Summer 2024 Breast Cancer Research Round Up

Welcome to The Breastcancer.org Podcast, the podcast that brings you the latest information on breast cancer research, treatments, side effects, and survivorship issues through expert interviews, as well as personal stories from people affected by breast cancer. Here’s your host, Breastcancer.org senior editor Jamie DePolo.

Jamie DePolo: Hello. Thanks for listening. My guest is Dr. Holly Pederson, professor of medicine and founder of the Medical Breast Program at Cleveland Clinic. Dr. Pederson is also a member of the Breastcancer.org Professional Advisory Board. She's going to explain some of the most important breast cancer research that was published over the last three months. Dr. Pederson, welcome to the podcast.

Dr. Holly Pederson: Oh, thank you, so much, for having me today. It's a pleasure.

Jamie DePolo: So, the first one I'd like to talk about technically isn't a study, but it always causes a lot of confusion, and I'm talking about the U.S. Preventive Services Task Force latest recommendations about when you should have a mammogram, when you should get screened for breast cancer. And these came out in April, but people are still talking about it. 

I always wonder why couldn't they just use language that everybody uses, because they talk about biennial screening. I, myself, look at this stuff every day. I still had to look up biennial just to make sure I understood, but essentially, it's saying that women who are 40 to 74 should be screened every two years, which is much less frequent than a lot of other organizations recommend. So, how do we take this?

Dr. Holly Pederson: I mean, you hit a lot of great points. It's confusing for patients. It's confusing for providers. It's impossible to keep track of everybody's updated recommendations. However, the USPSTF does impact insurance coverage for mammograms for women in this country, and that is really important that we keep up on what USPSTF is recommending, even if we don't completely agree with it, and I'll go into that.

They recently updated their guidelines from 2009 and 2016, now recommending mammograms every other year, or biennially, from age 40 to 74, as opposed to from age 50 to 74, which is what they had recommended up until now. It does make it more clearly aligned with other screening recommendations in starting at 40, but it's not enough to go every other year.

When they made their recommendations, they commissioned a systematic review to evaluate the comparative effectiveness of different mammography-based cancer screening strategies on the incidence of and progression of advanced breast cancer, breast cancer mortality, and breast cancer specific or all-cause mortality. Essentially, they split the modeling estimates into four scenarios.

They looked at every other year screening from 50 to 74, which is what they had previously recommended. They looked at every other year screening from 40 to 74, their current recommendation. They did look at annual screening from 40 to 74 and 40 to 79, and for the first time, they split out the 12 to 13 percent of Black women, that were -- self-reported Black women -- that were in the group to look at them separately.

As we know, young Black women can be prone to earlier onset breast cancer and to triple-negative breast cancer in particular, which is a biologically aggressive type, and the mortality in Black women in this country from breast cancer is 42 percent higher than for white women, which is something that we really need to address.

With these modeling analyses that they requested, as well as a review of the literature, they were able to show that the mortality reduction with what they're currently recommending, the every-other-year from 40 to 74, the mortality reduction, overall, would be 30 percent, which is decent, but if you did annual screening from 40 to 79, you'd have a 42 percent reduction in mortality.

Jamie DePolo: So, that's a 12 percent difference.

Dr. Holly Pederson: Twelve percent difference. Now, in Black women, if you stick with their current recommendation, they have a 24 percent reduction in mortality, further widening that disparity gap between white and Black women in mortality. And if you do annual screening on Black women between 40 and 79, there's a 40 percent reduction in mortality.

Jamie DePolo: I don't want to interrupt, but I'm going to have to, because…

Dr. Holly Pederson: No, please.

Jamie DePolo:  What that says to me is that you, Preventive Services Task Force, don't really care about that 12 percent or that 20 percent in Black women. And I am offended by that because you're saying I don't matter, essentially. 

Dr. Holly Pederson: Oh, yeah. Well, I can't I'm not going to say that.

Jamie DePolo:  Yeah. No, I know.

Dr. Holly Pederson: No, I'm not going to say that, and you know, given this information, as well as the Breast Cancer Surveillance Consortium demonstrating a greater risk of later-stage and larger tumors in women who are screened every other year, pre-menopausal women with extremely dense breast tissue had a higher rate of larger tumors and later-stage disease when they were screened every other year versus every year.

