Germline Signatures of Toxicity: A Fertile Field

David J. Kerr, CBE, MD, DSc


December 23, 2021

This transcript has been edited for clarity.

I'm David Kerr, professor of cancer medicine from the University of Oxford. Today, I'd like to talk about a study from Annals of Oncology, written by a group of distinguished Japanese investigators, several of whom, Professor Ohtsu and so on, are friends and collaborators of mine.

They undertook a large genome-wide association study to see if they could pick up a germline DNA signature that might identify patients who are more at risk for peripheral sensory neuropathy from the drug oxaliplatin, which is a drug very widely used in the treatment of a whole range of gastrointestinal malignancies.

They said, and I agree with them, that although there have been several previous attempts to determine these germline signatures of toxicity, they've all failed. There are no tests that we have in conventional clinical practice that identify patients who are more at risk for neuropathy before we initiate treatment. These studies have been bedeviled predominantly by small sample size, mixed ethnicities, poor statistics, and retrospective designs. There's a whole host of reasons that have made the interpretation of their results rather difficult.

This was a large prospective study of around 1400 patients. It was done at Japanese centers, so it was ethnically very straightforward. There were very good bioinformatics and it was a very well-conducted study.

The bottom line was that despite all of that — excellence, attention to design, clever bioinformatics — they failed to come up with something. It shows how difficult it is that when one is looking for a needle in a genetic haystack, even with some of the best groups in the world, this might never quite be the case.

One could make arguments still, with 1400 patients, that may not be sufficient at describing the phenotype — the endpoint that we link the genetic analysis to — can sometimes be difficult. Again, they did a good job of separating early-grade toxicity vs more significant toxicity. They looked at outliers — people with no toxicity at all.

I thought they really did a good job, but it didn't quite make it. We've learned that genome-wide association studies are not quite the key that we'd imagined to unlocking the pharmacogenetic genome that we'd hoped for. I think we need larger studies, to be honest with you.

You may not know this, but with my fantastic friends in genetics, particularly Ian Tomlinson from Edinburgh, I was one of the inventors of a new science. Did you know that? Toxgnostics with a G. As Oxford dons, of course, we must sort of mention our training in the classics, and the greats, and so on.

If you look at toxgnostics with a G — look it up on Wikipedia — you'll see that we wrote a seminal discursive review in one of the decent Nature journals. We conducted the work on our own, looking particularly at 5-fluorouracil/fluoropyrimidine toxicity. It's how you invent a new science; you get a Wikipedia, you write three or four articles in good journals, you add a G to make it toxgnostics, and you become founding father of a whole new branch of medicine.

I don't think we've been set back by this work done by the Japanese group. I still think it's a very fertile ground that we should be looking at with very large numbers, even looking at combinations of drugs. I think it's a fertile ground that we should be able to mine in the future for these germline genetic signatures that predict who is at greater risk for potentially life-threatening toxicity or toxicities that would significantly impair the quality of life.

It was a negative study, but not the end of the road. Again, I ask you all to look up toxgnostics with a G in honor of us Oxford dons and our classical training.

Thanks for listening. Have a look at the study and see what you think of it. It was a great group, and a very well-conducted study. Don't give up on toxgnostics. I'd be grateful for any comments you might wish to make, and we'll hopefully speak soon. Bye-bye and thank you.

David J. Kerr, CBE, MD, DSc, is a professor of cancer medicine at the University of Oxford. He is recognized internationally for his work in the research and treatment of colorectal cancer and has founded three university spin-out companies: COBRA Therapeutics, Celleron Therapeutics, and Oxford Cancer Biomarkers. In 2002, he was appointed Commander of the British Empire by Queen Elizabeth II.

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