Dr. Zhao, thank you so much for joining us today.
Dekuang Zhao: Hey, thank you, Dr. Ballas, for the introduction. It's my honor to be here. I'm going to share about some of our studies presented at ASTRO, the stories about early detection of metastatic progression by circulating tumor DNA in patients undergoing bladder-preserving trimodality therapy. We know that for muscle-invasive bladder cancer, the standard care including neoadjuvant chemoimmunotherapy followed by radical cystectomy or by trimodality therapy, which is a combination of transurethral resection of the tumor followed by chemoradiation.
Also, based on the largest studies about propensity score-matched analysis, there are no differences in terms clinical outcome between these two treatment modalities. However, you see that there's still high risk of distant metastasis after finishing the treatment. Specifically, about five years, about 25% patient may develop metastasis.
So in that, bring the question, when patient after treatment, whether we have way to detect metastasis in the surveillance setting, that will be provide some useful information for the patients, specifically the circulating tumor DNA had been studied in many cancers, and now, also recently studying the muscle-invasive bladder cancer.
We know that in 2019, the demo group showed that in the radical cystectomy setting, ctDNA positivity actually can predict worse recurrence-free survival and overall survival. Then the question is how about in the TMT space? There's a limited data and studies to show the clinical value about ctDNA yet, so that bring to this project that we want to study that, and this is actually single institution in retrospective studies. We have patients that were treated by TMT, also had at least one post TMT circulating tumor DNA testing including this cohort.
We stratify patients by TMT status after TMT at either positive or negative. We're looking at the clinical outcomes, specifically, metastasis-free survival and recurrence-free survival. So the metastasis-free survival is a time between the end of TMT and any clinical evidence on metastasis. The recurrence-free survival is a time between the TMT and also any, either metastasis or local recurrence. That's a composite of both.
So first, the patient and treatment characteristics, you see, we have 42 patients including in this cohort. The median age about 73 years old, and most patients are male, had T2, N0 urothelial carcinoma histology.
In terms of treatment, almost every patient gets both bladder radiation and also pelvic lymph node. The dose is about 55 million doses for bladder and 40 Gray for the pelvic lymph node. About a half-half patient receive either concurrent cisplatin or gemcitabine.
So first, this table show that, in general, in this 42 patients, have the clinical outcome and will follow up with just a little bit over one year, and we found that six patients were actually ctDNA positive and 36 patients were negative. In these six patients, we found that five patients actually developed metastatic progression. This is either to the lymph node or lung metastasis. However, in the negative group, there's no clinical evidence of metastasis.
I want to point out that, interestingly, we also have a patient that developed non-muscle-invasive recurrence. This is all in the ctDNA negative group, but not positive group. Then we look at the metastasis-free survival. As you can see here, the ctDNA positive group really has worse metastasis-free survival compared to the negative group.
We also look further about the timing between ctDNA positive and also the clinical detection metastasis. As you can see here, these five patients we list here, in general, there's a median leading time about two months, that in terms of ctDNA positive and the clinical evidence metastasis, then we look at further recurrence-free survival, which is combination of either metastasis and local recurrence. Similarly, we see that ctDNA positive seem to also associate with worse recurrence-free survival.
In UV analysis, ctDNA positive status is the only viable affected associated with worse recurrence-free survival. So the summary and takeaway from this study that we found that ctDNA may serve as an early biomarker for metastasis in patients undergoing TMT and this ctDNA positivity seem to be identifying metastasis progression with a positive leading time. Although I want to say that the sample is a little small.
Based on this, we think that ctDNA positivity, when you have TMT, have ctDNA positive, this may provide opportunity for our surveillance intensification, also, potentially identify some patients with had high risk of development metastasis, and this may be suitable for early salvage therapy.
Of course, there are the limitations for this study that this is retrospective single institution study. The sample size is not big sample size, and also, another one that we not have upfront standardization of a ctDNA assessment. So actually, nowadays, in our institution, we are trying to incorporate ctDNA to be more standardized assessment at regular intervals.
Lastly, I want to give acknowledgement to my mentor, Dr. Daniel Grass, for his support and lead for this study. Also want to give thanks to my residency program at Moffitt Cancer Center for their support of this project. Thank you for your attention.
