The International Breast Cancer Overview has clearly demonstrated that adjuvant ovarian ablation significantly reduces mortality in premenopausal women, and tamoxifen reduces mortality in both pre- and postmenopausal women with ER-positive tumors. Current clinical trials are addressing a number of important issues related to these two key interventions, including the impact of combining these therapies with chemotherapy. Trials are also underway combining anastrozole with ovarian suppression in premenopausal women, an interesting combination in light of the recent ATAC outcome data.

INTERGROUP 0101 STUDY OF ADJUVANT OVARIAN ABLATION

The study was designed a long time ago, at a time when there was increasing interest in ovarian ablation, because of the meta-analysis and the availability of drugs that could lead to chemical castration as opposed to surgical ablation. In the best of all worlds, we would have had a 4th arm of CAF followed by tamoxifen. At the time, however, we weren't sure that we could pull it off statistically — that we could accrue to that trial in a timely fashion and have something to talk about. The disease-free survival was better for the group receiving CAFZT compared to CAFZ. There was a borderline improvement with CAFZ compared to CAF. An unplanned preliminary, retrospective subset analysis demonstrated that younger women — arbitrarily defined as women under the age of 40 — seemed to do better with goserelin. Perhaps that's not surprising, because those women are the least likely to be made postmenopausal by chemotherapy. There’s also a suggestion that women with premenopausal estrogen levels after chemotherapy were destined to derive benefit from goserelin. The big clinical question now is what to do with the young woman who is premenopausal at the end of chemotherapy? Most of them receive tamoxifen as a matter of routine. I personally am not using LHRH agonists in that situation right now, but some of our very good colleagues have looked at these trial results and said that they think it is legitimate to do.

—Nancy E Davidson, MD

ADJUVANT OVARIAN ABLATION IN A NONPROTOCOL SETTING

We now have several trials demonstrating that, in receptor-positive premenopausal patients, ovarian ablation is as effective as CMF. In fact, there’s almost a suggestion that it is better. In the ECOG study (Intergroup 0101), patients received CAF, which everyone would consider state-of-the-art chemotherapy. In that trial, there was additional benefit from adding ovarian ablation to CAF — certainly among women under age 40. That study really changed my thinking. If a woman receives adjuvant chemotherapy and does not stop menstruating, I routinely add the LHRH agonist, goserelin with tamoxifen.

—I Craig Henderson, MD

EST-5188, INT-0101: PHASE III RANDOMIZED COMPARISON OF ADJUVANT THERAPIES IN PREMENOPAUSAL WOMEN WITH RESECTED NODE-POSITIVE HORMONE RECEPTOR-POSITIVE ADENOCARCINOMA OF THE BREAST CLOSED PROTOCOL PROJECTED ACCRUAL: 1,537 patients we re entered into the trial.   CAF=cyclophosphamide, doxorubicin, fluorouracil; Z=goserelin; T=tamoxifen     ABCSG-12: OVARIAN SUPPRESSION PLUS ANASTROZOLE OR TAMOXIFEN IN HORMONE RECEPTOR-POSITIVE, NODE-NEGATIVE OR NODE-POSITIVE BREAST CANCER OPEN PROTOCOL PROJECTED ACCRUAL: 1,250 patients will be accrued to this study.   All therapy given for 3 years.     INTERNATIONAL OVERVIEW RESULTS OF ADJUVANT OVARIAN ABLATION, TAMOXIFEN AND CHEMOTHERAPY Adapted from Lancet 1996;348:1189-1196. Abstract Lancet 1998;353:930-942. Abstract   In addition to chemotherapy, which adjuvant endocrine therapy, if any, would you recommend for the following 43-year-old premenopausal women with ER-positive, HER2-negative breast cancer? O N C O LO G I S T S TUMOR SIZE/ NODAL STATUS TAMOXIFEN ANASTROZOLE* LETROZOLE* OVARIAN SUPPRESSION/ ABLATION 2.2 cm tumor 10+ nodes 80% 5% 5% 10% 2.2 cm tumor 2+ nodes 80% 5% 5% 10% 2.2 cm tumor neg nodes 75% 15% 5% 5% 0.8 cm tumor neg nodes 80% 5% 5% 10% *Aromatase inhibitors are not recommended to premenopausal women without ovarian suppression.

Ovarian ablation for early breast cancer. Early Breast Cancer Trialists’ Collaborative Group. Cochrane Database Syst Rev. 2000;CD000485. Abstract

Early Breast Cancer Trialists’ Collaborative Group. Ovarian ablation in early breast cancer: Overview of the randomised trials. Lancet 1996;348:1189-1196. Abstract

Davidson N et al. Effect of chemohormonal therapy in premenopausal, node (+), receptor (+) breast cancer: An Eastern Cooperative Oncology Group phase III Intergroup trial (E5188, INT-0101). Proc ASCO 1999; Abstract 249A, 67A.

Henderson IC. Ovarian ablation comes around again. Breast Diseases: A Year Book Quarterly 2000;11(2):117-120. No abstract available.

Klijn JG et al. Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: A meta-analysis of four randomized trials. J Clin Oncol 2001;19:343-53. Abstract

Michaud LB, Buzdar AU. Complete estrogen blockade for the treatment of metastatic and early stage breast cancer. Drugs Aging 2000;16:261-71. Abstract

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