Companies engaged in developing liquid biopsy technologies and clinical applications face a host of challenges
Interview by Steve Halasey
Over the past decade, the quest to improve cancer care has spurred the development of so-called ‘liquid biopsies’—minimally invasive methods of capturing disease biomarkers from readily accessible body fluids as an alternative to traditional solid tumor biopsies.
Although pathologists’ use of liquid biopsy technologies is still relatively limited, advances in the analysis of biomarkers recovered via the technique seem destined to usher in improved standards of care for cancer screening and monitoring alike. In particular, technology has been developed that can enhance the clinical utility of liquid biopsies, and allows repeat monitoring of a patient’s cancer at a reasonable cost. Such ongoing monitoring is impractical via traditional biopsy, which is conventionally conducted just once, at the outset of treatment. Further, liquid biopsies can be targeted to detect specific mutations in a patient’s cancer that develop over time, enabling clinicians to modify a course of treatment as the disease progresses.
With promising new applications of liquid biopsies being reported almost weekly, the number of companies working in the field is growing rapidly. One such company is Precipio, New Haven, Conn, which has developed an exclusive technology—improved and complete enrichment coamplification at lower denaturation temperature (ICE COLD PCR)—thatcan be used when laboratories conduct their own liquid biopsies. ICE COLD PCR is a chemical-based platform that preferentially enriches mutant DNA sequences through selective amplification of the mutant DNA, with the result being a 500-fold increase in sensitivity in identifying mutations. To find out more about the current status of development and adoption in the field of liquid biopsies, CLP recently spoke to Ilan Danieli, CEO of Precipio.
CLP: What have been the key challenges and achievements leading to the current state of development for liquid biopsies?
Ilan Danieli: As is the case for many new technologies, a key challenge has been adoption by the user. Many physicians still rely solely on information from tumor biopsies, and they are reluctant to consider the alternative of a liquid biopsy. And while some of the platforms in use for such testing offer extremely large and expansive panels—especially in the case of next-generation sequencing (NGS)—the very scale and breadth of such platforms can call into question the clinical utility of the panels.
Such questions affect physicians’ expectations about the clinical utility of the tests as well as payors’ willingness to reimburse for tests that are perceived to have limited utility. Nevertheless, there is little doubt in anyone’s mind that liquid biopsies will play a substantial and transformative role in how patients are screened and monitored.
CLP: A great deal of the work related to the development of liquid biopsies is going on in academic and other research settings. Is the direction of this work clear?
Danieli: Much of the exploratory work now being conducted is directed toward developing deeper understandings of the genetic composition of tumors and their response to various treatments (both existing and in development). Indeed, much of the field of personalized medicine centers on the biology of tumors and the effects of genetic mutations on patient treatment. In that regard, academic centers are paving the way for exciting discoveries of cancer-related genes and subsequent therapies that will improve patients’ chances in battling disease.
CLP: At what stages of clinical application do you think liquid biopsies will prove to be most useful? For instance, will they work best for disease screening, diagnosis, monitoring of disease progression, or some combination of applications?
Danieli: I expect the most significant impact of liquid biopsies will be in patient monitoring. Today—and for the foreseeable future—most cancer patients are diagnosed via a tumor biopsy, which provides the primary and most reliable source of information for determining the patient’s diagnosis and genetic profile. However, it is virtually impossible to obtain an additional tumor biopsy once a patient is undergoing treatment, with the result that many patients continue to receive treatment far beyond the point at which it is having a positive effect.
We know that a patient’s genetic profile can change through the influence of either internal biological drivers or external drivers such as chemotherapies. To avoid treating patients with therapies that are no longer effective will require consistent and repeated monitoring, so that changes in the patient’s genetic profile can be detected as early as possible.
Liquid biopsies present a very real and practical alternative, providing real-time information on disease progression and identifying changes to the biology of the disease that may indicate a need to change treatment.
CLP: At this stage of development, how much work is being devoted to discovering and refining clinical applications, and how much is devoted to developing relevant technologies?
Danieli: This is of course very difficult to quantify, but I would guess that the majority of current work is focused on clinical applications. Despite its challenges, NGS is on its way to establishing itself as the gold standard for molecular diagnostics, and while it is likely that work is being done to discover alternative technologies and platforms, most R&D resources are focused on developing clinical applications, including the discovery of genetic mutations and their correlation to various therapies.
CLP: Despite the significant promise that liquid biopsies have shown over the past few years, adoption has been slow. What do you see as the key obstacles to quicker adoption?
Danieli: In my opinion, the key obstacle has been the economics surrounding liquid biopsies. The current major players in the field offer broad and sophisticated NGS panels for liquid biopsy testing. But while these platforms are extremely attractive for the purpose of screening—casting a ‘broad net’—at a price tag of $5,000 to $8,000 per test, they are economically unfeasible for clinical situations that require repeat testing in order to monitor patients’ disease progression and response to treatment.
Companies such as Precipio that are developing low-cost, targeted panel solutions will make it economically feasible to conduct repeat testing at reasonable cost. And ultimately this will accelerate the adoption of liquid biopsies.
CLP: Are reimbursement coverage and payor pricing major problems for liquid biopsy developers? How can companies overcome such challenges?
Danieli: Yes, very much so. Physicians are reluctant to order tests that may end up saddling their patients with a hefty bill, and payors are reluctant to reimburse for tests that have limited clinical utility. Panels that test for more than 200 genes may have tremendous research value. But from a clinical perspective, if only a handful of those genes can direct a clinical action, it becomes challenging to justify the cost of such a broad approach.
Creating more targeted, focused panels that have a direct correlation to clinical utility—where each interrogated gene produces an actionable result—will lower the cost of testing and provide a compelling rationale for reimbursement.
CLP: As an advanced diagnostic technology, do liquid biopsy technologies get any preferential pricing under the Center for Medicare and Medicaid Services’ new clinical lab fee schedule?
Danieli: Not that I am aware of.
CLP: To advance liquid biopsies toward adoption in everyday use, what do you see as the key challenges to be overcome during the next 2 to 5 years?
Danieli: The clinical utility of liquid biopsies must be demonstrated unequivocally. At the most basic level, liquid biopsies are merely vehicles for obtaining genetic information to assist in customizing patients’ treatment. But to improve adoption rates, liquid biopsies must offer an effective and cost-efficient alternative that provides clear utility.
As further discovery and development yield new genes and their correlated effects on treatment, liquid biopsies will essentially be able to scale-up their utility as information delivery vehicles.
Steve Halasey is chief editor of CLP.