booming in recent years, as companies scramble to commercialize technologies that can extract genomic information from ctDNA and other blood- or urine-based markers without the need to rely on often difficult-to-obtain tissue samples.

In the study highlighted at ASCO, the Guardant360 next-generation sequencing test, which targets 70 genes, was used to analyze somatic mutations among patients with 50 different tumor types. Most of the results were compared with data from The Cancer Genome Atlas (TCGA) and some were correlated with results of genetic testing on tumor tissue.

“The major finding of the study was that ctDNA mutation patterns were highly concordant with tissue analysis as reported by the TCGA and plasma analysis as reported in this study,” said research presenter Philip Mack, PhD, professor and director of Molecular Pharmacology at the University of California Davis Comprehensive Cancer Center, during an ASCO press briefing.

Mack said conducting mutation testing on tissue samples is still the gold standard but that the quantity and quality of tissue available for genomic testing after pathological analysis is often inadequate. He also noted that liquid biopsies would be particularly useful for assessing patients during the course of their disease.

“Probably the biggest role for plasma analysis will be occurring down the road as patients are progressing on therapies as their tumors are evolving as a way to monitor progression of those cancers,” said Mack.

Mack and colleagues analyzed samples from 15,191 patients with advanced lung cancer (37%), breast cancer (14%), colorectal cancer (10%), and other cancers (39%). In all, 17,628 blood samples were tested for ctDNA; most results were compared with the TCGA, while findings for 398 patients were correlated with results of genetic testing on tumor tissue.

The correlations between the assay and multiple cancer genes and classes of alterations ranged from 0.92 to 0.99. For example, the correlation with EGFR drivers between the ctDNA test and TCGA was 0.92. For the available tumor samples, the assay matched testing for key abnormalities in EGFR, BRAF, KRAS, ALK, RET, and ROS1, at the rate of 94% to 100%. Additionally, the assay was able to detect mutations at low levels of ctDNA. Half of all alterations were detected at or below ctDNA of 0.4%, Mack indicated. Overall, ctDNA mutations could be detected in 83% of the blood samples analyzed.

However, not all patients had sufficient ctDNA for the plasma-based test particularly individuals with glioblastoma, which researchers believe might be because the cell-free DNA cannot traverse the blood-brain barrier. As a result, researchers are seeking to improve the sensitivity of the test for extremely low levels of ctDNA, according to an ASCO press release.

Notably, ctDNA testing for the EGFR T790M resistance mutation did not correlate with the TCGA, probably because patients in the tissue-based population had not yet received the anti-EGFR inhibitor therapy that promotes the mutation, researchers indicated.

In the area of clinical utility, the assay pointed to potential treatment options for nearly two-thirds of the patients, including FDA-approved drugs and agents being evaluated in clinical trials. Mack said that alterations detectable in ctDNA fractions as low as 0.06% responded to treatment.

For patients with lung cancer, liquid biopsy would be particularly helpful, the research indicated. Of 362 lung cancer cases, 63% had insufficient tissue for testing, but these samples could be evaluated for ctDNA.

Investigators said the research suggests 4 classes of clinical outcome benefit using the liquid biopsy:


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