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Overlooked Biomarker May Predict Cancer Immunotherapy Response

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

Hi. I’m David Kerr, professor of cancer medicine from the University of Oxford.

As you know, I’ve believed for some time that ploidy (the number of sets of chromosomes in a cell) measurements have been largely overlooked in terms of the relative importance of prognostic markers for the whole range of different cancer types. One of my friends and colleagues, Prof Håvard Danielsen, from the University of Oslo, has established what I consider one of the best assays in the world for measuring ploidy and DNA content in tumors, and characterizing it from paraffin-embedded tissue. ‘It’s a very available system.

New Data on an Overlooked Biomarker

To this end, a really interesting study was recently reported in Science by Teresa Davoli and colleagues,[1] who looked at ploidy across a whole range of tumor types and tried to relate ploidy measurements to the hallmarks of cancer. A ploidy is also known as somatic copy number alterations (SCNAs), and [the authors] refined the definition of ploidy a little, into [SCNAs] that were predominantly focal or [SCNAs] that mainly correlated with whole-arm ploidy, or changes in DNA content in that way.

This was a fascinating study, in which they found that ploidy was indeed associated with prognosis, but also with signatures associated with proliferation, increased expression of the gene’s enzymes involved in control of proliferation and cell cycle—this was mainly for the focal SCNAs. The larger, long-arm, and chromosomal ploidy tended to be associated with reduced expression of immune signature and immune infiltration.

This is an important first step in showing that ploidy does correlate with drivers or hallmarks of cancer. There are some subtle differences that lead you toward increased proliferation or increased immune invasion, both of which work in terms of establishing the cancer.

The researchers then retrospectively analyzed ploidy levels in melanoma tumor specimens saved from two large trials using immune checkpoint inhibitors. What they showed was that aneuploid tumors (eg, elevated levels of SCNA) were indeed more resistant to immune blockade.

It’s a really fascinating new potential use of ploidy, which has been around for decades and has been much overlooked. Not only is it a prognostic marker and therefore gives us important information about the biological behavior of our patients’ tumors, but it may also be a predictive factor in that aneuploid tumors may be relatively resistant to immune checkpoint blockade.

[Because this study was conducted] retrospectively, there’s much work yet to be done. [However, it offers] a really interesting insight for a marker, which I think could be delivered relatively easily in a sophisticated way in every pathology lab in the world. It surprises me that we don’t measure ploidy more. [It is] another interesting insight—some beautiful basic science uncovering the subtle differences in ploidy, how it links to the different hallmarks of cancer, and how it may aid us in selecting patients who may benefit less from immune checkpoint inhibitors.

Thank you for listening. It will be really keen for you to have a look at the Science paper and post any comments that you may care to talk about. This is an unfinished story but one that must be followed up prospectively.

As always, thanks for listening. For the time being, Medscapers, ahoy.

– GDMeds, an India Pharmacy Service company

 

 

 

 

 

 

 

 

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