by Jax DiEugenio
Although the risks of cancer developing in females harboring germline BRCA1or BRCA2 mutations are understood and have propelled genetic testing and preventative measures for this population, more work is required to amplify the rates of this testing and develop tailored screening and treatment methods for males, according to Kara N. Maxwell, MD, PhD.
In a review published in JAMA Oncology, Maxwell and colleagues found that despite BRCA mutations being known actionable alterations, genetic testing rates for these aberrations are significantly lower in males compared with females. The study authors detailed that identifying more male carriers of BRCA mutations could help improve early detection, risk management, and treatment strategies.
“Women start to go to the gynecologist during their teenage years or early 20s, and they have that [experience] with the health care system as a young individual that many young males don’t have. Where can we bring this information forward [to males] and [tell them to] think about their family history and how it might be important to their own health?” Maxwell said in an interview with OncLive®.
In the interview, Maxwell, who is the director of the Men and BRCA Program at the Basser Center and an associate professor of medicine (hematology-oncology) at the Perelman School of Medicine of the University of Pennsylvania in Philadelphia, discussed the need for tailored screening guidelines and risk reduction strategies for men carrying germline BRCA1 and BRCA2 mutations; explained how the presence of BRCA mutations in males relates to the risk of developing certain types of cancer; and identified disparities in genetic testing rates among the male population.
OncLive: What was the rationale for conducting deeper research into germline BRCA mutations in the male population?
Maxwell: This has been an exciting journey between Heather H. Chang, MD, PhD, of the University of Washington [and Fred Hutchinson Cancer Center] and myself at University of Pennsylvania. As with many things we do, [this idea] came from our patients. I am the director of the Men and BRCA Program at the Basser Center, and Dr Chang is on the scientific advisory board of the CureBRCA Foundation. In both of these foundations, our patients have pushed us to say there’s so much information about BRCA mutations out there, but almost none of it focuses on men. That was the impetus to put [this research] together. [We wanted] to get a lot of the experts in the field to help write something that was completely focused on [BRCA mutations in] male individuals.
What are the primary cancer risks associated with pathogenic variants of BRCA1/2 in male carriers, and how do these compare with female carriers?
I always try to separate it because BRCA1 and BRCA2 have very different cancer spectrums. That’s one thing that we wanted to [clarify] in this review. To be clear, [this research focused on] individuals who were born with male sex at birth. This review didn’t target some of the issues that are important to the transgender male community.
[For men], one of the things that we know is that there is a bit of difference between BRCA1 and BRCA2 mutations [themselves], and [there are differences] between men and women. For BRCA1 mutation carriers, the most important cancer risk is breast cancer. The big difference is that for female BRCA1 carriers, the risk of [developing] breast cancer is upward of 60% to 80% over their lifetime; whereas for male BRCA1 carriers, that risk is approximately 5%. The thing is that [the 5% risk] is highly elevated over the general male population, [whose risk of developing breast cancer in their lifetime is approximately 0.1%]. [Developing breast cancer] is not something that men think about as much [compared with] women who would be getting mammograms [and other screenings]. Even though the absolute risk [for developing breast cancer] over a [male] BRCA1 carrier’s lifetime is not that high, that 5% is high when you put it in context [of the overall male population].
In addition, male BRCA1 carriers are at increased risk for pancreatic and prostate cancer, which is similar to BRCA2 but not quite as high of a risk. For BRCA2 male carriers, the most [heightened] cancer risk is prostate cancer. That risk can be upward of 50%, but there’s a big range for BRCA2 male carriers and their risk of prostate cancer. That’s different vs BRCA1, where the risk [of developing prostate cancer] is a little bit lower. However, I am hedging [with these estimates] because we lack quite a bit of data on the specific cancer risks in [the BRCA-mutated male] population.
Finally, pancreatic cancer affects both males and females with BRCA1/2[mutations]. That risk is approximately 3% to 5% in individuals with BRCA1and BRCA2 mutations, regardless of gender. Those are the major risks associated with BRCA1/2. We often also say the BRCA genes are involved in the overall suppression of tumor formation; therefore, there may be other slight increases in cancer risks where we just don’t have enough data yet to [fully] understand [the increased risks for carriers of BRCA mutations]. However, the ones we discussed [here] are the major cancer risks [for male BRCA mutation carriers].
What are the current genetic screening guidelines and preventative strategies for males, and how do they differ from the guidelines for females?
