Melanie Cole, MS (Host): Research shows that men can carry mutations in the BRCA1 and BRCA2 genes that can increase their risk of several cancers. Welcome to the podcast series from the specialists at Penn Medicine. I'm Melanie Cole, and we have a thought leader panel for you today with specialists from Penn Medicine and the Hospital of the University of Pennsylvania, highlighting men and the BRCA gene mutation.

Joining me is Dr. Kara Maxwell. She's an Assistant Professor of Medicine in Hematology Oncology. Dr. Jenny Zhang, she's an Assistant Professor of Surgery in the division of Breast Surgery. Dr. Dan Lee, he's an Assistant Professor of Urology in Surgery. And Dr. Bryson Katona, he's the Director of the Gastrointestinal Cancer Genetics Program.

Doctors, thank you so much for joining us today. Dr. Maxwell, I'd like to start with you. Can you please tell us the basics on men and the BRCA genetic mutation or pathogenic variant? 

Kara Maxwell, MD, PhD: Oh, absolutely. I think that we've known in our own small field for a long time that there are risks of cancer in men who have BRCA1 and BRCA2 pathogenic variants, or we'll use the word mutations tonight. So we've always known that there's cancer risks, but I feel like that was not as well communicated out into the community and to the lay audience because these genes are named after breast cancer and the syndrome is named hereditary breast-ovarian syndrome.

And so it's very understandable why people would get confused that this seems like just a problem for women. But, as we know, all genetic changes inherited in families go through both men and women. And so, one of the things is just to remind people of that genetic piece that you can inherit that pathogenic variant from either mom or dad.

Host: Well, then, Dr. Maxwell, what should primary care doctors know? As we're talking about this, what are the indications for genetic testing in men that are thought to be at risk for BRCA pathogenic variants?

Kara Maxwell, MD, PhD: We are in general, trying to engage our primary care colleagues more.

We recognize that our primary care docs are just very overburdened. There's so many things that they have to do. Primary care docs often make decisions on whether or not their patient should undergo basic cancer screening like colonoscopy, prostate screening, etcetera.

And so for men, I think they're already thinking about this. So asking that family history, which they very well might be doing about prostate cancer, colon cancer, just adding on that asking about family history for breast and ovarian.

And then, we always say that we'd rather get more referrals for genetics that don't really need testing, than not get enough referrals and miss those people who do. And so, I think that the biggest thing is making sure that primary care docs know how easy it is to get people into genetic testing now, that it's not as expensive as it used to be, and making those referrals, even if it's perhaps a lower indication that somebody might need testing.

Host: And Dr. Maxwell, one more question for you here. Just give us a quick overview of the cancers that are connected with the BRCA mutation in men specifically.

Kara Maxwell, MD, PhD: Some cancers are just seen in men, which of course would be prostate cancer, and that's the one that we worry about most with our BRCA gene carriers, but particularly BRCA2 positive men have perhaps up to a 40 percent risk of getting prostate cancer. Depends a lot on their self identified race, genetic ancestry, family history, a lot of factors can modify that, and so that's one that we worry about the most.

But men can get breast cancer too, and that's something that almost every man diagnosed with breast cancer tells me that he didn't know he could have been diagnosed with breast cancer. And it's rare, it's really rare, even in BRCA1 or 2 carriers maybe 5 to 10 percent of BRCA2 carriers, for example, also in BRCA1 but it can happen and that most men are unfortunately diagnosed late with their breast cancer, which I think we'll get into later and that's because men aren't often thinking about that area of the body as a part that could get cancer.

And then men just like women are at increased risk of pancreatic cancer with BRCA1 or 2 mutations. And then there's probably, just a slight increased risk of a lot of different cancers and a lot of the work that we're doing in the  Basser Center is to try to help define some of those other cancers that BRCA1 or 2 carriers might be at risk for, that probably don't have any sex differences and so it's more just making sure that men know that all these other cancers exist, that they could also be at risk for not just breast and ovarian.

Host: This is so interesting, and Dr. Lee, are there signs or indications in prostate cancer specifically that might lead one to suspect an association with the BRCA mutation?

Dan Lee, MD, MS: Well, so that's the tricky thing. And thank you again for this invitation to talk. Prostate cancer is exceedingly common, but unfortunately the vast majority of men actually do not have any symptoms. So same goes for those who have the BRCA mutation. And so that's one of the common things that we often relay to our men when we're talking about screening is that you shouldn't rely or wait until you have symptoms for when you start the screening process, again, because the vast majority of these cancers are found without any symptoms.

