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The Role of Biomarkers in Bladder Cancer

Panelists:Raoul S. Concepcion, MD, FACS, Urology Associates; Michael S. Cookson, MD, MMHC, University of Oklahoma Health Sciences Center; Daniel P. Petrylak, MD, Yale School of Medicine; Daniel I. Quinn, MBBS, PhD, FRACP, FACP, University of Southern California; Neal D. Shore, MD, FACS, Carolina Urologic Research Center; Charles J. Ryan, MD, UCSF Helen Diller Family Comprehensive Cancer Center
Published: Monday, Aug 29, 2016


Transcript:

Raoul S. Concepcion, MD:
To change the scenario a little bit, what about upper tract urothelial tumors, especially high-grade, or a patient that presents with a mass that appears to be a urothelial-invasive tumor?

David I. Quinn, MBBS, PhD: So, my approach to these is that we need to get a biopsy, which is not always easy. We get a biopsy, and it’s high-grade. If I can see it on scan, I want to give cisplatin neoadjuvant chemotherapy, if I can. And we don’t have as good an evidence base as for bladder cancer. But the problem is that if we do a nephroureterectomy, which is where they’re headed, then the opportunity to give that patient chemotherapy is going to be majorly limited subsequently. Unless there are imperatives that make me not want to do that, like renal dysfunction that’s independent of that kidney or other issues that mean they’re not going to be cisplatin-ineligible, I like to do neoadjuvant and then to have the nephroureterectomy done.

Raoul S. Concepcion, MD: Dan, same?

Daniel P. Petrylak, MD: I agree. And, in fact, there’s a study that’s being done through the Intergroup that’s actually going to ask that question. It’s giving cisplatinum-based chemotherapy for those patients who have adequate renal function or carboplatin for those who don’t have adequate function neoadjuvantly, and then looking at just simply the response rates. Now, there’s this thought that the upper tract tumors may behave a little bit differently than lower tract tumors. There may be a higher mutational rate than in lower tract tumors. It will be interesting to see whether you’re going to get the same results that you do with standard therapy for bladder cancer.

Raoul S. Concepcion, MD: Like anything else, I think as we move into this world of personalized and precision medicine, what are the needs, from a biomarker standpoint, that is out there for bladder? One of the needs is clearly who might be a responder to neoadjuvant chemotherapy. Who’s going to be that pT0 patient versus somebody that’s going to have leftover residual muscle-invasive disease? Where do we stand with biomarker development in both muscle-invasive and non-muscle invasive bladder cancer?

Daniel P. Petrylak, MD: I think Dave had outlined before some of the issues that are going on with PD-L1 expression. Certainly, we need to start phenotyping tumors better. From the TCGA (The Cancer Genome Atlas) database, we know that there are FGFR3 (fibroblast growth factor receptor 3) mutations. That’s predominantly in earlier-stage disease rather than in late stages. It’s not as prominent in late-stage disease, but nonetheless, it’s being attacked as a therapeutic target. mTOR is also—the PI3 kinase pathway—a big player. HER2/neu is also involved; it’s expressed in about 20% to 30% of metastatic lesions. So, certainly, I think we need to start designing treatments based upon those particular markers. And, again, the year of precision medicine will come forth for both upfront and refractory patients.

Michael S. Cookson, MD, MMHC: One of the things that, in the meantime, has been shown to be beneficial for the non-invasive bladder components is what the urine markers can tell you. And I think the MD Anderson group, Ashish Kamat, and some others have shown urinary FISH (fluorescence in situ hybridization) testing at that 6-week marker after 3 and 6 months, after you’ve done the BCG (Bacillus Calmette-Guérin). If you have a positive FISH, we used to just think it was “anticipatory-positive” if the look in the bladder was negative. But what’s coming out now is that within a short period of time, those patients will declare themselves as failures. So, another definition of BCG-unresponsive, this molecular failure using a FISH assay, rather than traditional cytology, has proven to be very powerful. And then urinary cytokines looking at collections of different substances in the urine after the treatment can also sometimes tell us what the bladder is doing and if we’re getting that immune-based response that we need as we wait for these much needed tissue-based markers.

