So at ASCO 2025 our group presented two interesting abstracts. The first was looking at the androgen receptor ligand binding domain mutations in patients with prostate cancer and also exploring them in other cancer types. To do so we used a large database of both circulating tumor DNA analysis and tissue biopsies from prostate cancer patients and also at least 20 other cancer types as well, non-prostate cancers...
So at ASCO 2025 our group presented two interesting abstracts. The first was looking at the androgen receptor ligand binding domain mutations in patients with prostate cancer and also exploring them in other cancer types. To do so we used a large database of both circulating tumor DNA analysis and tissue biopsies from prostate cancer patients and also at least 20 other cancer types as well, non-prostate cancers. We have known for many years that certain mutations in the androgen receptor activate the androgen receptor. They are found within the ligand binding domain. These are also called AR-LBD mutations. And we wondered whether those mutations might be different in their prevalence between primary tissue biopsies versus liquid biopsies, in other words, circulating tumor DNA. We also wondered whether these mutations might be present in non-prostate cancers as well. So, the first observation was that these mutations are more readily detected at higher prevalence from liquid biopsies, in other words, circulating tumor DNA analysis, compared to tissue biopsies. So just to give you a sense, in metastatic prostate cancer patients, from a tissue biopsy, these AR-LBD mutations were found in about 4% or 5%, whereas in liquid biopsy circulating tumor DNA tests, we found those in 20% to 21%. We were also amazed and slightly surprised to find out that we didn’t detect these AR-LBD mutations in any of the multiple other cancer types that we interrogated. So these truly, with extremely rare exceptions, there are some exceptions, truly do seem to be limited or greatly enriched in prostate cancers compared to other cancers. And that makes sense because prostate cancer is an androgen receptor-addictive disease. And these mutations enhance the activation of the androgen receptor. So why is this important? It’s important because there are now a number of therapeutics in the prostate cancer space that appear to work better, their efficacy is greater, in the context of a mutated AR-LBD. So detection of these mutations might, for example, enhance the efficacy of certain medications that might have a greater clinical activity when those mutations are present, and perhaps a lesser clinical activity when those mutations are not present. The question that this study answered is that when looking for these mutations, it’s better to search for them in a liquid biopsy and not from a tumor biopsy. You have four times or five times the odds of finding them in a liquid biopsy compared to a tumor biopsy. And perhaps that makes sense. In a liquid biopsy, you’re sampling potentially different clones of that cancer in one blood test as opposed to the area that you happen to be putting the needle in. And the second thing is that the liquid biopsy allows you to study the tumor evolution. These are mutations that may not occur in hormone-sensitive prostate cancers, may begin to emerge in castration-resistant prostate cancers, and then maybe increase even further in prevalence in patients that have received one or more AR pathway inhibitors. So in the future, we’ll be using the blood-based analysis of ctDNA for AR-LBD mutations to perhaps select for certain novel therapeutics such as a medication called opavostat, which is an oral CYP11A1 inhibitor, to perhaps give more benefit to those patients who have those mutations as opposed to those without them.
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