Treatment Talk | Genetics and Bladder Cancer Treatment

Treatment Talk | Genetics and Bladder Cancer Treatment

Year: 2022

You can read the full transcript of Treatment Talks | Genetics and Bladder Cancer Treatment at the bottom of this page.

Part 1: What are Germline and Genetic Mutations in Bladder Cancer

Video (22 min) | Transcript (PDF)

Part 2: The Patient Experience with a Genetic Testing for Bladder Cancer

Video (12 min) | Transcript (PDF)

Part 3: What is and How to get Genetic Testing

Video (10 min) | Transcript (PDF)

Part 4: Question and Answer about Genetics and Bladder Cancer

Video (15 min) | Transcript (PDF)

Full Transcript of Treatment Talk | Genetics and Bladder Cancer Treatment

Stephanie Chisolm:

So, welcome to Treatment Talk: Genetics and Bladder Cancer Treatments. My name is Stephanie Chisholm, and I’m the Director of Education and Advocacy at the Bladder Cancer Advocacy Network.. We often hear that many patients patient have no known exposure risk factors to bladder cancer, such as smoking, and they wonder how they develop bladder cancer, and should they be worried about their siblings or their children being diagnosed at some point. BCAN is really pleased to welcome Dr. Guru Sonpavde, Director of GU Oncology at Advent Health Cancer Institute in Florida, Dr. Marianne Dubard-Gault, Director of the Cancer Genetic Service at Seattle Cancer Care Alliance in Washington, and also delighted to have the director of bladder cancer research at Wheel Cornell University, Dr. Bishoy Faltas with our patient advocates, Melanie P. and Ken D., on our Treatment Talk program.

Today’s program, our presenters will share the clinically significant genetic changes known as germline variants that exist in some bladder cancer patients, but not all. And our patient advocates are going to share their experience with finding out about their own germline variants. So, Dr. Sonpavde and Dr. Faltas, welcome. You both are doing a lot of research on what is known as germline variants in bladder cancer, so we’re really looking forward to finding out what some of the most common genetic alterations are in the disease and how they impact the treatment for bladder cancer. So, Dr. Sonpavde, I know you had some slides, so if you want to share your screen, you can help explain it with your slides first, and then we’ll let Dr. Faltas add any comments at the end.

Dr. Sonpavde:

Thank you, Stephanie. Thanks for the invitation to give a brief lecture on the genetics of bladder cancer. So briefly, we are going to be talking about inherited mutations in this talk. So, we are not really talking about mutations found on profiling and studying the tumor tissue itself. I’m at the Advent Health Cancer Institute in Orlando. These are my disclosures. So, there are some broad indications for germline evaluation to see if the patient has any mutations they were born with that makes them susceptible to cancer. And this is of course, young age of cancer diagnosis. When you suspect this, if you have a family history of cancer, especially in a first degree relative, if you have multiple or prior cancers, if you have bilateral cancers, or if you have some suspicious DNA mutations in the cancer cell itself when you are studying the cancer biopsy specimen. And of course, you do this because you want to see if you can help with risk-reducing surgery, chemo prevention, cancer surveillance, and cascade testing in other people in the family if a patient has a mutation that might increase the risk of cancer.

So, there are some specific indications for germline evaluation of patients to see if they were born with certain mutations that lead to cancer. So, this includes patients who are younger with colon or uterine cancer, younger breast cancer patients. Now, we do it in metastatic prostate cancer patients and localized high risk, high Gleason score prostate cancer because there are therapeutic implications with PARP inhibition treatment.

Localized breast cancer that is now eligible for adjuvant olaparib PARP inhibitor where it’s approved in patients with germline alterations. And also, any malignancy where you have something called MSI high or a deficient mismatch repair, you want to look at whether these patients have a germline alteration because some of these syndromes, especially the Lynch syndrome, is associated with MSI higher deficiency in mismatch repair. Also, in certain cancers, germline testing of patients is done in any stage of cancer with male breast cancer, triple negative breast cancer, ovarian cancer, and pancreatic cancer, and perhaps colorectal cancer is now the emerging cancer where we are thinking of doing it in everybody regardless of stage.

Now, just a little bit of background on bladder cancer, we see approximately 80,000 new cases a year in the US. There is a strong environmental influence. We know about cigarette smoking, dyes and paint exposure that increases the risk of bladder cancer. It’s an older person’s disease. The median age is almost 70 years. There is a male predominance of the disease, approximately 70% are male. We don’t really understand why, but this is a field for study. Approximately three-quarters of patients have non muscle invasive disease, so still not invading the muscle, deeper layer of the bladder or beyond. And we know that once it invades the muscle, it becomes very aggressive. You can have microscopic distant disease, and this is difficult to cure. Once it metastasizes and it becomes visible on scans or clinically, then you are really facing mostly incurable disease, unfortunately. There is not an established role for screening and chemo prevention medical therapy to prevent cancer at the moment in all patients with bladder cancer.

