Syed Muneeb Alam, MD, from Memorial Sloan Kettering Cancer Center, shares some details about the abstract he presented at ASCO GU 2024 on the definition, diagnosis, and new technologies available for physicians treating patients with urothelial carcinoma.

Transcript:

Muneeb Alam: My name is Syed Muneeb Alam. I'm a urologic oncology fellow at Memorial Sloan Kettering Cancer Center in New York City.

Can you provide a brief summary of the abstract you presented at the 2024 ASCO Genitourinary Cancers Symposium?

Muneeb Alam: So, the purpose of the abstract was to evaluate genomic features of MSI high urothelial carcinoma, and to assess response to immune checkpoint blockade in the metastatic setting. We have seen in numerous clinical trials, that tumors that are MSI high or micro satellite instability high as well as tumors that are mismatch repaired efficient or DMR have notable sensitivity to immune checkpoint blockade. We're still searching for biological determinants of response to mean checkpoint blockade and urothelial carcinoma, and we've seen the indications for mean checkpoint blockade growing in numbers across the spectrum of disease in urothelial carcinoma and so that was really the impetus for this particular study. For this study, we looked at about 3,000 urothelial carcinoma tumors that underwent targeted sequencing, using the MSK impact assay at our institution. We used a previously validated score. The MSI sensor score to categorize microsatellite status, either MSI high MSI indeterminants. These tumors often have issues with low tumor purity, or microsatellite stable or MSS tumors and this particular score was done based on interrogation of microsatellite sites across the sequenced genome as part of our analysis, we derived mutational process signatures and performed gene enrichment, analysis, and in particular, comparing microsatellite instability, high to microsatellite stable tumors, and we also looked at a clinical analysis, focusing on progression free and overall survival in a subset of patients with metastatic disease who received immune checkpoint blockade. So, of around 3,000 tumors, 2.1%. urothelial carcinoma were MSI high, and the Median tumor mutational burden in this group was around 52 mutations per base and this was significantly higher in the MSI. High group as compared to Msi. Indeterminate or MS Cases. The most frequently altered MMR Gene that we observed in the MSI High group was MSH2, and mutations in PMS2 were quite rare, and among patients for whom Germline testing was available just under half carried germline MMR alterations suggesting that many of these MMR Alterations are actually sporadic. When comparing MS urothelial carcinoma to MSI High urothelial carcinoma, we saw enrichment in mutations of FGFR3. Specifically, we saw enrichment in FGFR 248 C mutations. This particular mutation has previously been described in lynch syndrome associated upper tract, urothelial carcinoma, and is a potential biomarker. In that setting we also saw enrichment of FGFR3G3AR mutations. This particular mutation is infrequently associated with MSI. MS high tumors are relatively rare otherwise, in urothelial carcinoma. It's actually more commonly associated with benign skeletal abnormalities, such as achondroplasia. Nevertheless, this particular mutation may warrant further investigation as it could potentially impact targeted therapies and finally, we saw enrichment chromatin, modifying gene alterations, such One A, and KMPT2D. Looking at mutational signatures across the cohort, we were able to perform mutation signature, calling again in around 3,000 urothelial tumors. About 2 thirds of these tumors had an Apec dominant mutational signature, and this is consistent with what we know about urothelial cancers. In general, 2.5% had a mismatch repair deficient or DMMR dominant mutational signature, and the vast majority about 90% of MSI high cases did carry this DMR dominate mutational signature. It was notable for us that a portion of the MSI indeterminant. Cases around 10% actually also carry this DMR dominated mutation signature and even a small fraction of the microsatellite stable cases carry this mutation signature and so this warrants further investigation. It's an area of ongoing interest for us particularly to validate this finding, to see if these may be an additional group of patients that could potentially have a DMR or MSI high phenotype, and then, looking at our clinical analysis, we focused on progression free survival and overall survival. Following the receipt of immune checkpoint blockade in a metastatic setting, and to kind of summarize a focus on overall survival so similar to what we've seen in other solid tumor types, patients with MSI high urothelial carcinoma had improved overall survival as compared to those with MSS. Urothelial and the mismatch repair deficient mutational signature, could potentially be a surrogate for MSI. High status in this particular case, according to our analysis. We also, stratified micro satellite stable tumors by tumor mutational burden greater than equal to 10 based on the FDA recommendations and we saw that patients with MSS, high urothelial carcinoma had improved overall survival as compared to those with MS below high urothelial carcinoma. But overall the patients that still did the best were those with MSI high urothelial carcinoma. Suggesting that tumor mutational burden alone is unlikely to explain the robust response in this particular group. So just to kind of summarize the most frequently altered MMR Gen, and MSI urothelial carcinoma. MSH2 over half of the MSI high cases did not harbor germline components. So many of these MMR alterations are expected to be sporadic and a small percentage, 2.1% of all your ethical carcinomas are MSI high now, and these particular tumors have a distinct genomic profile, which is characterized by high tumor, mutational burden, enrichment. FJFR3, and chromatin modifying gene alterations and defining mutational signatures, and importantly MSI high urothelial carcinoma does appear to be exquisitely sensitive to immune checkpoint blockade.

