Q&A with Yassmine Akkari, PhD, FACMG
Legacy Laboratory Services
The following represents the personal opinions of Dr. Akkari, not necessarily those of the institution.
Medical Lab Management: Where do your laboratories stand regarding the use of liquid biopsies?
Yassmine Akkari: Our laboratory has not implemented liquid biopsies into clinical workflow, although the concept has become quite compelling over the last few years with particular promise in oncology applications. Currently, there is interest from multiple clinical disciplines to incorporate liquid biopsy technology. From a practical application standpoint, one primary challenge to widespread adoption of liquid biopsy methodologies is a lack of generally accepted guidelines for how to specifically utilize the information that liquid biopsy techniques can reveal.
Leading agencies and organizations such as the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), Association for Molecular Pathology (AMP), and others help to define how a scientific and technological concept such as liquid biopsy can be used to diagnose, treat, and/or monitor a disease state. This would be similar in construct to the ASCO and CAP algorithm for evaluation of HER2 protein expression. Practical use guidelines provide two important elements to laboratory operations, the first being availability of evidence-based information (ie, clinical utility) and the second, justification to offer a certain test. In the case of an inspection from The Joint Commission, or CAP, or any other agency, when asked why the laboratory is performing certain patient care activities, and by and large, the answer is that the laboratory is operating under a guideline. Second, guidelines serve to frame essential activities on how to validate, interpret, and report based on data or information derived from any given technology platform. This prevents us from operating in a vacuum and enables standardization.
In the current literature, there is little to no consensus on leading guidelines for liquid biopsy use, but there is a tremendous amount of data. Anecdotal reporting of data is widespread but lacking that consensus of approach or interpretation of results, we have yet to hit a tipping point in the adoption of liquid biopsy in our laboratories.
MLM: If a laboratory’s institution wants to move forward with liquid biopsies in its clinical operations, what should drive implementation?
Akkari: Beyond guidelines, a broad-based need is required in whatever system your laboratory is servicing. Currently, the push to adopt liquid biopsy technologies is largely driven by oncologists. Surgeons’ area of expertise remains physical biopsy, so oncology needs to put forward its best case for the benefits of liquid biopsy. That said, requests for this kind of testing may (and likely will) come from other specialties as well. For example, radiology could benefit from liquid biopsies when a mass is visualized but it is difficult to access, physically. Given the diversifying interest in liquid biopsies, a tumor board perspective is one avenue for vetting its utility to a specific laboratory, hospital, or health system.
Certainly, any discussion of adopting liquid biopsy methodologies must also take into account the practical operations, including how the data would be interpreted and who would perform the necessary operational functions (eg, a geneticist/molecular pathologist). Ultimately, widespread requests with guideline-driven proposed benefits will drive this technology implementation, not one single specialty.
MLM: What types of institutions are considering liquid biopsy as a viable solution in the near future?
Akkari: When it comes to liquid biopsy, hospital laboratories tend to be divided into three categories: First, those that are already performing their own liquid biopsy activities (either under a clinical or research umbrella, such as large cancer centers and laboratories). The second group includes institutions that are in some stage of adoption. Whether they are waiting for guidelines or developing their own, these institutions are somewhere in the instrumentation and test kit review and acquisition pipeline. The third group is by far the largest group, which is the group we are in, and these institutions are interested in liquid biopsy as a potential addition to laboratory services. By this I mean, most laboratorians, oncologists, geneticists, and molecular pathologists are aware that liquid biopsy has the potential to be extremely beneficial to disease (particularly cancer) diagnosis, treatment, and monitoring. However, as most of the institutions in this group do not have the resources to develop and validate their own use guidelines, we continue to wait until these processes coalesce.
As with most breakthroughs, we are all relying on each other to develop expertise that can be shared among colleagues. So, in addition to lung cancer (specifically non-small-cell lymphoma), liquid biopsies are being used to explore breast cancer, as well as other solid tumors where biopsy is difficult, such as the pancreas. There is also the potential use of liquid biopsy for patient samples other than blood or plasma, such as urine or CSF.
