The spring has brought a wave of exciting news for Next-Generation Sequencing (NGS) tests in oncology and for liquid biopsy technologies. Liquid biopsy, typically non-invasive blood-based tests for circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs), has been long-hyped as a potential game-changer for cancer treatment. By identifying tumor-specific molecules in the bloodstream, a liquid biopsy can reduce or eliminate the need for invasive tissue biopsy, detect tumor mutations, and could help enable earlier diagnosis.

Start-up companies like GRAIL, Guardant Health, Natera and others have raised more than $1 billion in venture capital funding on the promise of more rapid tumor genotyping, repeated monitoring for resistance mutations, and less invasive diagnosis and screening.

At the annual conference of the American Association for Cancer Research (AACR) in April, liquid biopsy tests received considerable attention, including the first presentation of the opening session on liquid biopsy’s quickly emerging role genotyping lung cancer. An array of companies presented data on their new liquid biopsy technologies, including traditional diagnostics companies like Qiagen and Bio-rad, and emerging companies like Natera, Exosome Diagnostics, Biodesix, Vortex Biosciences, and others.

Also in April, and perhaps most significantly, Foundation Medicine’s expanded version of FoundationACT liquid biopsy was granted a Breakthrough Device designation by the FDA. If approved, FoundationACT would be the first FDA-approved liquid biopsy test to incorporate multiple companion diagnostics and biomarkers (>50) into a single test. To date, Roche’s COBAS assay for EGFR mutations in NSCLC is the only liquid biopsy test that has garnered an FDA approval (PMA), while several other less broadly standardized lab-developed tests (LDTs) are also available.

There is little doubt that liquid biopsy tests will continue to be rapidly incorporated into clinical care, especially for genotyping tumors to inform treatment decisions. In several recent consulting projects, we have seen the use of liquid biopsy in lung cancer increase significantly, moving from academia to the community. However, there are still challenges ahead and voices of caution.

In March, a joint statement from American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) found insufficient evidence of clinical validity and utility for the use of most liquid biopsy assays in patients with advanced cancer, although the review is based on findings and literature review from 2017. The panel argues even in the most obvious applications—testing EGFR mutations in NSCLC patients—these liquid biopsy assays have demonstrated clinical validity, but the clinical utility remains uncertain especially in comparison to traditional tissue biopsies. More data are required linking testing results to treatment decisions to improved patient outcomes.

Beyond genotyping diagnosed cancers, the ultimate goal for liquid biopsy is to enable screening and early detection for asymptomatic, early-stage tumors. As ASCO 2018 in June, Grail presented data from the Circulating Cell-Free Genome Atlas (CCGA) study, suggesting liquid biopsy can diagnose cancers with promising accuracy. In the study, liquid biopsy could accurately detect around 40% of early-stage lung cancers (stage I-IIIA), with 98% specificity—only two false positives per 100 healthy patients. These results are promising but suggest substantial room for improvement before liquid biopsy can is used for this purpose in clinical practice. Low-dose CT scans, currently used to screen smokers at high risk of lung cancer, can detect 80-90% of early-stage lung cancers in similar setting.

While scientists and clinicians unravel the best clinical uses for liquid biopsy, and in the context of an ever-evolving diagnostic landscape, oncology drug developers should incorporate the following strategic approaches:

· Focus on benefits of serial testing for better treatment approaches: Liquid biopsy can enable serial tumor monitoring for resistance mutations, evolving tumor mutation burden (TMB), or other biomarkers, especially when reducing/eliminating the need for repeat tissue biopsy after each line of therapy.

o In lung cancer, the experience with liquid biopsy at progression for the EGFR T790M resistance mutation, targeted by osimertinib (Tagrisso), is the first example.

· Ensure closer linkage between drugs/ liquid biopsy diagnostics: Incorporating liquid biopsy, instead of or in addition to a traditional biopsy equivalent, directly into the trial design for interventional trials will help justify both liquid biopsy testing and forge a stronger link between the test and drug candidate.

· Consider partnering with liquid biopsy companies for data and expertise: Incorporating liquid biopsy and its potential serial applications, into trial design and patient enrollment will further strengthen the data available to companies like Foundation Medicine and others. Foundation’s offerings like SmartTrials, highlighting the frequency and even patient targeting for specific mutation trial recruitment/enrollment may become even more powerful. Partnering with these companies to inform the development and identify the most relevant patient segments may be a powerful tool for drug developers.

· Remember, screening applications remain to be proven: The potential for liquid biopsy to detect early disease, a key factor for improving cancer outcomes, remains elusive. Challenges around false negatives, limits of detection, as well as sensitivity and specificity in unenriched patient populations, complicate this obvious application. The potential to supplement low-dose CT screening for lung cancer in patients with a history of smoking or to detect disease recurrence may be early applications where the diagnostic value of liquid biopsy will prove its value.

As the technology and surrounding data improve, we expect liquid biopsy to have an enabling (and potentially transformative) impact on treatment on a broader array of tumor types and applications. Just as drug developers consider how their drugs will fit into an evolving treatment paradigm, it will be crucial to similarly monitor how liquid biopsy tests and other emerging diagnostics and prognostics will affect clinical practice.