The MTAP pathway and genomic classification of genitourinary cancers

Methylthioadenosine phosphorylase (MTAP) is a useful biomarker for the detection and treatment of genitourinary cancers.

Philippe E. Spiess, MD, MS, FRCSC

A recent study presented at the 2022 ASCO Genitourinary Cancer Symposium investigates how MTAP deletion can be used specifically for cancers that are difficult to treat. In this study, Philippe E. Spiess, MD, MS, FRCSC, FACS, and coauthors performed genomic profiling on 12,000 tumors, evaluating where MTAP deletion is a potentially actionable mutation and whether there was differences in MTAP loss among a large cohort of advanced genitourinary tumor. He discusses the takeaways of the study in an interview with Urology Times®. Spiess is a genitourinary oncologist and assistant chief of surgical services at the Moffitt Cancer Center in Tampa, Florida.

Please discuss the background for this study.

This is potentially impactful work work that I'm privileged to be involved in as part of a collaborative with several other institutions [and] tertiary care referral cancer centers, which has been led by Foundation Medicine. [They have] really done some great work in genomic profiling of tumors, particularly in tumors that we treat and struggle in management, which are genitourinary-specific—the ones that are resistant to certain types of current therapies. Unfortunately, we know that for certain types of prostate cancers, bladder cancers, [and] kidney cancers, we have great initial first-line systemic treatments to use, but we have somewhat limited resources [for] those patients who don't respond to certain agents. In the last couple of years, we've understood some of the genetic and important biological pathways. One of these is the MTAP pathway, which is actually specifically involved in carcinogenesis. And so, this work [was initiated to] look at subsets of cancers, [ones in] which we know we're having a challenging time treating and understand [whether] this MTAP deletion—[a technique] believed to be important in certain types of cancer—is something we [can] take advantage of, in utilizing certain types of novel therapies.

What were the notable findings of this study? Were any of them surprising to you or your co-authors?

There were. We looked at over 12,000 tumors in this. So, obviously, a huge study looking at genomic profiling across many tumors—close to over 8,000 metastatic prostate cancers, close to 2,500 bladder cancers, and about 2,200 kidney cancers. What we interestingly found is there are very unique differences in the incidence of MTAP, or loss associated with them. We saw that in about 25% of bladder cancers, there was an MTAP deletion, vs in the others it was only about 2% to 5%. So, that tells us that bladder cancer seems to be [the disease] where the MTAP pathway has the greatest importance and [gives the most] opportunities to develop novel therapies. What we found, interestingly enough, is when you start looking specifically at the MTAP mutations, you see that tumors are actually very different, depending on whether they have a deletion or not in terms of what their comprehensive genomic profiles. That tells us that maybe we need to look at tumors a little bit differently. Not so much put them in the same categories based on conventional sites of origin or histologies, but really look at them based on whether the mutation is as identified based on the deletion of MTAP.

How will these findings impact the way you treat advanced genitourinary cancers in the future?

As we strive to understand and treat patients who are resistant to certain treatments, [this study highlights that] maybe MTAP is something specifically in bladder cancer—especially [in patients who] are resistant to chemotherapy—[that we need to explore]. If [patients do have an MTAP deletion], it may open additional opportunities to target that specific biological pathway using specific compounds. Some of them are actually new compounds, antibodies, and drugs such as PRMT5 and MTA2 inhibitors.

Is there further research on this topic planned? If so, what will its focus be?

I think the next step now is to, number 1, validate a lot of our findings and start diving into this a little bit more in detail. Yes, there are specific subsets of tumors where the MTAP loss is identified. A lot of these have the FGFR3 or TSC1 mutations, and that is something [that] we're currently focusing [on in terms of] developing certain compounds and drugs. I think the next step is understanding a little bit more in terms of, how do we specifically use that information [for] application into clinical practice? So, if we're able to validate our results, probably in a different, larger subset, and in particular, in a prospective group of patients, I think the next step is designing these types of early phase 2 trials, specifically using these compounds to really offer patients some new treatments that [are not] currently available.

What is the take-home message for the practicing urologist?

I think [one] important message here is that MTAP is an important novel pathway in carcinogenesis, particularly bladder and urothelial carcinomas. It is one [of] which we don't typically see highly mutated in kidney cancer and in prostate cancer, [so probably] has less of an importance. But I think we also have to look at tumors a little bit differently as well, and really start focusing them specifically on whether or not they express these mutations to start developing what I would say is personalized therapeutics and agents for them.

Is there anything you feel our audience should know about this topic?

I think, as we all know, the field of research is evolving very quickly. One area that I'm very excited about is genomic profiling. The benefit of that is we're able to look at a large group of patients [from] a very consistent [and] high-volume standpoint. And so, I think the benefit of this type of research is [that other times when] we do clinical trials, we're only able to look at a few hundred patients, [whereas] here, we looked at over 12,000 patients. There's power in completing such large and innovative comprehensive genomic profiling studies most notably in areas where we have limited effective systemic therapies. No question these are very exciting times, and I strongly believe this type of research may help novel effective systemic therapies for our cancer patients most in need.

Reference

1. Spiess PE, Necchi A, Grivas P, et al. Genomic classification of clinically advanced major genito-urinary cancers (GUca) based on methylthioadenosine phosphorylase (MTAP) genomic loss. Paper presented at: 2022 ASCO Genitourinary Cancers Symposium; February 17-19, 2022; San Francisco, California. Abstract #164