So, we have known that there is a familial aggregation of bladder cancer. When you see historically back in the 1960s, we’ve had case reports and series which described families with the concentration of bladder cancer in several people in the same family. So, there seem to be a genetic and environmental interaction. In most cancers, we think there is an interaction, of course, of something the patient was born with and interaction with something in the environment. For example, cigarette smoking could be that risk. There is also, we know that there would be a role for surveillance of high risk patients and prevention of known carcinogen. So, if you know somebody’s at high risk cause they have a born with their mutation, you might want to surveil them and keep a closer eye on them. And also, in high risk relatives of cancer affected patients, you want to keep a closer eye on them.

Now, one study found that familial clustering is rare. Now, one of the problems is there might be underreporting of familial clustering because it first felt that if many people in the same family develop cancer, it might be because they shared the same exposure. So, if somebody smokes in the family, for example, everybody in the family is exposed to second hand smoke. Is it because of that, or is it because they were born with a certain mutation that led to and increases SC bladder cancer? Or were they born with some mutations and some genes that slows down the metabolism of some toxins and therefore increases the risk of cancer? So, not directly causing cancer, but slowing down the metabolism of certain toxins. So, we found, in Dana Farber, that there was a 4.3% incidence of familial bladder cancer defined as bladder cancer in a person and one more first degree relative with bladder cancer.

And we found interestingly, there was no association with age. So really, it was not like older patients had a higher risk of family through bladder cancer in a first degree relative, but the shared environmental risk was unclear in the study. Now, what we know interestingly is that a family history of bladder cancer and smoking in the person cooperate to increase the risk of bladder cancer. So, interestingly in the study, those who smoked and had a positive family history had a much higher risk of bladder cancer, and especially those who smoked, and had a family member diagnosed at a young age, that really increased the risk, 6.894, as you see here. So, really looked like family history of bladder cancer and smoking, cigarette smoking cooperate to increase exponentially the risk of bladder cancer, really suggesting that smoking is never good, but smoking, especially with the history of bladder cancer in the family is even much worse.

So, Lynch syndrome is a syndrome. It’s a hereditary predisposition syndrome with certain mutations I show you here that patients are born with, and we know that this is a syndrome well known to be associated with colon cancer. However, we also know that this is associated with bladder and urinary tract, upper tract urinary tract cancer. So, approximately 7.5% of men and 1% of women with Lynch syndrome developed urinary tract cancer over a long period of time by age 70. So, really the author here suggested that, based on these findings, patients who have a known Lynch syndrome, especially the MSH2 gene, perhaps they should consider surveillance from age 40 and up every one to two years. There is a different study here also that looked at several Lynch syndrome families and found an approximately 7% risk of urinary tract cancer by age 70. Now, 7%, just to put it in perspective, it’s higher than baseline of course, but it’s not as high as the penetrance of Lynch syndrome for colon cancer. So, if you have Lynch syndrome, the risk of colon cancer is perhaps approximately 50%, while bladder cancer is much lower, 7%. So, really the penetrance is not high, fortunately, but there is clearly an association with urinary tract cancer. So, what is the hereditary component of urothelial carcinoma? This is essentially the most common cell type of cancer of the urinary tract. We know, in a large study that I show you here, the heritability of cancer, overall, what is the hereditary component of cancer, approximately 33%. And as you can see here, bladder cancer is right there in the middle of that range. So, really the heritability of bladder cancer is about average when you compare across different cancer. So, it’s not at the highest. You see here, prostate cancer is much higher, 57% inheritability, for example. Now, this is a study that at [inaudible 00:11:51] looked at patients who were unselected, so any urinary tract cancer patients, urothelial carcinoma patients who were selected, close to 600 patients. And they found that 14% of patients had one of these DNA damage repaired gene mutations.

You see here, some of the Lynch genes are in there, the BRCA genes are in there, well known to be associated with breast cancer. And what was found was that younger age was enriched for these alterations. So really, again, suggesting that perhaps in younger age patients, you should have a lower threshold to test for germline mutations that these patients may have been born with. This is a different study we did at Dana Farber, which is from a commercial company, and more than a thousand patients. This was a somewhat more selected group. So, we sent patients blood for germline testing if we think they’re at high risk for some inherited gene mutation. So, this was somewhat more selected, somewhat younger population, 58 years. So, you can see here 24% of patients had a pathogenic mutation they were born with, and 18.6% of them overall had an actionable, so-called actionable mutation, again, enriched for some of the Lynch genes and the BRCA genes.

Now, there’s a recent study that looked at patients, specifically patients who had non-muscle invasive bladder cancer, so cancer that was not yet invading a muscle and beyond. The interesting finding here, was that patients with high grade non-muscle invasive cancer were enriched for germline mutations, 13.5%, while the low grade patients did not have this mutation. So, this is somewhat interesting, suggesting some association of higher grade non-invasive disease with these mutations. So, as you know, we are doing tumor tissue testing a lot these days to select patients for certain drugs based on mutation found in the tumor. So, not germline, not what you were born with, but in the tumor. So, one of the questions that arises is, should you do germline testing if you find certain mutations in the tumor? So, in fact, the NCCN suggest that in patients who have certain mutations that would be high risk if they were germline.

