Pausing Hormonal Therapy Treatment to Have a Child: The POSITIVE Trial

Jamie DePolo: Hello, everyone. Welcome to the Breastcancer.org podcast. I'm Jamie DePolo, the senior editor at Breastcancer.org. Our guest today is Ann Partridge, MD, and she's the founder and director of the Program for Young Women with Breast Cancer and the Adult Survivorship Program, as well as senior physician, at the Dana-Farber Cancer Institute and associate professor of medicine at Harvard University. Dr. Partridge is a medical oncologist focusing on the care of women with breast cancer and has a particular interest in the psychosocial, behavioral, and communication issues in breast cancer care and treatment.

In this podcast, we're going to talk to Dr. Partridge about the POSITIVE Trial. This study is looking at whether women diagnosed with hormone-receptor-positive disease who stop taking hormonal therapy after about 1.5 to 2.5 years of treatment to get pregnant have a higher risk of the breast cancer coming back, which doctors call recurrence. Most women diagnosed with hormone-receptor-positive disease take hormonal therapy for about 5 to 10 years after surgery. In the POSITIVE Trial, the women who want to get pregnant are stopping hormonal therapy for up to 2 years to become pregnant, deliver the baby, and breastfeed. Then the women start hormonal therapy again. Dr. Partridge is leading the United States arm of this study. Dr. Partridge, welcome to the program.

Ann Partridge: Hi, Jamie. Thanks so much for having me.

Jamie DePolo: Tell us a little bit about the background of this study. The number of women interested in this outcome, I'm assuming, is on the smaller side. But my suspicion is that the women who are interested in this are extremely interested in the topic. So, how did the idea for the study come about?

Ann Partridge: Sure. Well, you've got it exactly right, that this is for a real, what we call niche, population. That being said, it's such a critical issue for our young patients. So, historically, when women get hormone-sensitive breast cancer, particularly at a young age, we've all said, “Oh my goodness, hormones are bad, we need to treat with anti-hormonal medications, of course.” That's a mainstay of breast cancer therapy. And the conventional wisdom was, having a baby after breast cancer, especially hormone-sensitive breast cancer, was like throwing gasoline on the fire and fueling the flames. And the fact is that many young women over the years can, and do, get pregnant after a breast cancer.

Jamie DePolo: When you say throwing gasoline on the flames, is this because the estrogen levels go up when a woman is pregnant?

Ann Partridge: Yeah. Yeah, because of the hormones in breast cancer, there's concern that it might be driven by a pregnancy, and drive the risk of recurrence to go up from where it would have otherwise been. But the data, when you look back and you say, “Wow, but you know what, women do get pregnant after breast cancer, and many of them do extraordinarily well.” So, let's look and say is that true, or is that a wives' tale, or just kind of being paternalistically protective for our patients when in fact we're protecting them from something that really matters a lot to them.

When they've looked back, done fairly rigorous retrospective work, it actually appears that women who have a pregnancy after breast cancer do just as well, if not better, than women who don't. And given that, and given some of the biologic reasons why they may even do better -- although I don't tell someone to go out and get pregnant to help their breast cancer risks -- we've said, “You know, this is a critical issue for young women, and there's reason to believe it doesn't likely cause harm to have a pregnancy after breast cancer, and they're going to do it anyway.” We know that many young women go and have babies anyway, because it's such a driver in their lives. Not all, but many. "Let's figure out a way to study this so we can more fully inform those decisions.” Which as you can imagine, and anybody who's listening who's ever been in this situation, I empathize with, it's a tough decision. A doctor is saying, "Take this hormonal therapy for 5 to 10 years," and you're saying, "Wait a minute. I wanted to have my babies and start my family."

You just can't reconcile that. So this is kind of a compromise, to say, "Let's study it in a careful way, and follow how women do, and see if there's hopefully not any truth in the wives' tale, or if there is, then we can use that to inform future patients."

Jamie DePolo: That makes complete sense. How many women are you thinking you need to recruit for this study to get really good results?

Ann Partridge: The plan is to recruit approximately 600 patients. And we're actually well on our way. So, last month we accrued our 100th patient, and that's worldwide. And we really just started to take off in terms of accrual in the United States, and North America overall, where I'm the principal investigator. So I'm pretty optimistic that we will get to our full accrual. Because as I said, the numbers of women who are young and get breast cancer is a minority, and then of those women, the numbers who will desire pregnancy and desire to stop early, and have hormone-sensitive disease are a minority, too. But they're there, and they're a critical minority of patients that we want to take care of and try and figure this out for them.

