Low-Dose Tamoxifen to Reduce Risk in Women Who Received Chest Radiation

Jamie DePolo: Hello, as always. Thanks for listening. Women with a higher-than-average risk of breast cancer often take tamoxifen to reduce that risk. There are a number of reasons why a woman might have a higher risk of breast cancer, including receiving chest radiation for childhood cancer, such as Hodgkin’s lymphoma. 

Our guest today is Dr. Sandhya Pruthi, professor of medicine and medical director of the Division of Health Education and Content Services at the Mayo Clinic, in Rochester, Minnesota. Her research focuses on using medicine to reduce the risk of breast cancer in women at high risk, as well as using complementary therapies to reduce side effects in women receiving treatment for breast cancer.

Dr. Pruthi joins us to discuss her research on using tamoxifen to reduce breast cancer risk in women who received chest radiation for childhood cancer. Dr. Pruthi, welcome to the podcast.

Dr. Sandhya Pruthi: Wonderful. Thank you for having me, Jamie.

Jamie DePolo: So, can you explain why women who received radiation to the chest as children have a higher risk of breast cancer? What's the mechanism behind that?

Dr. Sandhya Pruthi: So, one of the things we know about women and female breasts, especially when women are younger, primarily before the age of 30, their breasts are very sensitive to what is considered carcinogenic effect of radiation. And it's thought that the radiation, as a carcinogen, could maybe alter the DNA or maybe make those cells that are in the breast interact in a different way that can lead to breast cancer.

Jamie DePolo: And is it because of their age, because the breast isn't considered mature yet? Is that part of the reason?

Dr. Sandhya Pruthi: Absolutely. There are certain times in which we call the proliferation, or there's a lot of changes occurring in the breast, one of which is around puberty, and then with pregnancy, and so, you would want to be thinking what are the cells doing? They're changing, they're proliferating, and maybe it's during those times that there's more of this sensitivity of these cells. And we call them almost like creating vulnerable breast cells that may be susceptible to becoming cancer or growing into cancer.

Jamie DePolo: Okay, thank you, and how much higher is the risk? I believe I've seen some studies that suggest that the risk might be as high as someone who has a BRCA mutation? Is that correct?

Dr. Sandhya Pruthi: Yeah. Actually, the numbers are quoted that the risk of a patient who's had radiation to their breast for other medical conditions, one of which commonly is known as Hodgkin’s lymphoma, that that risk of developing breast cancer later in their life is up to 40%. Now, mutation carriers, depending on which mutation, BRCA1 mutation carries, for example, their lifetime risk is anywhere from 40% to 85% to 90%. 

So, you kind of have to remember which mutation you're comparing it to, so, but in general, the risk is high, where large doses of radiation to the developing breast. And the time period in which we worry about that radiation exposure is after age 10 and before age 30, if that was when radiation was received, and that is where you then say, their lifetime risk can be anywhere up to 40%.

Jamie DePolo: Okay. Now, in 2021, you and your colleagues published a paper that strongly suggested that low-dose tamoxifen could reduce breast cancer risk in women who received radiation to the chest as children. So, could you tell us a little bit about how that study came about, what made you decide to investigate that, and then what the results were?

Dr. Sandhya Pruthi: So, remember, earlier, when I mentioned that there are certain times where the breasts are proliferating, and there are changes in the breast? Well, there's also larger amounts of estrogen, estrogen around puberty, estrogen with developing breasts, and estrogen when you're pregnant. That is the concept behind: Are the radiosensitive cells, those that I talked about being more likely to alter DNA, happening because of the influence of estrogen in that specific time period? 

And so, that is the thinking behind why this study was designed in this specific group, was if we knew estrogen could contribute to maybe these cells being more radiosensitive or carcinogenic from radiation, could an anti-estrogen potentially be protective against breast cancer developing in this high-risk group? And so, tamoxifen is an anti-estrogen. 

That means it blocks estrogen from getting to the breast, and by doing so, then, there's maybe a lower risk of getting breast cancer. And so, the design of this trial was to identify those women who had received radiation in this time period that I mentioned -- after age 10, before age 30 -- who were receiving a certain amount of radiation to their chest that was considered high, and it was anywhere from greater than 12 Gy. So, these were for significant treatment of cancers, like Hodgkin’s lymphoma, that that amount of radiation could expose…I'm not talking about chest x-rays or someone who had a scan for, a chest CT scan for something else. 

