Drs. Cianfrocca and Wolff have provided a thoughtful and thorough review of the current data regarding the use of endocrine therapy in women with hormone receptor-positive breast cancer. We have made significant progress in our understanding of the basic mechanisms of endocrine therapy and resistance, as well as improvements in the clinical care of women with hormone receptor-positive breast cancer. Many questions remain unanswered, however, and the recent progress should not give rise to complacency.

Uncertainties of Treating Premenopausal Women

We still know far less about endocrine therapy in younger women than in their older counterparts. In older women, we have entered a post-tamoxifen era, in which we have treatments that have proven to be better than tamoxifen(Drug information on tamoxifen) alone. In contrast, a 5-year course of tamoxifen therapy remains standard in premenopausal women, and the role of additional treatment is still uncertain. Among the unanswered questions in premenopausal women with hormone receptor-positive breast cancer is whether ovarian suppression/ablation (OS/OA) adds to the benefit of chemotherapy plus tamoxifen, or even tamoxifen alone. Is OS/OA with an aromatase inhibitor better still? The ongoing Suppression of Ovarian Function Trial (SOFT), Tamoxifen and Exemestane(Drug information on exemestane) Trial (TEXT), Premenopausal Endocrine Responsive Chemotherapy (PERCHE), and Austrian Breast and Colorectal Cancer Study Group (ABCSG) trials should provide critical answers.

Many more questions exist and punctuate our discussions with patients in clinic. Which groups of premenopausal women with hormone receptor-positive breast cancer should be treated with chemotherapy vs endocrine therapy vs both? We know that, as a group, patients with hormone receptor-positive breast cancer benefit from the addition of chemotherapy to hormone therapy.[1] However, data from studies utilizing the multigene assay Oncotype DX suggest there is a subset of patients who receive little or no benefit from the addition of chemotherapy to tamoxifen.[2] It is likely that there are women who similarly receive little benefit from endocrine therapy.

In general, we are willing to consider endocrine therapy in exchange for a very small benefit because it tends to be so well tolerated. Nevertheless, a 5-year (or longer) course of such therapy can be costly and may be associated with a constellation of side effects, including vasomotor symptoms, bone loss, and sexual difficulties. As we try to become more selective about our use of breast cancer treatments, it will be important to identify patient populations with hormone receptor-positive breast cancer who may not need or benefit from endocrine treatment.

Treatment Duration and Late Recurrence

The optimal duration of endocrine therapy remains a critical question. There is a growing appreciation of the risk of late recurrences in women with hormone receptor-positive disease. More than half of all recurrences are identified more than 5 years after diagnosis.[3] In addition, the results from the MA.17 trial unequivocally indicate that an active treatment can significantly lower the risk of late recurrence.[4] For some patients, however, the risks of therapy will outweigh the benefits. We will need to develop predictors of late recurrence, with the hope that we can be more selective in our treatment decisions in that setting as well.

Finally, what is the role of extended therapy in premenopausal women? At the present time, a woman who remains premenopausal at the completion of a 5-year course of tamoxifen has no established treatment options, and clinical trials are not addressing this group of patients. Although it would take a multinational effort, a trial looking to reduce the risk of recurrence in this patient population is warranted.

Trials of New Targeted Agents

The development of a new generation of targeted agents has raised a number of questions about the role of endocrine therapy administered in conjunction with other treatments. The TAnDEM trial, a randomized, phase III trial evaluating anastrozole(Drug information on anastrozole) (Arimidex) plus trastuzumab(Drug information on trastuzumab) (Herceptin) vs anastrozole alone in postmenopausal women with advanced, HER2-positive breast cancer demonstrated a doubling in progression-free survival from 2.4 to 4.8 months (P = .0016) and an increased response rate from 6.8% to 20.3% (P = .018). These results clearly indicate that there is a group of patients for whom endocrine therapy is not effective, though it is uncertain if the benefit of trastuzumab is additive or synergistic.