Leslie Ballas: Thank you so much. So tell me, what was the average time from completion of TMT to the first ctDNA blood draw?
Dekuang Zhao: Yeah. So yeah, the patients had, like I said, limitation that we don't have upfront standardization, and based on the cohort we have, the median time since the end of TMT and the ctDNA draw is about one month, although the variation between most patients actually have three months to six months after TMT that had the first ctDNA draw. But just look at the cohort we have in the median is about one month each.
Leslie Ballas: Okay. What was the sort of median time from TMT to positive ctDNA in a population that started off as negative?
Dekuang Zhao: Yeah, that's a very, very good question, actually. Based on... We have, like, six patients, right? In the ctDNA positive group. We look at this time between the TMT and the ctDNA become positive, it's actually about six months. The mean time, that's six months, they become positive.
Leslie Ballas: Did you have serial ctDNA blood draws on all of the patients such that you knew when they became positive effectively?
Dekuang Zhao: Yeah, that's a very, very important and interesting question. Actually, I look at the patients, actually. We have about 19 patients that had both pre and post-TMT ctDNA. That's about 45%, and about 23 patients that only have ctDNA after TMT. So in the 19 patients that had both pre and post-TMT ctDNA, two patients were positive before TMT, and one patient actually converted to negative after TMT and stayed negative. But one patient seem to be still keep having ctDNA positive, although the value decrease to some point, but still defined as a positive in that two patients. Other 17 patients, three developed positive afterwards. But all these three were negative before TMT.
So that being said, the 19 patients, two positive pre-TMT, and one converted negative, one stayed positive.
Leslie Ballas: That's interesting because when I think of ctDNA, I think of it as a marker more of metastatic disease, metastatic potential, but to have one of the patients convert to negative from TMT makes me wonder if there's a local component or if that patient responded to the concurrent chemotherapy. What do you think?
Dekuang Zhao: I think it's hard to say exactly what's the reason, but as I said, in our treatment, we not only treat primary tumor, we all to cover the pelvic lymph node. That's one thing. At the same time, patients also get, as you mentioned, concurrent chemotherapy, so that is likely, this ctDNA conversion to negative maybe partially from chemotherapy, maybe there's already some lymph node because we know some time, the patient end stage with before the treatment. There may be some lymph node metastases already going on, but the radiation cover that lymph node.
So I'm not sure exactly whether it's the radiation, or the chemo, or potentially both, that converted that to negative.
Leslie Ballas: Yeah, I guess along the same vein of the patients that were ctDNA positive, that I guess, developed metastasis, and I think you showed this in your table, so just remind me, did any of those develop local disease along with the metastatic disease?
Dekuang Zhao: Yeah, that's also an excellent question because we know circulation tumor DNA, usually, is check your blood. That is a more systemic test rather than check the local recurrence. Actually, we saw that in the ctDNA positive group, none of them develop local recurrence. But in the ctDNA negative group, there are eight patients develop non-muscle invasive local recurrence, which none of them was ctDNA positive.
Leslie Ballas: Sorry. Just to be sure, just to be clear about it, so in the ctDNA positive patients that developed metastatic disease, when they were discovered to have a lung met, somebody also looked in their bladder with a cystoscopy?
Dekuang Zhao: Yes.
Leslie Ballas: Okay.
Dekuang Zhao: All the patients had a regular surveillance protocol with cystoscopy every three to six months after TMT. In that patient, there's no evidence of local recurrence based on cystoscopy.
Leslie Ballas: Okay. Because sometimes when mets are developed, people then don't continue to do the cystoscopies to see if there's local, also, recurrence. So that's why I was just checking.
Dekuang Zhao: At least at the time the metastatic developed, that happened, we don't have any evidence of local recurrence.
Leslie Ballas: Got it. Okay. Well, this is really exciting, and as you indicated, there's a need to understand how to use ctDNA, I think, globally, in the treatment of bladder cancer, but very much so in the post-TMT space and the combination of your work and the small series that's been published from Dana-Farber is important to add to our knowledge of ctDNA and TMT. So thank you so much.
Dekuang Zhao: Thank you for having me.