JCO PO authors Dr. Abhishek Tripathi and Dr. Salvador Jaime-Casas at City of Hope Comprehensive Cancer Center share insights into their article, “Comparative Genomic Characterization of Small Cell Carcinoma of the Bladder Compared With Urothelial Carcinoma and Small Cell Lung Carcinoma.”  Host Dr. Rafeh Naqash and Drs. Tripathi and Jaime-Casas discuss a novel understanding of the genomic alterations underlying SCBC, revealing actionable mutations that could serve as potential targets for improved clinical outcomes.

TRANSCRIPT

Dr. Rafeh Naqash: Hello and welcome to JCO Precision Oncology Conversations, where we bring you engaging conversations with authors of clinically relevant and highly significant JCO PO articles. I am your host, Dr. Dr. Rafeh Naqash, Podcast Editor for JCO Precision Oncology and Associate Professor at the OU Health Stephenson Cancer Center at the University of Oklahoma.

Today, I am thrilled to be joined by Dr. Abhishek Tripathi, Associate Professor in the Department of Medical Oncology and Experimental Therapeutics Research at the City of Hope Comprehensive Cancer Center, as well as his mentee, Dr. Salvador Jaime-Casas, postdoctoral research fellow and first author of the JCO Precision Oncology article entitled "Comparative Genomic Characterization of Small Cell Carcinoma of the Bladder Compared with Urothelial Carcinoma and Small Cell Lung Carcinoma".

At the time of this recording, our guest disclosures will be linked in the transcript.

Abhishek and Salvador, welcome to our podcast and thank you for joining us today. This is a very interesting topic given that at least the landscape for neuroendocrine carcinomas, where small cell lung cancer is on one end of the spectrum, has been changing, at least on the lung cancer side, with recent approvals and some new ADCs. So, of course, understanding the genomic and transcriptomic similarities or differences between pulmonary small cell and extrapulmonary small cell is of huge interest. Could you tell us a little bit about small cell bladder cancer, current approaches to treatment of small cell bladder cancer, and then why you wanted to investigate that in this project as far as the genomic differences or similarities are concerned?

Dr. Salvador Jaime-Casas: Well, first of all, thank you very much for having me. I am very excited to be here. And really what served as backbone for this research project was the notion that there is a currently evolving genomic landscape in the area of bladder cancer. We know this is a highly heterogeneous disease when it comes to molecular underpinnings and mutational profile. Specifically, we know that the most common histologic subtype is urothelial carcinoma. Small cell bladder cancer represents a histology that is found in less than 1% of all bladder cancer cases. However, it is one of the most aggressive histologies. It presents with a very poor prognosis to patients and very poor response to treatment, which is why we attempted to really elucidate what is the mutational profile behind this and provide a comparison contrast between small cell bladder cancer, small cell lung cancer, and conventional urothelial carcinoma.

As your question mentioned, in terms of treatment, the conventional urothelial carcinoma and small cell bladder cancer are two distinct pathways when it comes to treatment algorithms. We know that in the current era there are newer and newer drugs being developed for conventional urothelial carcinoma. We have perioperative immunotherapy in the context of metastatic disease. We have antibody-drug conjugates such as enfortumab vedotin. But really, this amazing track record of drug development hasn't been mirrored in small cell bladder cancer. And here most of the therapy is usually extrapolated from studies from other small cell histologies like you mentioned earlier, small cell lung cancer has given some form of background in terms of what therapies are used here. Cytotoxic chemotherapy, for some patients with localized disease and small cell bladder cancer, concurrent chemotherapy and radiotherapy or perioperative cytotoxic chemotherapy have been the cornerstone of treatment for many years now. However, like I mentioned, the oncologic outcomes are very suboptimal when it comes to comparing it with other disease histologies, which is why we really wanted to describe the landscape here and provide this comparison across three different groups.

For this particular study, we leveraged the Tempus dataset. So, include patients with urothelial carcinoma with small cell bladder cancer and small cell lung cancer. We included their demographic information, as well as the frequency of most common genomic alterations identified. And really, it was a very comparable Table 1. We see the demographic data across the three groups was very similar. One key thing that we identified was the female prevalence was a little bit lower in patients with small cell bladder cancer when compared to small cell lung cancer. But other than that, the age, race, ethnicity, was comparable across groups, and even the smoking history. Most of the patients in this cohort were former smokers, which we believe comes to explain that regardless of any mutational profile that we talked about in a few minutes, there are shared commonalities between these histologies and shared environmental exposures and risk factors that are going to be implicated in the disease biology for these three histologies.