This was over that time period where the treatment required large doses of radiation, and that radiation was to the mantle. That's the thoracic cavity, we call it, the chest, where the breasts obviously sit. And what the design was, it was actually a double-blind, randomized, controlled trial, where those individual patients who were identified who met that radiation criteria, and the age had to be greater than 25 and under age 50, and then they would be randomized to one group got tamoxifen at 5 milligrams a day, and the other arm of the trial was placebo. 

That's why you have a randomized, controlled, placebo trial. And the plan was for the patients to take the drug, either the placebo or the tamoxifen, at 5 milligrams, for two years. And then they were going to look at certain markers. They looked at the density of the breast tissue. They looked at tolerance of the drug. They looked at side effects from the medicine, and then they also looked at these markers in the blood that could predict if there was more of the growth factors that are contributing to breast cancer. They call it IGF, insulin-like growth factor.

Jamie DePolo: Excellent, and I want to ask, before you go on and tell us the results, could you talk a little bit…this was a low dose of tamoxifen.

Dr. Sandhya Pruthi: Yeah.

Jamie DePolo: So, how does that compare to say what somebody would get for treatment, who has been diagnosed with breast cancer?

Dr. Sandhya Pruthi: Excellent question. So, we've all been very familiar, for many, many years. Tamoxifen has been prescribed at a 20-milligram-dose per day, and in the treatment in somebody who had breast cancer and were prescribed tamoxifen for hormone-feeding breast cancer was told to take 20 milligrams of tamoxifen for five years. And more recently, they've even now allowed women to take 20 milligrams of tamoxifen for 10 years, if they had more aggressive hormone-sensitive breast cancers. But where this came, then, from that concept, was why go to a lower dose? 

Maybe, is it potentially because of better tolerance to the drug? Maybe less life-threatening side effects from tamoxifen with the lower dose? And there were studies showing that the lower dose, at the 5 milligram, earlier studies showing that it could actually even change the mammogram density. So, from taking someone from a very dense breast by blocking estrogen from getting to the breast, maybe they were less dense. And we also know density, especially very dense breast tissue, when compared to fatty breast tissue, was more of another risk factor for breast cancer. 

So, that was the theory behind the fact that the 5 milligram had some benefits to using a lower dose. Now, I do want to also qualify that more recently, in 2018, yes, around 2018, there was a trial that had also just been published, looking at low-dose tamoxifen. They called it baby tam, prescribed at 5 milligrams a day, for high-risk women who had atypical hyperplasia or DCIS. Another example of ways that studies are looking at a prevention use of tamoxifen at a de-escalation, or a lower dose. So, this concept of 5 milligrams a day has been looked at in multiple trials, and it was another example, with this study, to see if women who were worried about the higher dose, especially in a prevention setting, could maybe benefit from a lower dose.

Jamie DePolo: Okay. Thank you. So, what did your study find? What did the results show?

Dr. Sandhya Pruthi: So, yes, what they did find that when the study enrolled 72 women. The trial was open across the United States in over 20 centers. And these women who met the criteria, who were given the tamoxifen versus placebo, the group that was randomized to the low-dose tamoxifen were found to have lower mammogram density compared to -- and it was significant -- compared to the placebo group. 

There were also lower or more significant blood levels of that IGF, that insulin growth factor that I talked about. But what was interesting was when it came to the life-threatening side effects of tamoxifen, they didn't see any significant difference. Nor were women less likely to complain of hot flashes with the lower-dose tamoxifen. Interesting, but we did also know we weren't powered. That means we weren't actually trying to see a big difference because there were only 72 women on study to actually see if the side effects were significant or going to be significant between the group that got the lower dose versus the placebo.

Jamie DePolo: Okay, and I'm curious, too. How long did you follow them? Because I know that's sometimes an issue in some studies where, you know, obviously, you can't get funding for 50 years of study, even though that would be ideal.

Dr. Sandhya Pruthi: Exactly.

Jamie DePolo: If we could follow people for that long. But I'm curious, did any of the women during the study time, when you followed them, did anyone develop breast cancer?

Dr. Sandhya Pruthi: So, they did not develop cancer, but there was a follow-up, I believe it was about two additional years after they had been on the drug, so, or on the placebo arm. So, in that time period, they did not see any breast cancer diagnosis.

They did find one participant on the low-dose tamoxifen arm did develop breast cancer, but three on the placebo arm had developed breast cancer. So, there were some very small numbers, but not significant in terms of the breast cancer development.

