This study provides key insights into the longstanding and vexing debate about optimal systemic therapy for these young women. We wonder about the role of tamoxifen, aromatase inhibitors, chemotherapy, and ancillary therapies like bisphosphonates,” said Nancy E. Davidson, MD, Director of the University of Pittsburgh Cancer Institute, who was formal discussant of the TEXT and SOFT trials during the Plenary Session at the ASCO Annual Meeting.

The joint analysis showed a highly statistically significant improvement in the primary endpoint of disease-free survival with exemestane plus ovarian function suppression. All subgroups benefited. And there was a significant improvement in secondary endpoints, she said. “But these positive findings have not translated into improved survival,” she added, noting that it is premature to evaluate survival.

Dr. Davidson cited several strengths of this trial. It was international, used a rigorous definition of premenopausal and hormone responsiveness, and had well-balanced arms and a pragmatic follow-up algorithm. Limitations included a revised analysis plan due to better-than-expected outcomes to compensate for a lower-than-expected event rate, short follow-up, heterogeneous patients, and a long period of accrual.

Further Considerations

Several factors to consider when evaluating the results of SOFT and TEXT compared to discrepant results of the older ABCSG-12 trial include the choice of aromastase inhibitor, the choice of luteinizing hormone–releasing hormone (LHRH) agonist, duration of endocrine therapy, different patient characteristics, the use and timing of chemotherapy, and the size and statistical power of the trial.

“Several of these factors may account for the differences. Longer follow-up may help us sort this out,” Dr. Davidson said.

The joint analysis of TEXT and SOFT suggests that some premenopausal women with early hormone-sensitive breast cancer will do very well on hormone therapy alone and can avoid chemotherapy, which is an important point. The decision to use chemotherapy should be individualized and based on discussions between the oncologist and the patient. “Not every premenopausal patient needs chemotherapy,” Dr. Davidson noted.

“More long-term follow-up of this analysis, as well as results of the tamoxifen arm in the SOFT trial are needed to finalize my approach. Additionally, we need to determine the role of obesity, and develop better predictive biomarkers in this setting. What we can say today is that exemestane plus [ovarian suppression] is another important option for premenopausal hormone-sensitive early breast cancer,” Dr. Davidson stated.

Another View

“Ovarian suppression is controversial in the United States. We are not sure what ovarian suppression adds beyond tamoxifen in this setting. And we don’t know that yet because the results of the tamoxifen-alone arm of SOFT are not yet available,” said Claudine Isaacs, MD, Professor of Medicine and Oncology at Georgetown University School of Medicine, Washington, DC.

“The question is: should I change my standard of care from tamoxifen to [ovarian suppression] based on this trial? I think we need to individualize therapy and consider risk of [ovarian suppression], age, and prior chemotherapy. The outcome is excellent with adjuvant tamoxifen alone in the majority of premenopausal women with hormone-sensitive breast cancer. From a quality-of-life perspective, it is important for premenopausal women to retain ovarian function. It behooves us to think about who needs [ovarian suppression] and to wait to see results of the tamoxifen-alone arm,” Dr. Isaacs said.

Also, she said it is difficult to know whether some patients would prefer exemestane and ovarian suppression for 5 years vs chemotherapy. “Some women may prefer the transient side effects of chemotherapy. This is a complicated question, and these results cause us to reevaluate our thinking,” she said. ■

Disclosure: Drs. Davidson and Isaacs reported no potential conflicts of interest.