Beyond the BRCA Gene: Other Factors That Shape Your Risk

BRCA mutations are just one piece of the hereditary cancer puzzle. In this expert panel, Drs. Dawson and Cheifetz, along with Genetic Counsellor Melanie O’Loughlin, explore how factors like breast density, lifestyle choices, and polygenic risk scores influence your personal cancer risk. Learn how tools like CanRisk combine these factors for a clearer picture and hear practical insights on personalized risk management. The session also includes a Q&A, giving you direct access to leading experts.

Find the recording here.

Q&A Transcript

Host: Perfect. Now, I see a hand raised, and my apologies, I don't see a name associated with you there, but you can go ahead and unmute.

Participant: I'm just interested in the reference to vitamin D. Is that a certain quantity? What is the link? Why is vitamin D a, a factor in decreasing the risk? And what are the quantities one should take?

Clinician (R.C): So, as I mentioned, this was a study not looking at amounts you should take, but comparing, people who had low measured vitamin D levels in their blood compared to people who had normal vitamin D levels in their blood, so it wasn't a study where they were giving people different amounts and going forward.The general recommendations, that said, for people is that we have a thousand international units of vitamin D daily in our diets. There's no recommendation that people actually have their blood vitamin D levels measured, per se. Most of us who live in British Columbia in the wintertime, particularly this week, have low vitamin D levels because we don't get very much sun exposure. So, that's a general dietary recommendation and I don't have the answer for you, sorry, on the mechanism by which they think that might actually, affect your breast cancer risk or other cancer risks. Sorry.

Host: Hey, does anyone else want to chime in and unmute, or else I'll go to some questions in the chat? No? Okay. So, we will send our attention over to the chat here. So, we had a question asking, do you know if BRCA breast cancers tend to be higher or lower grade? Have there been studies on that correlation?

Clinician (R.C): They're almost uniformly high grade.

Host: Thank you. Another question noted, I had not realized that height was a risk factor. Can you elaborate on this risk factor?

Clinician (L.D): Yeah, I mentioned this, I answered this in the chat. We have no idea how that, you know, of all of the many factors that various studies will look at, they will include a lot of things and see what signals come out for which I can't biologically understand why height would bubble up. It… to me, I don't… I can't… I can't explain it, but it did show up in a big model.

Host: Interesting. And another question, I'm wondering, are these scoring systems used in triaging patients wanting surgeries, are able to have them? So, as a triaging factor?

Clinician (L.D): I can… no, they wouldn't be in routine use for triaging surgeries, but I… we're talking mostly about BRCA today, but I do say… I will say that CAN risk can be very helpful in people with some of those other more moderate penetrance genes, like RAD51C and D, PALB2, and BRIP and I use it a lot in those people, because there will be a lot of variation in the ovarian risk. And Dr. Kafetz and I work together on people with those moderate penetrance genes to use CAN risk sometimes to help figure out if we can get them eligibility to see the high-risk clinic or have MRI. So, I think, like Melanie said, you know, for BRCA carriers, we're less likely to change things. We're not going to triage surgeries but they can help people get a better sense if they're a less penetrant gene.

Clinician (R.C): I think that, I mean, just to elaborate a bit more on the example that Melanie gave, I don't do the calculations in clinic, but the concept that if you're 65 and newly diagnosed as a BRCA carrier, your future breast cancer risk is not 72%, like we quoted, lifetime risk, and for those patients, the benefit of having prophylactic mastectomies is clearly much less than if you have a 72% future risk of breast cancer. So, I don't… we don't really need a specific number to show that, but we… the value of prophylactic surgery for breast decreases with age.

Host: Okay. Protection of oral contraceptives were mentioned. Are Depravera and hormonal IUDs also protective for ovarian cancer?

Clinician (L.D): Super great question, and very relevant question. So, the systemic we say oral, but systemic contraception, like the oral contraceptive or the patch contraceptives that anything that suppresses ovulation will give protection. Depro-Provera would also suppress ovulation, less so, so likely provides some benefit.In the domain of the hormonal IUDs, we just had a master's student look at all the BC data on this question of people who had those IUDs, and we were not able to get a statistically significant result, so we just didn't have enough people.to answer it. IUDs for… hormonal IUDs, for the most part, don't really work by suppressing ovulation.So, we're not really so sure yet. They wouldn't compare to the pill but they do substantially reduce uterine cancer in people who might be at risk for that but they're not the same animal. The amount of hormone in the Marina IUD, or the hormonal IUDs, is quite a little, but it works where you put it.

Host: Is the CAN risk tool useful in determining future risk of someone who has already had breast cancer two times in the past from the age they are now going forward?