So, the American College of Radiology looked at this same data. The USPSTF, given this data, chose to screen women from 40 to 74, every other year, did not make any accommodation for the data demonstrated in Black women. Furthermore, they said there is no evidence to support screening in women over the age of 74, and evidence is insufficient to recommend supplemental screening in women with dense breasts. How about if we talk about that for a minute?

Jamie DePolo: Sure. Yes. Let's, because a lot of doctors recommend that if you have dense breasts, because you're considered at higher risk.

Dr. Holly Pederson: Well…

Jamie DePolo: Well, I guess, here's a question because the task force is always very clear, saying these are for women at average risk. So, if you have dense breasts, aren't you automatically at a higher-than-average risk of breast cancer, or no?

Dr. Holly Pederson: So, the answer is if you have dense breasts, it may mask breast cancers on your mammogram. They may not be identified, and extremely dense tissue, which is only present in about 6 to 10 percent of women, is an independent risk factor for the development of breast cancer, and so, all women who have dense breasts should not panic that they're at increased risk.

Forty to 50 percent of America is dense, including myself. And women, though, starting Sept. 1 of this year, per federal law, will get on their mammogram another new phrase that says you are mammographically dense, and it would be prudent for you to discuss the option of supplemental screening with your healthcare provider or your clinician.

And now, with USPSTF not supporting supplemental screening, yet a federal law is in place to discuss supplemental screening with your provider. I'm just not sure how that's going to go. And I guess the idea would be if they wanted to have supplemental screening, they would be entitled to pay for it. I'm not sure. We'll have to see how that plays out. But supplemental screening modalities, such as fast or abbreviated MRI or contrast-enhanced breast imaging can really help see through that dense tissue.

Whole-breast ultrasound, which is still really commonly being performed, is not as sensitive. It's just not as sensitive in picking up cancers. If you screen 1,000 women with digital mammograms, you know, the old-fashioned 2-dimensional digital, you'll pick up about five breast cancers per thousand women screened. If you add the tomosynthesis, you pick up an additional 1.5 cancers per thousand women screened.

If you add whole-breast MRI, you get a whopping 1.1 additional breast cancers detected per thousand women screened. But contrast-enhanced mammography is about 13 to 15 additional, and MRI is about 15 to 27 additional cancers per thousand women screened.

And so, what we commonly do at our practice is recommend a fast or abbreviated MRI, particularly for any woman with extremely dense tissue. But women with heterogeneously dense tissue may also wish to consider that additional screening, which I don't know will be covered because of this recommendation.

Jamie DePolo: Okay. Okay, and then I don't want to belabor the point because it's something at Breastcancer.org, we don't necessarily agree with these recommendations, but it also, as a person who is getting older, the idea that women older than 74 don't need mammograms, I'm offended by that, too.

Dr. Holly Pederson: Oh, you are?

Jamie DePolo: I am.

Dr. Holly Pederson: I like your I like the things you're offended to. They send me right off into being offended, myself. And you know, it's like 70 percent of breast cancers are diagnosed in women over the age of 70.

Jamie DePolo: Exactly.

Dr. Holly Pederson: And they've done Social Security tables so that you can help to estimate your future needs, financially. And if you live to 75, you are likely to live to 86. I mean there's like a formula where the older you get, the older you are likely to get, and so, to discriminate against, you know, not only the young pre-menopausal Black woman who's getting mammograms every other year and should definitely be getting them every year, but also, the older healthy woman who is likely to live 15 years after the age of 74, you know?

And so, these are judgment calls. This is not new data. These are modeling projections and review of previous data. No data has really come out since 2016 that's new and life-changing in terms of making these recommendations. They're choices. They're choices that people are making, and my recommendation would be to start at 40 and go every year, as long as you are healthy.

And what that means, as long as you are healthy, is, you know, is there any reason, right now, that I might not be around in 10 years? Yeah, I might have another reason that would preclude me from living 10 years. Then you may not want to do screening mammography, but otherwise, every year, starting at 40, right?

Jamie DePolo: Okay. I absolutely agree with you. And one last question on that, is there a set time period that the task force updates their recommendations? Or is it just as they think? Because, as you said, no new data came out, so I was just curious as to why they…

Dr. Holly Pederson: As to why they might've done it?

