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Leslie Ballas: Hi, thank you for joining us. I'm Leslie Ballas. I'm a Radiation Oncologist at Cedars-Sinai Medical Center in Los Angeles, and I am joined today by Professor Syed Hussain, who is a Professor and Consultant in Medical Oncology at the University of Sheffield.

He presented on histologic subtypes of bladder cancer at ESMO, and we are lucky enough to get him to give us a recap today. Welcome, Syed. Thank you so much for joining us.

Syed Hussain: Thank you, Leslie. Real pleasure to be here. Thank you so much for this invitation. I think it's really important to highlight these variant subtypes of bladder tumors because unfortunately, these cancers do not do well. Remember, 10, 15 years ago, urothelial cancers were in a similar stage. We used to call it as a Cinderella cancer, but urothelial cancers really turned the tide. With the advent, we were focusing on platinum-based chemotherapy. Now we have got immune checkpoint inhibitors, we have got conjugate antibodies, and the field continues to evolve, and the landscape is changing.

I think for ESMO as well, to highlight this important disease subtype, looking at the subtypes of bladder tumors was really a key thing and a key move forward. These are my conflicts of interest. I started with this case who unfortunately passed away. This was a 51-year-old patient who presented to us in November '23 with a big urachal tumor, which was adenocarcinoma as well as neuroendocrine small cell tumor component was there.

We proceeded with four cycles of platinum and etoposide-based chemotherapy treatment. Post-chemotherapy, the scan did not show any decent response from treatment, and the urachal tumor was seen to be in close proximity to the adjacent sigmoid colon. This patient—this was the neuroendocrine component and adenocarcinoma component as well to show. This patient had partial cystectomy under the care of my colleague, Professor Catto. But unfortunately, within six weeks of surgery, the disease had come back, and it basically had significant recurrence, and within four weeks of that, further scans showed disease progression, and the patient passed away at the end of the month of August.

And that case really highlighted how these young patients who have got these variant histologies—one thing which is common with those variant histologies is that they do quite poorly. Their prognosis is poor, their survival is poor. And again, I touched on all these different subtypes of variant histologies of bladder tumors. I won't go into all of these. These will be present in my ESMO presentation. But key thing to mention was that things like plasmacytoid, small cell neuroendocrine, micropapillary—they all have one thing in common, which is poor prognosis and poor survival. And where we don't know really how to treat them, what systemic treatments to offer them, because all what we are seeing is that these patients are not living longer.

One thing is key here is that central pathology review. This was highlighted—this is from ABACUS-2 trial, which is led by Tom Powles running in the UK. And what it showed, and Bernadette presented that last year at ESMO, and what it showed is that once you review centrally the pathology review, the pathology changes. For example, squamous differentiation was actually plasmacytoid. One of these, similarly micropapillary again moved in towards another micropapillary.

You can see that some of those which were called squamous differentiation, they might move to sarcomatoid. Central pathology review is key, and again, because many of these subtypes of bladder tumor may share different tumor biology, and that may be the reason they have different outcomes. For example, looking at the ABACUS-2, which is a window of opportunity trial giving two cycles of atezolizumab treatment followed by cystectomy, you can see the pathological response rates in sarcomatoid tumor was significant—62%, five out of eight cases. But in squamous, it was only one out of 12 cases—that is 8%.

It's important. Again, these are small data sets, small sample sets in small numbers—we need to look at it carefully, but that is how things are. This is from the United study, which looked at different subtypes of bladder tumor. And when you look at basically urothelial predominant and you look at basically predominant variant histology, the response rate changes.

That again tells you, for example, in enfortumab vedotin response in squamous where there is a predominant urothelial with minor component of squamous, the response rate is moving into 55%, but that response rate drops to 33% when basically it's a predominant variant histology. The same for micropapillary. I think it is interesting and important to understand that these variant predominant tumors are separate to tumors which are predominantly urothelial with some minor component of variant histology.

I think it's important that what is driving the biology of the tumor, what is driving the outcome and prognosis of this tumor, and that's why it's important to do big international clinical trials as GU global community to move the field forward. Again, this was a SEER database, and the Washington group with Bakaloudi and Petros Grivas—they published that data in August. It's the retrospective data set. It's important to understand this is a review of the institutional database and that reviewed number of patients through the SEER database as well, and the median overall survival with neoadjuvant chemotherapy—this is small cell bladder cancer.

Neoadjuvant chemo plus cystectomy was 46 months and 45 months in the institutional and the SEER database. But for the median overall survival for concurrent chemotherapy was 26 months and 23 months in the institutional and SEER Medicare database. But again, important to understand that these are two different groups of patients and more unfortunately, often less fitter patients who are not fit for systemic chemotherapy treatment are moving on towards trimodality treatment, and they're not receiving neoadjuvant chemotherapy in this setting. Again, in small cell bladder cancer. In most practices nowadays, you'll be using chemotherapy before radical treatment.