Why is it important to define the features of urothelial carcinoma?

Muneeb Alam: So I think it's really important to evaluate both the genomic and molecular features of urothelial carcinoma. I think that we've been continuing to build upon the success of particularly the TCGA thinking about the cell paper that was published in 2017 and we've come a long way in better understanding the mutation signatures and the transcriptomic signatures, etc., that are associated with urothelial carcinoma. I think the challenges that remain are twofold: number one, really trying to better understand the clinical implications of these mutational and transcriptomic signatures. For example, trying to develop clinical trials, for example, based on tumors that are stratified by particular findings within the DNA or the RNA and number 2, really trying to continue to utilize cutting edge technologies, to better understand the phenotypes that we see within urothelial carcinoma. I think one great example is the use of spatial transcriptomics. This particular technology allows us to really at a granular level, look at gene expression as it relates to morphologic heterogeneity and phenotype of these tumors and so we've come a long way, obviously, and a lot of great work is ongoing and I think this will really allow us to better identify targeted therapies and management strategies that can benefit our patients.

What do you hope to accomplish at the 2024 ASCO Genitourinary Cancers Symposium?

Muneeb Alam: Yeah. So, I'm very excited to be here at the GU ASCO symposium this year in San Francisco. This is my first meeting, so I'm particularly excited to be here. I'm a urologist as well as a trainee, and so I think that really sets me up to really take in the breadth of the conference this is, historically been a very multidisciplinary conference and so getting to hear from medical and psychologists and radiation oncologists and pathologists about what is going on within the world of genitourinary malignancies is really, I think, meaningful for me. It's also a great opportunity to network and to see friends. And so there's, of course, a social element to it as well. But for me it's really a learning experience. I think the most important aspect of it is trying to get an understanding of what's going on in the field across our different cancer types that we're interested in and to see how I can not only improve care for my patients, but potentially engage in meaningful, impactful research.

What surprised you the most about your findings from this study?

Muneeb Alam: Yeah. So there were a few interesting findings. I think that we are really trying to look into a bit more carefully, you know, one important finding, I think, is that many of these patients do not have a germline MMR component and this has important clinical implications in terms of how we identify these tumors. Of course, it's a small percentage about 2.1 of these tumors that have this particular phenotype, but that can still represent a large number of patients that could potentially benefit from a new checkpoint blockade. So trying to better understand a way to identify these patients will be important, for example, orthogonal, sorry, orthogonal testing through, I mean histochemistry in combination with NGS technologies and how can we advance upon things like the MSI sensor score? Using some computational methods and deep learning to really really identify the largest number of patients that can benefit. I think that particularly relates to the finding that many patients who are MSI indeterminate and even small percentage that are MSS. Have a mismatch repair deficient mutational signature, and so trying to, for example, validate this looking at immunochemistry of these patients and using some of our computational message to confirm whether or not these patients may have an MSI High or DMR phenotype will be really important moving forward.

Is there anything else you would like to expand on?

Muneeb Alam: Yeah. So I think studies such as this are important because they allow us to guide clinical trial development and further translational research. You know, the role of mean checkpoint blockade is really been cemented. Now, I think in certain settings for your urothelial carcinoma, and of course, we're starting to see combination therapies have great success with the use of antibody drug conjugates. But I think one particular area of interest is, is identifying patients who may benefit from a mean checkpoint blockade for organ sparing strategies and so, for example, many patients at our institution. In fact, nearly all patients with upper tract urothelial carcinoma will receive some sort of MMR Testing to identify if there is a mismatch repair deficiency. I think that allows us the opportunity to develop clinical trials for organ sparing, for example, patients not just in urothelial carcinoma, but across the breadth of janitor malignancies that have an MMR deficiency or an MSI high status. These are patients that could potentially be considered for organ sparing or impactful new admin therapy.