Jamie DePolo: Yeah.

Dr. Holly Pederson: Well, you know, one reason might be that mammographic participation was examined, and the percent of women undergoing mammography decreased from 70.4 percent in the year 2000 to 64 percent in the year 2015. 

So, it could be that, you know, they recognized that the mortality reduction is so much better at the age of 40, but they still wouldn't go the every year route, but it's data such as that, that women are not getting screened as often. And probably, we're going to see, you know, later-stage disease presenting, you know, as a result of those prior recommendations. There's a delay, you know?

Jamie DePolo: Sure. Sure. All right. Well, I'll take my outrage.

Dr. Holly Pederson: Thank you. Thank you for your comments.

Jamie DePolo: So, there was another study about having a double mastectomy after you were diagnosed with breast cancer, in one breast, I should say.

Dr. Holly Pederson: Yeah.

Jamie DePolo: So, you're diagnosed in just one breast, you decide to have a double mastectomy because that's what's right for you. The study found that it reduces the risk of cancer in the other breast, obviously, because the other breast has been removed, but it doesn't decrease the risk of dying from breast cancer, which is kind of puzzling. So, can you help me understand that?

Dr. Holly Pederson: Yes. You know, every woman, when she's diagnosed, wants to do all she can, you know, all she can to be healthy in the future. And sometimes, that may, they may think that doing a bilateral mastectomy is part of that, doing everything that they can at the time of diagnosis.

But unless you have a genetic mutation that markedly increases your risk for disease on the other side, most women don't realize that, really, the rate of getting breast cancer on the other side, in the absence of a genetic mutation, is about 0.4 percent, per year, for 20 years, post-diagnosis.

Jamie DePolo: Does that stat apply to all subtypes, because I know sometimes, at least I've seen studies, saying that triple-negative disease, or hormone receptor-negative disease, is, if it's going to recur, is more likely to happen in the 5 years after diagnosis, whereas hormone receptor-positive disease, the recurrence risk is out to 20.

Dr. Holly Pederson: I love that you brought that up, Jamie, because they're two separate topics.

Jamie DePolo: Okay.

Dr. Holly Pederson: We're talking about breast cancer recurrence, which is what's going to affect mortality, and I'm talking about development of a new cancer on the other side.

Jamie DePolo: Oh, so, that's what the stat is about?

Dr. Holly Pederson: And that's why it doesn't help to take off the other side, you know? It helps to focus on your chemo and everything that you're getting for your triple-negative disease because that's what can potentially, you know, be life-changing is if that triple-negative recurs outside of the breast, you know? 

I mean, there are rare circumstances where it can recur, you know, in the contralateral lymph nodes. It almost never recurs in the contralateral breast, but women think that it might help to have that other breast removed, and really, it's focusing on their treatment for their breast cancer so that it doesn't recur elsewhere. That's the important thing.

You know, but that's not true if you have a BRCA1 or BRCA2 mutation. 

It's been shown that contralateral mastectomy improves survival in that group, and two other genes have been identified with significant contralateral rates. The paper was published, last year, in the Journal of Clinical Oncology, looking at CHEK2 and PALB2 having PALB2 really has similar rates of contralateral breast cancer as BRCA1 and BRCA2. CHEK2 is lower, but in some women, they may make that decision for bilateral mastectomy on the basis of CHEK2.

But most women who don't carry a genetic mutation really don't need to worry about contralateral risk as much as they are worried about it. I think that they're mixing the worry about their current diagnosis and the worry about developing a new cancer.

Jamie DePolo: Well, and it's interesting because I never knew, as you just said, that recurrence was not very likely in the opposite breast.

Dr. Holly Pederson: Yeah.

Jamie DePolo: I thought recurrence could happen pretty much anywhere. So, that is good to know, but it also sort of makes me want to ask another question, which is about genetic testing. Because most people know about BRCA1, BRCA2 mutations, but PALB2 is it CHEK2 or just CHEK?

Dr. Holly Pederson: Yeah. No. That's a great question.

Jamie DePolo: And not everyone, as far as I know… Again, the genetic testing recommendations are almost as confusing as the mammogram recommendations because all the different organizations have different recommendations, but it seems like anyone who's diagnosed should then get genetic testing, so they know, because sometimes there is no family history, and there's still a mutation.

