SOFT Yields Hard Data on Hormone Therapy

Kathy D. Miller, MD; Ann H. Partridge, MD, MPH


December 22, 2014

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The Long-Awaited SOFT Results

Kathy D. Miller, MD: I'm Kathy Miller, professor of medicine at Indiana University School of Medicine in Indianapolis. Welcome to this edition of Medscape Oncology Insights.

Long-awaited data on hormone therapy have been presented here at the 2014 San Antonio Breast Cancer Symposium. Here to discuss these data is Dr Ann Partridge, associate professor of medicine at Harvard Medical School, and director of the Adult Survivorship Program at Dana-Farber Cancer Institute in Boston, Massachusetts. Welcome, Ann.

It feels like we have been waiting for decades for the SOFT trial.[1] Tell us about the SOFT trial and how we got to this point.

Ann H. Partridge, MD, MPH: For decades, we have been wondering whether suppression of the ovaries in addition to tamoxifen would improve the outcomes of women with hormone-receptor–positive premenopausal breast cancer. The SOFT trial was designed to address that question on the basis of a lot of data that suggested that it might help, especially in very young women.

We had no good prospective data looking at what we wanted to know: Does ovarian suppression add to tamoxifen, and if so, at what cost? The SOFT trial was designed to compare tamoxifen vs tamoxifen plus ovarian suppression vs exemestane plus ovarian suppression. The sister trial (TEXT),[2] which was published 6 months ago, compared exemestane and ovarian suppression with tamoxifen plus ovarian suppression; it also looked at the SOFT data.

Dr Miller: The TEXT trial, we used to call the "true believers trial"—for those who were already convinced that ovarian suppression was helpful and just wanted to know what hormones to add to it. We haven't really had firm data that ovarian suppression was helpful. We had hints and real concerns about toxicity.

Dr Partridge: Ovarian suppression is potentially very toxic for individual women in terms of side effects, especially concerns about quality of life, sexual dysfunction, and menopausal symptoms. The TEXT trial told us that exemestane plus ovarian suppression had slightly better disease-free survival (than tamoxifen and ovarian suppression), but no survival advantage. Most of us didn't switch our patients over because with no survival advantage and without knowing what ovarian suppression adds, we said let's wait for the SOFT results. Today, finally, we heard from SOFT.

Hormone Therapy Biggest Bang for the Buck—for Some

Dr Miller: So, does ovarian suppression add benefit?

Dr Partridge: It does for some, but not for all. Once again, it's a nuanced result. The study showed that overall, tamoxifen plus ovarian suppression is a little bit better than tamoxifen alone on average. When you dig deeper, there is a big difference to adding ovarian function suppression in very young women who remain premenopausal after chemotherapy.

Dr Miller: How young were the women in this group?

Dr Partridge: They broke it down into age 35 years or younger, which is the group of women who historically do the worst in terms of disease-free survival. The good news is that we have something else to add in terms of options for therapy for young women who have disease of high enough risk to receive chemotherapy and who need hormonal therapy as well.

Dr Miller: In that youngest group of patients, how big a difference are we talking about?

Dr Partridge: It was pretty striking. In the under-35 group who received chemotherapy, the difference in disease-free survival between tamoxifen and tamoxifen and ovarian suppression was about 10%, and between tamoxifen and ovarian suppression plus exemestane, the absolute difference was about 16%. So it was the ovarian suppression that made the big difference. The exemestane edged out the tamoxifen a little bit in terms of absolute difference.

Dr Miller: That is a bigger difference than many of us expected. We were expecting that if there was a difference, it was going to be small and we would spend lots of time arguing about the side effects and whether that difference in is worthwhile. That is a bigger difference than we have seen in a lot of chemotherapy studies.

Dr Partridge: It is a tremendous difference, and it tells us again that in hormone- sensitive disease, hormones are the biggest bang for the buck, most likely. Then again, most of these women received chemotherapy; at least 90% of them did.

Ovarian suppression is still not the right thing for everyone. There were still young women with lower-risk disease who didn't receive chemotherapy and weren't in that group. We can't generalize and say that all young women need chemotherapy, but if you are going to be giving them chemotherapy and they remain premenopausal, then this is very good.

But Don't Forget the Toxicity

Dr Miller: We do have to think about the toxicity. What were the toxicities, and how big a problem were they, especially in this youngest group of patients?

Dr Partridge: Before I get into the toxicities, the other big issue was that the comparison didn't show any difference in survival, at least not yet. We have to wait on that as well.