For example, the Lynch genes, the BRCA genes, when you find them in the tumor, should you be doing a germline test of the patient’s blood or saliva to see if they were born with some of these mutations? So, this is what the NCCN suggests, at least to consider this in patients who have this high risk mutations in the tumor itself. And in fact, there is a different study here that found that tumor sequencing is actually pretty good at catching germline mutations, but it does not catch everything. So really, the author suggests that really to capture all the patients with germline mutations, you would have to do germline testing in everybody and not do it as a reflects based on tumor testing. So, this is one direction the research and the body of research is going, is to do universal testing in everybody regardless of what mutation is in the tumor. One other question that arises is we are doing circulating tumor DNA testing, so this is DNA in circulating freely in the plasma, in the blood, not in the blood cells.

So, when we do this, we are looking at really… We are trying to look at whether the patient has mutations in the tumor that are detected in the blood. So, it turns out that if you have a high threshold and you try to catch these mutations with a high, so-called high allele fraction present in a high fraction, then you can actually catch hereditary DNA mutations that the patients may be born with, even in circulating tumor DNA. So, you should pay attention to what mutations are seen in the allele fraction, even in the circulating tumor DNA, which we do usually just to look for mutations as a reflection of mutations in the tumor itself. So, the universal germline testing is emerging. We know that when you look at across different studies, when you just test everybody with any solid tumor, you see between five and 15% of patients having some germline mutation that is relevant. And in fact, many of these have therapeutic implications. We know that many of these drugs here are approved based on germline mutations in these BRCA genes, the MSI high tumors with the deficiency in mismatch repair. So, as you can see here, several therapeutic implications based on germline mutations. And in fact, in bladder cancer, there’s a study that looked at rucaparib, a PARP inhibitor in patients with metastatic cancer as a maintenance following chemotherapy setting. And it turns out that patients with either tumor or germline mutations, most of them had pretty much tumor actually, but germline mutations were allowed on this study, there was an improvement in outcomes in patients with a DNA damage or pain mutation at the tumor level of the germline. So, I’ll just give you quickly, a summary conclusion slide. So, clinically significant germline variants found in mostly DNA damage repair genes are found in approximately 15% of all patients with urothelial carcinoma, but there is not a single dominant gene with a high penetrance that causes cancer. As I said, Lynch syndrome, only 7% penetrance.

So, we should really use general prudent principles to refer patients for germline testing, younger patients, other primaries, bilaterality. Especially non-smokers with cancer, there is no known environmental exposure, really should have a low threshold to test these patients. If you have done tumor profiling, you should consider germline analysis, especially if you see a mutation that is of significant relevance if it’s present at the germline, for example, a BRCA gene or a Lynch gene found in the tumor testing. And some of these variants in mutations, of course, could guide therapy on trials and trigger cascade testing, the so-called cascade testing of other people in the family, especially the first-degree relatives, if the patient has one of these mutations. Family history is insensitive. Family history is something that patients don’t usually recall very well, occasionally, and actually, quite commonly, upper urinary tract cancer is frequently misrepresented as kidney cancer, which is it’s not. It’s a urinary tract cancer. So, that is a frequent source of confusion for family history. And surveillance, although it’s not done in everybody, surveillance and Lynch syndrome, patients starting in the mid thirties to 40 should be considered.

And patients with these germline mutations, especially Lynn syndrome, should, of course, stop smoking because of the cooperation of an environmental insult and a germline alteration. And studies should really focus on underrepresented populations. All of these germline studies that I showed you, they were really studied for Caucasian population. So there was not much for Asian population or African American population. And then finally, the momentum for universal germline genetic testing of all patients with advanced solid tumor building, because this can capture alterations that will not be always captured on tumor testing. So, this is where the field is going, but this need for the thought and for the study. With that, I ended in my talk here.

Stephanie Chisolm:

So, Dr. Faltas, I know you’re doing a lot of research. Do you have any comments to add about some of the work that you’re working on in this particular germline area?

Dr. Faltas:

Thank you, Stephanie. Dr. Sonpavde is always a very hard act to follow because I think he’s covered all the important points. Just a couple of points that he’s already mentioned that I would like to touch on briefly. So, I think family history is actually quite an important point. And this is an example… This whole topic of joint line mutations of bladder cancer is an example of a topic that the more we ask about family history and the more we look for these mutations, the more we find them. And as clinicians, we haven’t necessarily been trained as genitourinary medical oncologists treating bladder cancer. To be very specific, so far, we haven’t generally been necessarily focused on the family history because up until the last few years, most of us haven’t really known that. Before this research came about, research from our group, Dr. Sonpavde’s group, Dr. Carla’s group, and many others, that these germline mutations are actually prevalent in patients with bladder cancer.

And we’re still debating what really to do about them, what are the implications that are empirically implications for cascade testing, and so on and so forth. And I know we’re going to discuss that today with Dr. Dubard. So, I think these are important points. Just to summarize this point, I think we’re all on a mission here to increase awareness of the high prevalence, relatively high prevalence of these alterations. And it’s very important to ask because although I agree with Dr. Sonpavde, the history is in insensitive tool, but sometimes also very important in terms of raising the red flags or the suspicion for testing. The second point I think that Dr. Sonpavde also touched on is that most of our knowledge about these germline mutations is coming from Caucasian patients, and specifically when it comes down to a point related to variants of unknown significance, which are essentially classification of these alteration that could come back.