In conclusion, I said basically key thing was that the diagnosis and management of variant histology of bladder tumor is a big challenge. It remains an area of unmet need as we encounter poor prognosis and survival in these cases. And I think it is fair to call this disease as an orphan disease today. Exclusion of many of these patients in clinical trials have led to poor prognosis and treatment for these patients with predominant variant histology.

There's importance of central pathology as reviewed by the ABACUS-2 trial as that was presented last year by Bernadette. And I showed that slide as well to show how the tumor pathology review changes the subclassification of the bladder tumors. Poor and slow recruitment in these ongoing trials addressing the management of these patients with predominant variant histology tumors highlights the need that we really need to work together as international efforts need to be focused in designing and delivering clinical trials as GU community has done it for urothelial cancers and other cancers like kidney cancers and prostate cancers.

I think it is time that we all work together, focus on these predominantly variant histologies of bladder tumor, understand the tumor biology, look at different treatment options that there are. And I can tell you that during the course of ESMO, we had interesting and exciting discussions with a lot of my global colleagues, including industrial partners who will be keen to look at towards developing these studies and designing and delivering these drugs and these treatments in future for our patients to improve the outcome for the young patient that I talked about at the beginning of my talk.

Thank you.

Leslie Ballas: Thank you, Syed, for that fantastic recap of variant histology. One question that I have that comes up a lot is: Should we be including these variant histology patients on urothelial trials to broaden their access to clinical trials? Or do you think we really need specialized clinical trials for just these patients?

Syed Hussain: I think, Leslie, this is a great question. There was a huge debate around that during the ESMO talk that I gave. A lot of questions around that because the first thing to think about is what is the definition of predominant variant histology? And I think one of the key things we thought about over 50%—if it is driven by variant histology, then that is predominantly variant histology. Rather because—is it 20%? The cutoff is 30%—the cutoff when you're looking at these pathology biopsies and tumor samples. There are a lot of questions around it.

As ABACUS-2 showed as well, that just by reviewing the pathology, you actually showed that the subclassification changed. I feel, as I said at the outset, urothelial cancer—I used to call it Cinderella cancer, which really did not change. Nothing changed for 30 years, and see what happened over the last 10 years. Those patients who used to have a median survival of 12 to 18 months, they are into 30, 36 months and moving forward. We are moving these treatments from metastatic disease, second line, third line to perioperative treatments now.

We're looking at adjuvant treatments making changes, and I feel that our patients with variant histology bladder tumor demand the same attention and same focus. I think we should be designing trials which are focusing on variant histology, predominant variant histology, because if you see many of these trials that we talked about in urothelial cancers, there is a subset of patients who had small components of some component, which nobody knows what that small component is—10%, 20%, which was there.

They look at that and they present that as well—that some of these patients had minor component of variant histology. I think the way the biology of these tumors are, as you see some sarcomatoid tumors responding well to IO or with EV, it could well be that this is a small subset that is giving me that answer. We need to do properly randomized clinical trials with these different subtypes and working together on focusing on those variant histologies if we work together with the input of EORTC, ASCO, ESMO, ICRI, which is the Rare Cancer Initiative and things.

But I think the key thing is really working together, designing these trials and delivering these studies together. That is my view that we should really focus on them as a separate entity and as a disease site. I think where we have struggled is that many centers, many countries are doing trials on their own, and that is where the struggle is—that one tumor type they're looking at, one subtype they're looking at, and they're struggling to put patients in those trials.

These patients progress rapidly. They come from where we think about they may have some—where you can go for curative treatment and you're thinking of surgery, and by then the patient has progressed already. There are a lot of questions, and when they present as metastatic disease as well, it is important to focus on those subtypes and put them into clinical trials.

Leslie Ballas: One practical question that comes up a lot in our tumor boards is what to do with a plasmacytoid patient who is opting for cystectomy, and whether or not to give neoadjuvant chemo prior to cystectomy in a plasmacytoid variant. Our practice has always been to shuttle these patients directly to cystectomy because plasmacytoid variant has a limited response to chemotherapy, and we want to make sure that obviously they get to the definitive therapy of cystectomy.

How are you guys handling these patients? I think it's a particularly challenging area.

Syed Hussain: Yeah, you're right. And often these are very young patients as well, and they present to you looking very young and fit. But unfortunately, the disease progresses rapidly. We have the similar—we do joint—we have an MDT, we have a joint urologic oncology clinic with myself, Jim Catto. We have got a urothelial—sort of more like a bladder cancer clinic that we run together. And that does help because we are a really big center for these sorts of cancers, both for cystoprostectomies or cystectomies and for organ preservation.