Jamie DePolo: Now, women who stop taking hormonal therapy for this study, if I read the parameters correctly, they need to wait at least 3 months after they stop hormonal therapy to try and get pregnant. Is that correct?

Ann Partridge: That's absolutely correct, and they need to enroll in the study, if they're going to do it formally as part of the study -- and thank you very much to women who are willing to enroll, because of course, they can go and get pregnant on their own, they don't need a study for that. But we're going to follow them very carefully and measure lots of things surrounding their decision, as well as medical and psychosocial outcomes and fetal outcomes, baby outcomes, if they're able to get pregnant and then have a child. And so the women need to enroll within a month of stopping their endocrine therapy, or enroll and then stop, and then there's a 3-month washout.

So, whenever they stop their endocrine therapy, we don't want them to start trying to become pregnant for 3 months. And the rationale for that is that tamoxifen, which is one of the mainstay hormonal therapies, takes a while to wash out of a woman's body. And tamoxifen, if it's on board, increases the risk of a birth defect, if a pregnancy or conception occurs while a woman still has tamoxifen in her system. So, we're being pretty conservative with that, and saying, "You know, really, we don't want you to start trying to become pregnant, and if you're using contraception, we'd like you to continue to use that until you're ready to start, which, we don't want you to start until 3 months into the wash-out period."

Jamie DePolo: I know the aromatase inhibitors, which is another type of hormonal therapy, are mainly used in postmenopausal women, so women who could not get pregnant. But I have seen some cases where an aromatase inhibitor is used in a premenopausal woman along with ovarian shutdown for various reasons. Are there any differences in your study between women taking tamoxifen and women taking an aromatase inhibitor?

Ann Partridge: Yes. So, the only difference there -- so, women taking aromatase inhibitor, if they're premenopausal or presumed to be, are also candidates for the study. The only big difference is that in order to take an aromatase inhibitor as a premenopausal woman, you also have to be on an ovarian suppression shot. Your ovaries have to be asleep with medication. And so that drug also has to wash out. Most women are, in order for their ovaries to function, because they're shut down temporarily. And so it doesn't change their eligibility, but it might change the timing with which their periods come back. Because some women on tamoxifen are just having periods through it if you're on tamoxifen alone.

If you're on ovarian suppression, which some women are taking with tamoxifen and some women are taking with an aromatase inhibitor -- you have to be on it if you're taking an aromatase inhibitor -- it may take a little longer for your periods to come back, especially if you got chemotherapy. And so, what I've been advising women is, some of them, especially if they're on tamoxifen, I've been saying, “You know, if you really want to get going, and you want to start right away” -- which most women do if they're going to take that break, you want to start trying to conceive as soon as the wash-out period's over -- I say, “then maybe you stop your ovarian suppression shot at the beginning. You know, maybe you stop it a couple months before you're ready to start, [then] stop the tamoxifen, and then you're only washing out the tamoxifen for 3 months, but your periods are more likely to come back faster.”

Now, obviously that depends on how much endocrine therapy and to what degree of the endocrine therapy I want to get into a woman and that she agrees to before she starts to try and become pregnant. So, there's lots of nuance there. And you can't apply that same logic to the aromatase inhibitor people, because women treated with an aromatase inhibitor, they can't take the aromatase inhibitor, or at least it won't work, unless they're on the ovarian suppression. And so, for those women, you would stop it at the same time. It wouldn't make sense.

Jamie DePolo: Is there a longer waiting period, if I understood what you said correctly, it sounds like the ovarian suppression shot may take a little bit longer to wash out of a woman's system?

Ann Partridge: Not about birth defects for that one, so we're not requiring any longer. It's really about your ovaries waking up. So, your ovaries on tamoxifen aren't asleep. So stopping that, we expect the ovaries, if they're going to function, to be working in 3 months. If you put them to sleep with a shot, it may take a little longer than 3 months. So, a woman who -- and presumably most women who are doing this want to kind of get pregnant when they're ready, and then get through that pregnancy, nurse a little bit, and then get back on -- because we wanted them to complete the full 5 years, or 10 years, depending on what they've decided over time with their doctors, and what's best for them and their disease risks.