Just like the cancer risks don’t have quite as much data [for male BRCAcarriers], neither do the screening guidelines and recommendations. That was one of the goals of this review. [We wanted] to point out that there are differences between different organizations [creating] guidelines, such as the European Society of Medical Oncology, the National Comprehensive Cancer Network, and others. Therefore, we focused mainly on screening in male carriers because we don’t have as many types of preventative options [for males] as we do for females.
For breast cancer in male BRCA1 and BRCA2 carriers, we recommend awareness of breast tissue and breast exams by a qualified professional once a year. Many men are unaware that they can have breast tissue. It may be taboo to talk about their breast tissue, and many men equate having breast tissue with being overweight; however, those things may not be true. A male can have more breast tissue and be a healthy weight. It’s important [for males] to recognize their body’s breast tissue and know what would be abnormal. Most men with BRCA mutations—and men in general—do find their own breast cancers. That’s fine, but we would love to be able to be able to identify those cancers earlier.
One question we have is whether mammography is important for men with BRCA1/2 mutations. We don’t know the answer to that question right now. There are some clear areas where if, for example, [a male patient with a BRCAmutation] has already had one breast cancer, I recommend getting a mammogram on the other breast for screening. For men who have never had breast cancer and have BRCA1/2 mutations, we like to have a discussion and figure out [things such as] how much breast tissue they have and what their preference is. Is getting that mammogram something that’s going to be reassuring to them? However, just having that awareness is important.
On the prostate cancer side, what’s been important to me is that the screening guidelines are sort of all over the map. In the time that I’ve been in practice, [the guidelines] have gone up and down in terms of who gets screening and who does not. The United States Preventive Services Task Force currently does not generally recommend prostate cancer screening for normal-risk men. It’s important for men to understand that if they do have a family risk, this may be [related to] BRCA1/2 [mutations], or it may be something else. However, for men at risk, such as BRCA1/2 carriers, it is important to have that discussion about prostate cancer screening with their primary care doctor. For those men, we do recommend that they start prostate-specific antigen [PSA] screening starting at age 40. There is a lot of interest in trying to figure out whether we should lower biopsy guidelines, perhaps for lower PSA values for men with BRCA1/2 mutations. It’s not just about the fact that these men are more at risk for prostate cancer; they appear to be at risk for more aggressive prostate cancer. Therefore, trying to find that cancer earlier would be important for quality of life and long-term survival in men with prostate cancer with a BRCA mutation. Right now, we’re not doing any sort of screening MRIs for either breast or prostate cancer. In male BRCA carriers, that is an interesting and active area of study.
The pancreatic screening space is changing by the minute. There is always something new in pancreatic cancer screening, which is exciting because that’s such a difficult cancer to identify. This is a cancer where maybe a BRCA1/2 carrier—whether they are male or female—may only have a 3% to 5% risk of getting [pancreatic] cancer. However, since pancreatic cancer is so deadly, we would like to have effective ways of screening. There are a lot of different options right now, with endoscopic ultrasound or MRI being the 2 major screening options. How you [go about screening], the exact frequency, the preferred modality, and whether certain blood tests can help are all active areas of study that many institutions, including our own, are looking at.
One of the things that’s gone back and forth in our guidelines is regarding skin cancer screening. I always tell people that if you’re of the non-sunscreen genre, having a dermatologist do a skin cancer screening if you’re a lighter-skinned individual makes sense anyway. We personalize that a bit as those guidelines have changed over time.
Those are the major screenings that we can do. As I mentioned, there’s really no prevention that we do in male BRCA mutation carriers, which is quite different compared with females, where we do recommend removal of the ovaries by a certain age in BRCA1/2 mutation carriers, and consideration for removal of the breast. We don’t recommend removal of the breast, prostate, or pancreas in male carriers.
The study also identified a disparity in the rate of genetic testing for BRCA1/2 pathogenic variants. What strategies can be implemented to increase testing among males, and how can health care providers improve the identification and management of male BRCA mutation carriers?
This has been an active area of interest for the Basser Center in general. One study that my group [published] this year looked at genetic testing for men with either breast, prostate, or pancreatic cancer, which would be an indication for testing in a private payer system, vs Veterans Affairs [VA], which is an equal access system for anyone who’s a veteran. We found that this disparity in genetic testing between self-identified White and Black individuals went away in the VA, which suggested that access to care in an equal-access environment could help to reduce a lot of those disparities. That piece is important and telling in that if we want to have genetic testing for all, which is one of our major goals, reducing the barriers to access to care, such as cost or finding the right provider in the system, is the ultimate first step. Patient education goes hand in hand with [testing], but we need to make sure that access is equal.
