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Prognostic Subgroups in Advanced Bladder Cancer

Panelists: Daniel P. Petrylak, MD, Yale University Cancer Center; Dean F. Bajorin, MD, Memorial Sloan Kettering Cancer Center; Robert Dreicer, MD, MS, Virginia Cancer Center; Arjun V. Balar, MD, Laura and Isaac Perlmutter Cancer Center; Elizabeth R. Plimack, MD, MS, Fox Chase Cancer Center; David I. Quinn, MBBS, PhD, USC Norris Cancer Hospital
Published: Tuesday, Mar 21, 2017


Transcript:

Daniel P. Petrylak, MD:
You were the first to describe the different prognostic subgroup that are involved in the treatment with chemotherapy for bladder cancer. Perhaps, you could elaborate a little bit on that because I think it’s important for the listener to understand that the bladder cancer is a very heterogeneous disease, even within the metastatic state.

Dean F. Bajorin, MD: It has been looked at a number of different ways, and all these studies point to the same conclusion. There are some patients who can do well, and those are patients who we would generally think have disease that is restricted to lymph nodes, so-called better disease prognostically, and that they have a good performance status. And really, I think the good performance status reflects tumor burden. So, those patients who have less of a tumor burden, have nodal-only disease, can do better than the patients who have visceral disease or encumbered from their disease due to the high volume of metastases or evidence of visceral disease like liver, lung, or bone. And so, when we look at these trials, we’ll be looking at subsets of those patients who are so-called good risk, that is node only, good performance status. And then, the other end of the spectrum, the patients who do very poorly, those who have visceral disease and have a poor performance status and for whom many times we can’t give chemotherapy, they might be opportune for immunotherapy. We’re going to see that for some of the data.

Daniel P. Petrylak, MD: And from that standpoint, too, we can also divide some of the sensitivity to chemotherapy based upon some of those subgroups that you mentioned before. Perhaps you can describe to the audience the differences in the different subgroups and how they relate to responsiveness.

Dean F. Bajorin, MD: These are emerging data from the TCGA and a number of different studies that are ongoing now. The backbone of these therapies is cisplatin, and there are genes that are responsible for repair for cisplatin. And so, data from, for example, Dr. Plimack’s work and our work suggest that there are certain genes that if they are altered in the patients’ tumors, it makes them much more sensitive to systemic chemotherapy, cisplatin-based chemotherapy. I shouldn’t talk for Betsy’s work, but, in terms of ATM (ataxia-telangiectasia mutated) and RB (retinoblastoma), that actually looked very encouraging; neoadjuvant setting, systemic chemotherapy, those patients did extraordinarily well. In our series and others, what we call “DNA repair response genes,” deleterious lesions within those genes confer exquisite sensitivity to cisplatin. So, these studies are now just emerging on how we might be able to select out those patients who respond to cisplatin-based chemotherapy and those who do not.

Daniel P. Petrylak, MD: Betsy, would you like to further elaborate on that? You’ve done a lot of good work in neoadjuvant therapy with looking at some of these different subgroups. Perhaps you’d like to expand on that.

Elizabeth R. Plimack, MD, MS: I think what Dean is talking about is more DNA repair lesion in the tumors, which is separate from the subgroups that were based on RNA expression, gene expression data. But the DNA repair lesions, what’s interesting—and a correlate to what you just described—is that we also see that those tumors with the highest number of alterations have the best response to cisplatin. And then, looking at the atezolizumab data that Jonathan Rosenberg presented and published, that high mutational load also portends a good response to immunotherapy. So, I think as we talk through all of these new options for patients, my concern is that it may be the same patients that respond to both tools we have, the chemotherapy and the immunotherapy. And we don’t know yet. I think we’ll have to look more closely at this to see, but just to emphasize that while these drugs are great—and I look forward to talking more about them—it’s for a subgroup of patients, and we need to focus on the rest as well.

Transcript Edited for Clarity
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Transcript:

Daniel P. Petrylak, MD:
You were the first to describe the different prognostic subgroup that are involved in the treatment with chemotherapy for bladder cancer. Perhaps, you could elaborate a little bit on that because I think it’s important for the listener to understand that the bladder cancer is a very heterogeneous disease, even within the metastatic state.

Dean F. Bajorin, MD: It has been looked at a number of different ways, and all these studies point to the same conclusion. There are some patients who can do well, and those are patients who we would generally think have disease that is restricted to lymph nodes, so-called better disease prognostically, and that they have a good performance status. And really, I think the good performance status reflects tumor burden. So, those patients who have less of a tumor burden, have nodal-only disease, can do better than the patients who have visceral disease or encumbered from their disease due to the high volume of metastases or evidence of visceral disease like liver, lung, or bone. And so, when we look at these trials, we’ll be looking at subsets of those patients who are so-called good risk, that is node only, good performance status. And then, the other end of the spectrum, the patients who do very poorly, those who have visceral disease and have a poor performance status and for whom many times we can’t give chemotherapy, they might be opportune for immunotherapy. We’re going to see that for some of the data.

Daniel P. Petrylak, MD: And from that standpoint, too, we can also divide some of the sensitivity to chemotherapy based upon some of those subgroups that you mentioned before. Perhaps you can describe to the audience the differences in the different subgroups and how they relate to responsiveness.

Dean F. Bajorin, MD: These are emerging data from the TCGA and a number of different studies that are ongoing now. The backbone of these therapies is cisplatin, and there are genes that are responsible for repair for cisplatin. And so, data from, for example, Dr. Plimack’s work and our work suggest that there are certain genes that if they are altered in the patients’ tumors, it makes them much more sensitive to systemic chemotherapy, cisplatin-based chemotherapy. I shouldn’t talk for Betsy’s work, but, in terms of ATM (ataxia-telangiectasia mutated) and RB (retinoblastoma), that actually looked very encouraging; neoadjuvant setting, systemic chemotherapy, those patients did extraordinarily well. In our series and others, what we call “DNA repair response genes,” deleterious lesions within those genes confer exquisite sensitivity to cisplatin. So, these studies are now just emerging on how we might be able to select out those patients who respond to cisplatin-based chemotherapy and those who do not.

Daniel P. Petrylak, MD: Betsy, would you like to further elaborate on that? You’ve done a lot of good work in neoadjuvant therapy with looking at some of these different subgroups. Perhaps you’d like to expand on that.

Elizabeth R. Plimack, MD, MS: I think what Dean is talking about is more DNA repair lesion in the tumors, which is separate from the subgroups that were based on RNA expression, gene expression data. But the DNA repair lesions, what’s interesting—and a correlate to what you just described—is that we also see that those tumors with the highest number of alterations have the best response to cisplatin. And then, looking at the atezolizumab data that Jonathan Rosenberg presented and published, that high mutational load also portends a good response to immunotherapy. So, I think as we talk through all of these new options for patients, my concern is that it may be the same patients that respond to both tools we have, the chemotherapy and the immunotherapy. And we don’t know yet. I think we’ll have to look more closely at this to see, but just to emphasize that while these drugs are great—and I look forward to talking more about them—it’s for a subgroup of patients, and we need to focus on the rest as well.

Transcript Edited for Clarity
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Online CME Activities
TitleExpiration DateCME Credits
Clinical Interchange™: Translating Research to Inform Changing Paradigms: Assessment of Emerging Immuno-Oncology Strategies and Combinations across Lung, Head and Neck, and Bladder CancersOct 31, 20182.0
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