And so, it's a little harder to assure the awakening of the ovaries with Lupron [chemical name: leuprolide] than it is with tamoxifen, although it's very variable between individuals, especially if women got chemotherapy, because their ovaries may be a little more sleepy because of the chemotherapy, too.

Jamie DePolo: Now, what about a woman who is listening to this and maybe has been on hormonal therapy for 4 years, and is thinking, "Can I enroll in this study?" Is that possible, or does it have to be kind of in the middle?

Ann Partridge: So, it has to be kind of in the middle. The experiment here is saying, "We're going to interrupt smack dab in the middle of your endocrine therapy, and then we're going to get you back on, and is that as good or good enough?” And we're actually going to compare the women in the study, we couldn't randomize women to, "You get pregnant and you don't," because obviously what woman would take that decision, you know, that choice? Nobody would enroll, which we understand. And so instead, we're going to compare the women in our study to women with similar disease risk in very recent clinical trials of young women, like the SOFT Study and the TEXT Study and some other data sets where we think we can do a nice job.

You know, you're not supposed to compare across studies, but sometimes you don't have a great choice, and that's our best choice. So, we have a modern series of women who've gotten various treatments like women are going to be getting who go on to this trial, or will have received to go on to this study, and we're going to compare them, therefore, to those historical controls.

Jamie DePolo: Now, has there been any other research looking at recurrence rates in women who've taken a break for hormonal therapy, whether to get pregnant, or just because the side effects were very debilitating, whether they stopped for any reason?

Ann Partridge: That's a little bit complicated. So, there are, I'll break it apart.

So first, there are studies that have looked at women who had a pregnancy after breast cancer and women who didn't. And presumably, the women who had a pregnancy after breast cancer would have come off any hormonal therapy during the time of their pregnancy. So, de facto, those women either stopped or interrupted their therapy. They might have been on it when they got pregnant, these things are not as well documented as we would like in these retrospective studies. And so, and those are the data I quoted earlier, where I said that there's actually evidence that the women who get pregnant, even in ER-positive disease, and also in ER-negative disease settings, seem to do just as well as the women who don't get pregnant after breast cancer with regard to their ultimate survival. So, that's the first question.

The second component of that is, and why this is not a no-brainer, is that we do also know that women who don't take their tamoxifen well, for example, or their aromatase inhibitor well -- and we term that, in the field, adherence -- they don't adhere to the recommendations of a daily pill for 5 years. And they either stop it early, or they take it intermittently, and, like, take the weekends off, or because they take long breaks because they can't stand it either because of side effects or because of other reasons. We do know that adherence is associated with doing better. So, women who adhere better have better outcomes.

Of course, that's not just in young women, though. That's across populations, and that's not to have a pregnancy, usually, because that would be the minority of people who'd be coming off, because we already talked about how much young women, especially those going on to have a pregnancy are a small group of the overall hormone-sensitive pool.

And so we don't have an answer to the question that you asked. We have bits of information that make it one of the great reasons why we're doing this study. We don't have the right answer to answer that question. We worry a little bit that taking a break might be harmful for someone. That's why it's part of a study, that's why it's a discussion you have -- you know, I as a doctor, say to my patient, "Okay, there could be risks here," and depending on that woman's risk of recurrence of her cancer to begin with, I am more or less enthusiastic about the study for that woman and her taking a break. So, for example, if I have someone who has a small, node-negative cancer, who's already at low risk of hearing from her cancer, and she's itching to get pregnant, we're all going to feel better because the risks are lower, and therefore, any risk reduction from full 5 years of therapy, or from that break part, is going to be small, because she's likely to do well anyway.

In contrast, if I have someone who has multi-node-positive breast cancer and I'm worried about her, just in general, I'm going to be more worried about taking a break for any period of time to get a pregnancy and have a pregnancy and all that. That being said, I also worry about that patient's emotional health, and her future, and her desires to get pregnant. And so, you know, I have a colleague, for example, who has a patient with multi-node-positive breast cancer, and the patient was saying no to endocrine therapy. She said, "No, I'm not taking it. I'm going to get pregnant. Can I go on after?"

