ASCO on Ovarian Suppression in Young Breast Cancer Patients

Zosia Chustecka

February 22, 2016

Last year's results on the use of ovarian suppression in premenopausal women with breast cancer, which were hailed as practice changing for some subsets patients, have now been incorporated into an update to clinical guidelines issued by the American Society of Clinical Oncology (ASCO).

The update, published online February 16 in the Journal of Clinical Oncology, is coauthored by a panel of experts led by Harold Burstein, MD, from the Dana Farber Cancer Institute, in Boston, Massachusetts.

The update concerns the use of ovarian suppression in addition to standard adjuvant therapy in premenopausal women with estrogen receptor–positive breast cancer.

The latest advice, prompted by the results from large clinical trials reported last year, is that "higher-risk patients should receive ovarian suppression in addition to adjuvant endocrine therapy, whereas lower-risk patients should not."

The new recommendations acknowledge that there is no proven overall survival benefit with this approach and that there is a trade-off between the benefit of slowing disease progression and the side effects of the ovarian suppression.

This latest 2015 update concerns only ovarian suppression in this specific patient population, the experts note. It is an addition made to the clinical guideline on adjuvant endocrine therapy for women with hormone receptor–positive breast cancer, which was originally issued in 2011 and was updated in 2013. "Those previous recommendations…remain current," the experts add.

New Results From Four Trials

The update was prompted by new results from four clinical trials, all conducted in premenopausal women with breast cancer, as follows:

  • Eastern Cooperative Oncology Group trial 3193 (E-3193),a phase 3 randomized trial that compared tamoxifen (multiple brands) and the combination of tamoxifen plus ovarian suppression

  • Suppression of Ovarian Function Trial (SOFT), a phase 3 randomized trial comparing tamoxifen, the combination of tamoxifen plus ovarian suppression, and the combination of the aromatase inhibitor (AI) exemestane (Aromasin, Pharmacia and Upjohn) plus ovarian suppression

  • Tamoxifen and Exemestane Trial (TEXT), a phase 3 randomized trial comparing the combination of tamoxifen plus ovarian suppression vs the combination of the AI exemestane plus ovarian suppression

  • Austrian Breast Cancer Study Group ABCSG-12, a 2 × 2 randomized study that compared ovarian suppression plus tamoxifen vs ovarian suppression plus the AI anastrozole. (A second randomization was to treatment with the bisphosphonate zoledronic acid or not).

The method for achieving ovarian suppression differed between the trials.

In the Eastern Cooperative trial, it was achieved with surgical oophorectomy, radiation ovarian ablation (20 Gy in 10 fractions), or by use of a gonadotrophin releasing hormone (GnRH) agonist, either goserelin (Zoladex, AstraZeneca Pharmaceuticals LP) (3.6 mg every 4 weeks) or leuprolide acetate (3.75 mg every 4 weeks). In both the SOFT and TEXT trials, ovarian suppression could be achieved with surgical oophorectomy, radiation ovarian ablation, or GnRH agonist treatment with triptorelin (Trelstar, Actavis) (3.75 mg every 4 weeks). In the Austrian trial, ovarian suppression was achieved by GnRH agonist treatment with goserelin (3.6 mg every 4 weeks).

In summarizing the results from these trials, the ASCO panel of experts notes that there was no overall survival benefit from ovarian suppression.

"Nonetheless, the addition of ovarian suppression to standard adjuvant therapy with tamoxifen or an AI improved disease-free survival and improved freedom from breast cancer and distant recurrence compared with tamoxifen alone among the subset of patients who were at sufficient risk of recurrence such that adjuvant chemotherapy was warranted," they add.

However, when compared with tamoxifen alone, ovarian suppression was associated with a substantial increase in menopausal symptoms, sexual dysfunction, and diminished quality of life, the experts point out. The most common toxicity of grade 3 or higher included hot flashes, sweating, decreased libido, weight gain, anxiety, depression, somnolence, and confusion. In addition, osteoporosis was reported in 5.8% of women receiving tamoxifen plus ovarian suppression vs 3.5% with tamoxifen alone.

Clinical Advice in the New Update

The panel of experts outline several recommendations for different cohorts of premenopausal women with estrogen receptor–positive breast cancer.

"For women at higher risk for cancer recurrence, despite tamoxifen therapy, because of tumor stage (tumor size, nodal status), grade, or other biologic features, and in whom chemotherapy would ordinarily be advised, the Panel's uniform consensus was to recommend ovarian suppression in addition to adjuvant endocrine therapy, as ovarian suppression was likely to achieve measurable gains in disease-free survival that would justify therapy," they state.