Host: And Dr. Katona, universal screening isn't currently recommended for pancreatic cancer. Are BRCA positive men an exception? Because pancreatic cancer is one of those more silent cancers. And is this a way that we can maybe suspect and catch it earlier?

Bryson Katona, MD, PHD: So thank you for that great question, and thank you also for the opportunity to join today. I think your first point about universal screening for pancreatic cancer not being recommended, that's an important one. The U. S. Preventative Services Task Force has come out very strongly on this, that individuals at average risk for pancreatic cancer really should not be undergoing screening. Now, that being said, we know both BRCA1 and BRCA2 carriers have an increased risk of pancreatic cancer with the risk for BRCA2 carriers being a little bit higher than that for BRCA1 carriers. 

And when deciding which BRCA1 and 2 carriers to offer pancreatic cancer screening to, in the past, we had always had to rely on whether or not there was a family history of pancreatic cancer. So, in fact carriers were only recommended to undergo pancreatic cancer screening if they had either a first degree relative, meaning a parent or a sibling, or a second-degree relative, like a grandparent or aunt or uncle with pancreatic cancer.

The issue, though, with using family history to decide who gets screening and who doesn't get screening is that sometimes people have small families. Sometimes people don't know their family history, or there may be miscommunication of family history. And then—especially when you're talking about hereditary cancer risk syndromes—sometimes people die of other cancers at very early ages.

And so using family history is certainly not perfect. I think it's also interesting to note that the majority of BRCA1 and 2 carriers who are diagnosed with pancreatic cancer don't have a family history of pancreatic cancer. And so that was a long winded response to get back to your initial question about whether or not all BRCA1 and 2 men are eligible for pancreatic cancer screening.

And really now the answer is the majority of them can be considered for pancreatic cancer screening if they're of appropriate age. And so in individuals without a family history of pancreatic cancer we can start the discussion of pancreatic cancer screening starting at age 50. If there is a family history of pancreatic cancer, we would either start at 50 or 10 years prior to the youngest pancreatic cancer in the family.

However, my last point is that guidelines are not consistent with this recommendation. So currently, the NCCN or the National Conference of Cancer Network guidelines recommend screening for all BRCA2 carriers, but require that BRCA1 carriers still have a family history of pancreatic cancer.

Whereas guidelines from the ASGE, which is a gastroenterology society, recommend that pancreatic cancer screening be offered to all BRCA1 and BRCA2 carriers, regardless of family history. So these guidelines being different is a little bit confusing for patients and providers, but at least it gives you a hanger to hang your hat on when you're ordering this you will have one guideline to back up your decision if your patient is very motivated.

Host: Well then, Dr. Maxwell, in men, are the risks and outcomes of cancer identified with BRCA1 different from those of BRCA2 and different in the general population? And if there's a difference between all of these, do we know why it exists?

Kara Maxwell, MD, PhD: Yeah, that's such a great question and something that I think is really important because so many of the studies that we quote in the BRCA field lump all of the BRCA 1 and 2 carriers together. And we recognize more and more that there may be differences between BRCA 1 and 2, not just in the risks, but also the outcomes.

And so for certainly between BRCA1 and BRCA2 with regards to risk, we know that prostate cancer is higher risk in BRCA2, for example, pancreatic cancer is also probably higher. But when we think about the outcome; right now, we don't really know if there's a difference between BRCA1 and BRCA2 carriers when it comes to things like, for example, responses to treatment.

For example, PARP inhibitors can be used in metastatic prostate cancer. We don't know if there's a difference between BRCA1 and BRCA2 in that context, even though we do know, that there's a difference in that treatment response compared to the general population. And I think the reason this question is so interesting is that, in general, a lot of BRCA1 and BRCA2-related cancers respond very well to treatment.

So, we often see, for example, in ovarian cancer, that a BRCA carrier will do extremely well with chemotherapy, probably due to significant response to say, platinum chemotherapy like carboplatin. And so we're seeing that across a lot of different cancers including those in men as well.

And so that's always the point I really like to be able to make is that a lot of times people equate having one of these genetic mutations as automatically meaning that the outcome is going to be worse and that may not be the case. Even in situations like breast cancer where we know that BRC1 carriers may have a worse type of breast cancer that may still not translate into a worse outcome, for example.

The last point I just want to make on this is that alluded to earlier with breast cancer. And, I don't think that necessarily BRCA1 and BRCA2 cause worse breast cancer in men. I think it more has to do with that awareness and not maybe getting diagnosed as early. And so, we really have to tease those things apart and why it's so important for all of our colleagues that aren't in cancer genetics, or aren't in medical oncology, to help us identify people earlier and not think that like, oh, well, we're finding this thing that's going to have this terrible outcome for our patients.