Dr. Rafeh Naqash: Thank you so much, Salvador, for that useful background.

I would like to shift to Abhishek real quick. Abhishek, you are a practicing clinician, you have led several studies in the GU space, especially bladder. Based on what you see in the small cell lung cancer space, how drug development is shaping up, which aligns with what you are trying to evaluate in this paper as targets, how do you see some of that being implemented for small cell bladder cancer in the current era and age?

Abhishek Tripathi: Thanks so much for the excellent question, Rafeh. As a GU investigator, small cell bladder cancer has always lagged behind in some regards regarding enrollment abilities for the novel clinical trials. And small cell lung cancer has paved the way and led the development of a lot of these drugs across the board. With the most recent sort of drugs targeting DLL3 already approved and several antibody-drug conjugates currently in development. That actually translates really well to how we should approach drug development in bladder cancer.

What we saw in the study is that although there are overlaps and similarities between small cell lung cancer and small cell bladder cancer, there are also certain differences. So the long-term assumption that all therapies for small cell bladder cancer can be extrapolated to small cell bladder], may or may not be true, and I think it is high time that we specifically investigate these novel agents in tissue-specific small cell carcinomas. To that effect, we are excited to be participating in trials that are looking at some of the novel DLL3 targeted agents, specifically bispecific antibodies and T cell engagers so to speak, and antibody-drug conjugates that are now starting to open enrollment specifically in non-lung cancer cohorts to evaluate its efficacy. So overall, I think studies like this have the opportunity to identify more putative targets for organ-specific development of these novel agents.

Dr. Rafeh Naqash: Absolutely, I could not agree more. I think tumor-agnostic therapies definitely have a place, but not all therapies work the same in different tumors with a similar histological or genomic background because there are definitely differences.

So now going to the comparison that Salvador, you guys did in this project, could you help us understand what are some of the things you looked at, what were some of the commonalities and the differences, and what were some of the conceptual thoughts that come out from those results?

Dr. Salvador Jaime-Casas: Of course. So, the first thing that we identified was which were the most frequent molecular alterations across these histologies. We actually provided a table showcasing how the most common mutations that we identified were TP53, TERT, RB1. However, like Dr. Tripathi mentioned, the distinction between these histologies is notable in the sense that some are more predominant in small cell-pertaining cancers such as bladder cancer and lung cancer. While some others are more common in bladder-pertaining malignancies like urothelial carcinoma and small cell bladder cancer. For instance, we saw that TP53 and RB1 were significantly more evident in small cell histologies, both small cell bladder cancer and small cell lung cancer, as opposed to conventional urothelial carcinoma, which really this mirrors what is known about these mutations and what has been published. These are markers associated with more aggressive disease with a worse prognosis and even to resistance to treatment.

We also identified how TERT mutations were characteristically more prevalent in small cell bladder cancer as opposed to small cell lung cancer, as well as in urothelial carcinoma. TERT mutations were more commonly identified than in small cell lung cancer. And we give a long list of these mutations that we identified, but really what we wanted to underscore here was, A, the most common mutations across histologies; B, the most common co-occurring mutations where we saw that these are not mutually exclusive. A lot of patients had co-occurring TP53 and RB1 or RB1 and TERT or RB1 and ARID1A, really elucidating how heterogeneous this molecular landscape is across histologies.

And the third one that we believe really brings down the clinical impact of this research was evidencing the idea of clinically actionable mutations. We also provided a table here showcasing how mutations like FGFR, DLL notch pathway, HER2, were evident in these histologies, and what is the current status of some clinical trials evaluating different drug designs for these mutations. Like Dr. Tripathi mentioned in the context of FGFR, approximately 6% of our cohort with small cell bladder cancer showcased mutations in FGFR3. However, up to 14% of them had mutations in any FGFR gene, which really underscores the notion that drugs like erdafitinib, which have been introduced in the market in recent years, could potentially showcase some response in the space of small cell bladder cancer. We actually provide the description of two trials, phase two, phase three trials, that are evaluating erdafitinib in the context of high-risk non-muscle invasive bladder cancer and even metastatic urothelial carcinoma.

Like Dr. Tripathi mentioned as well, antibody-drug conjugates, another very interesting area of drug development targeting HER2, we included evidence on how disitamab vedotin and trastuzumab deruxtecan are currently being explored across different phase two and phase three clinical trials, both as part of basket trial designs for solid malignancies expressing HER2, but also for patients with urothelial carcinoma where there is evidence of HER2 expression. So, we believe that the landscape is shifting in the right direction in the sense that therapies are becoming much more personalized and targeted against these known molecular profiles.