But I think the key thing is that these patients really need treatment and need treatment as soon as possible. In most cases, they go straight for surgery. My other feeling is that when you go for a cystectomy, often you find that actually what we thought was predominantly plasmacytoid, you might find that actually they are urothelial with plasmacytoid, and that changes the outcome because you know that treatment options are significantly more if they have more urothelial cells and urothelial components as well.

I think if you have the potential opportunity where you can go for cystectomy, I will go for it. And I think again, they do not usually respond well. Resistance to treatment is again a key issue here as well. In most cases, the recommendation will be to move straight to surgery and then follow them depending on what the pathology—what the high-risk disease it is, what the histology is—you can consider them for adjuvant treatment afterwards.

Leslie Ballas: I also really liked the way that you framed the University of Washington SEER study in small cell cancer, just really using it to show that these patients unfortunately have poor outcome and that selection bias is a huge component. I mean, when you look at that study, they really weren't comparing apples to apples. As you mentioned, most patients with small cell bladder cancer who opt for a bladder preservation treatment would get true neoadjuvant chemotherapy followed by radiosensitizing chemo and radiation.

Whereas in that SEER study, they were really just comparing neoadjuvant chemo with cystectomy to patients who had sort of the radiosensitizing chemoradiation. I think it's always important as we analyze data in these subsets and certainly any time you analyze data from SEER to make sure that we are understanding what's being compared.

Syed Hussain: I completely agree with you. This is really key here that what you're looking at often—unfortunately, organ preservation has often sent patients who are not fit for surgery, which I'm delighted to say now the tide is changing, and it's changing in North America as well. Huge work has been done by North American colleagues. Princess Margaret Hospital has played a key role. Boston played a key role. A lot of these centers, and we did 20 years ago—again, I don't know, Leslie, you know or not—22 years ago actually, I presented—I published my phase one trial in Annals of Oncology on the mitomycin 5-FU used as a radiosensitizer. Then I published the phase two trial in British Journal of Cancer phase two, and then the phase three randomized trial, BC 2001, we published in New England Journal of Medicine.

I remember 20 years ago, 23 years ago, when I presented my phase one/two data in North America at one of the ASCO meetings, I was asked a question, "Don't you have urologists in your country? Why don't you take the bladders out?" And I think it is such a huge change I'm seeing, and I completely agree with you. This SEER database showing patients, and it just looks like—if you look at the headline, it looks 45 months versus 23 months. But again, when I was talking to Petros Grivas as well, they all agree that actually it's not the same patients. Patients who could not—was not fit for any chemotherapy went for radiotherapy treatment.

I think really with the change that is happening, the RTOG studies happening with atezolizumab in addition to radiosensitization—in UK, we are doing a RAIDER trial adding durvalumab into mitomycin 5-FU, so all these sorts of things. Then there is a study that Arjun Balar presented with pembrolizumab as a radiosensitizer. A lot of these things which are happening in North America is really moving and changing from a predominantly 80, 90% cystectomies to where we are in UK for the last many years, which is about 40, 50%.

I did a trial called Neoblade, which is a neoadjuvant bladder tumor trial, which was looking at nintedanib plus Gem/Cis followed by cystectomy or organ preservation. We designed the trial allowing both cystectomy or organ preservation. And the reason I'm just mentioning that—that trial very clearly showed that almost 60% had cystectomy and 40% had organ preservation. That is to say this is a trial we published in Lancet Oncology a year ago.

That is just to say that in UK practice, in Europe mostly, we get about 40%, 50% organ preservation, which I think is the right way to look at. These are not competing treatments. These are complementing treatments, and it's important that patients get the option of selecting the best treatment that is best for them rather than...

Sorry to digress from the topic we had, but when you talked about...

Leslie Ballas: No, I actually completely agree. I mean, if you look at the timeline of bladder cancer treatment in the US, and for the most part worldwide, there have been not many changes in the drugs that were being used over 40 years. And it was pioneering work by you, Nick James, the group in the UK, Ananya Choudhury, and the group that looked at BCON, that has over time chipped away at that resistance of American urologists at the idea of bladder preservation. Let this be a big thank you to you and your work that you've done.

Syed Hussain: I met Bill Shipley many years ago and Mary Gospodarowicz because they were a big influence when, again, with myself, Nick James, Peter Hoskin did BCON, and Ananya did amazing work with gemcitabine and other colleagues as well. I think it has been a teamwork where all of us have worked together, but it's good to see that patients will have the option of considering both treatments. That's the key thing which we want to drive—patients choose what is best for them.

Leslie Ballas: Agreed. Well, Syed, thank you so much for being willing to discuss this topic. It is an important topic that we need to highlight and understand. It was truly a pleasure to get to have this conversation with you.

Syed Hussain: Thank you very much for inviting me. Really enjoyed discussing with you. Will be great to catch up again at some point soon.