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For Premenopausal Breast Cancer Patients, Part of Ovarian-Suppression Riddle Solved with New SOFT Study

Susman, Ed

doi: 10.1097/01.COT.0000461151.36748.4d
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SAN ANTONIO—Premenopausal women diagnosed with low-risk early-stage breast cancer will likely do well without chemotherapy or ovarian function suppression, but high-risk women will most likely require ovarian suppression regimens. That was the conclusion of a study reported here at the San Antonio Breast Cancer Symposium.

The big unanswered question, though, is how to treat patients who fall between those groups—i.e., those at intermediate risk.

As reported by Prudence Francis, MD, Associate Professor of Medicine at the University of Melbourne/Peter MacCallum Cancer Centre, in a plenary session, the Suppression of Ovarian Function Trial (SOFT) showed that women at low risk did well whether they were on tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression: “After 5.6 years of follow-up we saw that there was a small, but not a significant improvement in disease-free survival among the women who received ovarian suppression.”

The five-year disease-free survival rates in the no-chemotherapy and chemotherapy groups were 84.7 and 86.6 percent, respectively. “The overall premenopausal population did not benefit from the addition of ovarian function suppression—some women do very well with tamoxifen alone,” Francis said.

“However, there were important differences between the two distinct patient groups.” In younger women, those around age 40, there was a 22 percent reduction in the risk of recurrence among the women who were treated with tamoxifen and ovarian suppression when compared with women treated with tamoxifen alone.

“For women at sufficient risk of recurrence to warrant adjuvant chemotherapy and who retained pre-menopausal estradiol, the addition of ovarian function suppression to tamoxifen reduced recurrence,” she said.

“Basically, in the group of women who had prior chemotherapy and still retained ovarian function, the best outcomes came with use of exemestane and ovarian suppression compared with tamoxifen alone, with a 35 percent relative risk reduction of recurrence of breast cancer.”

While the addition of ovarian function suppression had benefits, Francis noted that it also increased the risk of menopausal symptoms, depression, hypertension, diabetes, and osteoporosis.

“The benefit from ovarian function suppression is most striking in women under the age of 35,” she said.

In the trial, 112 women under the age of 35 were assigned to tamoxifen only and about 68 percent of those women were free of breast cancer at five years; 121 women under age 35 were assigned to tamoxifen plus ovarian suppression and 79 percent of that group were free of breast cancer at five years; 117 women under the age of 35 were given exemestane plus ovarian suppression and 83 percent of them were free of breast cancer at five years.

Francis said that the women who received no chemotherapy—possibly because they were deemed to be at a lower risk of recurrence due to favorable tumor and other factors—did quite well. The 476 women in this group who received only tamoxifen for five years following surgery achieved a 95.8 percent disease-free survival rate.

Of the 473 women given tamoxifen and ovarian suppression, 95.1 percent achieved a five-year disease-free survival rate, and the 470 women who were treated with ovarian suppression and exemestane achieved a 97.1 percent disease-free survival rate at five years.

PRUDENCE FRANCIS, MD. PRUDENCE FRANCIS, MD: “While the addition of ovarian function suppression had benefits, it also increased the risk of menopausal symptoms, depression, hypertension, diabetes, and osteoporosis. The benefit from ovarian function suppression is most striking in women under the age of 35.”

“These women had excellent outcomes,” Francis said. “We see no advantage for adding ovarian suppression in this group.”

Discussant: New Algorithm for Treatment

Commenting on the trial as a Discussant, Hope Rugo, MD, Professor of Medicine at the University of California, San Francisco, cautioned interpretation of the results.

“It's still early,” she said. “We can't possibly expect to see survival differences now. It is a short follow-up for overall survival in this population. And attention must clearly be made to management of toxicities such as hypertension and bone health.”

She said the study creates a new algorithm for treatment. The women who do not take chemotherapy and have smaller tumors, negative nodes, and low-grade tumors can be reasonably well-treated with tamoxifen for at least five years, she said. “We haven't answered the duration question yet.

“For patients who have clearly high-risk disease, particularly for those patients who are less than 35, ovarian suppression appears to provide a marked and clinically significant reduction in breast cancer recurrence. Whether to treat with tamoxifen or exemestane due to differences in toxicity needs to be made on an individual basis. We still remain with the question of what to do with the intermediate-risk patients—those with low-grade, but larger tumors; low-grade tumors but with nodal involvement.”

Rugo asked: “Is there a group of patients where we could use endocrine therapy and ovarian suppression or endocrine therapy alone? My argument would be that in premenopausal women, endocrine therapy and ovarian suppression would be reasonable.”

Study Specifics

In performing the SOFT trial, Francis and colleagues needed the strength of an international collaboration, she said—patients were recruited from 426 centers in 27 countries on all six inhabited continents. Women who were assigned to receive ovarian suppression were given the choice of being treated with triptorelin, bilateral oophorectomy, or irradiation.

In the trial 1,018 women were assigned to treatment with tamoxifen only; 1,015 women were treated with tamoxifen plus ovarian suppression; and 1,014 women were treated with exemestane and ovarian suppression.

The women were about 43 years of age, about 35 percent were lymph node positive (just nine percent of the women who were not receiving chemotherapy were lymph node positive); about 14 percent of the women not receiving chemotherapy had lesions smaller than 2 cm in size compared with 47 percent of the women assigned to chemotherapy.

The study, which was simultaneously published in the New England Journal of Medicine (DOI: 10.1056/NEJMoa1412379), was co-sponsored by the Breast International Group; the North American Breast Cancer Group, and the International Breast Cancer Study group. Financial support and drugs used in the trial were supplied by Pfizer, Ipsen, and the U.S. National Cancer Institute.

iPad Extra!

In a podcast report on the iPad edition of this issue by OT reporters Sarah Maxwell and Peter Goodman, Dr. Francis further discusses the findings, and Symposium Co-director C. Kent Osborne, MD, Director, Professor of Medicine and Molecular and Cellular Biology and Director of the Dan L. Duncan Cancer Center and Breast Center at Baylor College of Medicine, adds additional commentary.


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