We know that there are more breast cancer events with ovarian suppression, but we have to wait for the survival advantage, because we don't know whether it is going to improve outcomes from a life-and-death standpoint. That's what you think about when you think about whether it is worth it. The side effects were substantial for this group, especially among the women who didn't receive chemotherapy. Now I'm switching gears.

Mostly older women (35-50 years of age) who were premenopausal and who didn't get chemotherapy had the biggest burden of side effects from the addition of ovarian suppression to tamoxifen or the aromatase inhibitor. The side effects were what you would expect: more vaginal dryness, more hot flashes. The group who received the aromatase inhibitor had more musculoskeletal complaints and more bone pain. We need to pay attention to that.

Two things were most striking about the study. One was a 50% depression rate on average in all of the arms, which is pretty shocking. I care a lot about these women, and I know you do too. To think about 50% of these women scoring as depressed on these symptoms is very scary.

Dr Miller: That is higher than many of us would have expected from our experience, which has me wondering how many of my patients are struggling with depression and I haven't asked the right questions to identify them.

Dr Partridge: We need to attend to that.

On the flip side, the good news from this study was that among the women who didn't receive chemotherapy—that was about 50% of the women, and most of them were older, meaning between age 35 and 50 years—the survival rates and the disease-free survival rates were amazing with hormones alone. Whether they were in the tamoxifen, the tamoxifen plus ovarian suppression, or the aromatase inhibitor plus ovarian suppression group, they had disease-free survival rates that were in the high 90s. That is very exciting, and it means for that group, we can choose to give them hormones only.

Dr Miller: I looked at this, and to me it became pretty simple. If a woman is particularly young and needs chemotherapy, I probably need to optimize her hormone therapy. That means ovarian suppression. If she is a little older and I don't think she needs chemotherapy, the good news is I probably don't have much to gain by adding ovarian suppression, and we could avoid those extra side effects.

Dr Partridge: Good news.

Wanting Best Therapy and Wanting Children

Dr Miller: That brings us to another problem, though. If we are going to think about ovarian suppression in our patients under age 35, that is a group of patients who may not have completed childbearing, and for whom fertility issues are likely to be paramount. Ovarian suppression and fertility are not necessarily a good match. This has been of big interest to our younger patients. How are you going to walk that line with your youngest patients?

Dr Partridge: In general, we know that chemotherapy can affect a woman's fertility. We know that the hormones don't cause infertility, but it's the time that women are on them when they are not allowed to become pregnant. They can become pregnant, but generally we recommend against it, and they are aging during that time.

Many women face this real tension of wanting to have the best breast cancer care—and that means 5 or 10 years of hormonal therapy – —but also wanting to complete their families. They want to have babies. They want to live life to the fullest.

For each patient, it becomes a negotiation of how high-risk her disease is; how much she wants to have a baby; and at what point we are comfortable saying, "You are done with hormones—go ahead and get pregnant." The good news is that very young women are the least likely to lose their fertility with treatment, and they often have time before menopause when their fertility won't go away. There are also such strategies as banking eggs or embryos, and now we can consider suppressing ovaries through therapy for selected patients to see whether that improves their later fertility.

Dr Miller: We have seen the strategy of suppressing ovaries during chemotherapy, reported at the American Society of Clinical Oncology (ASCO) meeting with the POEMS trial.[3] But that trial was limited to women who were estrogen-negative who could receive ovarian suppression only during chemotherapy, partly as a way to protect the ovaries, and there wouldn't have been a concern about the need for ongoing suppression. Would you think about starting ovarian suppression during chemotherapy in a younger woman, 30 or 20 years old, with an estrogen receptor (ER)-positive tumor who has those similar interests about preserving fertility?

Dr Partridge: Yes. We have had some good data recently to inform that discussion and decision with patients.

In the POEMS trial, all of the women were ER-negative. In part, that was done to remove the confounding effect at follow-up of tamoxifen and other endocrine therapies in women were pre- or postmenopausal and having ovarian function—and also for safety reasons. They didn't want the confounding hormonal effects to interfere with the outcomes. At the same time, they didn't know whether it was safe to suppress the ovaries during chemotherapy.

The PROMISE trial, which was published in JAMA[4] a few years ago and at ASCO Breast Cancer Symposium[5] this fall, included hormone-sensitive patients as well as hormone receptor-negative patients. In those patients, similar to what was done in TEXT, women who received chemotherapy were suppressed through therapy.