And that, in fact, it's probably going to help them quite a bit in a variety of different ways.

Host: Dr. Zhang, I'd like you to speak about prophylactic mastectomy options. Are they available for men at high risk with BRCA genetic mutation, and are there reconstructive options? Tell us a little bit about what's going on in that realm.

Jenny Zhang, MD: Hi, yes, thank you so much for inviting me to be on the podcast as well. So, maybe I can just start with just the basics of the treatment paradigm in terms of surgical management of men who have breast cancer. In general, it's often very similar to how women are treated. Because in males, most of the breast tissue is concentrated behind the nipple-areola complex, that's where the vast majority of cancers end up being found. And so, often when a site of cancer is close to the nipple areola it is very common for us to have to remove the nipple.

And so, I would say that the vast majority of male breast cancer patients will end up having a mastectomy. However, breast conservation which may be less well known is definitely an option for men with breast cancer as well; about 10 to 25 percent of patients will actually have breast conservation, which is a lumpectomy with preservation or with removal of the nipple areolar complex followed by radiation and keeping the rest of the breast tissue intact.

Now, for men who elect to have a mastectomy or need to have a mastectomy what do we do for options for contralateral prophylactic mastectomy? Typically the risk is pretty low and that most people don't need it for cancer reduction. But, I think there has been a lot of increase since the 2000s, in terms of contralateral prophylactic mastectomy. There's probably about an overall incidence of 6 percent of people choosing to do contralateral prophylactic mastectomy, I think this is an area that probably is somewhat understudied and certainly could use more data as well.

As far as reconstruction, I think this is a poorly explored area in men who have breast cancer. In general, surgeons are not offering reconstructive options to men and I think this is something that we are interested in exploring more here at Penn. Essentially reconstructive options include, especially for significant contour deformities, chest wall reconstruction with local tissue rearrangement or autologous flaps such as the latissimus flap and other local tissue rearrangement options. Sometimes, fat grafting can also be performed to help with contour defects.

If the concern is the lack of a nipple and the lack of symmetry, with that regard there are options for nipple reconstruction as well as nipple tattooing, including 3D tattoos that actually can look really nice and many of our female patients also pursue this type of nipple tattooing as well.

Host: This is a riveting discussion. And Dr. Lee, I'd like you to talk about the PATROL study, evaluating people at risk for prostate cancer because they carry one or more genes that are known to increase prostate cancer risk. What then is the link between PSA and management of the BRCA1 and 2 prostate cancers? Speak about the study for us.

Dan Lee, MD, MS: Sure. Thanks for the invitation for that. So, the whole concept for us as cancer doctors, geneticists, and primary care doctors, is to find the disease early in its disease course when you can make significant changes, when you can really impact how people do throughout the whole journey.

So the concept is if we can find the disease earlier when it's still curable and treatable, then, that's a win. Now, the tricky thing with BRCA mutations was a significant study that was done in the mid 2010s that showed that folks with BRCA mutations were found to have significant cancers, even at much lower PSA levels than what we usually attribute or what we are usually concerned about. For most normal men, we consider PSAs around 3.5 or 4 if you're in your 50s or 60s to be considered normal. But what they found was that for men with BRCA mutations, you can still find significant cancer at lower PSA thresholds.

So, the PATROL study that you mentioned before is a multi institute, national study, it's led by Dr. Chang and Dr. Lin out of the University of Washington. We at Penn are one of the leading partners and collaborators with them. And the purpose of the study is to see if by lowering that PSA threshold and utilizing MRIs we can find these significant prostate cancers earlier in the course before they become metastatic.

And we've been enrolling patients for the past year and a half now and we just enrolled our 100th patient. So, we're very, very proud of that and very glad to have the support and collaboration of the  Basser Center and our sponsors here for this because we've already found at these lower thresholds, some significant prostate cancers at localized areas and treated them successfully and patients are now disease-free; when the PSA that they've had would never have been a trigger for a threshold before. Meaning because of this screening study, we've found these significant cancers—when if we tried to use regular PSA thresholds, it probably would have been much more advanced disease. So we're very excited about these results and for collaborating in this study.

Host: Wow, absolutely an exciting time in this genetic field and I thank you all so much for joining us today and sharing your incredible expertise for other providers. That was an excellent discussion and To refer your patient to our specialists at Penn Medicine, please call our 24/7 provider only line at 877-937-PENN or you can submit your referral via our secure online referral form by visiting our website at pennmedicine.org/referyourpatient. That concludes this episode from the specialists at Penn Medicine. I'm Melanie Cole. Thank you so much for joining us today.