So, yes, there is an alteration on genetic testing or a mutation, but we don’t know its clinical significance. And these VOSs or variants of unknown significance are a lot more prevalent in non-Caucasian patients, the patients from other diverse ancestry, mostly because we really haven’t been studying these patient populations in the past. We’re working to correct this in our own research, but that’s an area that I think we all need to be aware of and to continue to work on, both to study these variants of unknown significance and reclassify them to try to understand really what their clinical significance is for patients from all ancestry. I’ll stop there.

Stephanie Chisolm:

Yeah, you guys are doing some amazing work, and I know that the future is going to look brighter because you’re digging deep or into so many of these things. So, Ken, you’ve got your microphone on, so why don’t you start, and then Melanie will share her story.


Great, thank you. So, first of all, I just want to start out by thanking Stephanie and BCAN and all the folks there. They’ve been an incredible resource for me as I’ve gone through and looking for providers, looking for information, and also thank you to all the providers and including Dr. Sonpavde, who I’ve worked with when we both were in Boston, but it’s really a group effort. The treatment of bladder cancer is not just one oncologist and one patient. So, I was diagnosed with bladder cancer eight years ago when I was 52, which was the same age that my father was diagnosed with pancreatic cancer, and he died soon after that. A few weeks after I was diagnosed, I saw a posting on Facebook actually from a second cousin whose sister had recently died of ovarian cancer. And she was educating people that, oh, we’ve got this rare variant of BRCA in our family.

And so I wasn’t surprised because of my father’s history. His mother also died of pancreatic cancer, his sister died of breast cancer, and several other family members, including a great aunt who had bladder cancer. And one of the things she explained at the time was that having a BRCA mutation can sometimes impact treatment. And so I was optimistic at the time. I had non-muscle invasive early stage bladder cancer, not a big deal. So, I put that at the side and I thought I’ll deal with that if I ever have to. Well, three months later, I had to deal with it. My bladder cancer came back very rapidly and it spread throughout my body. I knew that because of course the normal symptoms of bladder cancer. I was peeing blood. But my back started being extremely painful.

And so the bladder cancer had spread to my bones, one spot particularly, which was in the spine. And so I went from stage one to stage four relatively quickly, never having gone through the muscle invasive stage and all the discussions that come with that. And so when I started seeing an oncologist, Dr. Sonpavde at Dana-Farber at the time, I raised the whole issue at that point of like, “Hey, I had this thing in my family.” And so he ordered a genetic test.

I actually met with the genetic counselor when I was getting chemo. I think was actually my first treatment. And when the test came back positive that I had a BRCA1 mutation, I wasn’t surprised. The amazing thing was, a few treatments later, the pain in my back started to ease. At that time I actually was scheduled for a second opinion with Dr. Rosenberg at Memorial Sloan Kettering, and I explained that my pain had been going away, and he let me know at that time that, well, the odds of platinum chemo working is actually a little higher for those who have a BRCA mutation. So, I was exuberant with joy hearing this. I went from thinking, oh, I’m going through treatment. It’ll extend my life a few months, hopefully a few years, all of a sudden thinking like, wow, I might actually get beyond this, which may have been over optimistic, but his words helped get me into that mindset, which was a big deal. It helped me get through treatment. The cancer did return a few times. I’ve had lung and brain surgery to remove those tumors, as well as additional radiation, but the last treatment I had was five years ago. And since then, I’ve had no evidence of disease, so I am extremely fortunate. But my own health is only half of my story. Knowing that I was BRCA positive, I restarted reaching out to family members. Turns out that both of my brothers are also BRCA positive, and so is my niece, one of my brother’s daughters who happens to be my goddaughter. And she’s been able to take some prophylactic steps since then to reduce her risks. But what I find the most exciting part of this story is two weeks ago, we went to my grand niece, my niece’s daughter, her first birthday party.

And both her and her brother were conceived through pre-screened IVF, assuring that we’re not passing the BRCA mutation onto the next generation of our family. So, I’m not only healthy at this point, knock on wood, will stay that way, but knowing the information and sharing it with family has led to us reducing the risk of cancer for future generations.

Stephanie Chisolm:

Thank you Ken, and that was such a positive story at the end. I think that’s wonderful. So Melanie, I know a little bit about genetics. You also have a story.


So, I was diagnosed with muscle invasive bladder cancer about three years ago, and I was 67 at the time, and I was immediately identified to have a T3, so pretty deep muscle invasive form. And so I was treated to the works. I had chemotherapy, so neoadjuvant chemotherapy, and then I had a radical cystectomy. And a year, it turned out of immunology or immunotherapy because of a study. I was given pembro every three weeks. So, so far over these last three years, my scans have been okay and I felt fine, but I think like many of us, I was pretty flummoxed by finding out I had bladder cancer. Somehow you have in your mind that if it’s not in your family, you’re not going to get it. Your mom is 99, so you’ll be 99 someday, and then you get a little surprised. But I was particularly interested for two reasons, and one was that I have a really large family and many of them are having children.

