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Sam Chang: Hi, my name is Sam Chang. I'm a urologist in Nashville, Tennessee. And we are quite fortunate to have an international guest today, Dr. Dag Stormoen, who is actually a researcher in radiation and medical oncology. He has actually done some research recently at Dana-Farber, and he is in Copenhagen, looking at the genetic profile of urothelial tract cancer, both in early and late stages. So Professor Stormoen, thank you again for spending some time with us, and we look forward to your presentation.

Dag Stormoen: Thank you very much for having me. So I will be talking about the ESMO Abstract 2007 named Similar Genetic Profile in Early and Late Stage Urothelial Tract Cancer. My name is Dr. Dag Stormoen, working at Copenhagen University Hospital.I'm going to begin by giving a brief background of the rationale for doing this study, and then we will dive a bit into the methods briefly, and we will look at the main results and findings.To begin with, bladder cancer is the ninth most commonly diagnosed cancer worldwide, with both incidence and mortality rates rising. Worldwide, about 615,000 new cases were diagnosed in 2022.It's imperative to understand that treatment between disease confined to the organ, usually the bladder, performs intrinsically better than disease that has escaped from the bladder into surrounding tissue, or metastasized. This is reflected by survival at different stages. So, you have muscle-invasive disease, with a five-year survival of about 50%, while metastatic or locally advanced disease only has a five-year survival of 5 to 10%. The early non-invasive stages have better survival and also account for the majority of new cases of bladder cancer.

So, the treatment differs in that locally confined disease is primarily surgical, with the option for some neoadjuvant chemotherapy. For metastatic or locally advanced disease, it's primarily oncological, and sometimes also includes radiation therapy.The method for this study was to compare muscle-invasive bladder cancer, untreated, with heavily treated patients. The patients in the CoPPO cohort (Copenhagen Prospective Personalized Oncology group) have received multiple lines of therapy, and there are no further standard treatment options. They also need to have an exemplary performance status of 0 or 1, which is rare after this many lines of treatment. After many lines of treatment, these patients received genomic testing with the intention of offering treatment based on targetable mutations.

So, in the comparison between the two cohorts, we first looked at all variants. Top mutations are shown here to the left. In the Phase I, or CoPPO cohort, we have the usual mutations, like TP53, ATM, KDM6A. And there are no statistically significant differences between the TCGA cohort and the CoPPO cohort, looking at all variants. While looking only at oncogenic or likely oncogenic mutations, which are more relevant in terms of targeted treatment, there were also no statistically significant differences.

Furthermore, I think it's imperative to look at survival between these two cohorts. Now, I'm not doing a direct comparison, but in the TCGA cohort, the M-0 represents the clear muscle-invasive group, while the blue line refers to unmeasurable metastatic disease. So we're unsure if they have metastasis. If we're taking a glance at the clear muscle-invasive cohort, they have a five-year survival of about 50%. So actually, they have a 50% survival probability of about five years, which is what I said initially as well.When we look at these heavily treated patients—two to three lines—I have here put in time from first-line treatment, metastatic disease, and first-line treatment. Even for the group of 23 patients not receiving any targeted treatment, they had a survival surpassing two years, which is rare for this patient group. For the nine patients receiving targeted treatment, we could see a survival surpassing five years at 50%.

So this is quite extraordinary for this cohort. It is a rare cohort, and whether it is due to heavy selection for treatment or the targeted treatment they received, that's difficult to answer from this trial, but it definitely makes you think.Furthermore, we looked at each of the oncogenic variants we found and categorized them according to OncoKB levels of treatment evidence, where level one indicates an FDA-recognized biomarker and an FDA-approved drug for bladder cancer. Only FGFR inhibitors were found in both cohorts here. Looking at level 3B, where there is compelling evidence to support a biomarker as predictive of response to a drug within another indication where it hasn't been thoroughly tested in bladder cancer, you can see there are a lot of drugs here. PARP inhibitors pop up and show possible activity for a lot of mutations. I will admit that PARP inhibitors have been tested in multiple clinical trials for bladder cancer, but results have not been clear. But there seems to be an agreement that subgroups with DDR deficiency (DNA damage repair deficiency) do have increased response to PARP inhibitors, but this is unclear as of yet.