Clinician (M.O): Unfortunately not. So CANRISC is really useful for a lot of different questions, but the question of a second or third breast cancer, it's not as useful for, so it will, give you a number for the chance of a second breast cancer if you've had one but there are some, limitations to the way it calculates that, so we, suggest being cautious about, about that, calculation. What it can't do is predict a third, so it will, it will sort of stop at that point of 2 .They are always evolving, though, and they're always adding more information and things, so hopefully in the future at some point.

Host: Okay, what is the typical recommendation if you've had your tubes removed in your 30s, when you should have your ovaries removed? Also, is there any time where the uterus should also be removed?

Clinician (L.D): So, that's a two-part question. So, the first part, you know, I'm hoping the person asking this is still in their 30s, because, you know, we're soon gonna have… those trials I mentioned are gonna be coming with results, not right away.Right now, until those trials are back, and we cannot quote people an exact extent of risk reduction, we're still going to recommend that they have ooforectomy, and in this case, we call it completion oophorectomy. After their cell pingectomy or tubes, within the recommended age range by the mutation they have. So, if they're 30… between 35 and 40, and they're BRCA1, we would say, have that surgery by the time you're 40. If you're BRCA2, have it by the time you're 45. I'm really hopeful with this evidence that it's going to bubble up to say that the extent of risk reduction is so much lower that maybe people might be able to delay that ovarian surgery and delay premature menopause, but I can't tell you to do it yet. In terms of the uterus, the… for BRCA2, certainly there is no recommendation routinely for hysterectomy. Adding a hysterectomy to the ovary tube surgery does make the surgery longer, adds a bit more complications, it's a bit more complicated. Bleeding is a little bit more. Still, those risks are small, though there have been some studies that question whether or not there was a higher rate of uterus cancer in BRC1 carriers. To be honest, I've never really been totally impressed that that… those stats are… are strong. I generally recommend people do not include hysterectomy. The only advantages would be if somebody's on tamoxifen, maybe the tamoxifen can cause some overgrowth in the lining of the uterus, maybe and so, for those people, it might simplify things. It does change, as well, the way we give our hormone replacement, and there's a lot of cool evidence coming out about that as well. So, some people choose to have it, but it's not part of my routine recommendation. For some people, if they don't want to take systemic progesterone or progestin, they can put that IUD in which protects the lining of the uterus without giving them systemic progestin or progesterone. There is another medicine, Dr. Kaif has mentioned about the breast density question. There's some really cool stuff coming out about a particular combined medication that has estrogen and a medicine in it called bazodoxifene, which is like a cousin of tamoxifen and that one, it is starting to begin to look like that particular hormone replacement regimen might decreased breast density, or at least won't proliferate it, and there is a paper that just came out, an abstract that just came out that said it was improving molecular markers in people with hyperplasia, ductal hyperplasia. So, stay tuned on that combined oral medication that's estrogen and basadoxapine. If it decreases breast density, it might be a really good medicine for BRCA carriers.

Host: Very interesting. Fructose-containing beverages, would that be any kind of pop, or specifically diet beverages? Do you have any more information about that?

Clinician (R.C): So that's not referring to diet beverages. Diet beverages have their own things that are bad about them, but this is specifically referring to sweetened beverages.

Host: And then what is the general recommendation, for… or for frequency of high-intensity activity?

Clinician (R.C): Oh, the Canadian Painful Guidelines is 150 minutes a week of moderate to vigorous exercise in at least 10-minute chunks. So, you're looking probably at about 3 times a week, of exercise, you know, that has a cardio benefit and then there's some further comments about strength training and weights, which is important for your bone health, particularly for postmenopausal women. I'm groaning because I'm not an exercise fan, and it takes a lot to get 150 minutes. You're not a fan, but I try.

Host: And in the case that someone is not a BRCA carrier, but has breast density level D, should these individuals request MRIs or other types of scans?

Clinician (R.C): So, MRI is not available in BC for this indication alone. The, in most health authorities in the province, supplemental breast ultrasound is available. It's not available everywhere. Your family physician would have to order it. It's not something that happens automatically through the screening program. I think about the only place you can't get it maybe is Fraser Health. It is a challenge, and there's a lot of… there's a big organization called Dense Breast Canada that's trying to, push for increased, access to, supplemental imaging, for particularly the level D density, but really for both C and D.

Host: Why does BRIP1, and my apologies, I don't know the correct label, maybe it's BRIP1, shows as a variant of unknown significance on genetic testing, as it seems like it's a known genetic risk versus a variant of unknown significance.