And then also that I am a genetic counselor. So, I worked in genetics for 30 years and I worked in a molecular lab, so my curiosity has always been out there. I know that genes always play a role in disease. That’s all I’m going to say. Everything is genetic. So, I spoke to my oncologist about possibly having genetic testing. Even though I had a negative family history, I had done some exploring myself in the medical literature and found that there were people who have germline variants detected even though they don’t have a family history of bladder cancer or other cancers. And I just felt like I would be personally reassured if I could have that test done. My oncologist really felt that it was not necessary. He says, “Genetics, it just doesn’t play a very big role in bladder cancer, and they’re so busy there that I hate to refer you, given this situation.”

And so I referred myself, mostly because I’m a genetic counselor. And I contacted Dr. Dubard-Gault, who’s at my medical center in Seattle, and she explored my family history and decided maybe it made sense to do a smaller panel of genes through Invitae, which is one of the labs that does a fair bit of cancer testing. And I think they looked at 30-plus genes. And at that point, they didn’t find a variant, and I was reassured. But then about three months later, my niece went in for preparation for in vitro fertilization and was required to have some genetic testing done. So, she had a list of things she could choose, and she chose comprehensive genetic testing, 300 genes. And she had a number of genes that came back with some kind of a rare variant, but one of them was a cancer causing gene or a cancer related gene called ATM.

By itself, it can cause a disease called ataxia-telangiectasia. But over the years, they’ve figured out that the people who are carriers seem to have more cancer. So, she told her mom, that’s my sister, and she told me, and the two of us got tested. I went back to see genetics again, and it was confirmed that I had the same ATM variant. It’s a missense variant in that gene, and it’s not reported a lot in the literature, but other kinds of mutations in that gene are definitely associated with cancer. So, did this variant actually caused my bladder cancer? And the answer is probably, possibly. It possibly plays a triggering role of some kind.

What I learned though was that the variant that was found in that gene really increases my risk for other kinds of cancer, which wasn’t exactly what I was trying to hunt down when I had this done. I wanted reassurance, but it’s not an easy thing to hear, I would say, when you get a result like that. You’re following your calendar and realizing that with each year, your risk for bladder cancer returning is reducing a little, you’re relaxing a little, and your anxiety goes down. Now, you have to consider other kinds of cancer. Genetics referred me to a high risk cancer clinic where they could sort of spell out specifically what cancers I might be at risk for and what those numbers will be. And the greatest one seems to be pancreatic cancer, and they’ll help me monitor that. I’ll go back to see them every once in a while.

But I think finding this out from my perspective, I still feel like it’s valuable, even though it was a little scary. The risk of other cancers isn’t huge in my mind, but it’s there. And I maybe could have saved somebody’s life by alerting my family to this risk. So, I have shared this information with my adult relatives, and they’re making decisions about whether or not to have testing. My 99-year-old mom, who’s doing well, was tested, and she has it too, but obviously, a lot of people have it, but it’s penetrance is low, so it could certainly be a factor in our family. And I guess the one thing I think about from having this genetic counseling perspective, but also the patient, is that we could do a better job of helping our urologists and our oncologists recognize who they might want to refer. And he’s right, I’m not that patient, probably.

Refer your young patients. It’s so tough to see young women with little babies that are diagnosed with muscle-invasive bladder cancer. If we could find them because of their family history, it would be awesome. So, anyway, that’s my story and I’m happy to answer any questions.

Stephanie Chisolm:

Great. Well, we’re saving the questions for the end, but again, that’s a very compelling story. So, Dr. Dubard-Gault, tell us a little bit about what patients should know about genetics and when and how they should connect with a physician who specializes in this. And should they engage genetic counseling?

Dr. Dubard-Gault:

I’ll just briefly, because a lot of things have been highlighted already… And thank you Melanie, for sharing your story a little bit in details for what’s happened afterwards. I really appreciate that. I trained briefly in medical oncology and genetics, so I have a little bit more of a background to ask questions when there are not enough of an environmental exposure or something that makes it still raise that flag that Dr. Faltas had mentioned, right? So, to really bring all the pieces to the puzzle to explain maybe or find part of the explanation.

If you could go to the next slide. So, we’ll talk briefly about the types of genetic testing. I know Dr. Sonpavde has mentioned a lot of them already. The genetic testing for bladder and urothelial cancer specifically, and the results of what might come your way with that, and then how to get it, how it’s done, and all the things that we think about around genetic testing. So, if you could go to the next slide. So, I always like to go back to the basics. When it comes to what people are doing at what time and using what sample, it’s useful to remember what we’re all looking at and what we’re looking for. So, the cells that Dr. Sonpavde mentioned originally was really the cells that are from the bladder. And then you isolate the DNA from that, and then the DNA gets transferred onto a testing platform, and then the results come back after all of these things are sequenced to have the results going forward.

So, if you could go to the next slide. And then there are different types of genetic testing. As Dr. Sonpavde mentioned, you could test the tumor, and that is done for people who have a diagnosis of bladder cancer or other cancers. And you can test for DNA. You can also test for another part of the information that we have is RNA or the chromosomes, as I showed you before. And then you can test also for people who have a diagnosis of cancer and/or are unaffected by cancer, like Ken’s niece, for example. You could test their blood, you could test their saliva, you could test their nails, and many other samples to test for a predisposition to cancer that is in their genetic makeup that we would not know that they have unless we start looking for them, as Dr. Faltas had mentioned. So, there are many different types.

