The addition of ovarian suppression to adjuvant treatment (post-surgery) with tamoxifen reduced breast cancer recurrence in young women with hormone-sensitive early breast cancer who received chemotherapy and had not reached menopause. The addition of ovarian suppression to tamoxifen did not benefit all young women. The International Breast Cancer Study Group (IBSCG) presented results of the randomized, phase III SOFT clinical trial at the 2014 San Antonio Breast Cancer Symposium and published the results online in the New England Journal of Medicine.
Treatment with tamoxifen plus ovarian suppression reduced the relative risk of developing invasive breast cancer recurrence by 22% in women who did not transition into menopause after receiving chemotherapy, when compared to treatment with tamoxifen alone. On average, these women were 40 years old when starting hormonal therapy after chemotherapy. A secondary analysis revealed that further benefit could be gained by treating these women with exemestane plus ovarian suppression, which reduced their relative risk of breast cancer recurrence by 35%, compared to tamoxifen alone, resulting in 7 or 8 fewer women out of 100 having a breast cancer recurrence within 5 years.
“These results will change clinical practice,” said study co-chair Prudence Francis, M.D., Head of Breast Medical Oncology, Peter MacCallum Cancer Centre, Australia. “For the youngest women with hormone-sensitive breast cancer, ovarian suppression will increasingly be recommended. For women who have not reached menopause and have hormone-sensitive breast cancer that carries sufficient risk of recurrence to warrant chemotherapy, doctors are likely to discuss the option of treatment with ovarian suppression plus an aromatase inhibitor as an alternative to tamoxifen.” Researchers designed SOFT (Suppression of Ovarian Function Trial) to assess the value of ovarian suppression in reducing breast cancer recurrence in young women receiving tamoxifen, and to assess the role of the aromatase inhibitor exemestane plus ovarian suppression in treating young women. Premenopausal women with estrogen and/or progesterone receptor-positive, or hormone-sensitive, breast cancer were randomly assigned to treatment with tamoxifen alone for 5 years, tamoxifen plus ovarian suppression for 5 years, or exemestane plus ovarian suppression for 5 years.
SOFT studied these treatments in two different groups of young women with early breast cancer: premenopausal women for whom the physician and patient considered tamoxifen alone without chemotherapy suitable treatment; and women who had already received chemotherapy and remained premenopausal despite chemotherapy. Chemotherapy can suppress production of estrogen by the ovaries and cause menopause, which is associated with reduced recurrence of hormone-sensitive breast cancer.
Tamoxifen has been the standard adjuvant hormonal treatment for premenopausal women with hormone-sensitive breast cancer. The benefit of adding ovarian suppression to tamoxifen was uncertain. The other treatment investigated, the aromatase inhibitor exemestane, requires suppression of estrogen produced by the ovaries to be effective in premenopausal women. Ovarian suppression was achieved by monthly injections of a GnRH agonist triptorelin (most common choice in SOFT), surgical removal of both ovaries, or radiation of the ovaries. The benefit of adding ovarian suppression to tamoxifen was most pronounced in women younger than 35, an age group at particularly high risk of recurrence. This benefit was even greater with exemestane plus ovarian suppression: after 5 years, 1-in-6 women under age 35 receiving exemestane plus ovarian suppression experienced further breast cancer, compared to 1-in-3 under age 35 receiving tamoxifen alone.
SOFT also enrolled premenopausal women whose systemic treatment included only adjuvant hormonal therapy without chemotherapy, as decided with their physician. These women typically were older (average age 46 years), closer to natural menopause onset, and had breast cancer pathology with a more favorable prognosis, compared to women who received chemotherapy. The group who did not receive chemotherapy did very well; more than 95% were free from breast cancer recurrence after 5 years with tamoxifen alone. No benefit from ovarian suppression in this group could be detected at this point in time.
Patient-reported quality of life assessed throughout the trial help put the treatments into perspective. Mood and physical well-being did not differ between the treatment groups. Although women treated with tamoxifen plus ovarian suppression initially reported worse hormone-related symptoms and sexual functioning than those receiving tamoxifen alone, after 2 years most differences between treatment groups were no longer apparent. Effects on sexual functioning were noted throughout the treatment with exemestane plus ovarian suppression.
“While ovarian suppression is not recommended for everyone, adding it to tamoxifen can reduce breast cancer recurrence in higher-risk patients who remain premenopausal after chemotherapy, particularly in women under the age of 35,” said study co-chair Gini Fleming, M.D., Clinical Medical Oncology Breast Program Director, University of Chicago, USA. “The combined analysis of IBCSG’s TEXT and SOFT trials confirmed adjuvant treatment with exemestane is more effective than tamoxifen in preventing recurrence when combined with ovarian suppression. Physicians and patients can use these outcomes and the related side effect information to tailor therapy for premenopausal women with hormone-sensitive breast cancer, based on age, breast cancer pathology and patient preferences.”
SOFT enrolled more than 3,000 premenopausal women with hormone receptor-positive early-stage breast cancer between December 2003 and April 2011. Trial treatment lasted 5 years; the women continue to be followed for life to assess long-term prognosis and side effects. The trial is led by the International Breast Cancer Study Group (IBCSG), in partnership with the Breast International Group (BIG) and the North American Breast Cancer Group (NABCG), and supported by IBSCG, Pfizer, Ipsen and the U.S. National Cancer Institute (NCI).
Adjuvant Ovarian Suppression in Premenopausal Breast Cancer, Prudence A. Francis, M.D., Meredith M. Regan, Sc.D., Gini F. Fleming, M.D., István Láng, M.D., Eva Ciruelos, M.D., Meritxell Bellet, M.D., Hervé R. Bonnefoi, M.D., Miguel A. Climent, M.D., Gian Antonio Da Prada, M.D., Harold J. Burstein, M.D., Ph.D., Silvana Martino, D.O., Nancy E. Davidson, M.D., Charles E. Geyer, Jr., M.D., Barbara A. Walley, M.D., Robert Coleman, M.B., B.S., M.D., Pierre Kerbrat, M.D., Stefan Buchholz, M.D., James N. Ingle, M.D., Eric P. Winer, M.D., Manuela Rabaglio-Poretti, M.D., Rudolf Maibach, Ph.D., Barbara Ruepp, Pharm.D., Anita Giobbie-Hurder, M.S., Karen N. Price, B.S., Marco Colleoni, M.D., Giuseppe Viale, M.D., Alan S. Coates, M.D., Aron Goldhirsch, M.D., and Richard D. Gelber, Ph.D. for the SOFT Investigators and the International Breast Cancer Study Group, New England Journal of Medicine, DOI: 10.1056/NEJMoa1412379, published 11 December 2014.
Source: The International Breast Cancer Study Group (IBCSG)