Ovarian Suppression in Breast Cancer Patients: Right or Wrong, Depending

Kathy D. Miller, MD; Harold J. Burstein, MD, PhD


March 18, 2016

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Kathy D. Miller, MD: Hi. It's Dr Kathy Miller from Indiana University. I am joined in the virtual world today by Dr Hal Burstein from the Dana-Farber Cancer Institute in Boston. Welcome, Hal.

Harold J. Burstein, MD, PhD: Hey, Kathy, how are you?

Dr Miller: It has been a great day here in Indiana. There has been a lot of change in hormone therapy over the past several years, and ASCO has just taken a fresh look at this important area and issued guidelines on hormone therapy in the adjuvant setting.[1] Why now? When is the last time ASCO took a comprehensive look at this?

Dr Burstein: The new focus was on ovarian suppression, which is both a very old and an au courant area of investigation for early-stage breast cancer. The debate for decades has been: What is the role of ovarian suppression in the management of younger women with estrogen receptor (ER)-positive breast cancer? It has been a debate because there have been inconsistent data. What we saw in the past year or two were two important clinical trials that probably gave us about as much information as we are going to have for the next 5 or 10 years on this topic, and that is what led to an update of the ASCO guidelines.

Three or 4 years ago, ASCO endorsed a Cancer Care Ontario guideline[2] that simply said the data were inconclusive for whether ovarian suppression added to [the benefit of] other adjuvant therapy for ER-positive breast cancer, and now we have the opportunity to revisit that on the basis of these newer data.

Three Trials the Basis for ASCO's Ovarian Suppression Guidelines

Dr Miller: Those two trials must be the SOFT and TEXT trials[3]: the SOFT trial, for those who agreed that [the benefit of ovarian suppression] was an open question and [the evidence] inconclusive; and the TEXT trial, for the true believers who were convinced that ovarian suppression was good but wanted to know what else to add. Can you remind our listeners of those trials and maybe their key results?

Dr Burstein: Absolutely. These were two studies run in parallel, as you just described. The TEXT trial was a study in which all premenopausal women who enrolled in the study had ER-positive breast cancer and they were all given ovarian suppression, with either an aromatase inhibitor (AI) or with the traditional standard tamoxifen. But as you alluded to, that study assumed that you needed the ovarian suppression, and it was really a question of the AI vs tamoxifen in these women.

The second trial, the SOFT trial,[4] was a study that looked at the question of whether ovarian suppression added [benefit] to other endocrine therapy. It had three arms: tamoxifen alone, tamoxifen plus ovarian suppression, or ovarian suppression plus an AI. Now, you will note that two of the arms in TEXT linked up to two of the arms in SOFT, and there has been cross-sharing of some of the data,[3,5] but the studies were accrued separately.

Actually, there was a third trial that was reported a little earlier, called ECOG 3193,[6] that you know well because it comes out of your ECOG group. That was a study of low-risk—essentially, stage I, but up to 3 cm, perhaps—ER-positive, node-negative cancers where, again, the question was tamoxifen with or without ovarian suppression.

Collectively, those three trials really frame the data on which we based the new guidelines.

Dr Miller: Let's take the TEXT trial, maybe the easiest of those, and a trial that, to me, honestly, has always been a little bit on the boring side conceptually. It asks the question: If you take a premenopausal woman and render her postmenopausal with ovarian suppression, does she behave like a woman who was postmenopausal when she walked in your office? As in, would an AI be slightly better than tamoxifen?

Is an AI slightly better than tamoxifen for a postmenopausal woman?—is probably the single most studied question in the history of medical oncology.

Dr Burstein: You are exactly correct. And, of course, that question—Is an AI slightly better than tamoxifen for a postmenopausal woman?—is probably the single most studied question in the history of medical oncology. Randomized trials involving somewhere close to 80,000 women looked at that question, and we know that AIs add a little bit beyond what tamoxifen adds. The TEXT trial, more or less, showed the same thing, which was that the women who got ovarian suppression plus the AI seemed to do a little better than the women who got ovarian suppression plus tamoxifen.

I think, though, that there are two caveats that you just have to bear in mind about those data. The first is that a very similar trial, the ABCSG12 study,[7] which also looked at ovarian suppression plus tamoxifen vs ovarian suppression plus an AI, showed no difference between those two options. That was, perhaps, a slightly lower-risk group of patients, which may account for the lack of a more startling benefit.