The study's long-term outcomes were similar to those of POEMS, showing that it appeared to preserve at least ovarian function as measured by menses. In both, there was a suggestion, although it was certainly not definitive, that more babies were born to the group that received ovarian suppression. Most important for the discussion, it appeared to be safe. Women who had ER-positive disease who were suppressed through therapy compared with women with ER-positive disease who were not suppressed did not do any worse from a disease standpoint. Granted, the numbers are relatively modest compared with our average breast cancer trial in which we are looking at efficacy of therapies, but there was no signal for bad outcomes from a disease standpoint, so that is reassuring.

Stop Hormones to Get Pregnant?

Dr Miller: The other safety question that comes up in clinic, and that I get called about, is what do I do with a woman who has been on hormone therapy for a couple of years in the interim? Perhaps she is married and she has decided it's time to have children. She wants to stop her hormone therapy and get pregnant. Oh my God, her tumor is ER-negative. What do I do? What do I tell her?

Dr Partridge: That's always a very tricky situation, and we don't have all the answers. We know that women do that: They will take a couple of years of hormonal therapy and then come off because they want to have a baby. Other people struggle with it and stay on hormone therapy.

The good news is that there are plenty of retrospective and cohort-based registry studies[6,7,8] that suggest that women who have a baby after breast cancer do just as well as women who don't have a baby after breast cancer. Of course, there are potentially confounding factors there, in what is called the "healthy mother bias," which means that women who went on to become pregnant were healthier and therefore more likely to become pregnant or had lower-risk disease. Even in studies in which they have compared apples with apples and matched for ER positivity and ER negativity,[9] the women who became pregnant seemed to do just as well.In some settings, they actually seemed to do better. I wouldn't tell someone to have a baby to do better, but the hypothesis is generating.

Dr Miller: If we are looking for harm, we haven't been able to find it.

Dr Partridge: We have not found clear harm. What we are doing now is trying to study this prospectively. We just launched a study internationally called the POSITIVE trial,[10] in which we are enrolling women who want to interrupt their hormonal therapy, whichever hormonal therapy they are on, to try and become pregnant.

We are enrolling women who are between 18 and 30 months into their therapy. We are going to allow them to try to become pregnant, either naturally or with banked embryos or eggs or however they need to do it, for about 2 years. Then we are going to recommend strongly that they get back on the hormonal therapy to complete the 5 or 10 years, depending on what they have decided to do.

We are going to be able to study this prospectively and allow women to be supported to make those decisions with their doctors. It's not going to be the right decision for everyone. We are also going to learn and have lots of correlative data that will surround this to try and understand a lot of the questions about the feasibility of getting pregnant, and of course prospectively about the safety of getting pregnant and the outcomes both for the mothers and the potential progeny.

Dr Miller: That is a fabulous study and will be very important data. That is a strategy that I have negotiated with several of my patients, but with qualms in the back of my mind and questions that we talk about a lot. It will be fabulous to have some data to share with these women to help them make these decisions. For some of them, that may just make them feel more comfortable with the decision they have made.

Dr Partridge: Absolutely. We know that the vast majority of our patients, even our young ones, are going to be long-term survivors. We need to figure out these important quality-of-life issues for these patients moving forward, because we also know that the young ones are going to do what they want to do. They may be noncompliant with our recommendations and feel unsupported if we don't figure out ways to better inform their decisions.

Dr Miller: In our last minute, the SOFT trial results clearly influence practice for our newly diagnosed, and especially our youngest, patients. When I get home on Monday and I am seeing someone who may be now be around age 35 or just past age 35 but was diagnosed a year or two ago and is still on tamoxifen, and still having menses, do I add ovarian suppression at this point?

Dr Partridge: We are going to consider that with patients. We will consider adding ovarian suppression. Depending on how the woman is tolerating the tamoxifen, we will also consider switching to an aromatase inhibitor and adding an ovarian-suppression medication. Of course, you are extrapolating in that setting.

In SOFT, they allowed women who were up to 8 months out from their chemotherapy and still premenopausal, at least by estradiol levels. So yes, we are going to have a lot of discussions with our patients.

The important thing is that there isn't a survival advantage yet. There's no rush to switch people. The other piece is that there are lots of nuances here. A lot depends on how people tolerate the drugs and how high a risk their disease is.

Dr Miller: The SOFT trial might have been the biggest news from this year's meeting, certainly to this point. Thank you for sharing it with us and helping us think about how we might bring this into our practices and all of the discussions to come.

Thank you for joining us for this edition of Medscape Oncology Insights. This is Kathy Miller, reporting for the San Antonio Breast Cancer Symposium 2014.


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