Dr. Holly Pederson: Right. Right, and you know, you bring up so many good points. What are the red flags for genetic testing, and who should go back for additional testing? Because in the fall of 2013 was when the genetic, the multi-gene panels came out, and so, if you had your genetic testing before the fall of 2013, you only got BRCA1 and BRCA2.

Period, right.

And after that, hopefully, you got panel testing, but some of the panels were incomplete. You should even have your clinician look at the panel that you've had done to make sure that all the important genes are on there. You know there are six highly penetrant breast cancer genes and six moderately penetrant breast cancer genes, and those affect the way that you might be screened or your family might be identified and screened and offered risk-reducing, you know, interventions, as well.

And so, I'll go through some of the major criteria, you know? The main ones are age under 50, triple-negative breast cancer, male breast cancer, ovarian cancer at any age, pancreatic cancer at any age. Really, you're looking for young people, and lots of them, who get breast cancer young or rare cancers like ovarian or pancreatic cancer.

Now, we're moving toward testing everyone. American Society of Breast Surgeons, in 2019, recommended that all breast cancer patients be offered genetic testing. But again, you know, they will go by NCCN guidelines or USPSTF guidelines. And the latest guidelines were put forth by ASCO and the Society of Surgical Oncology, and they recommended, essentially, that all women 65 and younger be tested, and only those over 65 who would've met the criteria before, be tested.

But you know, it's not unreasonable for any breast cancer survivor to go back and ask, should my family undergo, should I undergo genetic testing, or should somebody else in my family undergo genetic testing, because we're really moving in that direction.

The other thing you brought up, kind of indirectly, is how should a survivor be screened, you know? Because those average risk guidelines from USPSTF don't apply to survivors.

And a lot of survivors wonder, should I be getting MRI, you know, for instance. And the American College of Radiology recommends, for survivors, that if you were diagnosed under the age of 50 and you still have remaining breast tissue, you know, whether it's dense or not, you should consider MRI screening. And the other one is if you have remaining dense breast tissue, regardless of your age, if you have heterogeneously dense or extremely dense tissue, then MRI is not unreasonable.

At Cleveland Clinic, we also offer MRI to patients who had lobular breast cancer because it's invisible on the mammogram 30 percent of the time, and so, that's another instance where MRI could be important for survivors.

Jamie DePolo: Okay. All right. Thank you. I'm going to move on. There were two studies I thought were interesting. They both sort of involve exercise. So, one was about neuromuscular training, reducing chemotherapy-induced peripheral neuropathy, which is a mouthful, but neuropathy, basically, the tingling, the pain, in the hands and feet from chemo.

And then there was another one that showed that about 90 minutes of moderate exercise a week, so 90 minutes a week of brisk walking, which really only breaks down to, you know, about 20 minutes, less than 20 minutes a day, so not a ton, it reduces the risk of distant recurrence of hormone receptor-negative breast cancer. There's a lot of caveats here, especially amongst pre-menopausal women, distant recurrence being metastatic recurrence.

And so, I kind of group those together because they're both showing that exercise can really help somebody who's been diagnosed with breast cancer.

And I know that doctors know this and people know this, but I feel… like it's a really big passion of mine that people understand how important it is. And the only other thing I would add is the neuromuscular training, just in case folks aren't familiar with it, it's basically a lot of like balancing or standing on a vibrating board. So, it's kind of, you're balancing on one leg, or you're balancing with your eyes closed to kind of train all the muscles in your body.

So, you, as an oncologist, Dr. Pederson, how do you interpret these? And I guess I'd ask you, too, ancillary, how do you talk to your patients about exercise?

Dr. Holly Pederson: So, I run the high-risk breast center, and I'm an internist by training.

Jamie DePolo: Oh, okay.

Dr. Holly Pederson: I'm not actually a medical oncologist.

Jamie DePolo: Oh, sorry.

Dr. Holly Pederson: But I can speak to these papers, certainly.

You know, exercise and weight control are probably two of the most important things that all women can do to both prevent breast cancer, to reduce breast cancer recurrence, and to reduce breast cancer-associated mortality. And there are so many, it's so fascinating that the mechanisms that are involved, both with diet and exercise, either if you feel like you might be at risk or if you're then diagnosed.

