Fall 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. As always, thanks for listening. My guest is Dr. Kathy Miller, the Ballvé-Lantero Professor of Oncology and professor of medicine at the Indiana University School of Medicine. Dr. Miller also serves as the associate director of clinical research at the Indiana University Simon Comprehensive Cancer Center, and is 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 from September to November 2024. So, essentially, this is our fall research roundup. Dr. Miller, welcome to the podcast.

Dr. Kathy Miller: Thank you, Jamie. It’s a pleasure to be with you.

Jamie DePolo: So, there were a lot of studies that came out, and there were a couple on hormonal birth control upping the risk of breast cancer and in a couple different populations. One specifically and one more general. So, if you could talk about both of those?

Dr. Kathy Miller: Sure. So, I think the most interesting results were in a large cohort of women who had BRCA mutations. So, this is from a huge, international consortium trying to better understand the biology of BRCA mutations, what increases risk, and how we can best serve those women. So, this study was about 3,800 women with BRCA1 mutations, about 1,500 with BRCA2 mutations, all under the age of 40. So, contraception’s still very important for them, and what they saw, I think, was a surprise to many people.

And it was a surprise, because most women with BRCA1 mutations who develop breast cancer tend to develop triple-negative breast cancers, and most women with BRCA2 mutations who develop cancer tend to develop cancers that are hormone sensitive. So, in that very simplistic view of the world, you might think the risk of hormonal contraceptives could be a real issue for women with BRCA2 mutations and probably not an issue for women with BRCA1 mutations, and the results were very much the opposite.

They did not see any risk in women with BRCA2 mutations. Looked very similar to a larger population of women without genetic mutations, so no concern there. Now, this study looked at all hormonal forms of contraceptives, so patches, pills, vaginal rings, Norplants, the drug-eluting IUDs. Did not matter. They lumped them all together. But in women who had BRCA1 mutations, there was definitely an increased risk for any use of oral contraceptives, compared to none or use of hormonal contraceptives, rather, compared to none.

And the longer women used those hormonal contraceptives, the more their risk increased. Now, talking about risk becomes difficult, because the studies report this in terms of relative risk, and that always makes the numbers sound bigger than the absolute risk. So, the relative risk for any hormonal contraceptives in women with BRCA1 mutations, compared to not, was 29%, and it went up by about 3% extra relative risk per year of use. So, I think this is really important for women with BRCA1 mutations.

Many of those women may not be interested in prophylactic mastectomy or prophylactic oophorectomy, particularly if they’re not done having their families, and those are the women who were thinking about contraceptives. Now, the good news is we have lots of contraceptive options, including barrier methods that are not permanent, but also non-drug-eluting IUDs and particularly for women who are stably partnered who are interested in a safe, no-fuss, effective contraceptive. That, I think, for many of those women, is probably going to be their best option.

Jamie DePolo: Okay. I have one question. Did the researchers talk at all about why there was this difference between BRCA1 and BRCA2, because, as you said, it was kind of the opposite of what everybody expected. Were there any insights into that?

Dr. Kathy Miller: So, from this study, no, but I can give you some extrapolations from other data.

Jamie DePolo: Sure.

Dr. Kathy Miller: So, we’ve seen, from studies from anti-estrogen therapies, that removing the ovaries in women with BRCA1 mutations reduces their risk of breast cancer. Tamoxifen reduces their risk of breast cancer. So, this is a bit of a counterpart to that. If lowering or blocking estrogen reduces the risk, it becomes less surprising. Increasing hormones increases the risk. From some research from some of my colleagues, we also have data that progesterone, in particular...so, not estrogen, per se, but progesterone might be particularly important in the very early carcinogenesis that leads to triple-negative breast cancers. It’s also very important in the early development, early carcinogenesis of high-grade serous ovary cancers.

So, we think of this a bit as, like, a spark that you need to light a fire. Once the fire’s going, you don’t need to keep giving it the spark, and stopping a spark, once the fire’s going, does nothing. But that spark is crucial at this very early time point.

So, I think we are starting to understand some of the biology that also could lead to other preventative options, or risk-reducing options, for those women who are not yet interested in prophylactic surgery. We’re not quite there yet to move those into the clinic, but I think you can start to see these different sorts of investigations, different sorts of research studies coalescing into a consistent theme, and that also is reassuring, I think, that these are not spurious results. It’s unlikely that, next year, we’re going to be talking about a study that came to the opposite results and has everybody throwing up their hands saying we don’t know what to do. These results are very consistent with other studies that came at the same question, but from a very different way.

