CAP TODAY Pathology/Laboratory Medicine/Laboratory Management
The key thing that will drive a shift to exome is probably the degree to which new genomewide meta-analyses become important, for example homologous or combination deficiency, mutational signatures, or high accuracy discrimination of very low-level tumor mutational burden. For example, there is suspicion that in prostate cancer, a low TMB cutoff may be useful for immunotherapy treatment guidance. Maybe that’ll force us into exome, or maybe it will be neoantigen determination.
On the interpretation side, we know what to say about only a few hundred genes. I don’t know what to say about mutations in the remaining 20,000 genes and don’t know how valuable those mutations could be clinically. So I think it will be these genome-scale meta-analytes that push us toward greatly expanded sequencing.
Does that reflect the views at Thermo Fisher as well?
Dr. Qureshi (Thermo Fisher): With a slight modification. We’ve come a long way since EGFR; there are a lot more biomarkers out there. And our mindset is one size doesn’t fit all. As Jeremy pointed out, TMB could be a biomarker with a different level of throughput. You might need an exome-level analysis, or you might just want to look at hot spots for therapeutic indications, depending on where you’re doing the sequencing and why it needs to be done. And people have different interests in the research setting. If there were a silver bullet, that would be fantastic. I don’t think that exists today. I agree with Jeremy that it isn’t a new technology. I think it will be NGS. It’s the most expansive technology out there to give you a broad view and a narrow view at the same time if you need it.
Are we launching enough panels to satisfy needs? Could you satisfy that same need with a single very large panel? I don’t necessarily know if that’s true, so our view of life, if you will, is that it’s not one size fits all. You’re going to need a few different panels at minimum to address the different needs.
Fiona, what are your thoughts about this?
Fiona Nohilly (Illumina): I look at it a little more broadly outside of just oncology. We think about people having large panels and they can filter through what genes are of interest to them if those are included in that list. We also have ways people can customize and develop their own panels. Or, if they want to have some of that information for later, they can do an exome or a genome, and we have many different instruments at Illumina that can solve for any of those things, on even one instrument.
Nohilly
In addition to oncology-related panels, you can do noninvasive prenatal testing in the reproductive health space, for example. Our sequencers are being used for genomic surveillance related to COVID-19. We see it as one instrument that can serve many applications, including many different types of panels as well as exomes and genomes, that would be run potentially in a given hospital.
Dr. Qureshi (Thermo Fisher): The question is if you have an NGS application or panel that doesn’t require you to reflex from a different test up front, why wouldn’t you use that technology? Take EGFR as an example; it’s the one that’s often tested first. If you now get an answer from NGS in the same amount of time that it takes you to do EGFR testing, then that, to us, in Thermo Fisher’s world, is the next step forward. We just launched the Genexus instrument, and on that instrument, if you can get the same answer for EGFR mutation as well as for many other mutations that will have a therapeutic indication, and get a patient on therapy much quicker than was previously possible, why wouldn’t it be used? So we are building these, and we have one on the market today. That’s why we feel that NGS is the future if it can be made simpler and faster and cost-efficient.
Several years ago one of the big topics related to large panels was the reporting of variants of unknown significance. At that time, the panels were not that large, but still it was a hot issue. Do we need to report these variants or not? What is the feeling about how hot that topic is and the solution to that question?
Dr. Del Moral (Illumina): It is definitely a hot topic. There are a lot of questions. The answer would now be to leverage the community. In the reporting setting that we talked about, we see the benefits of leveraging a reporting solution that enables inputs or findings from the community to help the interpretation of these variants of unknown significance as a plus. NGS has opened the door to detecting all of these variants, but the interpretation is becoming one of the hurdles. Having a community-based sharing of information helps in dealing with it.
Jeremy, how hot a topic are the variants of unknown significance?
Dr. Segal (University of Chicago): Occasionally it can be very difficult for us to decide between VUS versus suspicious for pathogenic impact for a particular variant. But the bigger problem for us is that we have so many VUS variants, and I just wish we were better able to say something meaningful about them. Probably the majority of the variants of unknown significance we’re putting into our reports are benign polymorphisms that the patient has that are not present in databases. But we come across interesting ones from time to time that certain functional studies might suggest are doing something.
