Commentary (Kaklamani/Gradishar): Adjuvant Hormonal Therapy in Early Breast Cancer

The use of adjuvant endocrine therapy in early-stage breast cancer is thought to eradicate micrometastatic disease that may lead to systemic recurrences. Until relatively recently, the standard adjuvant endocrine therapy option was tamoxifen. Data from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview analysis reported a 50% reduction in the risk of relapse and a 28% reduction in the risk of death in estrogen receptor (ER)- positive patients treated with 5 years of tamoxifen.[1] This benefit was observed regardless of menopausal or lymph node status and whether or not patients were receiving chemotherapy. There was no such benefit documented in ER-negative cancers receiving tamoxifen. Tamoxifen has also been associated with a 47% reduction in the risk of developing contralateral breast cancer.[1] With the completion of several large clinical trials incorporating aromatase inhibitors, these agents are now considered reasonable alternatives to tamoxifen or in addition to tamoxifen in postmenopausal women. Furthermore, in premenopausal women, new trials are under way to evaluate the role of ovarian suppression. In this issue of ONCOLOGY, Drs. Kumar and Leonard present a well-organized, comprehensive review on this topic. Benefit/Risk Considerations
In approaching the topic of endocrine therapy in postmenopausal women, one has to take into account several issues:
(1) Tumor characteristics may guide our treatment decision. As noted by the authors, there are good clinical data that tumors overexpressing HER2/neu respond better to aromatase inhibitors than tamoxifen. A neoadjuvant trial conducted by Ellis et al[2] randomized women to receive tamoxifen or letrozole (Femara) for 4 months. When looking at the subgroup of patients with HER2/neu-positive tumors, the response rate for the aromatase inhibitor was 69% vs 17% with tamoxifen. In the same study, the response rates for the two agents in HER2/neunegative tumors were 53% and 40%, respectively. Another trial of similar design confirmed the above findings. More specifically, the Immediate Preoperative Anastrozole, tamoxifen, or Combined with Tamoxifen (IMPACT) trial randomized patients to 3 months of neoadjuvant tamoxifen or anastrozole (Arimidex).[3] When looking at patients with HER2/neu-positive tumors, the investigators found that the response rate for anastrozole was 58% compared to 22% with tamoxifen. Another subgroup of patients who seem to benefit from an aromatase inhibitor is the ER-positive/progesterone receptor (PR)-negative subgroup. A subgroup analysis of the Arimidex, Tamoxifen, Alone or in Combination (ATAC ) trial showed that the relative benefit from anastrozole in this subgroup of patients was 57%, whereas in the ER-positive/PRpositive subgroup, the benefit was 16%, and for the whole group of patients, it was 21%.
(2) It is well established that aromatase inhibitors increase the incidence of bone loss, and in studies where they were used upfront, the fracture rate increases.[4] Furthermore, some data suggest that aromatase inhibitors are associated with increased cerebrovascular and cardiac events.[5]
(3) Aromatase inhibitors may offer more protection against contralateral breast cancer compared to tamoxifen. Indeed, the ATAC trial showed that patients randomized to the anastrozole arm had a 53% relative reduction in the incidence of a second primary, compared with the group receiving tamoxifen.[6] Ovarian Suppression
Castration was first reported as an effective therapy for metastatic breast cancer over 100 years ago, at a time when hormones had not been characterized.[ 7] Several different means of causing ovarian ablation have been studied in the interim: surgical oophorectomy, radiation-induced ablation of the ovaries, and more recently, medical therapy with leuteinizing hormone-releasing hormone (LHRH) agonists. In premenopausal women, the available data on the role of ovarian suppression are still not sufficient. Studies have shown the equivalence of CMF/CAF (cyclophosphamide and fluorouracil with either methotrexate or doxorubicin [Adriamycin]) chemotherapy with ovarian suppression in women with hormonereceptor- positive tumors.[8,9] Furthermore, premenopausal women who become amenorrheic after adjuvant therapy have a better disease-free survival compared with women who do not achieve amenorrhea.[8] Three international trials are currently addressing the role of ovarian suppression. The Suppression of Ovarian Function Trial (SOFT) is addressing the question of endocrine therapy in patients who remain premenopausal 6 months after adjuvant chemotherapy or who receive tamoxifen as definitive treatment. In this trial, premenopausal patients are randomized to tamoxifen, ovarian suppression and tamoxifen, or ovarian suppression and exemestane (Aromasin). Both the Tamoxifen and Exemestane Trial (TEXT) and Premenopausal Endocrine Responsive Chemotherapy (PERCHE) trial address the issue of ovarian suppression after surgery and randomize patients to ovarian suppression with tamoxifen or exemestane. As the next generation of trials evaluating ovarian suppression in premenopausal women are completed, we hope to answer questions on the use of aromatase inhibitors in the younger population as well as the potential additional benefit of ovarian suppression to tamoxifen or other endocrine agents (ie, aromatase inhibitors). However, some questions will remain unanswered: What is the adequate duration of ovarian suppression? In what patient population can we safely substitute chemotherapy for ovarian suppression? In the near future, molecular characterization of breast cancers will allow us to individualize our treatment decisions. Until then, a detailed discussion with our patients on the available data, as well as the potential side effects of therapy, must guide our treatment recommendations.

Disclosures:

The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References:

1. Polychemotherapy for early breast cancer: An overview of the randomised trials. Early Breast Cancer Trialists’ Collaborative Group. Lancet 352:930-942, 1998.
2. Ellis MJ, Coop A, Singh B, et al: Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: Evidence from a phase III randomized trial. J Clin Oncol 19:3808-3816, 2001.
3. Dowsett M, Ebbs SR, Dixon JM, et al: Biomarker changes during neoadjuvant anastrozole, tamoxifen, or the combination: Influence of hormonal status and HER-2 in breast cancer-a study from the IMPACT trialists. J Clin Oncol 23:2477-2492, 2005.
4. Group TAT: The ATAC (‘Arimidex’, Tamoxifen, Alone or in Combination) trial in postmenopausal women with early breast cancer- updated efficacy results based on a median follow-up of 47 months. Breast Cancer Res Treat 76(suppl 1):12, 2002.
5. Thurlimann BJ, Keshaviah A, Mouridsen H, et al, for the BIG 1-98 Collaborative Group: Randomized double-blind phase III study to evaluate letrozole (L) vs. tamoxifen (T) as adjuvant endocrine therapy for postmenopausal women with receptor-positive breast cancer (abstract 511). J Clin Oncol 23(16S):6s, 2005.
6. Howell A, on behalf of the ATAC Trialists’ Group: The ATAC trial in postmenopausal women with early breast cancer-updated efficacy results based on a median follow-up of 5 years. Breast Cancer Res Treat 88(suppl 1): S7, 2004.
7. Beatson GT: On the treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment, with illustrative cases. Lancet 2:104-107, 1896.
8. Davidson N, O’Neill A, Vukov A, et al: Chemohormonal therapy in premenopausal node-positive, receptor-positive breast cancer: An Eastern Cooperative Oncology Group phase III intergroup trial (E5188, INT-0101) (abstract 15). Proc Am Soc Clin Oncol 22:5, 2003.
9. Arriagada R, Le GM, Spielmann M, et al: Randomized trial of adjuvant ovarian suppression in 926 premenopausal patients with early breast cancer treated with adjuvant chemotherapy (abstract 14). Proc Am Soc Clin Oncol 22:4, 2003.