Jamie DePolo: Okay. Thank you, and then there was another study, the one you just talked about that, as you said, looked at all forms of hormonal birth control. There was one that looked specifically at...and I’m going to mess up this word. Levonorgestrel IUDs, which...

Dr. Kathy Miller: Levonorgestrel IUDs. So, these are some of the drug-eluting IUDs. So, this study was not specifically for women with any sort of genetic mutation or other risk factors, but it was a very large study, 78,000 and change Danish women. So, pretty homogenous population. Also young, so contraceptive is a question, and they looked at the risk associated with using a drug-eluting IUD, and there is an increased risk, but this, we also need to put in context. So, they report their numbers differently, and I think, in a way, that would be a little bit easier to understand.

So, the risk in this population of women who were not using drug-eluting IUDs was one Danish woman diagnosed with breast cancer out of 204. So, one in 204 over the period of follow-up of this study. And the women who were using drug-eluting IUDs, it was 1.4 women out of 204 for the same period of follow-up. Now, because this is a really large study, that small absolute difference reached statistical significance, but I think it’s probably not a level of difference that is really going to impact the contraceptive decisions for the majority of women.

Jamie DePolo: Okay, and I guess I was curious, is it possible that women with a BRCA1 mutation were sort of driving this increase in risk, given that the increase was kind of small? I don't know. What do you think?

Dr. Kathy Miller: So, certainly could be. This study did not report subsets based on genetic testing. It was a large population study. So, there are, undoubtedly, women with BRCA1 mutations in this group, and we don’t know who they are. We don’t have, from this study, a lot of other information about family history, previous biopsies, number of children, other risk factors to really say, is that risk equally distributed across the population?

It’s almost certainly an average of some women who had a greater increased risk, perhaps those with BRCA1 mutations. Others that had no increase. So, I think still helpful information, and like lots of good research, leads to more questions than it answers, but I think it’s also reassuring for the average-risk woman who is looking at her contraceptive choices to know that, while the numbers say there is an increase, the absolute increase is really vanishingly small, and is probably, I think for most women, not going to really impact their choices.

Jamie DePolo: Okay. Great. Thank you, and kind of sticking with that same age group, there was another study that found breastfeeding after treatment seemed safe, and I know, just given some of my friends who’ve been diagnosed at a young age, that is always a big concern.

Dr. Kathy Miller: So, so much good news for our young patients. For decades, young women were told that thou shalt never get pregnant if you’ve had breast cancer, and if you get pregnant, you should immediately terminate, and if you don’t do that, god forbid, don’t breastfeed, because there were concerns that the hormonal changes with pregnancy, with delivery, and with breastfeeding would increase the risk of recurrence of previously-diagnosed breast cancer or of new breast cancers.

So, two studies here, as well. One defined clinical trial, the POSITIVE trial, which I think is one of the most important trials that the world has come together to do in a long time. The POSITIVE trial enrolled just over 500 pre-menopausal women with ER-positive breast cancers who desired pregnancy. They were all on hormone therapy for 18 months to three years. They then interrupted hormone therapy for up to two years for attempts at conception, delivery, breastfeeding. Then resumed hormone therapy after those things had been completed, or if unsuccessful, they had abandoned attempts at conception.

In that group, we’ve talked about their pregnancy outcomes, but of the women who delivered children, about 60% of them wanted and were able to breastfeed, and we saw no difference in their outcome compared to the larger control group that POSITIVE was compared to, or compared to POSITIVE patients who did not have pregnancies and did not breastfeed. There also was concern about this for women with BRCA mutations, and we have, also, a big international consortium providing data for about 5,000 women, with a mix of BRCA1 and [BRCA]2 mutations, all less than 40.

And when they compared women who’d had babies, who breastfed versus not, they saw no difference in recurrence of prior breast cancers or no breast cancers. So, I think we have really solid data to be able to tell our young patients, even those with hormone-sensitive tumors, that interrupting hormone therapy for pregnancy is not an exceedingly risky thing to do, and that, if they want to breastfeed those babies, that’s a great thing for their babies and for them, and they can do so without worry that they are increasing breast cancer risk.

Jamie DePolo: Yes. Those were such great results. It was good. Now, the last couple studies I want to talk about may take a little bit more explanation, but they looked at the long-term risk of late...which means recurrence after five years, and then distant recurrence, which means metastatic recurrence, recurrence somewhere else in the body besides the breast, and there were the overall results, and then there were the results for specific age groups. So, if you could talk about that.

Dr. Kathy Miller: So, one of the reasons, I think, that we’ve been able to make progress in breast cancer faster than in other solid tumors, until fairly recently, is that we’ve done large clinical trials much earlier, and we have come together, as an international community, to compile the data from our different trials, to be able to ask questions that couldn't be conclusively answered in any one trial. So, that process, scientifically, is called a meta-analysis. That’s how you bring together these different results, and the breast cancer community does this every five years.