MLM: What technologies are needed to perform and analyze liquid biopsies?
Akkari: At its base, liquid biopsy relies on DNA extraction and amplification. The amplification can be driven by highly sensitive PCR technologies (eg, Bio-Rad’s digital droplet PCR), which can render results from a minuscule sample amount. The first step is to isolate the target DNA, the circulating tumor DNA (ctDNA), which is usually 200-300 base pairs. The idea is that liquid biopsy can help identify those base pairs released into the blood stream as sloughed tumor cells break apart. Because there is such a small amount to be found (a few hundred base pairs), a highly sensitive platform is needed for this kind of amplification.
Many laboratories have technology to extract and amplify DNA. Perhaps not to the extent needed for liquid biopsy, but the technology is not necessarily a roadblock to implementation. Ultimately, the question is what to do with the data, and the sky is the limit. Do you want to look at one variant or start to sequence every single variant you find? The question grows more complex with every step.
Another question is, are additional found lesions or DNA fragments related to an existing tumor? How can we tell? One phenomenon we encounter involves the use of liquid biopsy techniques on elderly patients. With these patients, it is common to find pathogenic mutations as a result of a natural aging process known as clonal hematopoiesis of indeterminate potential (CHIP). As humans age, they begin to accumulate distinct subclones defined by recurring somatic mutations in hematopoietic cells. These pathogenic mutations can show up in a liquid biopsy, clouding any determination that can be drawn from the sample.
In many cases we may not know if what we are finding is related to a known tumor or whether there is another tumor we are unaware of. This is an inherent benefit and conundrum of liquid biopsies at this point; having the potential to find evidence of pathogenic mutation where before we could not, but only finding some evidence and no other information, such as location, source, type, or status. Part of the ongoing research into liquid biopsy is determining how to qualify all the data that can be acquired through those processes.
MLM: As many institutions await definitive guidelines on liquid biopsy use, what other approaches can be considered for the near future and what questions do those raise?
Akkari: Many in the oncology field are remaining conservative. If a tumor is discovered by whatever means, it is important to get a biopsy when possible. Having tissue to establish a baseline is crucial to current cancer diagnosis. Here is where liquid biopsy can come into play. Can it help with progression studies? This is an interesting topic in the cancer genomics community.
If radiology does not find a tumor, this can be reassured by also not finding any sloughing ctDNA in a liquid biopsy sample. That said, consider the following example. A mass is discovered and biopsied, and an EGFR mutation is detected. The patient is treated and the tumor shrinks. After 6 months, imaging shows no sign of the tumor, nor does a liquid biopsy find any sign of mutation, and the patient is feeling well. However, 6 months after that, imaging still finds no reoccurrence of the tumor, but an EGFR mutation is detected in liquid biopsy, having risen from 0% at the first 6-month review to 2% now. This presents several scenarios, but the main question would be, how does such a finding affect the course of treatment? Is it a potential sign of relapse? Is the percent increase clinically significant, or it could be from a separate neoplastic event all together? Furthermore, could this be standard deviation, and should we wait 3-6 months and retest? This is where guidelines and medically relevant literature would normally come into play, but we do not have those yet. Amongst colleagues, we are asking these questions. In the absence of clinical change, what do we do with this information?
Looking ahead to when guidelines and checklists are available, then specific areas of focus should be determined. Certain cancers are already highly treatable though traditional means, so focus will likely be placed on currently intractable cancers such as lung and pancreas. As with many expensive or limited-resource tests, a collaborative approach to proper utilization of liquid biopsies will be key.
Yassmine Akkari, PhD, FACMG, is the scientific director for cytogenetics, the technical director for molecular pathology, and manager of genetics laboratory operations at Legacy Laboratory Services in Portland, Oregon.
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