February 2016 Edition Vol.11, Issue 2

Hope and Hype: Questions Surround Liquid Biopsies

Hope and Hype: Questions Surround Liquid Biopsies

By Kathy Boltz, PhD

Questions surrounding liquid biopsies are plentiful. Such as, what is the correlation between blood and FFPE biopsy tissue? What about location and stage of disease? Along with, what should be tested, how comprehensively to test, and how to keep the price feasible?

To address some of the uncertainty surrounding liquid biopsies in oncology, we interviewed both Vincent Miller, MD, Chief Medical Officer of Foundation Medicine and David Spetzler, PhD, MBA, Chief Scientific Officer of Caris Life Sciences for this article.

Comprehensive genomic profiling through liquid biopsy

Liquid biopsies are noninvasive tests, usually of blood, that detect DNA, cells, or pieces of cells that are shed from tumors, including primary and metastatic sites. The appeal is obvious. Use a blood draw, rather than a biopsy of a solid tumor, to conduct comprehensive genomic analyses on patients whose solid tumor samples will not allow for that; monitor disease and its response to treatment through serial blood draws; and ideally, detect cancer very early through the blood testing.

According to Vincent Miller, MD, Chief Medical Officer of Foundation Medicine, genomic profiling is becoming accepted as warranted and helpful for patients with advanced stage disease. However, the amount of tissue obtained under an initial diagnostic biopsy may not be enough to allow genomic profiling for some patients. Patients with insufficient tissue may not be able to undergo a new biopsy because of their condition, the treating physician’s preference, or issues such as time and logistics. So, Dr. Miller feels that the clearest indication of when to use a liquid biopsy is in patients where no genomic profiling would be feasible from a traditional tissue-based biopsy.

Liquid biopsies have the potential to allow patients whose tissue biopsy is nondiagnostic or who do not have an area of tissue amenable to biopsy access to clinical trials. Foundation Medicine will soon launch Foundation Act, a genomic profiling circulation tumor DNA (ctDNA) assay that is designed to allow for the richest profiling possible from ctDNA.

This type of biopsy assay may benefit both patients seeking treatment in clinical trials and pharmaceutical companies seeking enrollment in clinical trials. As more genomic data become available, biopharma will be able to further analyze trial outcomes and possibly pinpoint biomarkers.

Dr. Miller sees two different types of liquid biopsies: the ctDNA genomic profiling assay and the monitoring type assay. “The ctDNA would be at a higher price point and it’s much more detailed and rich on the genomic side,” he said, while the monitoring assay “would be done at a lower price point and have narrower genomic content.”

Along with Foundation Act, Genomic Health is also launching a liquid biopsy assay, called Oncotype SEQ™, in the first half of 2016. Oncotype SEQ is a blood-based mutation panel that uses next-generation sequencing to identify actionable genomic alterations for the treatment of patients with late-stage lung, breast, colon, melanoma, ovarian, or gastrointestinal cancer. Genomic Health has plans to deliver several more liquid biopsy tests through its Oncotype IQ™ Genomic Intelligence Platform.

Monitoring biomarkers in NSCLC

Non-small cell lung cancer (NSCLC), which is typically detected at a late stage, has been an active area in the development of liquid biopsies. Difficulties obtaining adequate tissue samples are not uncommon in NSCLC. As third-generation EGFR tyrosine kinase inhibitors (TKIs) targeting the EGFR mutation T790M are becoming available, noninvasive approaches to detecting T790M are increasingly important to guide treatment over the course of the disease.

To examine the use of liquid biopsies for detecting the EGFR T790M mutation, a multi-institutional Stand-Up-To-Cancer collaboration compared tumor biopsies with analysis of circulating tumor cells (CTCs) and ctDNA from blood samples in 40 patients with NSCLC.1 The CTC- and ctDNA-based genotyping were unsuccessful in 20%-30% of the cases, but combining the analyses together enabled genotyping in all patients who had a blood sample available. The combined analyses identified the T790M mutation in 35% of patients (14/40) whose concurrent biopsy was negative or indeterminate.

At ASCO 2015, an innovative study in NSCLC was presented on monitoring urinary circulating tumor DNA for the early acquisition of T790M and understanding ctDNA kinetics in patients on second-line anti-EGFR treatment.2 When urine T790M was compared with tissue-positive samples from 14 patients, the sensitivity was 100%. Further, urine liquid biopsy detected the EGFR T790M mutation as much as 3 months before radiological progression occurred based on data from 24 patients, and ctDNA spikes that possibly correlated with tumor lysis were observed among the 13 patients monitored who were treated with second-line, anti-EGFR TKIs.

A different study in patients with NSCLC compared circulating free DNA (cfDNA) in baseline blood draws with biopsy tissue with known mutations.3 The study analyzed samples from 97 patients whose tissue samples indicated 1 of 2 EGFR mutations was present: either the exon 19 deletion or the L858R mutation in exon 21. These mutations were successfully assessed in corresponding cfDNA from baseline blood in 76 of the 97 patients (78%). 

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