Clinician (M.O): Yeah, so, I guess a couple… a couple of things to tease apart here with this question. So, BRIP1 is a gene that, when it is disrupted, when there's a change that is causing a disruption in the gene, is a moderate risk gene for ovarian cancer, but a variant of uncertain, or unknown or uncertain significance does not necessarily mean that that gene is disrupted. It means we saw one of those letter changes or variants in the gene, and the lab can't say for sure, is this change in the gene causing a disruption, or is this just part of those 3 to 5 million normal benign variants in this person that we happen to see? in the BRIC1 gene. Many, many of us, if we had a genetic test, a hereditary cancer genetic test, would have a VUS come up. It's very common for us all to… to have that variation, and it doesn't mean that there's a risk there, necessarily. It means we don't know enough yet to say if that particular variant is causing a problem in the gene, but when we find a pathogenic variant in BRIP1, that does cause a moderate risk for ovarian cancer.

Host: Can you provide the CanRisk website for the general population? I've checked, and it seems it's only for practitioners.

Clinician (M.O): Yeah, so the new version's not out yet, so they are developing that one still, and it's still in the works, but, you know, hopefully not too far off. But the version that's available now, you know, you can develop… you can register an account, but it's more designed to be used for healthcare professionals, or… yeah.

Clinician (L.D): They won't make you prove you're a practitioner.

Clinician (M.O): No, no, not at all. It's just the interface and, like, the user-friendliness.

Host:  Is there anything being done to broaden who can be screened for genetic risk outside of family history? Would love to see the opportunity for more providers, versus cancer survivors.

Clinician (L.D): We have a lot of research going on about this question. I mean, what I think many of us would love to see is something called population-based testing, where everybody can have access to know their BRCA status. It turns out that's a really complicated thing to implement in a healthcare system, so it's going to take some more research to figure out the right way to do it. You know, Mel can speak to all the many things the Hereditary Cancer Program is trying to do to open up the doors and access testing, not the least of which is the fact that healthcare practitioners who are not genetics, per se, can now order testing for people with… with some eligibility criteria. So, the doors are getting… not blown open yet, but they're getting wider.Is that fair, Mel?

Clinician (M.O): Yeah, absolutely. So that… we're generally… definitely aiming to increase access through, what you mentioned we're calling mainstream genetic testing, where, providers outside of, the Hereditary Cancer Program can order testing.We're looking to increase the volume of those tests, increase the percentage of those tests that are done outside the hereditary program, and look at other people that might be able to access things that way. For example, family testing for BRCA1 and 2 is a potential option that's been proposed. That's not happening quite yet, but that would mean that instead of accessing things through a hereditary program. That could be ordered by a family doctor or other practitioner. We're also looking at other, sort of, online tools to help expand that access, like online portals where people can access, you know, get started directly finding out about the options for genetic testing. So there are, you know, things in the works, and we are also very interested in trying to increase this testing and get that access to people who need it.

Host: Just reading out Lisa's comment here in the chat, just noting that the Mediterranean diet has also been shown to significantly decrease cardiac disease and dementia.

Clinician (L.D): Mediterranean spelled properly, sorry.

Host: Good.

Clinician (R.C): I think, actually, can I just add to, you know.

Host: Yep.

Clinician (R.C): One of the things when we talk about all these lifestyle modifiers is that you aren't just your BRCA gene. You're unfortunately entitled to get everything that everybody else is at risk for, and so all of these lifestyle factors, I mean, you don't want to do, you know, have your breasts removed, have your ovaries out, and then get lung cancer because you smoked. So you need to think of yourself as a whole person, not just your genes.

Host: And we've got the last two questions here in the chat. So, is there any recommended screening for ovarian cancer while someone awaits for surgery?

Clinician (L.D): I wish there was. What I say to people is, you know, I… I can't tell you if you have ultrasound and blood work, I can't look you in the eye and give you any assurances that that test is gonna definitively screen you for early disease. You know, we strongly encourage people to enter clinical trials, and there are a couple… there's a very cool one now going on that we have here and across the country called the CHERM study. That's being run through the Hereditary Cancer Program. The website is called CHARM Consortium, which is a new technology that's using circulating tumor DNA as a possible screen. Not proven yet, but possibly promising, but you cannot take an ultrasound and blood work to the bank. I don't know, maybe Rona's the best person. The next question about mutations with lower or higher risks, there are some particular spots in genes and then higher risk.

Clinician (M.O):  There is one change in BRCA1 that is associated with a more moderate risk, so a lower risk of breast and ovarian cancer compared to other variants. It’s also been suggested that there are regions of both BRCA1/2 that are slightly more associated with ovarian cancer compared to breast cancer or vice versa. In general, though – a change that disrupts the BRCA1 gene is associated with a high risk of breast and ovarian cancer, and we don’t generally quote specific risks by variant. In BRCA2, it has been suggested that there is a region that is associated with a more moderate risk of  breast and ovarian cancer, this is an area of ongoing research. Many of these right now are classified as uncertain variants so unlikely to apply to anyone here.

Host: Any remaining questions before we move on to some closing remarks? I'll just pause for a moment. Okay, so with that, I'm just gonna stop this recording.