It’s known in the business as the Oxford Overview Analysis, because there’s a big meeting in Oxford, England that reviews the data, talks about what questions we want to ask, and we get this kind of big influx of data each time this happens. So, we have the most recent reports from that overview analysis. This combines data from almost 156,000 women who were enrolled in 151 breast cancer trials that had overall survival as one of the end points, and they get updated individual patient data for these. They don’t rely just on what was in a report that might have been published years ago, rather than updating the follow-up.

Here is the really good top-line news. If you are a woman diagnosed with breast cancer today, you have about a 20% lower risk of ever developing metastatic disease than if you had been diagnosed before 2000. So, in the last two decades, the risk of ever developing a distant metastasis, which is our biggest concern, because that’s what’s life-threatening, has gone down by 20%. Some of that is still increased awareness and increased screening and early detection, but a lot of that is improvements in the therapies that we can offer women.

Now, the late recurrence, recurrences elsewhere in the body five or more years after diagnosis, is of particular concern for women with ER-positive disease. That is fairly uncommon for late recurrences to happen in women with ER-negative disease. So, even with that risk of late recurrence, that has also reduced, and that has reduced by about 10%. So, improvements there, as well. That is a really big area of research, trying to both understand what is happening to those cancer cells for all of those years, when they appeared to be gone or quiescent. What woke them up, got them angry again so that a late recurrence became clinically apparent?

But also thinking about longer durations of hormone therapy, and can we better individualize who’s at greater risk, who has more benefit for longer durations of hormone therapy, rather than lumping everybody together and doing more for everyone. And I think that is a general theme that we will see in breast cancer practice and in treatment trials over the next decade, trying to better individualize who needs what, rather than trying to slowly move the needle for the whole population by doing everything to everyone.

Jamie DePolo: Okay, and then there was a study also...it wasn’t part of the Oxford Review, but it was published in one of the JAMA articles, that found that age did affect that risk of late distant recurrence, and I believe, if I’m remembering correctly, it was that younger people had a higher risk of that, which sort of makes sense to me, because, if you’re younger, you have that many more potential life years ahead of you. Like, if you’re diagnosed when you were, say, 35 versus somebody who was diagnosed at 80, but perhaps I’m looking at that too simplistically. I don't know if you want to discuss that?

Dr. Kathy Miller: So, this was a large population study from Korea. So, also fairly homogenous population, but very large population-based study, followed for a long time, and you’re quite right, Jamie. They did find that younger women with ER-positive disease tended to have a higher risk of distant recurrence than older women with ER-positive disease. Now, certainly, that age issue always becomes tricky, and part of it is just the longer you live, the more likely you might be to have an event.

You know, my patients diagnosed in their 80s have an annoying habit of dying of other things. It reduces their risk of recurrence of breast cancer. Also makes it harder to show improvements with therapies. So, if you gave me an 80-year-old woman and I had some crystal ball that I could know that, without therapy, she would have a recurrence of her breast cancer at year four, and with the therapy I’m recommending, she would not have that recurrence, you would think I’ve done great things, but if that same 80-year-old is going to die from a heart attack at year two, in the data, I don’t get credit for fixing her breast cancer, because she’s still no longer with us.

So, that’s part of it. I think, actually, a bigger part of this is that, until fairly recently, we have undervalued the importance of hormone therapy and the role of ovarian suppression in pre-menopausal young women, particularly with high-risk ER-positive disease. So, we’ve seen that with the long-term follow-up of the SOFT and TEXT trials that looked at ovarian function suppression and an aromatase inhibitor, compared to other options for hormone therapy in pre-menopausal women with ER-positive disease. This is another one of those studies where lumping everybody together, you’re struggling with a small benefit.

But we now have 12-year follow-up of the SOFT and TEXT trial data that really allows us to say that the women who really need that maximum, optimal hormone therapy are our youngest patients, diagnosed age 35 or younger, those with grade 3 tumors, those with node-positive tumors, or those with tumors that are bigger than 2 centimeters. Those were the really significant high-risk factors that said maximizing the hormone therapy had a pretty substantial benefit, including, in some of those subgroups, more than a 5% absolute improvement in overall survival at 12 years.

So, I think that is probably the bigger thing that we’re seeing in the Korean data. One of the challenges with ER-positive disease is that risk persists for a long time. So, if you want to see improvements in overall survival, you have to be really patient. You have to continue to follow patients for a decade or more, which means there’s a big lag in getting those clinical trial results into the standard practice and incorporating that.