And my colleague said, "You know, I really want you to get risk reduction. There's a survival advantage to taking tamoxifen." I forget exactly what she was treating her with. And the patient said no. The patient said, "Absolutely not. I refuse. It's more important to me to have a pregnancy." And my colleague was able to actually convince her to take some [hormone-blocking medicine] because of the POSITIVE Trial. She was able to say, "Will you at least take 18 months, and therefore you'll at least get that degree of risk reduction under your belt, because we know that is better than nothing in the first year or 2, and then try and have a pregnancy?"

And the woman agreed to that. So, you know, in some ways, it's a compromise, because there are real risks. And for that woman, the default decision for her was, "I'm not going to do what the doctor's recommending because this is such a critical life thing for me," and so this was a way to manage that. Not everybody's to that extreme, and I've talked people out of the study before. So I'm going to be very honest. You know, it's an experiment, and if I'm worried about your risk of recurrence, and you can find another way to have a baby, or you can wait because of where you are in your biologic clock or in your social life, then for a lot of women I say, "You know, finish your 5 years of your [hormone-blocking medicine]. Use your banked eggs or embryos then, and then get back on." It really very much depends on that person's desires and situation, as well as their disease risk, in terms of how I counsel someone.

Jamie DePolo: That all makes good sense. It's very individualized. And I'm curious, too, are there any other safety concerns for the woman besides an increased risk of recurrence with stopping the hormonal therapy, or is that really the biggest issue?

Ann Partridge: So, the safety concerns surrounding pregnancy are myriad, right, because pregnancy is not a spectator sport, whether you've had breast cancer or not. Anybody who has been pregnant or knows a pregnant person, ever, knows that. Fortunately, in the developed world, most women do great through pregnancies, so we shouldn't be afraid of it. That being said, there are risks that surround pregnancy baseline, and when we were trying to get the study approved by our ethics board, they kept bringing up the risk of pregnancy. And we kept saying, "Yes, we understand there are risks to pregnancies, but women are going to have pregnancies. That's kind of, you know, biologically how we continue as a species."

And so the question is, is there more risk for these women because of their history of breast cancer. And the answer is yes. So, it very much depends. But the first thing, and the thing we worry the most about, is what if the cancer comes back during the pregnancy. And fortunately, that's rare. Thank God that's rare, because that's bad. That is hard. You know, if it comes back just in the breasts or in the chest wall area, it's doable, and you can take care of that woman, and she can be okay, and that baby can be okay, or the unborn, the fetus. But if it comes back elsewhere in the body, and you're facing a, "I need to treat the cancer because the woman's going to get sick and it can hurt her, but it could hurt the baby, the unborn fetus, the fetus, if I treat the mom," that's a real problem. Right?

So, we deal with it, and it does occasionally happen, but that's the worst part. So that is what we worry about the most. That's one, because these women are at risk. Right? Just because we don't think it increases the risk doesn't mean they don't have risk. The second thing is, are they at higher risk of pregnancy-associated complications? So, for example, if a woman got chemotherapy in her past, and she got Adriamycin [chemical name: doxorubicin], very commonly given for breast cancer, and her heart was fine through the treatment, is she at more risk than the average of having a problem with her heart around the pregnancy? And the truth is, we don't know the answer to that.

So, part of this study will gather information on those things. Anecdotally, we don't think it's a very common problem, because a lot of us have had people have babies after breast cancer, including anthracycline-treated women, and we haven't seen a whole lot of florid heart failure after these women went on to have babies, but we've never gathered the information systematically. So we don't know the answer to that question. So this study will also address that and things like that. Do they have more peripartum complications?

By the same token, the question is, are the babies at more risk, right? And you know, do they come out sooner, because you've been treated with tamoxifen, and is the uterus different? Is the baby smaller, because that woman got treated with tamoxifen? I mean, we have no idea. We don't think so. Again, there's no kind of speculation that they would be worse off, those babies. When we look at adult survivors of childhood cancers, which is a group who got treated for cancer, grew up, and then were able to have babies, both men and women, there's not any evidence that the children, or the pregnancies, of those patients -- assuming that they weren't radiated in their pelvic organs and all their parts are in place -- there's not any evidence that pregnancy is worse for those patients if they remained fertile.