"In general, if the risk of recurrence despite tamoxifen was sufficient to warrant consideration of chemotherapy, then the Panel believed that patient should receive ovarian suppression," they add.

In addition, the panel particularly encourages clinicians to consider ovarian suppression in women younger than 35 years, for whom subset analyses (SOFT) suggested substantial clinical benefits with ovarian suppression.

"With similar conviction, but at the other end of the risk spectrum, the Panel advised that in women with lower-risk tumors that were typically stage I with low to intermediate grade and in whom chemotherapy was not advised, there was no demonstrable benefit to ovarian suppression treatment," they conclude.

Practice Changing in Subset of Patients

The clinical advice in the new update reflects to a large extent the initial reactions from breast cancer experts that Medscape Medical News reported in 2014, when the results from these trials were published. Several experts said that they considered the results to be practice changing for some subsets of patients.

For instance, Beverley Moy, MD, clinical director at the Massachusetts General Hospital Cancer Center, in Boston, told Medscape Medical News that the breast cancer community had been waiting for years to hear these data on whether there was an extra benefit from ovarian suppression.

Commenting last year on the results from the SOFT and TEXT studies, she said that there was no significant benefit in the overall study population but that a significant difference was seen in the population of women who were premenopausal after chemotherapy. tThese women tended to be younger and have more aggressive disease, she said. In absolute terms, these women, after 5 years, had 7.7% fewer breast cancer events with exemestane and ovarian suppression compared with women receiving tamoxifen alone.

"I do think the data are practice changing in this subset of patients," Dr Moy told Medscape Medical News. "However, you have to temper that benefit with the fact that the combination had significantly more side effects. Making premenopausal women abruptly menopausal can lead to many side effects — hot flashes, sexual dysfunction, depression...and also joint pain and potentially osteoporosis with the aromatase inhibitor.

"You have to weigh the risks against the benefits," she said. "It's a difficult clinical situation that we face. These are young women with aggressive disease, and I'm delighted that we have found a treatment option that provides benefit, but it comes at a cost."

Another expert, Claudine Isaacs, MD, from the Georgetown Lombardi Comprehensive Cancer Center, in Washington, DC, also considered the new results to be practice changing. She said that clinicians will now be grappling with these new data and how to integrate ovarian suppression, with all its attendant adverse effects, into the treatment of premenopausal women with breast cancer. She told Medscape Medical News that she felt the data were convincing for two subsets — women younger than 35 years, and those who remain premenopausal after chemotherapy. There is a pretty significant benefit for those subsets of patients compared with women who receive tamoxifen alone, which is currently the standard of care, she said. These women are at high risk for recurrence, and the addition of ovarian suppression made a big difference, she said. "It may not be suitable for every woman in these subsets, but this new option should now be discussed with these patients," she said.

Also speaking to Medscape Medical News last year, one of the authors of the new update, Clifford Hudis, MD, chief of the Breast Cancer Medicine Service at Memorial Sloan Kettering Cancer Center, in New York City, commented: "I think these data contribute to an evolving change in the standard of care," adding that "this is the end of a very long story."

The idea that ovarian suppression would be of benefit was first reported in 1896, when a Scottish surgeon showed that removing ovaries led to breast cancer becoming smaller, he said. "We know now that this was a result of reducing estrogen in the circulation."

Decades later, this effect was achieved by the drug tamoxifen, but it was only in 1995 that the world reached a consensus that tamoxifen was useful in premenopausal women with breast cancer, he noted. This was the beginning of standardization of adjuvant therapy globally, he said, and tamoxifen alone has been the standard of care for premenopausal women with breast cancer.

"But there has always been this assumption that the low estrogen environment resulting from removal or blockade of the ovaries would allow conventional endocrine therapy with tamoxifen or others to work better," Dr Hudis explained. "But historically, clinical trials in this area have not been very positive...and the side effects of ovarian suppression in young women are real and long-lasting, and so there has been this tension in our field where there is a bias that this is the right thing to do, but mixed evidence of benefit, and clear evidence of toxicity."

The new data from the TEXT and SOFT trials provide some answers.

“Now we can see that indeed tamoxifen plus ovarian suppression is nominally better than tamoxifen alone. There was a trend, but the difference was not significant,” Dr Hudis said. "But the big step up was adding exemestane to ovarian suppression.”

So exemestane plus ovarian suppression will now become a standard of care for high-risk premenopausal women with breast cancer, Dr Hudis suggested. But he emphasized that there is a trade-off in terms of adverse effects, and so the benefit has to be weighed up against the risk, he added.

J Clin Oncol. Published online February 16, 2016. Full text

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