Raoul S. Concepcion, MD: I think most people don’t realize that bladder cancer from diagnosis to death is one of the most expensive cancers to actually take care of. And it’s not always because of therapy. Since the majority of patients present with non-muscle invasive bladder cancer, as urologists, we’re doing constant surveillance, cystoscopy, and imaging with the fear that we just don’t have a great marker for who is going to progress and who is going to stay with that TA (non-invasive papillary carcinoma) lesion, low-grade, high-grade, that will never progress to muscle-invasive disease.

Michael S. Cookson, MD, MMHC: I’ve heard some famous medical oncology urologists say that bladder cancer traditionally was the most depressive disease to treat. Once you failed platinum, you had very little to offer. We could be on the cusp of something really big and really exciting for our patients and for our medical oncology colleagues to get engaged in the treatment as these immune therapies become available. So, I’m excited about it.

Raoul S. Concepcion, MD: Dan, you’ve given a tremendous amount of these immune therapies. Are these anti-PD-1, PD-L1 drugs pretty well tolerated by the patient?

Daniel P. Petrylak, MD: They’re fairly well tolerated, but you also can’t get lulled into a false sense of security with some of these immune checkpoint inhibitors. Diarrhea is managed very, very differently in a patient who’s on immune therapy. You can get a checkpoint inhibitor-induced colitis. You can get pulmonary changes. Interstitial pneumonitis can also occur in about 5% of patients, and that needs to be managed with steroids and supportive care. Compared to chemotherapy, it’s much, much easier to tolerate. Bu, you can’t get lulled into the false sense of security that you’re home-free. And I think that’s going to become more evident as we combine some of the checkpoint inhibitors together, particularly drugs such as ipilimumab and any of the CTLA4 (cytotoxic T-lymphocyte antigen 4) inhibitors. Those can, when combined with a PD-1 or PD-L1, have significant toxicity.

Raoul S. Concepcion, MD: So, the CTLA4s, those are primarily at the lymph node level, correct, as opposed to being at the primary, or do you see a lot of activity there?

Daniel P. Petrylak, MD: No, they both act on the T-cells. It’s just simply a different receptor that’s been targeted.

Transcript Edited for Clarity
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Transcript:

Raoul S. Concepcion, MD:
To change the scenario a little bit, what about upper tract urothelial tumors, especially high-grade, or a patient that presents with a mass that appears to be a urothelial-invasive tumor?

David I. Quinn, MBBS, PhD: So, my approach to these is that we need to get a biopsy, which is not always easy. We get a biopsy, and it’s high-grade. If I can see it on scan, I want to give cisplatin neoadjuvant chemotherapy, if I can. And we don’t have as good an evidence base as for bladder cancer. But the problem is that if we do a nephroureterectomy, which is where they’re headed, then the opportunity to give that patient chemotherapy is going to be majorly limited subsequently. Unless there are imperatives that make me not want to do that, like renal dysfunction that’s independent of that kidney or other issues that mean they’re not going to be cisplatin-ineligible, I like to do neoadjuvant and then to have the nephroureterectomy done.

Raoul S. Concepcion, MD: Dan, same?

Daniel P. Petrylak, MD: I agree. And, in fact, there’s a study that’s being done through the Intergroup that’s actually going to ask that question. It’s giving cisplatinum-based chemotherapy for those patients who have adequate renal function or carboplatin for those who don’t have adequate function neoadjuvantly, and then looking at just simply the response rates. Now, there’s this thought that the upper tract tumors may behave a little bit differently than lower tract tumors. There may be a higher mutational rate than in lower tract tumors. It will be interesting to see whether you’re going to get the same results that you do with standard therapy for bladder cancer.

