The Emerging Role of Liquid Biopsies in Lung Cancer

H. Jack West, MD


June 11, 2015

I participated in a CME symposium about emerging treatments for EGFR mutation-positive non-small cell lung cancer at the American Society of Clinical Oncology (ASCO) annual meeting on Monday, June 1, focusing particularly on acquired resistance. My talk centered on the need for a rebiopsy to document the acquired resistance mutation T790M, which has been required for most trials of the novel third-generation EGFR tyrosine kinase inhibitors rociletinib (CO-1686) and AZD9291. As you might expect, there are situations in which getting a repeat biopsy in the setting of progression can be challenging, and I've had an occasional patient who has had a nondiagnostic biopsy or no areas that were amenable to biopsy, which precluded them from participating in a trial with one of these very promising agents.

In my talk I included the emerging work on "liquid biopsies," running serum samples from blood draws that can be tested for circulating tumor cells or circulating free DNA. This was also the subject of several posters in the lung cancer section at ASCO, and even one poster from Dr Hatim Husain[1] at University of California, San Diego, that describes work on DNA testing from urine. This field is still evolving, but at this point I would say that these technologies are really on the cusp of being clinically useful. The work presented at ASCO by Dr Lecia Sequist[2] from Dana-Farber Cancer Institute on rociletinib, as well as a publication by Drs Karachaliou and colleagues[3] in JAMA Oncology earlier this year, demonstrates that the sensitivity for EGFR mutations is in the 80% range in reasonably large studies.

Although that's not 100%, we need to remember that tissue biopsies don't have a sensitivity of 100% and aren't a clear gold standard. Many studies have demonstrated that there is a 15%-25% discordance rate between mutation tests in different parts of the same tumor, between the primary tumor and distant metastases, or between different lung nodules in multifocal metastatic disease. So both approaches are inherently fallible, but serum or perhaps urine testing can potentially overcome spatial heterogeneity by providing a view of cancer throughout the body—not limited to a specific location.

A recent patient died within weeks of a repeat biopsy that demonstrated that she had a T790M mutation, which had followed delays due to difficulty getting to an accessible lesion. We missed the opportunity to treat her with a potentially effective agent for her. Since then, I've tested an assay of circulating free DNA from serum on a few patients, documenting an activating EGFR mutation in a patient who has responded to erlotinib (Tarceva®) but tested as EGFR wild type from tumor. Another patient with minimally progressing acquired resistance, still on erlotinib, was just found to have both her original activating mutation and T790M in serum. In both cases, a blood-based test has provided results that will change management. It hasn't been perfect and it won't replace tissue biopsies, but I think that serum-based testing (and perhaps eventually urine-based testing) of circulating free DNA and perhaps circulating tumor cells will play a central role, especially as we have a greater incentive to do repeat biopsies in our patients.


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