Blog June 26, 2017

Liquid Biopsy – Looking Beyond EGFR

In April, two important reports were published — one in the New England Journal of Medicine, one in Nature — that added evidence in support of liquid biopsy as a means of monitoring for the recurrence of cancer and to predict a patient’s response to adjuvant therapy. Both studies were based on data from the 900-patient “Tracking Cancer Evolution through Therapy (TRACERx)” trial in the United Kingdom, which aims to systematically characterize the genomic paths that non-small cell lung cancers (NSCLC) take as they grow, spread, and become resistant to treatment.


In the NEJM report, which compared genetic features of different regions of tumors taken from the first 100 patients in the trial, the investigators wrote that intratumoral heterogeneity that was mediated through chromosomal instability was associated with an increased risk of cancer recurrence or death — thus supporting the value of chromosomal instability as a prognostic predictor. In the Nature paper, the researchers analyzed blood samples from the same 100 patients using a liquid biopsy test developed by Natera. They took results from the sequencing of each patient’s tumor to design individualized multiplex PCR tests, and then used those to search for mutations in the cell-free tumor DNA (ctDNA) in each patient’s blood. Their results showed not only that tumor evolution could be tracked prospectively via liquid biopsy, but early disease recurrence could be detected and treatment outcomes predicted from such analysis.


Cancer is a disease that changes over time. Tumors are diverse, containing cells of different types and different genetic and epigenetic make-ups. Changes in these cells allow cancers to adapt to alterations in their environment, become resistant to therapies, and spread throughout the body. The ability to track such changes in real time and in response to treatment, to guide clinical decisions, and to predict and detect recurrence at the earliest — and most treatable — stages of disease is an important set of goals. Liquid biopsy methods — which look for circulating tumor cells and/or pieces of ctDNA from dead cancer cells in blood or urine — offer the potential for achieving this aim as well as for advancing our understanding of cancer mechanisms and potential new drug discovery targets in a non-invasive manner.


So far, most clinical experience with liquid biopsy approaches has been in identifying actionable mutations in patients with later-stage cancers, where tumors are bulky and prone to shedding cells. The majority of these approaches remain costly laboratory developed tests (LTDs), which do not require approval or clearance by the U.S. Food and Drug Administration. Clinicians have raised concerns regarding the analytical and clinical validity of many of these tests, and groups like the American Association of Cancer Research (AACR) and the Association of Molecular Pathology (AMP) and others are working to establish guidelines around these issues.  But in June 2016, Roche gained approval for a blood-based test to detect EGFR mutations associated with NSCLC, for use as a companion diagnostic to help identify patients appropriate for treatment with Genentech’s Tarceva (erlotinib) – a first for a liquid biopsy test. And in September 2016, the FDA expanded the labeling for this test to be employed as a companion diagnostic to AstraZeneca’s Tagrisso (osimertinib) in cases of NSCLC where a tissue biopsy cannot be obtained. The Roche EGFR test was originally approved in 2014 for use on DNA derived from NSCLC tumor biopsy samples.


But liquid biopsy is a rapidly advancing field, where a wide variety of technologies are being applied — including those employing NGS, PCR, and proteomic, exosomic and cell-based methods. Moreover, there is considerable and growing investment in the liquid biopsy field. Grail has raised $1 billion from investors including Amazon, Merck, Bristol-Meyers Squibb, and Johnson & Johnson’s venture capital arm to advance its technology for the early detection of cancer. Freenome has raised over $65 million, and Guardant Health has raised $190 million so far, both from prominent venture investors. And numerous other start-ups and established companies are active in the field.


More work remains to be done to verify the clinical utility of this technology, and the high cost of most approaches needs to come down. But liquid biopsy is on its way to becoming a useful, easier way to monitor tumor evolution, predict recurrence and guide treatment — and eventually, enable the detection of cancer at its earliest stages.