Jamie DePolo: Okay. Thank you. I want to ask about side effects. Tamoxifen, as you said, does cause some very troubling side effects. I know there have been other studies out there suggesting that…and I know the number varies, too, but between like 30% to 50% of women stop taking it because of side effects. And you didn't see any differences in that? Was it no difference in severity, or was it no difference in the numbers of people who had the side effects?

Dr. Sandhya Pruthi: Great question. So, in general, women who take tamoxifen, the concerns that women share most often are hot flashes, night sweats. Some women complain of vaginal dryness, and then those are kind of the main symptoms that are considered bothersome enough to impact their quality of life. In the study, what they found that there was no difference in the severity. Women still got the hot flashes, but they weren't less severe because they got the low-dose tamoxifen.

Jamie DePolo: Okay, and I'm assuming women who were taking the placebo did not get hot flashes, or did they, because I know sometimes you get the placebo effect, so you don't know.

Dr. Sandhya Pruthi: Exactly. There were, of course, going to be women in those groups who, especially those who were closer to menopause, who were in the study were going to experience some of the common side effects of going into menopause that they could've had some hot flashes, but there was not a significant difference between those on the placebo or those on the treatment arm.

Jamie DePolo: Okay, and then the last side effects question, I know that tamoxifen has also been linked to endometrial cancer. Now, is that a concern, still, at this low dose, or does the low dose help offset that a little bit?

Dr. Sandhya Pruthi: So, again, the study was not designed to look at that level of difference in terms of the concern that, yes, tamoxifen is associated with a risk of uterine cancer. And let me just qualify that. The uterine cancer risk in tamoxifen is estimated at anywhere from two to four per 2,000 women, okay? Now, this risk is actually seen primarily in women who are post-menopausal. That means their periods have ended. We don't see that risk in pre-menopausal women, and remember, the design of this study was primarily, were pre-menopausal women. 

Jamie DePolo: Okay.

Dr. Sandhya Pruthi: So, we were already sure, going in, that the tamoxifen and uterine cancer, endometrial cancer, was not a concern. The same thing with blood clots. Blood clots is another concern with tamoxifen, again, more common in women after menopause, less so in pre-menopausal women. So, in general, there wasn't a higher clotting or uterine cancer risk anyway, but we also had a pre-menopausal population of patients on the study.

Jamie DePolo: Okay. Thank you for explaining that. Now, I'm also curious, are there any other options for this particular group of women if they wanted to reduce their risk, but didn't want to take tamoxifen? Or are there not, and that's why you did the study?

Dr. Sandhya Pruthi: So, until this study was actually designed and open for recruitment, there was nothing that we had available to prevent breast cancer in this very high-risk group of patients who were exposed to radiation when they were younger. Significant radiation from these illnesses, like Hodgkin’s lymphoma. Now, going forward, are there other drugs that are being studied, currently? 

No. But there is still something that I tell women who don't want to take tamoxifen is to think about lifestyle factors. If I did share with you that an anti-estrogen may be one way to reduce your risk. Other things that we know about lifestyle, primarily, things such as exercise, maintaining a healthy weight, alcohol in moderation -- that means less than one alcoholic beverage per day -- these are other things that have been shown to be associated with hormone-dependent breast cancer. 

So, even though I don't have a perfect pill or a study, we don't have one today, other than the low-dose tamoxifen. It still is important to counsel patients about the importance of maintaining a healthy lifestyle, healthy weight, and those are controllable risk factors. They can modify that in their lifetime to be able to reduce that other element of risk associated with hormone-positive cancers.

Jamie DePolo: Okay. I'm wondering about preventive surgery. Some women who do have a genetic mutation decide that's what they want to do. Is that considered an option for this particular group?

Dr. Sandhya Pruthi: So, let's talk about preventive surgery, known as a prophylactic mastectomy, where you remove all that tissue and you leave the skin behind. Yes, that has been associated with anywhere up to a 90% to 95% reduction in breast cancer. Now, in a group of patients who have the mutation, that is the BRCA1, the BRCA2, and other very high-risk mutations, such as ATM, CHEK2 mutations, those are women that are considering and are pursuing these types of prophylactic surgeries. 

No one has done any studies showing that the women who had exposure to radiation has a benefit in reducing breast cancer risk, right now, from a surgery like that, but certainly, you weigh other risk factors. There may be other factors that these women who've had radiation may have already been identified to have a precancerous condition, such as atypical hyperplasia. A strong family history. They don't have a mutation themself, or there are other factors that play into their risk, such as having very dense breast tissue, multiple breast biopsies, things that are going to be concerning to this already high-risk group. 

