This transcript has been edited for clarity.
I'm David Kerr, professor of cancer medicine at the University of Oxford. I'd like to talk to you today about a really lovely paper published earlier this year in Annals of Oncology by an outstanding French group. As you know, we're very interested always in precision medicine and trying to improve how we match drugs to patients, their tumor genotype, their pharmacogenetics, and so on.
They've done a really nice piece of work looking at how we can identify patients who are likely to be more responsive to immune checkpoint inhibitors. The study included 110 patients with metastatic colorectal cancer who had been treated with programmed death-ligand 1 (PD-L1) inhibitors plus or minus a cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitor. It's a reasonable cohort to study. They looked at DNA and RNA sequencing. They took a discovery-and-validation approach across this cohort.
What they found was really interesting. They looked at tools that we had considered to be reasonable markers of response, such as tumor mutational burden, other work that had been done taking a deeper dive into microsatellite insufficiency and infiltrating immune cells — things that seem very plausible in terms of identifying patients who would respond better to immune manipulation, if you like.
However, these didn't figure when they made their deep sequencing effort.
If you take a harder look at the genes associated with microsatellite instability (MSI) and the whole set of 182 RNA sequences, which were around the transforming growth factor beta (TGF-beta) pathway, we know that TGF-beta is a very important player in terms of controlling the immune microenvironment. It has an anti-immunological effect.
By putting two new components that they've discovered through the sequencing experiments, they've come up with a rather nice set of biomarkers that do identify patients with a significantly higher chance of responding to treatment.
This is a lovely piece of science using a really good approach in terms of using the discovery-then-validation set. The numbers are still rather small, one would have to say. Extending the size of their observation, I think, would be important along with testing it prospectively.
The question is: If patients did not have this positive selection biomarker would you not treat them with the immune checkpoint inhibitors? I think the answer probably would still be no. You could super select patients who are likely to do very well, but I think the work is not compelling enough to say that there's a group of patients who don't have this signature that we would not treat.
It shows how the field is moving in the right direction. It shows how, by taking this deep sequencing approach, new biomarkers can be discovered, and clearly, this is all to the good.
Wouldn't it be wonderful to have a biomarker that was binary that said these expensive drugs are effective in this group of patients and completely ineffective in the other group? Having that sort of binary discrimination would be enormously helpful in terms of selecting the right patients at the right time. It would have huge health economic benefits.
This is a step in the right direction. We're not quite there yet, but this is a very commendable piece of work, and one I'd be very interested in you to have a look at and post your own comments. Do you think this is a step in the right direction? Can you imagine in your own clinical practice using these sorts of biomarkers to super select patients who will benefit most?
Perhaps above all, in your practical clinical experience, what are we looking for in a biomarker that selects patients who will have that increased benefit? How discriminatory need it be between good and bad, yes and no, effective and ineffective? Where do we draw the line?
For that, I think we need to do some work looking at the wider community of oncologists to get feedback from the frontline. To those of us who are interested in biomarkers, what do we need to design into our biomarker studies to make them sufficiently compelling to be used by the clinical frontline? I'd be very interested in your ideas.
Thanks for listening as always. For the time being, Medscapers, over and out. 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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Any views expressed above are the author's own and do not necessarily reflect the views of WebMD or Medscape.
Cite this: David Kerr. New Research Points to a Better Biomarker for MSI Metastatic Colorectal Cancer - Medscape - Jan 02, 2024.
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