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 In Advanced Applications, Cofactor Genomics, Molecular Diagnostics, Q&A

More Precise Treatment Decisions Rely on Better Biomarkers

This week’s Q&A features Eric Duncavage, MD, the Medical Director at Cofactor Genomics. He is a Board Certified Clinical Diagnostic Pathologist, co-directs clinical assay development at the Washington University, serves as a member of the clinical laboratory standards institute (CLSI) for sequencing-based clinical diagnostics, and trains fellows and residents in molecular diagnostics, informatics, and molecular oncology. You can also listen to the entire interview here

Q: Are there any potential uses for ImmunoPrism™ that you find particularly exciting?

A: ImmunoPrism™ can be used to find potential biomarkers for response to immunotherapy, which is probably one of the most exciting uses. Currently, there are markers that predict response to immunotherapies, but they’re not great. PD-L1 is a good example that provides some stratification, but is not perfect. Tumor mutational burden (TMB) is another marker that’s come out more recently. They’re both good starts, but neither is perfect; with TMB there’s always going to be responders that have low mutation burden or non-responders that have high mutation burden. This reveals an opportunity to better address the real biological question in terms of infiltrating immune cells rather than measuring surrogate markers like PD-L1 expression or overall tumor mutational burden. One of the biggest advantages is that it runs from formalin-fixed tissue, which was a major problem of early RNA-seq assays that only ran on fresh frozen tissue. Unfortunately, fewer than 1% of cancer patients have fresh frozen tissue banked because it’s too challenging to acquire and store. This is an assay that is feasible to implement for clinicians treating cancer patients, which I think is very exciting.

Q: Tell me about your role at Washington University.

A: I am the Director of Hematopathology here at Washington University. I oversee molecular testing, specifically sequencing based diagnostics as they pertain to Hematopathology. We’ve developed several assays, mostly DNA based, to look at mutation profiles in hematologic malignancies, and some newer assays that look very deeply at minimal residual disease (MRD) detection. Others that are not necessarily deep but wide, such as whole genome based sequencing assays to identify translocation or copy number variants and things like that. Washington University has really been the earliest academic lab to get into clinical next-gen sequencing. We launched our first clinical NextGen essay in 2011, before anyone else had really gotten started.

Q: What is the College of American Pathologists (CAP) and what is your role there?

A: CAP is an organization that’s composed of pathologists, laboratory technicians, and other  professionals involved in diagnostic testing. The College provides education through annual meetings, webinars, and other channels. They also provide guidance on how testing is performed. For regulatory purposes, they have a relationship with the federal regulatory agencies, so they are allowed to inspect laboratories and issue guidelines for how clinical laboratories can operate in terms of what requirements these assays have to meet. At Cofactor, we are CAP/CLIA accredited lab and we use the CAP guidelines to develop our testing. The CAP guidelines provide an extra degree of rigour compared to CLIA guidelines. This insurers an even higher quality of testing. I am a member of CAP, give lectures at the annual meeting, serve on a committee that develops reporting guidelines, and inspect other laboratories. CAP members peer review other laboratories, so as the Medical Director of the Cofactor lab, I also go to other labs and inspect them to make sure they’re abiding by the CAP guidelines. In return, other laboratory directors come to Cofactor to insure that we’re abiding by the same guidelines.

Q: When did you start as the Medical Director at Cofactor? What made you want to take the position?

A: I started in 2015, but have known Jon Armstrong (Cofactor’s CSO) for a long time. We worked together on some of the earliest capture-based sequencing methodologies at the Genome Institute over 10 years ago. We have the first papers to show that you could do capture-based sequencing from formalin-fixed tissues, which is the format for almost all pathology tissue. FFPE is more difficult to deal with than fresh tissue used for research. Jon and I spent about a year or so working on that, and then several years later, Cofactor reached out to me when they were looking for a Medical Director.

Q: What disease areas do you think better biomarkers are poised to make the biggest impact?

A: That’s a great question. It’s difficult to pick a particular disease category, but I would say in general, solid tumors. One of the key questions is figuring out who is more likely to respond to a specific therapy, which is where ImmunoPrism potentially fits in to stratify patients. These drugs are fairly expensive, so you want to use them judiciously and give them to a patient that has a high chance of responding. The flipside is if you treat a patient with a drug that they’re that they’re unlikely to respond to, then you’re losing precious time that could be spent treating with a different drug that might be more effective. This is especially the case in higher stage solid tumor cancers. I think that’s where ImmunoPrism initially will have the most utility.

Q: How do better biomarkers improve patient’s treatment decisions?

A: If you’ve got a biomarker that predicts response, then you can make better treatment decisions by giving patients drugs they’re more likely to respond to right off the bat. Currently, we march through these lines of treatment. Chemotherapy is the first line because a high percentage of patients respond to it, but if the patient doesn’t respond, then you move on to the second line of treatment. Biomarkers allow for a personalized and more precise approach rather than the current treatment plan that is one size fits all.  

Q: How do RNA diagnostics fit into a world that’s saturated with DNA and protein assays?

A: RNA is very labile and hard to work with, which is probably why it’s taken a long time to make it to the clinical laboratory. It’s something we had to work on with ImmunoPrism in order to make sure that the data quality was consistent. There’s a lot of pre-analytical factors that affect RNA stability and most of them aren’t accounted for, like how long the specimens were fixed for, how long it was processed, and how it was processed. That data is not usually captured, and it can affect the performance, so you have to design an assay that’s very robust to overcome these pre-analytical factors. This is most likely why RNA based assays haven’t caught up in the clinical lab. The advantage of RNA assays is that they give you information that you can’t get by DNA sequencing alone. RNA provides specific gene expression, specific mutations and whether they’re expressed or not, and fusions or translocation, so it provides a different kind of diagnostic level than DNA based assays. To clarify, they’re not mutually exclusive and in most cases, complementary. We’re starting to do DNA sequencing in patients, but I envision in five years or so, we will also start routinely doing RNA sequencing to provide additional information.

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