It helps every step along the way, and you know, it really is fascinating. You know one study that had caught my eye was this study in BRCA1 mutation carriers, where exercise actually up-regulated the activity of their BRCA1 gene, making it more effective. It up-regulated BRCA1 protein expression and improved anti-oxidative status without showing an increased inflammatory response, meaning you can alter the expression of your genes with appropriate diet and exercise.

And that doesn't just apply to BRCA1 carriers, you know? It applies, really, to everyone. They did one study, looking at, it was in breast cancer survivors who had exercised in the past, and healing skeletal muscle actually possesses an epigenetic memory of earlier stimuli, such as exercise. And so, you can get back what you had, you know, not only with the way your body feels but the way your DNA is functioning by exercising.

Jamie DePolo: Interesting.

Dr. Holly Pederson: I mean, I just think that's amazing, you know?

Jamie DePolo: That's fascinating.

Dr. Holly Pederson: They looked at methylation in skeletal muscle biopsies and showed that, you know, women who exercised like de-methylated the promoter regions of the bad parts of their genes, you know, and…

Jamie DePolo: So, what does that mean? I'm sorry.

Dr. Holly Pederson: What it means is that the more you exercise, up to an hour, five times a week, there was no benefit beyond that in terms of this current study. But exercising an hour a day, five times a week, what it does is changes the methylation, which is just it's like a top coating to your DNA, and almost like a frosting. It changes that structure, which can alter how those genes are turned on or turned off. And it actually creates a less tumor-friendly environment by the way that it alters that DNA methylation.

And so, it's super interesting, and you know, I think that those epigenetic changes are going to be the next, you know, layer of risk stratification, as well. But exercise, you know, it does so many things. It boosts your immune system. It can even like alter your bile acids so that carcinogens aren't exposed, you know, you don't absorb carcinogens the same way.

It reduces insulin levels and glucose levels, as well as estrogen levels, which all influence the tumor microenvironment. And it obviously changes body mass and body composition, you know, making you less likely to develop a new breast cancer, but it's just very interesting. It's anti-inflammatory. I mean, there's all sorts of mechanisms by which exercise is good.

But the NCCN currently recommends, and that's the National Comprehensive Cancer Network. That's a national group of experts that review the literature and make recommendations based on the evidence. They recommend 150 to 300 minutes per week of exercise, which is a half an hour to an hour, five days a week, and to do resistance training twice a week for half an hour, and to stretch twice a week for at least half an hour.

I'm on this Down Dog app that is just wonderful. I do restorative yoga at night and stretch, and it's just fabulous. But any sort of stretching that you can do twice a week is important, too.

And you know, look for ways to get extra steps. Go up the stairs. Park far away, you know, so your car doesn't get dinged anyway. You know, there's also sort of things you can try to do to increase your exercise.

Jamie DePolo: Yeah. I guess the thing I liked about the one study, the 90 minutes of moderate exercise a week, you know, sometimes, reading those NCCN guidelines, it can feel very daunting. Like 300 minutes a week, plus resistance training, plus stretching, plus this.. And I think sometimes people read all that, and they sort of give up before they even start.

Dr. Holly Pederson: Oh, exactly.

Jamie DePolo: So, you know, that's why 

Dr. Holly Pederson: It’s like Nike, that Nike ad, just do it. Just do it.

Jamie DePolo: Exactly.

Dr. Holly Pederson: It's like a self-breast exam. Don't worry if you're doing it wrong. Just do it.

Jamie DePolo: Yes. So, that's why I thought, well, 90 minutes a week, that's divided by 70, that's just like 15 minutes a day.

Dr. Holly Pederson: You can walk from the car, into the parking lot, and go up the stairs, you know what I mean?

Jamie DePolo: Yeah.

Dr. Holly Pederson: Whatever you can do, and don't worry about if you're doing, you know, the right amount of minutes.

Jamie DePolo: And I just wanted to clarify one thing. You mentioned the study in people who had a BRCA mutation. And I think sometimes people, they hear things and they'll say, well, I have the gene, but in reality, everybody has a BRCA1 and BRCA2 gene. It's the mutation that's the problem.

Dr. Holly Pederson: Yes.

Jamie DePolo: And so, when you were talking about exercise, like the exercise is actually helping the BRCA genes do their job better, even if they do have a mutation. So, it's sort of offsetting the mutation? Am I understanding that correctly?

