Dual Targeting of CDKN2A and PIK3CA May Offer Better Outcomes in Urothelial Carcinoma

Bishoy M. Faltas, MD

Genomic testing plays an increasingly important role in urothelial cancer (UC), with several actionable mutations including FGFR3, PIK3CA, and CDKN2A.

Genomic testing varies in the academic and community setting. For community settings, commercial panels are available. However, academic settings have access to tools that provide a more comprehensive views of the genome.

Investigators used patient-derived UC organoid (PDO) harboring FGFR3, PIK3CA, and CDKN2A mutations. Dose-response curves of alpelisib (Piqray), abemaciclib (Verzenio), and erdafitinib (Balversa) were created using the PDO cells to determine IC50concentrations for each. Changes were measured using the single-cell DNA sequencing (scDNA-seq) with the Tapsteri platform. Overall, the study showed the feasibility of using scDNA-seq to observe the clonal evolution of patterns in PDOs. Further, the data suggest that targeting CDK4/6 and PIK3CA can be more effective than targeting PIK3CA alone.

Bishoy M. Faltas, MD, assistant professor of Medicine and assistant attending for the Genitourinary Oncology Program in the Division of Hematology & Medical Oncology at Weill Cornell Medicine, discussed the use of genomic testing in urothelial canncer in greater detail, in an interview with Targeted Oncology™.

TARGETED ONCOLOGY™: What is the current role of genomic testing in bladder cancer?

FALTAS: We've been learning a lot over the past few years about the genomic underpinnings of bladder cancer. And the role of genomic testing is expanding almost every year, as we learn more about the role of genomic alterations in the pathogenesis, the natural history, and response to treatment in patients with bladder cancer. So, for example, this year, we are learning a lot more about the role of the germline variants in urothelial, cancer. Germline variants are these alterations that we're all born with, that are inherited. This year, we published a manuscript in Nature Communications that looked at the role of germline alterations or germline variants, in bladder cancer patients. We identified several common germline variants in these patients, which is consistent with other findings that are emerging from other groups. Now, we're trying to understand how these germline alterations interact with the cancer, somatic alterations to shape the course of bladder cancer.

Is genomic testing widely practices in community settings? How do these practices differ in the academic and community settings?

We're fortunate to have several different options for genomic testing in bladder cancer patients. Again, that depends on whether this is somatic testing, meaning testing the cancer cells, or germline testing, meaning testing the constitutive DNA that we're born with. Or are we testing both? And we're starting to have different commercially available panels in the community that are available to oncologists and the community to order. In tertiary academic centers, there are several, either custom made panels or other tests that are whole exome, even whole genome testing, that offer a more comprehensive view of the genomic alterations, whether somatic, or germline. I think that the real important thing here is to understand the difference between all these tests, and also to understand the difference between a research grade and a clinical grade test or assay, and then finally, how to really interpret the meaning of the results that will be yielded by any of these tests. It's not that one test is superior to the other, it really depends on the question and it depends on the interpretation or actionability of the findings and those tests.

What are the 3 common mutations found in these patients with urothelial cancer, and what agents are currently available to target these mutations?

We're learning more and more about the common genomic alterations in urothelial carcinoma. One of the genes that are commonly altered in urothelial cancer patients or bladder cancer patients is a gene called FGFR3. And this is a receptor tyrosine kinase. And it is frequently involved in by either mutations such as S249C, activating mutations, or actually by fusions with other gene partners that activate FGFR3 signaling. And right now, we have an FDA approved agent, erdafitinib (Balversa), which is a drug that targets FGFR3, and it's approved in bladder cancer patients who were previously treated with chemotherapy. We now have several FGFR3 inhibitors that are in clinical trials in several urothelial cancer patients.

What was the rationale for your study of alpelisib in this patient population?

The rationale for our study of this PIK3CA inhibitor in urothelial cancer patient is that PIK3CA is actually genetically altered, meaning mutated or amplified in 22% of bladder cancer patients

In the study, we found that using patient derived organoids, these are established by taking a piece of the tissue from a patient's bladder cancer and growing it in the laboratory. And then we're able to establish this mini tumor in the lab and have an infinite resource of these cancer cells that we can test with drugs in the laboratory, in a so called co-clinical trial, so we're able to identify which drugs are most effective against those cancer cells. And in one instance, we took a patient derived organoid from a urothelial cancer, or bladder cancer we then performed whole exome sequencing and identified at PIK3CA mutation and FGFR3 mutation and a CDK2A deletion in that particular organoid. And we were able to test different targeted agents against each of these genomic alterations. And we found that we could actually track the evolution of the cancer cells, which cancer cells are going to be killed by the cancer drug. For example, the FGFR3 inhibitor in which cancer cells are not going to be killed by the drug that are within the same organoid.

There is a concept called tumor heterogeneity, meaning that there are different cancer cells with different genetic makeups within the same tumor. We're finding that some of these cells may respond to a different drug, whereas some of the other cancer cells within the same tumors would not respond to the same drug. And In this study, we were able to actually show that using single cell DNA sequencing.

What are the implications of these results? And are there any next steps with the research?

These results improve our understanding of the role of genomic heterogeneity in response to targeted therapy. This is going to become particularly more relevant as we get more of these targeted agents approved in the clinic. So, this is something that we're starting to understand deeply because if we can identify strategies, combinations strategies, for instance, to target all the different cancer cells with their different sensitivity, or drug sensitivity, or drug resistance profile, then essentially, we would be able to have higher cure rates.

_REFERENCES:

_{Shody K, Liu W, Alonso A, et al. Single-cell DNA targeted sequencing (scDNA-seq) to test therapeutic vulnerabilities in urothelial cancer (UC) patient-derived organoids (PDO). J Clin Oncol 2021; 39(6):464. DOI: 10.1200/JCO.2021.39.6_suppl.464}