An Issue of Incomplete Ovarian Suppression From GNRH-Agonists

The other caveat is something we are learning from the very detailed work that surrounded the TEXT trial, which is: In a small percentage of women, there may be incomplete ovarian suppression, and many of us use gonadotropin-releasing hormone (GNRH)-agonist therapy to achieve ovarian suppression, as opposed to going to an oophorectomy. And in many of the women—probably around 25% of the women who were given such treatment—there was concern that the ovarian suppression may not be complete. The estradiol levels came a little above that very undetectable threshold, and there were secondary changes in pituitary hormones that made you think there may be some estrogen production. That is a very interesting observation.

It has actually influenced my practice. When I do give ovarian suppression, I typically give tamoxifen, unless I am really, really certain that the patient is going to be postmenopausal. In the TEXT subanalysis, the women who were less likely to have these fluctuations in their estradiol or follicle-stimulating hormone levels were those who were older or who had had chemotherapy in addition to ovarian suppression and antiestrogen tablets. So in those women, you might have more confidence that the GNRH-agonist treatment is going to be fully adequate to achieve menopause.

That is sort of an interesting sidebar that we learned as part of the analysis of TEXT.

Dr Miller: I think we also have to be clear that the TEXT and SOFT trials used monthly GNRH agonists. They did not allow the 3-month depot.

Dr Burstein: That is exactly right.

Dr Miller: Often, when I see people do this in the community, they use the depot formulation, and I wonder whether, for those patients for whom you don't get complete control with the monthly formulation, you may have even bigger issues of completeness and consistency of ovarian suppression with the longer-acting forms.

Dr Burstein: Obviously a very important point, and you are exactly correct. The studies all used monthly triptorelin, as it turns out—a GNRH agonist marketed in Europe. In the United States, typically people use goserelin or leuprolide acetate.

My historic practice has been to give the every-3-month injections because it is so inconvenient for patients to come in every month.

I confess that my historic practice has been to give the every-3-month injections because it is so inconvenient for patients to come in every month and get those treatments. But when we met about this on the guideline panel, we had a hard time reaching consensus. The data were derived with monthly therapy. There are these lingering concerns about incomplete ovarian suppression.

So the guidelines ended up favoring the monthly treatment because of both the way the data were derived and these lingering concerns about incomplete ovarian suppression.

SOFT: A Tale of Low-Risk and Intermediate-Risk Patients

Dr Miller: Take us now to the SOFT trial, the trial that, I think, for many of us, had the biggest change in our practice. Is there a benefit to ovarian suppression?

Dr Burstein: The SOFT trial sort of looms as the definitive study here. Again, just to recap, it was a three-arm study of tamoxifen alone, tamoxifen plus ovarian suppression, or an AI plus ovarian suppression. The top-line result was that there was no major benefit for ovarian suppression.

The interesting thing about the SOFT trial is that it became a study of two very different patient cohorts. There was a low-risk cohort, which was almost numerically exactly half of the patients. These women typically did not receive chemotherapy. They had a median age of around 45 or 46. They tended to have lower-stage tumors—typically 1, 2, or 3 cm and node negative. Almost all had low- or intermediate-grade cancers. The clinical team had made the decision that the patient did not warrant chemotherapy on the basis of this constellation of factors at their presentation. In that group there was, again, no benefit for ovarian suppression beyond the outcome seen with tamoxifen alone, and presumably this is because this group had a very good prognosis.

Dr Miller: Hal, that cohort is remarkably similar to the 3193 study.

Dr Burstein: You are exactly right.

Dr Miller: Premenopausal but older, lower risk, no chemo.

Women in their mid-40s, small tumors, node negative, lower grade have no benefit from ovarian suppression.

Dr Burstein: That's right, and in the guideline we actually explicitly draw that [comparison], putting side-by-side the 3193 cohort and the SOFT cohort to make the point that women in their mid-40s, small tumors, node negative, lower grade have no benefit from ovarian suppression.

I think the data were very clean on that group of women, and that is, obviously, a big group of women. Given the prevalence of mammography and the early detection of cancers, that is a very large group of patients who probably do not need ovarian suppression.

Dr Miller: Good news, because the lack of benefit was perhaps driven by the fact that they just do so well with tamoxifen that it is hard to improve.