Dr. Holly Pederson: That's exactly right. We all have BRCA genes, you know, BRCA1, BRCA2. We all have PALB2 genes, and we all have two copies of each of our genes, one from our mom and one from our dad. So, if one of them is not functioning properly, due to a mutation or a pathogenic variant in the DNA sequence, the other one has to do all the work.

And so, if you can up-regulate that allele's ability to suppress tumors, if you can upregulate the good one, you know, you're in better shape. And it would make sense for all of us to up-regulate our tumor suppressor functions to suppress tumors, you know, in general. I mean, these are the driver mutations, essentially.

Jamie DePolo: Perfect. Thank you for thank you for clarifying that.

And then one last study I wanted to talk about that caught my eye was that hormonal therapy seems to reduce the risk of Alzheimer's disease and related dementia, especially among Black women age 65 to 74.

I find that fascinating, but I also know that a lot of women have a lot of really bad side effects from hormonal therapy. They either don't take it as prescribed, or they stop taking it early, and I get that, hot flashes, joint pain, a lot of things. But this, to me, is like one maybe good thing that hormonal therapy seems to do. So, how do we interpret this, and how did this even, like, how did this even get studied? Like, who thought of that?

Dr. Holly Pederson: Yeah. Who thought of that? So, I don't like the wording.

Jamie DePolo: Okay.

Dr. Holly Pederson: Hormonal therapy really implies like estrogen and progesterone, you know?

Jamie DePolo: Okay.

Dr. Holly Pederson: It really and when we're talking about are the anti-estrogens, you know, that are used in treatment.

Jamie DePolo: Right.

Dr. Holly Pederson: And so, I want people to really understand that we're not talking about hormone therapy, estrogen and progesterone in survivors, you know? We're talking about the anti-estrogens.

Jamie DePolo: Right, tamoxifen, aromatase inhibitors.

Dr. Holly Pederson: Yeah, tamoxifen and aromatase inhibitors. Exactly. That's exactly right. 

And what they showed was that during an average of 12 years of follow-up, 24 percent of the hormone users and 28 percent of the non-hormone users developed Alzheimer's disease or related dementia. You know, so, the difference was not profound, you know? 

Overall, there was a 7 percent lower risk, and for Black women, it seemed to be more significant.

But where this kind of came from, I think, is that we know from women who undergo early surgical menopause that, you know, say for a BRCA mutation where their risk for ovarian cancer is very high, we know that if estrogen is not given at that time, particularly, there's accelerated rates of osteoporosis and cardiovascular disease, as well as probably dementia.

And so, that's kind of where this came from, is if we're taking estrogen away from young women, and it may cause dementia, if we're giving anti-estrogens to older women, is it going to cause dementia? And actually, not only does it appear not to cause it, but it appears to be protective, somewhat, which is reassuring, you know? 

I think that it's very different to be menopausal and take anti-estrogens, as opposed to being pre-menopausal and either having your estrogen completely depleted or completely depleted, plus taking anti-estrogens, you know? I think it's reassuring that the women who are later in life, and this study was done, you know, in older women.

Jamie DePolo: Right. Yeah. I should've pointed that out. They were 65 years and older.

Dr. Holly Pederson: Yeah.

Jamie DePolo: So, it was women who, I would assume, had all gone through menopause.

Dr. Holly Pederson: Right. So, that was really the thing, you know?

Jamie DePolo: Okay.

Dr. Holly Pederson: Since it causes dementia in younger women not to have estrogen, would the same be true in older women who are taking anti-estrogens? And no, it's very reassuring that women can take their anti-estrogen therapy for their breast cancer.

And you bring up such a good point about the side effects and women not being compliant. You know, there are other choices than the one you're on.

And so, if you're having side effects with the medication that you've been asked to take for five, or seven, or 10 years, and you're miserable, please just talk to your provider because there are other options.

Jamie DePolo: Right.

Dr. Pederson, thank you, so much. This has been so helpful. I feel like I learned a lot, and I understand these studies so much better. So, thank you.

Dr. Holly Pederson: Oh, thank you, and thank you for being upset at all the right things. 

Jamie DePolo: Yes, my outrage gets high, but thanks again.

Dr. Holly Pederson: Thank you. Have a good day.

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