There are many different ways you can go about it. And obviously, each answers you’re looking for is based on what samples you’re going to look for. All right, go to the next slide, Morgan, please, and then keep going. So, as we’ve talked about it, and I agree with Melanie a hundred percent, everything’s genetic, right? We are born with a certain amount of genetic mutations and these mutations can very well cause certain things to happen in the right environment or in the wrong environment. And then some of the cells have those protection mechanisms to get rid of any damage or repair the damage before the cells go on. Sometimes though, when that does not happen, you could have a cancer develop, if you go to the next slide, and those mutations will accumulate and cause of cancer. So, in my mind, cancer is genetic for sure, but not all cancers have this inherited component to them that drove the cancer in one direction.

And so there is a distinction between the hereditary kinds of cancer and the cancers that happen by multiple reasons, if you go to the next slide, which is why, and go a little bit further, which is why not all genetic testing is created equal. If you see what’s done most often is in the kind of salmon orange color where we want to test the tumor to identify biomarkers or things that will help decide which treatment would work better. If you look on the blue side, sometimes that could be matched with a blood or saliva sample at the same time to look for something inherited that either explains the cancer that is there or partly explains it, or maybe gives a risk to another cancer in the future. And if you go to one more, and sometimes there is something in the middle here that works together to say, okay, from this point on, how do we make sense of this information and how do we go forward with genetic counseling? As Ken mentioned, and Melanie, how do we make sense of this information, and how do we turn it into an action plan?

Yeah, exactly. Go to the next slide. Now, I think the important part here is also, as this has been mentioned already, is where is the genetic mutation? Is it solely or only in the tumor, the bladder cancer or the breast cancer or the pancreatic cancer, or is it part of the makeup that is passed down from one generation to the next? We know in the cancer genes that we are all talking about, these tend to be passed down from one generation to the next. So, it’s most often, as Melanie shared, that it was inherited from the generation prior, either biological paternal side or biological maternal side, and it really helps then also test other family members to make sure that they can take actions as well for their own either screening or treatment if they were to need it.

And then I won’t go into too many details about this because Dr. Sonpavde did mentioned, but really knowing this information is really useful for picking the right medication, whether it is an immune checkpoint, as Melanie mentioned, or PARP inhibitor as in the Atlantis trial, or other medications that are coming on and being available for treatments of bladder cancer. So, how do we get genetic testing? Number one would be with your oncologist who feels comfortable, has experience in ordering genetic testing. Number two would be to be referred either by your oncologist or your primary doctor or self, by your yourself to a genetic counselor. And genetic counselors are exactly the right person to help review your family history and decide how likely it is that you will have a positive genetic result and what that positive genetic result would mean and help you through the process of getting that testing done, whether it is on the tumor, on the blood or saliva, or as a combination of the two, to really get to the implications of the results and what they mean for the treatment and the family members.

And then I think this is a resource that is underutilized, but is a website that was established by the National Society of Genetic Counselors to really help people out there find a genetic counselor near them, whether it is on telemedicine or in person. Every single state has genetic counselors, and so that’s an easy way to find them. If you go to the next slide. And then the two things that I want to mention there briefly, because this comes up every single time, is genetic testing covered by my insurance. And in the cases where you have a family history, most often, the genetic testing will be covered. Or if there’s a known mutation as Dr. Sonpavde mentioned, or as in Ken’s story, then for sure the genetic testing will be covered, but it is often that for bladder cancer, the genetic testing is not covered yet, meaning that sometimes, you’ll have to have an out of pocket cost or pay for the testing yourself, especially if some of these criteria are not met, until we get to the time where we will test everyone every time when they’re diagnosed with a cancer.

And the other thing I’ll mention there is that sometimes the genetics clinic will not be able to see patients with bladder or cancer because of the busyness of the clinic, and sometimes this is something that can be done separately through a website or another mechanism to be able to get the genetic testing part of things. And then where are the genetic testing results stored? Are they safe? And who has access to them? So, the genetic results are clinical medical tests, and so they are safely saved in your chart. They’re only shared with who you’d like them to be shared with, and they’re private. So, they’re protected under the HIPAA, protection law for confidentiality, and also under the GINA law that is for protecting genetic information specifically. So, this information is not utilized for healthcare coverage or for employment if the person is still working or family members are looking for a job.

And I think that is my last slide. And so the take home points to really bring all of these thoughts that we’ve put together is that between 10 and 20 patients with bladder and urothelial cancer have an inherited cancer gene mutation. Your medical oncologist can order your biomarker testing to help identify the best treatment. Sometimes that will uncover an inherited mutation and will refer you to a genetic counselor to discuss how to confirm that and to take the next appropriate steps. Genetic counselors are amazing. Thank you, Melanie. They’re here to help you and your family understand the meaning of the results and to take the next steps for early screening and detection. And obviously, the genetic testing results can help you and your family for the future. And I’ll stop there. Thank you.

Stephanie Chisolm:

Wow, this has been an incredibly comprehensive discussion. I really do appreciate it. We did have a few questions come in, and then somebody retracted their question because you already answered it. But one question is, why isn’t somatic testing done when a tumor is profiled otherwise? If they’re going to do pathology, why don’t doctors just have somatic testing at least to find out what’s going on in mutations?