Raoul S. Concepcion, MD: Like anything else, I think as we move into this world of personalized and precision medicine, what are the needs, from a biomarker standpoint, that is out there for bladder? One of the needs is clearly who might be a responder to neoadjuvant chemotherapy. Who’s going to be that pT0 patient versus somebody that’s going to have leftover residual muscle-invasive disease? Where do we stand with biomarker development in both muscle-invasive and non-muscle invasive bladder cancer?

Daniel P. Petrylak, MD: I think Dave had outlined before some of the issues that are going on with PD-L1 expression. Certainly, we need to start phenotyping tumors better. From the TCGA (The Cancer Genome Atlas) database, we know that there are FGFR3 (fibroblast growth factor receptor 3) mutations. That’s predominantly in earlier-stage disease rather than in late stages. It’s not as prominent in late-stage disease, but nonetheless, it’s being attacked as a therapeutic target. mTOR is also—the PI3 kinase pathway—a big player. HER2/neu is also involved; it’s expressed in about 20% to 30% of metastatic lesions. So, certainly, I think we need to start designing treatments based upon those particular markers. And, again, the year of precision medicine will come forth for both upfront and refractory patients.

Michael S. Cookson, MD, MMHC: One of the things that, in the meantime, has been shown to be beneficial for the non-invasive bladder components is what the urine markers can tell you. And I think the MD Anderson group, Ashish Kamat, and some others have shown urinary FISH (fluorescence in situ hybridization) testing at that 6-week marker after 3 and 6 months, after you’ve done the BCG (Bacillus Calmette-Guérin). If you have a positive FISH, we used to just think it was “anticipatory-positive” if the look in the bladder was negative. But what’s coming out now is that within a short period of time, those patients will declare themselves as failures. So, another definition of BCG-unresponsive, this molecular failure using a FISH assay, rather than traditional cytology, has proven to be very powerful. And then urinary cytokines looking at collections of different substances in the urine after the treatment can also sometimes tell us what the bladder is doing and if we’re getting that immune-based response that we need as we wait for these much needed tissue-based markers.

Raoul S. Concepcion, MD: I think most people don’t realize that bladder cancer from diagnosis to death is one of the most expensive cancers to actually take care of. And it’s not always because of therapy. Since the majority of patients present with non-muscle invasive bladder cancer, as urologists, we’re doing constant surveillance, cystoscopy, and imaging with the fear that we just don’t have a great marker for who is going to progress and who is going to stay with that TA (non-invasive papillary carcinoma) lesion, low-grade, high-grade, that will never progress to muscle-invasive disease.

Michael S. Cookson, MD, MMHC: I’ve heard some famous medical oncology urologists say that bladder cancer traditionally was the most depressive disease to treat. Once you failed platinum, you had very little to offer. We could be on the cusp of something really big and really exciting for our patients and for our medical oncology colleagues to get engaged in the treatment as these immune therapies become available. So, I’m excited about it.

Raoul S. Concepcion, MD: Dan, you’ve given a tremendous amount of these immune therapies. Are these anti-PD-1, PD-L1 drugs pretty well tolerated by the patient?

Daniel P. Petrylak, MD: They’re fairly well tolerated, but you also can’t get lulled into a false sense of security with some of these immune checkpoint inhibitors. Diarrhea is managed very, very differently in a patient who’s on immune therapy. You can get a checkpoint inhibitor-induced colitis. You can get pulmonary changes. Interstitial pneumonitis can also occur in about 5% of patients, and that needs to be managed with steroids and supportive care. Compared to chemotherapy, it’s much, much easier to tolerate. Bu, you can’t get lulled into the false sense of security that you’re home-free. And I think that’s going to become more evident as we combine some of the checkpoint inhibitors together, particularly drugs such as ipilimumab and any of the CTLA4 (cytotoxic T-lymphocyte antigen 4) inhibitors. Those can, when combined with a PD-1 or PD-L1, have significant toxicity.

Raoul S. Concepcion, MD: So, the CTLA4s, those are primarily at the lymph node level, correct, as opposed to being at the primary, or do you see a lot of activity there?

Daniel P. Petrylak, MD: No, they both act on the T-cells. It’s just simply a different receptor that’s been targeted.

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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