Then there's a conversation they have to have with their surgeon about the pros and cons of having a surgery like this. There is still the option to monitor, and we call that intensive surveillance. And there's an MRI of the breast and a mammogram that can also be offered to these women. I screen these women with this type of intensive surveillance, breast MRI and mammogram, alternating every six months, to watch them, like I would with a mutation carrier who is not yet ready to remove their breasts. And many women choose to continue with observation using these very intensive monitoring imaging modalities.

Jamie DePolo: Okay. So, it sounds like, just sort of paraphrasing, you can tell me if I'm correct, that it's really a conversation between a woman and her doctor and weighing that particular woman's individual risk factors and then deciding what makes her most comfortable.

Dr. Sandhya Pruthi: Exactly, and making sure they're aware of what they can do to continue with surveillance until the time is right in their life when they want to pursue a surgery like that. And then understanding, just like you said, it's a woman's discussion that they have to have a shared decision-making with their doctor about the pros and cons of proceeding into a prophylactic surgery.

Jamie DePolo: Okay, and then, finally, I did want to go back to your research. Now, your study, I believe you said it was 70-some women that were in this study?

Dr. Sandhya Pruthi: Yes.

Jamie DePolo: So, that's relatively small. Going forward, for low-dose tamoxifen to start to be considered in sort of the realm of care, what do you think needs to happen, or is this study enough? Are people considering this a treatment option if a woman wants it?

Dr. Sandhya Pruthi: So, the trial was conducted through Dr. Smita Bhatia. She's actually the primary investigator on the trial. So, it was her trial. Mayo Clinic was one of their recruiting sites. So, it's not necessarily my trial. I would love to hear where she would like to go with this. At this point, I don't see and have not heard that there's other future studies underway.

I, today, in clinical practice, if I identify a patient who meets the very similar criteria of having been exposed to radiation from their chest at that time period, where they're at risk for breast cancer, I do offer them tamoxifen, low dose. And I tell them based on a trial that we published in the Clinical Cancer Research Journal that there was a benefit in reducing density, which is a biomarker for breast cancer risk. They are taking it. They're more than happy to try it because at least that is a option versus having none. So, today, that is a clinical option, a risk-reducing medication option that we can give to these women.

Jamie DePolo: Okay, and is that commonly done, do you think? Like, do most oncologists offer that to women who've had chest radiation as children?

Dr. Sandhya Pruthi: So, yes, they are starting to talk about it. It doesn't happen right away because there's another time period which you have to think about. These are younger women, and if they're still childbearing, then you don't want to prescribe tamoxifen because of the teratogenic to the fetus, the risk to the baby, if they got pregnant. 

So, you would want to wait until they've completed childbearing and then there's some form of contraception. So, these are discussions they have over time. And the other thing to remember about the exposure and radiation to the breast, it is generally recommended that the risk, and when to start considering, is eight years after the treatment for radiation. So, you would want to time that before you started risk-reducing medicine.

Jamie DePolo:  I see. So, say if you had radiation when you were 10, you'd want to wait at least until you were 18.

Dr. Sandhya Pruthi: No. 

Jamie DePolo: Oh, no?

Dr. Sandhya Pruthi: No, you wouldn't. Then you would want to wait until at least 25, because I don't want…remember, they're still too young.

Jamie DePolo: Okay.

Dr. Sandhya Pruthi: And then they've had to have completed childbearing age, so, childbearing. So, you've got to, again, individualize it to your patient. I wouldn't even start tamoxifen on someone in their 20s. I'd like to wait until they're in their 30s.

Jamie DePolo: Okay. I'm sorry I misunderstood. So, you want to wait until they've completed…?

Dr. Sandhya Pruthi: Yeah. I'm talking about their risk doesn't even take off until eight years after they were diagnosed [with childhood cancer].

Jamie DePolo: I see.

Dr. Sandhya Pruthi: In those women, that's when we even start the mammogram/MRI surveillance. But you have to be very careful. You don't even want to put them through a mammogram, which is radiation, until age 30.

Jamie DePolo: Okay.

Dr. Sandhya Pruthi: So, there's a lot of factors. That's why patients who have been exposed to this radiation, are high-risk. Should be followed with breast health specialists who can guide them on the timing on when to start surveillance imaging and then when to consider the prevention medicine.

Jamie DePolo: Okay. Thank you, so much, for explaining that, and thank you, so much, for your time. This has been really helpful.

Dr. Sandhya Pruthi: You're welcome. Thank you for having me.