Dr Burstein: The other half of the SOFT trial was equally interesting. These women were younger. Their median age was 39 or 40. Almost all had received chemotherapy, just because the clinical team thought they warranted chemotherapy, but they had remained premenopausal despite having received chemotherapy. They typically had larger tumors or node-positive breast cancer. The skew in terms of grade was more toward intermediate- or higher-grade cancers.

In this group there actually was benefit from ovarian suppression—in fact, a fairly robust benefit in terms of preventing recurrence of the breast cancer. It was about a 4% or 5% difference for the average patient, and in the very young women—under age 35—there was actually a 13%-15% reduction in the risk for breast cancer recurrence. I mention that absolute difference because that is as powerful as the adjuvant effect of a drug such as trastuzumab, which is sort of a wonder drug for HER2-positive breast cancer.

Younger women [at higher risk] actually get a lot of benefit from ovarian suppression.

On the basis of these experiences, I think we can go back to our patients at the extremes of risk and tell them a lot of very solid news that is encouraging.

For premenopausal women with lower-risk breast cancers, tamoxifen is the standard. Ovarian suppression does not add meaningfully to their outcome. That is good news.

For women at higher risk—typically women who would warrant adjuvant chemotherapy—ovarian suppression is helpful and it further lowers their risk for recurrence. The younger women actually get a lot of benefit from ovarian suppression.

So at those ends of the risk spectrum we have very clean data, which have already influenced my practice and the practice of many others.

Balancing Ovarian Suppression, Side Effects, and Fertility

Dr Miller: Now, Hal, before we let you go, putting those recommendations for those higher-risk women—where this is really practice-changing—into practice brings a couple of considerations: pregnancy and fertility for those youngest patients who have estrogen-positive tumors. And you are now going to be talking about ovarian suppression and impacts on bone health.

Do the guidelines address those important considerations?

All of the symptoms that you imagine going along with antiestrogen therapy...are turbocharged by the ovarian suppression.

Dr Burstein: These are very important real-world considerations. Again, credit to the investigators; they did some very nice quality-of-life work to accompany the analyses in SOFT and TEXT—in fact, some of the most detailed, patient-reported symptom profiles we have seen in the endocrine literature. What is clear is that adding ovarian suppression ratchets up the hormonal side-effect profile, so there are much more intensive menopausal symptoms, such as hot flashes and night sweats; more intensive sexual dysfunction; more vaginal dryness. All of the symptoms that you imagine going along with antiestrogen therapy—arthralgias and hair thinning—are turbocharged by the ovarian suppression. One of those, of course, is accelerated osteoporosis, which goes along with onset of premature menopause.

For many women, the side effects are manageable. But for some, ovarian suppression proves not to be worthwhile, and that is where the art of introducing these drugs is going to be important for managing patients.

With respect to bone health, in particular, there is good common-sense advice about weight-bearing exercise and calcium and vitamin D supplementation. Many of these women will probably also be getting pharmacologic interventions with other drugs that help preserve bone density, be it bisphosphonates or denosumab. Interestingly, as you know, there are also emerging data that those drugs might even help prevent breast cancer recurrence,[8] though we are not sold on that 100%, I guess.

The fertility questions are also very challenging. For any young women who have ER-positive breast cancers, we know that many years of antiestrogen therapy is important for preventing cancer recurrence, and those are obviously times when the fertility issues are paramount. Yet, you don't want to get pregnant when you are on these treatments. And if you are on ovarian suppression, of course, you cannot get pregnant.

For the very young women still considering reproduction after breast cancer diagnosis, I think they are going to have to interrupt these treatments. They will have aged in that interval, which might diminish their natural fertility, and it certainly may have an impact on their plans for future childbearing.

It is something that you have to think about with the patient as you are making these decisions.

Dr Miller: It strikes me that in breast cancer we started with taking out the ovaries, with that first report back in 1895.[9] We, maybe, spent some time in the wilderness thinking that ovaries and ovarian suppression weren't so important, and now with these fantastic results from these studies we are kind of back where we started. Hormone therapy is paramount for these patients, and ovarian suppression for those higher-risk patients has much more benefit than I think most of us ever expected.

For women with premenopausal breast cancer, it is a lot of good news in both directions [of risk].

Dr Burstein: For women with premenopausal breast cancer, it is a lot of good news in both directions [of risk]. It was great to be part of a group of wonderful colleagues who had the opportunity to analyze these data and do the best job we could in putting forward recommendations.

Dr Miller: Hal, thank you for your work, and for taking us through the studies and the nuances of their results. And thank you, our listeners, for joining us.


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