In general, we’ve had a lot of discussions about [genetic testing] because there are big differences in health care between men and women. Because BRCA1 and BRCA2 may have reproductive implications, [this may be one opportunity for testing]. There are some disorders where if both partners are carriers—for example, with BRCA2, a child has a risk of Fanconi anemia. Those discussions in the reproductive setting could be helpful. For a young man who is thinking about starting a family, thinking about his family history could be a great place to try to bring that knowledge forward in thinking about BRCA1/2 [mutations].
Of course, [approaching testing from the reproductive setting] won’t get everybody since not every young man is going to be interested in starting a family, and some may not have access to those types of discussions, either. This is why different organizations like the Basser Center are trying to make sure that there’s good web content that is reviewed and accurate for men to go to. It’s been interesting on our own website, our male-centered pages tend to be some of our [most popular] pages, probably because there just isn’t as much [male-directed] information out there. It is encouraging that people are talking about it more; however, more work needs to be done.
What are some of the areas of ongoing research and clinical trial opportunities that could influence the development of these new guidelines and preventative measures for males carrying germline BRCA mutations?
When we think about the clinical research space, there’s a lot of work that needs to be done on screening, detection, and prevention, and that goes across all cancer-risk syndromes for men and women. However, particularly for male carriers, [it is important to] figure out the answers to some of these questions. What kind of breast screening is necessary? What kind of things could be done to help prevent prostate cancer in male carriers? Those screening and prevention studies are important, and we need to understand more about how cancer develops in these males to be able to direct some of those studies.
From the treatment standpoint, PARP inhibitors, which we use in BRCAmutation–related cancers, there have been great pushes to show that those drugs are useful in men with metastatic prostate cancer. However, there needs to be some more work [looking into whether] we should be pushing the use of those drugs earlier in high-risk men. For example, in men diagnosed with localized prostate cancer at a higher-risk stage, should PARP inhibitors be part of that treatment? There are some trials open across the country, including at Penn, that are looking at that question.
For breast cancer, one thing that’s always been difficult is that men haven’t been part of a lot of studies; therefore, we assume that everything we do for breast cancer in women will work [in men], including PARP inhibitors, but we don’t necessarily know that for sure.
These are tough problems to address because getting enough people in one place to do that trial is difficult. This is a situation where the analysis of real-world data might be helpful, where you can create cohorts out of electronic health record systems to see if men respond to therapies the same as women. [These real-world studies can also help identify] gaps that need to be studied in a prospective fashion where we need to put in the effort to recruit for these rarer patient populations. Pancreatic cancer screening affects both males and females and is still an exciting, active area of research.
However, right now, for anyone who has patients who are male BRCAmutation carriers, the prostate cancer and breast cancer screening questions are active ones where we have opportunities for trials, and we’re excited about trying to tackle these cancers early on.
What would be your main message for colleagues based on this review?
We need to make sure male patients with breast, prostate, and pancreatic cancer get genetic testing. If your health care system doesn’t have that, how can that be implemented? All male patients with breast or pancreatic cancer, regardless of their stage, should get testing. Prostate cancer gets complicated, and it goes back and forth; however, anybody who had advanced or metastatic [disease] should be tested. Figuring out how to do that in an [accessible] way [is important], and we must recognize that it’s not cost prohibitive. Insurance companies will pay for all this testing with those diagnoses.
As far as cancer treatment, we have had so many advances and people are living longer. That’s where family history comes into play. You see a patient with one cancer, and a family history shows that this man’s mother died of ovarian cancer, we are going to try to make sure that they get genetic testing. This is such a changing field in oncology, [and it is important to be aware of] any sort of clinical trial options available, particularly in the prostate cancer space. For example, this idea of trying to incorporate PARP inhibitors earlier on in the treatment of prostate cancer is important. Thinking about [clinical trials] with new patients is important.
Reference
Cheng HH, Shevach JW, Castro E, et al. BRCA1, BRCA2, and associated cancer risks and management for male patients: a review. JAMA Oncol. Published online July 25, 2024. doi:10.1001/jamaoncol.2024.2185
This article was published by: OncLive