New study shows better biomarkers for MSI mCRC

This transcript has been edited for clarity.

I’m David Kerr, Professor of Cancer Medicine at the University of Oxford.Today I would like to talk about the following A really great paper published earlier this year Oncology annual report By an excellent French group. As you know, we have always had a strong interest in precision medicine, and we strive to improve the way we match drugs to patients, tumor genotypes, pharmacogenetics, and more.

They did some really cool research looking at how we can identify patients who are more likely to respond to immune checkpoint inhibitors.The study included 110 metastatic patients colorectal cancer Patients treated with programmed death ligand 1 (PD-L1) inhibitors plus or minus cytotoxic T lymphocyte-associated protein 4 (CTLA-4) inhibitors. That’s a reasonable group to study. They looked at DNA and RNA sequencing. They adopted a discovery and validation approach across this cohort.

What they found was really interesting. They looked at tools that we thought were reasonable markers of response, such as tumor mutational load, microsatellite dysfunction and other studies that delved deeper into infiltrating immune cells. . If you’re willing, you’ll probably respond better to immune manipulation.

However, these were not found when they conducted a thorough sequencing effort.

A closer look at genes associated with microsatellite instability (MSI) and the entire 182 RNA sequences surrounding the transforming growth factor beta (TGF-beta) pathway reveals that TGF-beta is critically important. You can see. It plays an important role in regulating the immune microenvironment. It has anti-immune effects.

By incorporating two new components that we discovered through sequencing experiments, we came up with a much better set of biomarkers that identify patients who are significantly more likely to respond to treatment.

This is great science using a very nice approach in that it uses a discovery → validation set. I have to say that the number is still quite small. I think it is important to test prospectively and expand the scale of observation.

The question is, if a patient doesn’t have this positive selection biomarker, why not treat them with an immune checkpoint inhibitor? I think the answer is probably still “no.” You could specifically select patients who would be treated very well, but I don’t think this study is convincing enough to say that there is a group of patients who don’t have this characteristic and therefore don’t treat them.

It shows how the field is moving in the right direction. This shows how new biomarkers can be discovered by adopting this deep sequencing approach, and it’s clear that this is all good.

Wouldn’t it be great if we had a binary biomarker that says these expensive drugs work for this group of patients and have no effect at all for other groups? If we had this kind of binary discrimination. , can be very helpful in selecting the right patient at the right time. It will bring significant health and economic benefits.

This is a step in the right direction. We’re not there yet, but it’s a very admirable piece of work and we encourage you to check it out and post your own comments. Do you think this is a step in the right direction? Can you imagine using these kinds of biomarkers in your own clinical practice to super-select the patients who will benefit the most?

Perhaps most of all, in your real-world clinical experience, what do you look for in a biomarker to select patients for greater benefit? Good and bad, yes and no, effective and ineffective? How should we distinguish between them? Where do we draw the line?

To do that, I think we need to look to the broader community of oncologists and work to get feedback from the front lines. For those of us who are interested in biomarkers, how do we need to design biomarker studies in order to be convincing enough to use in clinical practice? I’m very interested in your ideas. there is.

Thank you for your continued attention. For the time being, Medscapers is over. thank you.

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