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Do We Need to Realign Evidence-Based Versus Precision Medicine?

An interview with geneticist and pathologist Gabriel Bien-Willner, MD, PhD, FCAP, on why we need to change our outlook toward precision medicine in oncology.
A Catch-22 Scenario
Speaking about Molecular Health’s overall mission and goals, Gabe said that “The mission of Molecular Health is to create software applications to allow physicians to make sense of complex clinical data, and right now, we’re focused on cancer and genomic data. But, ultimately, the position of the company is to go well beyond both cancer and genetic data.” Gabe noted that when he was first brought on board, “We were not only focused on the development of software, but we decided to showcase that software by starting a commercial laboratory and medical service, which I had been running. The company has refocused solely on software and software development. The service we were offering was very comprehensive and included a medical review by experts. So you were not just getting a test result, you were receiving an interpretation from a real expert into what these complex results mean.” 

I told Gabe that I had been particularly interested in the fact that Molecular Health was offering such specific medical expertise and just how valuable a service this was, since, as he’d stated at the beginning of our conversation, there is simply no way that we can expect all oncologists to become experts in how to communicate genomic and genetic information and how to interpret it. “Yes,” he said, “so it’s a Catch-22 scenario, because there are not enough people like me and other molecular pathologists who are really well-grounded in NextGen sequencing as well as in genetics and genomic principles. You can try to make them accessible to as many people as possible—and I think that, in the future, it will be an entirely new subspecialty of medicine. But today it’s difficult to have those people available to everyone.” 

Gabe continued: “But one way that you can make them accessible to everyone is with software that enables you to better understand and interpret the results, that can make people who are not quite experts good enough to understand the information that’s coming out of the system. So, I would say that that’s the direction of the company, and it’s something that I’m helping the company do. I’m not sure whether in the future, even in the long-term future, that’s sufficient, but it’s certainly the biggest dent we can make with this real problem. Yet I do think that there is this future of genomic medicine, that there are going to be people with these skill sets who are more widely available, and I think that they have a critical role to play.”
I responded by emphasizing that I appreciated the development of software to enable the delivery of reports that make clinical sense to the ordering physicians, assisting them in their decision making. So lacking an actual clinical consult with a molecular pathologist, they would still have the report explaining the genetic variants identified, their significance, as well as clinical recommendations, and perhaps clinical trials that would be appropriate for these patients.

He agreed, noting that providing such data interpretation is a large part of what they offer and that his focus with the company is “Also, creating a clinically verified or validated knowledge set—that is, a knowledge database of what variants mean in different disease types, so that there can be an automated interpretation for the high-yield, commonly seen or more well-characterized variants, where experts would tend to agree on the significance. That may be helpful for most patients. There’s always potentially going to be cases where you need a little bit more insight, but it’s a great first step into this field to make it more accessible and understandable to people.”

VUS Results: Challenges for Clinical Management
Variants of unknown significance (VUS) are results where DNA alterations are detected, but there is not currently sufficient data to classify whether it is neutral or deleterious. For example, with the BRCA1 and BRCA2 genes,2 initially sequenced and characterized in the 1990s and, by far, the most comprehensively studied human genes, multiple deleterious mutations have been identified that result in a significantly increased risk of developing breast cancer, ovarian cancer, and several other cancers. However, new VUS in BRCA1 and BRCA2 continue to be identified.

During the ASCO pre-meeting, Gabe had said that it was extremely irresponsible not to share potential knowledge about the existence of these variants or what some of these variants can mean—a perspective that truly resonated with me. He had given the example of an epidermal growth factor receptor (EGFR) point mutation of unknown significance. In the United States, approximately 15% of patients with non-small cell lung cancer have mutations in EGFR. Certain EGFR mutations have been identified that may predict a positive response to particular agents, known as tyrosine kinase inhibitors, that target EGFR. Gabe noted that if an EGFR VUS were identified that was likely damaging and in a known regulatory domain of the protein, you could make a reasonable clinical judgment about the mutation’s potential significance. I asked whether he could expand on this critical perspective. 

“The standard right now is that we’re looking at NextGen sequencing and precision medicine through the prism of non-complex clinical laboratory testing,” Gabe noted. “We want our laboratory testing to be precise, right? With most of this testing, there’s 1 value that we care about where we want to know with a high degree of reliability and precision that we have the right answer.”

“For example,” Gabe continued, “if you’re having a blood test for hemoglobin, you want to know whatever that number result is. As a physician, you know how to interpret that, and you want to know from a laboratory perspective that that is the accurate reading. We know that there is a normal range of distribution of signal, below which and above which is abnormal and within that range is considered a normal range. That’s a typical laboratory test. The problem is that with NextGen sequencing, it’s not one test.”

 “Rather,” Gabe said, “you are testing for every nucleotide position, for everything you’re sequencing, which could potentially be mutated in a number of different ways. So, in reality, the number of variables in that test, depending on the size of the panel that you’re testing and the kind of testing that you’re doing, can seem to approach the infinite. And when you’re looking at all that data, it’s not a test result like other chemistry tests, it’s not a yes or no or normal or abnormal, it’s a very complex relationship of multiple variables all at once—and up to thousands at a time if you’re doing an exome sequencing capture. So you’re really practicing medicine by interpreting the complexity of the data to summarize what that data means.” 

In other words, as he explained, “It may be similar to a primary care physician’s interaction with a new patient. A patient encounter can be broken down to a series of variables, and each variable seen as a ‘test’: the way they look, their chief complaint category and description, every component of the physical exam, the lab test that was ordered, everything you do with that patient. But the reality is that the doctor does not see it that way. The doctor looks at the patient as a whole, he thinks about what’s best for the patient in light of all the evidence presented before him—and that’s really how I see the interpretation of these complex data. You also have to consider the patient, their history, and their family history sometimes while reviewing the sequencing data. You need to consider all the genes that are sequenced, what the variants are, what the disease is—and the fact that the same variables in different diseases do, in fact, give you different answers. So looking at this exercise as a lab test is overly simplifying a complex process. Practicing medicine by interpreting results is how you’re going to get the most out of this and the most out of precision medicine.”

The sophistication of the analysis also raises the specter of confronting the challenge of VUS. Gabe continued, “From a traditional laboratory test perspective, if you see a variant that you’ve never seen before, you don’t know what it means because there’s no evidence that it means anything, so it’s reasonable to ignore it. That’s not the right approach. Instead, the correct approach is ‘What is this patient’s disease? Let’s look at this with suspicion. What is the patient’s age? What is the patient’s sex?’ A BRCA variant for breast cancer in a 36-year-old means something very different than it could in an 87-year-old with prostate cancer. And then you can go into more details.” 



 
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