They are more likely to not be fertile, and that's a different issue. But if they have pregnancies, there's not evidence that those patients have a much harder time with their pregnancy, or more likely, if they go in healthy, there's not evidence that they are going to come out less healthy. And then, the second thing is, there's not evidence that their babies are more likely to either have a complication, again, if the mom went in healthy, and didn't have some known leftover problem from her cancer that would affect fertility or child-bearing. And there's also not evidence that the genetics of that baby whose mother or father got exposed back when -- especially the eggs, which are there from when a woman is born -- to chemotherapy, as long as you're far enough out from the chemotherapy, it doesn't appear that the eggs of that, that may turn into that embryo, and then fetus eventually, are damaged any more than they otherwise would have been based on the age of that mother, because that does increase the risk of egg abnormalities and chromosomal abnormalities.

So I think that's reassuring, but I also think that we don't know the full answer to that question, and that's part of what the study is going to look at.

Jamie DePolo: So, the women in the study who have a baby, they breastfeed, does that offer them any recurrence risk, because I've seen some studies showing that breastfeeding can reduce risk of breast cancer, having pregnancies can reduce the risk of breast cancer. So, in this situation, does having a baby help, or is that something else that you hope to be gathering answers about?

Ann Partridge: Yeah. So, that's a tricky question, because what you're talking about is preventing breast cancer, and what we're really focused on here is not getting in the way of prevention of recurrence, which are different, right? Because one is primary prevention, where there is good evidence that having a baby before 30 and breastfeeding is associated with women being less likely, especially in their postmenopausal time, to get breast cancer. Very well studied across many, many studies.

Now we're saying, "Okay, if you're a survivor of breast cancer, how do those things affect a new primary breast cancer, but most importantly, the risk of recurrence of the cancer you've already had.” And we don't know the answer to that. And yes, we are collecting those things, although the issue about prevention of new primary cancer would take a long, long time to study and a lot more patients than 600, because the rates of developing a new primary cancer are much lower in general, even in breast cancer survivors, than the rates of recurrence, unfortunately. So, our primary outcome is looking at risk of recurrence in our group.

Jamie DePolo: So if a woman is listening to this podcast and she is perhaps interested in being part of this study, what should she do? I'm going to put the link to the ClinicalTrials page on our website, but is there something else she can do? Does she need to talk to her oncologist first? Does she need to be referred to this study? How does that work?

Ann Partridge: Sure. So, if a woman is interested in being a part of the POSITIVE Trial, it is running at select sites throughout North America, in the U.S. and Canada, and that ClinicalTrials.gov website lists the sites. So if you're in a city, because most of them are in cities where the study is open -- not every site opened that's part of this group, the Alliance, which the study is being run through, but it's also being run through the other National Cancer Institute-sponsored groups. Many sites have opened it, even though this is a small group of patients, because they realize how important it is. Doctors and researchers realize that we need to help these young women to learn more.

In that situation, you can go online and see if there's a city near you or a site near you. And then, I always think it's best to talk to your doctor about it first so that you can get their perspective. You don't have to, and you can just reach out to that site, and reach out and ask questions about whether or not the person who's running the study or one of their colleagues could see you in consultation about the POSITIVE Trial.

I'm in Boston, Massachusetts at Dana-Farber Cancer Institute, and I've been taking calls about this and speaking to women a fair bit about whether or not it makes sense for them, even if they're not in Massachusetts. And I often know who's got the study open, so I'm more than happy to vet some of those calls. You can call our office at 617-632-3800, and I'm more than happy to help triage if someone truly thinks they're a candidate, and to refer them either back to their own doctor, or, depending on what the issue is, to the website, or to a specific site.

I can say that it is open across the country at many sites, including in New York City, and Atlanta, Boston, and Texas, and California, and Chicago, Seattle, it is being opened all over the country. And there's community sites and there's academic sites. And so, I think, you know, the good news is it's supposed to open ultimately at about a hundred sites. So there should be some place that's not too far. Like, I'm taking care of a lady who's from upstate New York, which is about 3 hours from me, who came to me for this problem -- her problem was she wanted to get pregnant, and she wanted to get good treatment for her breast cancer, and this is how we're dealing with her problem, which is putting her on the study.

Jamie DePolo: Dr. Partridge, thank you so much for being on the podcast today and talking about this study. I think what the results find will be hugely helpful to a number of women, and I'd like to invite you right now to come back after this study is complete and you have some results, to talk about that.

Ann Partridge: You got it.

Jamie DePolo: Thank you again.