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Ovarian suppression plus tamoxifen reduced breast cancer recurrence in high-risk premenopausal women
SAN ANTONIO — The addition of ovarian suppression to tamoxifen reduced breast cancer recurrence among young women with early-stage, HR-positive disease who did not reach menopause after chemotherapy, according to results of a randomized phase 3 study presented at the San Antonio Breast Cancer Symposium.
A secondary analysis showed ovarian suppression in combination with the aromatase inhibitor exemestane further reduced recurrence.
“I believe this is a practice-changing trial,” Prudence Francis, MD, head of breast medical oncology at Peter MacCallum Cancer Centre in Melbourne, Australia, said during a press conference.
“It doesn’t answer every question that we have in premenopausal women, but if I see a woman under age 35 with hormone-sensitive breast cancer, I will know what to advise that woman,” Francis said. “For women who have not reached menopause and have hormone receptor-positive breast cancer that carries sufficient risk of recurrence that they receive chemotherapy, physicians are likely to discuss the option of treatment with ovarian suppression plus an aromatase inhibitor.”
Tamoxifen is the standard adjuvant hormonal treatment for premenopausal women with hormone receptor-positive early breast cancer, but the benefit of adding ovarian function suppression to adjuvant treatment has been unclear.
In the SOFT trial, Francis and colleagues assessed the benefit of adding ovarian function suppression treatment to adjuvant tamoxifen in premenopausal women with hormone receptor-positive early breast cancer. As a secondary component of the study, they evaluated the effect of ovarian suppression plus exemestane in this patient population.
Researchers enrolled 3,047 premenopausal women with ER-positive and/or PR-positive early breast cancer.
A little more than half of patients in the cohort underwent chemotherapy and remained premenopausal after completion. They entered the trial within 8 months of chemotherapy completion. The cohort also included women who were chemotherapy-naive, and they entered the trial within 12 weeks of surgery.
Researchers divided patients into three groups: 1,018 received 5 years of tamoxifen alone; 1,015 received tamoxifen plus ovarian suppression; and 1,014 received ovarian suppression plus exemestane.
The primary analysis compared DFS between those assigned to tamoxifen plus ovarian suppression vs. those assigned tamoxifen alone. Median follow-up was 5.6 years.
In the overall cohort, the addition of ovarian suppression to tamoxifen did not produce a significant DFS benefit (HR=0.83; 95% CI, 0.66-1.04).
Researchers then evaluated outcomes in all three treatment arms and stratified results by patient characteristics.
Among those who underwent prior chemotherapy (mean age, 40 years), researchers observed a 22% (HR=0.78; 95% CI, 0.6-1.2) reduction in relative risk for recurrence among those who received tamoxifen plus ovarian suppression compared with those who received tamoxifen alone. The decrease — which was not statistically significant — equated to four or five fewer patients out of 100 developing recurrence within 5 years.
Researchers observed a 35% (HR=0.65; 95% CI, 0.49-0.87) reduction in risk for recurrence among those who received ovarian suppression plus exemestane compared with those who received tamoxifen alone. The decrease translated to seven or eight fewer patients out of 100 developing recurrence within 5 years.
Among all women aged younger than 35 years, the rate of 5-year RFS was higher among those who received ovarian suppression plus exemestane (83.4%; 95% CI, 74.9-89.3) compared with those who received tamoxifen plus ovarian suppression (78.9%; 95% CI, 69.8-85.5) or tamoxifen alone (67.7%; 95% CI, 57.3-76).
One in six women assigned exemestane and ovarian suppression developed breast cancer recurrence within 5 years, compared with one in three women who received tamoxifen alone.
The chemotherapy-naive women (mean age, 46 years) in the cohort demonstrated high rates of 5-year RFS with all three treatment regimens: tamoxifen alone, 95.8%; tamoxifen plus ovarian suppression, 95.1% (HR=0.95; 95% CI, 0.54-1.69); and ovarian suppression plus exemestane, 97.1% (HR=0.59; 95% CI, 0.31-1.14).
Ovarian suppression increased menopausal symptoms, particularly in the first 2 years, but overall quality of life was not reduced, according to researchers. The combination of exemestane plus ovarian suppression affected sexual functioning.
Francis and colleagues intend to continue following patients enrolled in SOFT to monitor recurrence rates, late side effects and OS.
“It is crucial that we get longer follow-up in the SOFT study because we don’t have mature survival data,” Francis said.
For more information:
Francis P. Abstract #S3-08. Presented at: San Antonio Breast Cancer Symposium; Dec. 9-13, 2014; San Antonio.
Disclosure: The researchers report to relevant financial disclosures.
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The combined analysis of the TEXT and SOFT trials comparing 5 years of therapy with an aromatase inhibitor plus ovarian suppression vs. tamoxifen plus ovarian suppression were previously presented at ASCO (Pagani O. Abstract #LBA1. Presented at: ASCO Annual Meeting; May 30-June 3, 2014; Chicago).
After a median follow-up of 68 months, those assigned aromatase inhibitor therapy plus ovarian suppression had a superior 5-year DFS compared with those assigned tamoxifen plus ovarian suppression (91.1% vs. 87.3%). Many oncologists have been waiting to find out how these results compare to giving tamoxifen alone. The SOFT trial presented at the San Antonio Breast Cancer Symposium provides additional information about the use of ovarian suppression in the premenopausal hormone receptor-positive breast cancer population.
In the SOFT trial, the addition of ovarian suppression to tamoxifen did not significantly improve DFS in the overall study population. However, in higher-risk patients who remained premenopausal after chemotherapy, the addition of ovarian suppression reduced breast cancer recurrence rates. This was especially significant in women aged younger than 35 years. There was an additional absolute improvement of 7.7% points with the use of an aromatase inhibitor therapy plus ovarian suppression when compared with tamoxifen alone.
Although longer follow-up is needed to evaluate OS, the addition of ovarian suppression to tamoxifen or the use of ovarian suppression plus an aromatase inhibitor may be considered as treatment options for the high-risk patients who remain premenopausal after chemotherapy, especially those aged younger than 35 years. However, patients need to be informed about the possible adverse effects, such as adverse sexual, menopausal and musculoskeletal symptoms. They also should be counseled about the additional risk for developing depression, hypertension, diabetes and osteoporosis. Longer follow-up also may reveal additional long-term toxicities.
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In practical terms, the breast cancer recurrence-free benefit of adding ovarian function suppression was about 7% at 5 years. That is definitely a benefit, and these results are potentially practice-changing. However, to sober some enthusiasm about these results, there are certainly more side effects to adding ovarian function suppression, especially if you use the aromatase inhibitor exemestane instead of tamoxifen. Women had significantly more hot flash activity and other menopausal-type symptoms, and they appeared to persist for several years.
Although adding ovarian function suppression didn’t really affect global quality of life, there were definitely more hot flashes and more sexual side effects, and this is relevant for all of our patients. But again, remember, these women are very young. Practically, as clinicians, we also have to remember these young women are weighing complex issues when it comes to choosing therapies, and many of them have planned future pregnancies. So doing something like this — adding ovarian function suppression with more endocrine therapy, which has more side effects — has more implications on their plans as far as fertility and family planning.
Although we are excited about these results, a lot of things have to be taken into consideration before we make the jump to automatically recommending this for everybody.
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