There’s not a great solution to that. If you want long-term follow-up, you’ve got to wait a long time, which means, in the interim, there were people who were treated without benefit of the knowledge of those results impacting their care. So, seeing improvements in a population-based study is going to take even longer, because you need to wait for the results to incorporate into practice and for, then, those women, who got the benefit of those therapies to be followed long enough, that you’re starting to see their long-term outcome.

Jamie DePolo: Right. That makes sense. I do have a question about, you know, young women, ovarian suppression, and an aromatase inhibitor versus tamoxifen. I’m not exactly sure what the standard of care is, time-wise, for ovarian suppression and an aromatase inhibitor. Is it five years? Is it 10 years? Could it, potentially, be longer? And then there’s the whole issue of side effects.

Dr. Kathy Miller: So, the short answer is we don’t know. The clinical trials picked an arbitrary duration in the SOFT trial here, which is the best one here because it directly compared tamoxifen to ovarian function suppression with tamoxifen to ovarian function suppression with an aromatase inhibitor, all in pre-menopausal women with ER-positive disease. It picked an arbitrary duration of five years because, at the time the SOFT trial was launched, five years was the standard duration of, pretty much, any hormone therapy.

Now, whether longer might be better, probably, in some of those women, we’re not so good at figuring out who they are now. So, just like we struggle in post-menopausal women thinking about who might be better served by taking hormone therapy for more than five years, we have the same questions with our younger women. It gets a bit more complicated, because if their form of ovarian function suppression is an LHRH agonist...and this was a particularly young woman, it is very possible and in fact, likely, that her ovaries may start functioning again. That could be good or not, depending on her risk of breast cancer.

So, being able to individualize those decisions is going to be really important for us. We do have to be concerned about long-term consequences of ovarian function suppression for our very young patients, particularly their bone health. Depending on that woman’s other risk factors, there may be some long-term risk of cardiovascular disease. We usually have not yet seen that in the SOFT and TEXT trials.

Though I would argue we haven't followed those women long enough to know if that’s the case. But at this point, with 12 years of reported follow-up and analyzed follow-up, particularly for the high-risk groups, it was not just an improvement in distant recurrence or an improvement in breast cancer survival. It was an improvement in overall survival, and that’s pretty hard to ignore, but even though there are those long-term consequences that we have to think very carefully about, we can tell those women, you’re more likely to be alive with this than without it.

Jamie DePolo: Well, and even, too, you know, you talked about the bone health and the heart health, but then there’s just the side effects of an aromatase inhibitor, like the joint pain, which I know, you know, you have better overall survival, but if your life is hell from joint pain, you know, just some of the people I’ve talked to, it’s a hard balance to find.

Dr. Kathy Miller: So, I think what is also helpful to remember is that these data are not telling us that tamoxifen doesn't work in these pre-menopausal women, and we need to be less dismissive about women’s day-to-day side effects and toxicity burden than we have sometimes been. The significant joint stiffness, the women who say, you know, I was 32, and now I feel like I’m 82, and I’m not 82. I can’t function like an 82-year-old woman and do the things I need to do. Those are quite real.

There are things that we know can help the aromatase inhibitor toxicity. While we’ve not, biologically, been able to explain why switching from one aromatase inhibitor to another is sometimes helpful in reducing toxicity, about a quarter of the time, a switch to a different AI is successful. About three-quarters of the time, the women have the same toxicity. I personally have switched women with toxicities to tamoxifen, because tamoxifen is tolerable for them, and the AIs, clearly, are not.

And that I think, mentally, is sometimes difficult for women who just heard me say the AIs and ovarian function suppression are better. They’re more effective. Who feel like, well, but I’m giving up on this. But for them, that’s not the relevant comparison, because they’ve told me, that’s not tolerable for me. So, for them, the comparison is not tamoxifen or an AI, it’s tamoxifen or nothing, because they’re not going to keep taking the AI, because they can’t. It’s truly not tolerable for them.

And as much as the AIs are slightly more effective, we have to remember they’re slightly more effective in women who were able to continue taking hormone therapy of some sort for a similar period of time. So, I would rather have those women on tamoxifen, assuming they can tolerate it and continue to be on hormone therapy for years, rather than struggle through 18 months of an AI, give it up, particularly not telling me they’ve given it up, and we all think they’re on hormone therapy, and they’re really not.

Jamie DePolo: Yeah. So important. Dr. Miller, thank you for explaining all this. This has been super helpful, and I really appreciate your insights.

Dr. Kathy Miller: It’s a pleasure, Jamie.

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