Has Genomic Medicine Delivered in Cancer?

David J. Kerr, CBE, MD, DSc, FRCP, FMedSci


August 26, 2019

This transcript has been edited for clarity.

I'm David Kerr, professor of cancer medicine from University of Oxford. I'd like to talk today about an article that was published recently in the New England Journal of Medicine (NEJM) by a colleague of mine from Oxford, Jeff Drazen.

He posed a question: "Has the genome granted our wish yet?"[1] It sounds like a fairy story, doesn't it? About a decade ago, he and colleagues wrote a very convincing article suggesting that we as physicians beware of genome-wide testing and the clinical utility of some of these tests that our patients can order online.[2] All of us are increasingly aware of this. Patients come to us in the clinic with genetic tests that they ordered themselves online and come with a myriad of often poorly described information, expecting us to interpret it and to make some intervention on their basis.

Jeff and the gang are interested in polygenic risk scores. Can we define the genetic susceptibility factors that render one open to developing a range of diseases in later life? Of course, I'm particularly interested in cancer, and Jeff uses breast cancer as one of the points in case. Thousands of patients have enrolled in genome-wide association studies. There has been increasingly refined mapping of single nucleotide polymorphisms (SNPs) and their impact on disease. We have meta-analyses of meta-analyses, a massive amount of data. One would have to say, and Jeff would agree, that for diseases like breast cancer, colorectal cancer (my particular specialty), and prostate cancer, genetic tests have reached a degree of stability. We now have so much information that it's possible, but increasingly less likely, that additional SNPs will come forward.

One of our recent publications in Nature Communications[3] on colorectal cancer discusses how we have a panel now of 80 to 90 SNPs that define most of the genetic or polygenic risk score for colorectal cancer. Breast cancer has a couple hundred SNPs now, so it's stable. Patients who are in the top 1% (who have accumulated the largest numbers of these SNPs) have perhaps a three- to fourfold higher lifetime risk of developing breast cancer, developing colorectal cancer, etc.

Jeff argues in his article that we still need more information. We still need clinical utility studies to demonstrate what the benefit of this knowledge might be. How would we as clinicians or health policy experts use these data in the real world? He is right, of course. We need more prospective studies.

But there is a bit of me from the point of view of colorectal cancer that would argue that the polygenic risks scores could be terribly useful even at the moment, even in advance of clinical utility studies because of the proven power of screening for colorectal cancer, the impact that it has on staging, saving lives, and so on. I think we could identify an algorithm that would allow us to place our polygenic risk score—susceptibility for colorectal cancer—into a population-based screening program. It would be reasonable that if I were presented with those data today, there is advice I could give the patient. There is lifestyle advice on how one might reduce the chance of developing colorectal cancer: less red meat, less processed meat, moderate alcohol, exercise, and so on. But also we have the power of screening, so [we could] put these individuals at risk, the top 1 percentile, into recognized screening programs. Some evidence suggests that it would be cost-effective and save lives. We don't have large prospective trials; these would be enormous and hugely expensive things to do but worthwhile. I have no doubt.

Whilst waiting for that, I genuinely think there is a role for these extraordinary sets of genetic data, where we could plug them into those tumor types with definite evidence that early detection makes a real difference, and proven screening programs that allow us to offer something to those deemed at high genetic risk.

Jeff concludes in his NEJM article that now, 10 years later, their advice would still be the same: Beware genetic testing and generate more data. It's hard to disagree with that entirely, but for colorectal cancer I would make the case that we could develop a screening algorithm based on that which we know.

Thanks for listening. Have a look at Jeff's article and our recent article in Nature Communications, and see what you think about it. Post any comments that you might care to make, and for the time being, Medscapers, ahoy.

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