So the take-home message from this trial is that there is a similar mutational profile between early and late-stage bladder cancer. There are multiple targetable mutations with existing drugs. Genetic testing early in the disease trajectory can show targetable mutations and offer more treatment options down the line. Thank you very much.

Sam Chang: Dr. Stormoen, thank you so much. I think, obviously, the first question that everybody will have is, boy, these heavily treated advanced-stage cancer patients, and your total number was small—just over 30.

Dag Stormoen: Absolutely. Absolutely.

Sam Chang: Their profile is not much different from the TCGA profile.

Dag Stormoen: Yeah.

Sam Chang: So the question, though, is, how did they get to this point? I mean, already, those that didn't have a targetable kind of actual mutational change, 50% lived two more years, you know?

Dag Stormoen: Exactly.

Sam Chang: And then those that had... So what do you think—obviously, this is pure conjecture—what do you think makes this cohort different, or do you have any idea?

Dag Stormoen: Well, first of all, these patients are kind of unicorns.

Sam Chang: Yes.

Dag Stormoen: Because they have been collected nationwide in Denmark over almost 8, 10 years, and we only have 31. It's important to remember, Denmark is a very small country, so we don't have many cases of bladder cancer. But these are definitely unicorns.On the other hand, they are also a bit younger than the median age of the TCGA cohort. So that can additionally explain prolonged survival. But no, we don't have a clear answer as to why these patients survive as long as they do, even without the targeted treatment.

Sam Chang: Yeah. I think the take-home message regarding the fact that doing the genetic testing of the tissue of the advanced disease stage shows that there are times when you can actually find an actual target that you can act on and go from there.

Dag Stormoen: Exactly.

Sam Chang: And so, where do we go next? What are your thoughts now regarding this evaluation? Are there going to be attempts to further define this unique cohort in terms of survivability? Is it to do more work on the actual targets? Where do we go next with this research?

Dag Stormoen: Well, I think what it showed us is that we need to prepare patients for targeted treatment earlier on in the treatment trajectory. This is a rare cohort, so most patients won't make it there because their performance status will deteriorate very quickly after first or second-line treatment. So they don't necessarily have the time to wait three months for genomic testing. So if we already have that up front, you can be prepared and start the next line of treatment with a targeted option, if you have that availability in your country.It differs a lot, what you have available and allowed. I know in the US, you're allowed to give more. If the drug is approved, I believe you are allowed to administer that on good indication. In Denmark, we need a clinical trial to do this. And actually, we need more clinical trials. So the paper has been published, and we will—as we suggest in the paper—need more, bigger international targeted clinical trials for bladder cancer patients.

Sam Chang: I think that's a really important message here. This work only raises more questions on the possible overall impact of performance status. I mean, we know that those individuals tended to be younger and healthier, but is it an overall lack of sarcopenia? Is it better cardiac health, better nutrition? All those things that could perhaps impact performance status. Really, maybe that's the tipping point, and it's not necessarily the disease itself but the overall health of the patient. So I look forward to you guys actually focusing in on that as well.

Dag Stormoen: I think that's a brilliant point you are making there, Sam. Because this patient group is known to have a lot of comorbidities related to smoking and poor lifestyle choices. So they have an increased risk of hypertension, diabetes. So yeah, if they have good performance status and good health at the beginning of the disease, maybe that's the group of patients we have included in our CoPPO cohort. Probably it is.When that is said, I think all patients should get the possibility of targeted treatment options, even those with poor performance status or smoking-related diseases if there is something to gain, and this needs to be checked.

Sam Chang: Dr. Stormoen, thank you so much for sharing the abstract that was presented at ESMO, focusing on the similarity in the genetic traits of both advanced and earlier-stage disease; and really shedding light on a unique prospectively gathered cohort of more advanced patients in Copenhagen. So we very much appreciate your time and your expertise, and we look forward to future research as well.

Dag Stormoen: Thank you very much, Sam. Looking forward to seeing you again.