Dr. Rafeh Naqash: Thank you, Salvador, for summarizing some of those very interesting results and providing a very unique conceptual context to that.

I would like to go to Abhishek this last portion. Of course, I am sure you guys will expand on this work and there are a lot of other interesting things that will likely come out from this work and hopefully you will publish that in JCO PO. But one of the very important things that I wanted to highlight from this podcast specifically was the science is obviously very interesting, but I feel the more important interesting aspect is giving trainees and fellows, residents, mentorship opportunities, mentoring them and giving them lead roles in projects like this, which is what Dr. Tripathi has successfully done for you in this project, Salvador. So, Abhishek, as somebody I have known for a couple of years now, more than a couple of years, as a very successful clinical translational investigator in the GU space in the early phase setting, Abhishek, really briefly, within a minute, could you tell us about your journey and what are some of the things that have worked for you as an early career investigator that you have learned from, and then your journey of mentorship, how has that been for you and what are some of the things that you take home from your mentorship role?

Abhishek Tripathi: Absolutely. And as you mentioned, mentorship has been pivotal for all early career investigators for them to really succeed. So, my journey, as you know, I started off as an early career investigator at another institution, and I think I owe it to my mentors even at that time and even now who are helping me develop some of these newer translational and clinical trial ideas, creating opportunities where we could really showcase some of the interesting work that we are doing. That actually goes a long way in terms of creating independence as an established investigator. And I think the sooner we start off with mentorship prospects, I think the better it is.

And paying it forward, I think I have been lucky to have mentees like Salvador who are just extremely talented, really committed, and goal-oriented. He really led the project right from the beginning in terms of initial analyses and looking up all the sort of correlative studies that we could do and the contextual data between small cell lung cancer and bladder cancer that we have delved into for the past several years. And it really showcases the ability of young mentees like Salvador to really excel given the right guidance and the support.

As a mentor, it has been a really rewarding experience. It is really helpful to actually learn from some of these mentees as well as to approach the same problem from a different angle and different thought process and guide them through the study. So, it has been incredibly helpful and rewarding both being a mentee and a mentor over the past several years as I have transitioned.

Dr. Rafeh Naqash: Thank you, Abhishek, for those very insightful comments on how both being a mentee and being a mentor helps shape you as an individual as well. And then you take a lot of pride in the success of your mentees.

Now real quick, Salvador, could you tell us a little bit about yourself, you know, how you ended up at City of Hope under Dr. Tripathi’s mentorship and what are some of the next important things that you are looking forward to doing?

Dr. Salvador Jaime-Casas: So, a little bit about who I am. I did medical school in Mexico City. I was born and raised there, and towards the end of my medical training, I started to be engaged in research projects. And through one of my mentors in Mexico, I was actually introduced to the team here at City of Hope, including Dr. Tripathi. And through this, we got the opportunity to have some conversations about what I wanted to do, become a physician-researcher in the area of genitourinary oncology and hopefully my transition to residency in a few years. And that is how I came to be his mentee here at City of Hope. I think it has been a very rewarding experience, like Dr. Tripathi said, having such an incredible mentor and really being with him both in the academic setting and in the clinical setting, in patients with clinic, seeing this curiosity and all these clinical trials, all of this evidence that we have coming together to generate this insight.

Dr. Rafeh Naqash: Thank you so much for both the scientific insights, as well as the journey of being a mentee for you, Salvador, and as a mentor for you, Abhishek. I really enjoyed talking to you guys about both aspects here today and hopefully we will see more of your work, Abhishek and Salvador, as far as understanding the transcriptomic heterogeneity in neuroendocrine tumors or neuroendocrine cancers of the bladder.

Dr. Salvador Jaime-Casas: Thank you very much. Thank you for having us.

Dr. Rafeh Naqash: Thank you for listening to JCO Precision Oncology Conversations. Do not forget to give us a rating or review and be sure to subscribe so you never miss an episode. You can find all ASCO shows at ASCO.org/podcasts.

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Dr. Abhishek Tripathi Disclosures

Consulting or Advisory Role:  Company: Aadi biosciences, Seattle Genetics/Astellas, Exelixis, Bayer, Gilead Sciences, Pfizer, Deka biosciences Speakers' Bureau: Company: Sanofi