Dr. Sonpavde:

So, somatic testing essentially is tumor testing. So, we do somatic testing quite routinely in metastatic urothelial bladder cancer, especially because we want to detect the FGFR3 three mutation or fusion, because for that mutation found in the tumor, we have actually a drug approved [inaudible 00:46:27]. The germline is where we are not doing it routinely in everybody at the moment, and this is where we want to select patients for it. And this is where, as you heard, approximately 15% of… If you select everybody and do it, you’ll see approximately 15% have a germline mutation that they were born with. So, that’s not just a tumor, but they were born with it. Again, if you choose younger patients or other families tree that’s known multiple cancers, previous cancers, then you increase, you enrich your population for the presence of germline mutations. I don’t know if you want to add to that, but yeah.

Dr. Dubard-Gault:

Well, I also find that it’s access to it, right? Even when that that’s true, you have to find the right person to help you through the process, right? So, that’s why I’m so glad. Thank you, BCAN, for doing this because the awareness is one step to the process that makes all the other parts maybe easier.

Stephanie Chisolm:

Yeah. Well, our goal is to at least give patients some good questions to ask their providers so that if it is appropriate, they can get access to genetic testing. So, I think that’s a big deal. And this is a common question that we see in here. Someone is concerned for their children. Her husband lost his bladder cancer battle in 2014 after 18 months of muscle invasive diagnosis. He was 54 years old. His younger brother has urothelial carcinoma in the kidney, and he’s a survivor. He was diagnosed at 46. What screening would you recommend for her children going forward?

Dr. Dubard-Gault:

I would start with testing the person who’s alive with germline genetic testing to identify if there is a common thread, right? Coming up with a positive result, there will give an answer as to why, and then a helpful tip as to what to do about the potential risks of either the bladder, the kidney, or other cancers like colorectal cancer where we would start a colonoscopy screening protocol sooner than age 45 or 50 or 40 if we didn’t know that information. And each person, I would also say, would be able to have their own genetic testing. Every person can have genetic testing, but having the first person who’s had a diagnosis of cancer be tested is useful as to make sure we can identify what it is we’re looking for because the screening protocol sometimes is based on the risks that are not only the familial risks, but also what is present in the genetic testing results. Does that answer the question

Stephanie Chisolm:

Yeah, this is great. This is so informative. And here’s a question. Does all circulating free DNA in serum originate from tumor tissue? In a given patient, do tumor and cell-free DNA all match? Can there be heterogeneity in that?

Dr. Dubard-Gault:

I can take that one, and then you can add to it maybe. So, you can have a benign tumor shed in the blood the same way the cancer malignant kinds of tumors would. We don’t know as much about what benign tumors shed or what we come up with if we were to test people with those. But uterine fibroids, for example, would shed things in the DNA, in the circulating blood. And then I find that the testing is not always done correctly, meaning that you may not always have enough coverage of everything to be consistent or be comprehensive of all the information, right? So, I don’t know if I would trust it completely, but I know that there are other things that can shed in the blood that would make it so you would want to pay attention. And Dr. Sonpavde can add to that.

Dr. Sonpavde:

I agree with everything Marianne said, and I think Bishoy has done a lot of work in ctDNA probably wants to add to that. But essentially, most of the DNA in the blood is actually not tumor DNA, right? It’s a very small component. Most of it is from all these other cells in the body, all the blood cells shed DNA. So, it’s actually very, very challenging to find circulating tumor DNA that’s originating from the tumor. And that’s actually why we don’t actually find it in a lot of patients at all. So, Bishoy, you want to add to that?

Dr. Faltas:

Yeah, so I completely agree. So, actually, most of the cell-free DNA… So, cell circulating tumor DNA is a very small fraction of the cell-free DNA. The majority of cell-free DNA actually comes from, as Dr. Sonpavde said, from peripheral mononuclear blood cells, so essentially white blood cells that we have. And that’s essentially why when we do the slide that you showed earlier, why we can detect germline mutations in cfDNA, it’s actually that those are coming from the white cells, which are normal cells. And based on frequency, we can actually tell if these are germline or somatic mutations. In terms of the heterogeneity aspect, so that that’s a little bit more complex. So, there’s somatic heterogeneity, which we call mosaicism, which is essentially, I could be born with a mutation, but then not all cells in my body. So, actually… Well, not born, but a germline mutation could develop at a later stage, but I’m born with that mutation, so maybe I didn’t inherit it, or maybe I did, but then some of the normal cells in my body have these mutations and some others don’t.

The same in terms of cancer and heterogeneity. There’s also the definitely process of cancer heterogeneity, and that could result in differences in terms of the alterations that we observe in the circulating tumor DNA as well.

Stephanie Chisolm:


Dr. Dubard-Gault:

I will just add, this is why the plug of doing it paired, even though the blood and the tumor at once rather than having to chase one or the other is most useful. So, if we can do it all at one time, it’s better.

BCAN Stephanie Chisolm:

Very, very helpful information. So, here’s a question I think more for the oncologists. If erdafitinib and PARP inhibitors didn’t work, could that mean that the patient didn’t have the right mutations?