Too frequently there isn’t any way for us to follow them up or say much more about them. And it’s a little disheartening sometimes to have to put it into the unknown significance bucket. In an ideal world you would put it into a pathogenic or a benign bucket and wouldn’t have the variant of uncertain significance. We’ll get there over time, but it’s going to take us a long time to figure out, and we’re going to need clever screens and studies to help us evaluate many variants in a high-throughput fashion. We need better data to work with.
One of the questions is how we will remember in a report we did two years ago that we had all these variants of unknown significance, and then in the meantime there are four drugs and multiple Nature Medicine articles about this variant. How can we be sure we don’t forget we had that with someone?
Dr. Segal (University of Chicago): It’s rare for a variant of unknown significance to become super important. It’s hard to remember the last time that’s happened. If it does happen, it’s easy to look back and see who else had the variant. But it would be nice if it happened more often.
So that anxiety then is overblown perhaps, or at least it was in the early discussions of this. Would you agree with that, Sohaib?
Dr. Qureshi (Thermo Fisher): I think there are two aspects. First there must be more of a community-based approach. I attended AGBT Precision Health a few years ago and a half day was dedicated to a discussion on how to better share data on variants of unknown significance within the medical community. Second, continuing to improve software solutions that can organize variants of unknown significance and can make data easily accessible is just as important as sharing the actual data to uncovering variants, which could eventually be super important.
Fiona, are there one or two items in the field of NGS that are less appreciated today than they should be and that you think will grow in significance in the next two or three years? Will we start seeing infectious disease be at least as important as oncology, for example?
Fiona Nohilly (Illumina): It’s already happening. Science, not just medicine, has had quite a moment over the COVID-19 pandemic to come to the forefront of people’s conversations, outside of this group and our own industry. People are talking about things like PCR as if it’s a COVID-specific term, but in reality it’s a technology that’s ubiquitous in the life science tool space. So I think the pandemic will change how NGS is seen in the world, especially within medicine. It’s allowed people to understand the power of this technology and how it can be used. It goes back to what Jeremy said about patients advocating for themselves. That’s where we will find that inflection point: when patients and doctors understand what they need and companies like ours provide the right technology. We are at an exciting time with people understanding a little more about this technology even from a layperson’s standpoint, and that will help us in the next few years to catalyze the uptake of NGS in the clinic.
Pierre, what about your crystal ball?
Dr. Del Moral
Dr. Del Moral (Illumina): Looking at oncology and cancer research, I would say that multiomic types of approaches will grow. Spatial transcriptomics, essentially the way down to the single cell level, is making its way into clinical research, clinical trials. It’s likely moving slowly into the pathology lab. So I would say it’s the combination of several technologies providing better answers. Not just genomics.
Then what do we do with the data? It’s the data aggregation part. Data is truly where the value is. We see that from Google and Facebook and others—data is gold. In terms of mining the best and providing the best outcomes for patients, nailing this down will prove to be important in the next decade.
Jeremy, what are your predictions?
Dr. Segal (University of Chicago): We will see a continuation of what we’ve already been seeing. There are areas in molecular pathology where there is rapid development and innovation. Then things become a bit stable and end up becoming mainstream or packaged into kitted solutions. For these basic tumor panels, we’re starting to see that. People are starting to build end-to-end solutions for tumor panels, either in companies or in large academic consortia. I think we’ll see more of that, especially as oncology NGS moves into community practices in smaller centers.
But there’s no end to the amount of innovation that is continuing to occur in the NGS oncology space. Circulating tumor DNA analysis is starting to move wholesale into the academic setting as well as heme malignancy measurable residual disease testing using molecular barcode technology to facilitate better monitoring of patients after treatment or bone marrow transplantation. We’ll see expanded use of RNA-based analysis to look for expanded sets of fusions and also gene expression metrics, and methylation analysis too, whether that’s for profiling individual samples or for doing blood-based analysis for early cancer detection. You’ll start to see a lot of these different types of applications begin to get refined down to practice at the clinical level.
Sohaib, would you like to add anything?
Dr. Qureshi (Thermo Fisher): I agree with all of the assessments about the technology. My own comment is more short term, and this is not a company perspective but my own. I’m hopeful that we’ll be ready with the right tools to address the cancer cases we will see post-pandemic, and I think NGS will play a large part in that. We as an industry need to be ready for it. We need to gear up to battle all of the cancer cases that are coming our way because they couldn’t be treated because of COVID. When we get over this, we’re going to have to attack cancer with speed.