Dr. Sonpavde:

So, maybe I’ll start and Bishoy can add. So, erdafitinib is approved in patients with FGFR3 activating or FGFR two activating mutations effusions in the tumor, so that’s somatic. So, the response rate in the, these were post platinum chemotherapy exposed patients with progressive disease, the response rate was 40%. So, having the mutation seems to be necessary for the activity, but is not enough for the activity. So, obviously that’s why we don’t have a hundred percent response rate, right? So, having the mutation increases your vulnerability to FGFR inhibition, but is obviously not enough. So, we really need some better combinations of the FGFR inhibitors plus something else to improve the response rate, obviously. And this drug also does not cure these patients. So, really we have a long way to go to understand the genomics and the genetics that lead to the very high response rate and curing these patients with targeted agents. PARP inhibition is very…

It’s still not approved in bladder cancer, so we only have trials showing that PARP inhibitors are active and improve outcomes in the short run in patients with a mutation in a DNA damage repair gene, mostly the BRCA genes, the combination deficiency positive patients with these mutations in the tumor. Mostly these were patients with mutations in the tumor in these trials. Germline patients, they were hardly any or none in these trials, but you can expect patients with the germline BRCA deficiency to have that in the tumor also. At the end of the day, there is some activity of PARP inhibition, but they’re not approved yet, and it needs more work to get these drugs into the clinic for these patients.

Stephanie Chisolm:

Great. Thank you so much. Okay, we have time for two more questions. I was recently diagnosed with adenocarcinoma bladder cancer. That’s more of a rare type of bladder cancer. Does any of this testing have any kind of impact? Is it going to be something he should do for his siblings to find out if there’s anything in there that is a variant?

Dr. Sonpavde:

All of the work, as I understand it, has been done in urinary trial or urothelial carcinoma. Adenocarcinoma is such a rare entity. It is really not been that much germline work done on unless Marianne or Bishoy know anything about it.

Dr. Faltas:

No, I agree. I think the short answer is that we don’t know, and I would say probably the same that applies to conventional urothelial carcinoma applies to these variants at this point, but we need more research.

Dr. Dubard-Gault:

And I would add that genetic testing can always be done later again. So, repeating testing is always a possibility, even if the person has had genetic testing already and was negative for it, for example. It’s sometimes because it’s inconclusive. It’s not because there wasn’t something to be found. And doing the genetic testing again in a year, two years or three years may very well bring an answer that we would’ve not been able to identify otherwise.

Stephanie Chisolm:

Right. And you bring up a good, another question that is here. Somebody had a radical cystectomy in 2017. Is it too late to get tumor tested for genetic mutations? Does pathology preserve the tissue for that long, or is there another way that they could find out if they have a genetic mutation or a variant?

Dr. Dubard-Gault:

I think at this time, given from what I’m hearing, the person’s is NED no active evidence of disease. Correct? I would start with the germline testing, because that would be more useful for the explanation or what to do if something was identified as a positive result, because the tumor testing may not be as useful for the time being. It doesn’t mean it’s not something interesting or important to look for finding the answer, but it may not be as useful high yield than the germline testing on the blood or saliva. And that could be done with a genetic counselor.

Stephanie Chisolm:

Okay. One last question. The mother was a smoker and had lung cancer, sister had lung cancer and also bladder cancer, but was a non-smoker, and this person had bladder cancer. Should they get genetic testing?

Dr. Sonpavde:

And how old was the… I guess we don’t know. I guess especially… I think in a non-smoker, I would have a low threshold to do it. One of the problems with a family this is this some kind of smoking exposure in the family as they were growing up, or is it some inherited mutation that led to bladder cancer and all these people in the family? So, I think when in doubt, I would lean towards doing it.

Dr. Dubard-Gault:

And if you have two relatives with lung cancer, we tend to say why not? Right? The testing would be covering the gene called EGFR. It’s a vascular growth factor may not be covered by the insurance, because as Dr. Sonpavde mentioned, you may not have enough to bring that threshold for genetic testing for criteria, but it never hurts, no.

Stephanie Chisolm:

Okay, great. So, one more question. While I was getting chemo, my oncologist asked if I would agree to genetic testing, I agreed and was told the results were good, no need to do more work in this area. Does that mean that they don’t have a gene that could cause their bladder cancer?

Dr. Dubard-Gault:

I can let Melanie answer that.


I felt like I was being asked it. Yeah. So, no, it doesn’t mean that necessarily. I mean, the number of genes that they can look at to see if you have an inherited form of cancer is a set number right now. And that number is changing all the time. And in another five years, another few years, there may be a new set of genes. And especially if they have a positive family history, it’s probably worth revisiting. But yeah, for now, I think you could be somewhat reassuring. Don’t you think?

Stephanie Chisolm:

Yeah. And thanks in part to phenomenal researchers who are doing all of this amazing research going on going forward. The next five years might shed even more lights on all of these different mutations and variants and what their influence is both on developing disease, but also on treating disease. So, this has been a fabulous program. I’d like to thank Melanie and Ken for sharing their stories. This has been so wonderful. I really think it adds so much to the whole discussion. And Marianne, thank you so much. Providing all this genetic information has been phenomenal, be a great resource. Dr. Faults and Dr. Sonpavde, again, thank you. This has been fabulous.