What is the optimal adjuvant endocrine therapy for premenopausal women with invasive breast cancer, including the role of ovarian ablation/suppression?

OVERVIEW: 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.

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?

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%

Which adjuvant endocrine therapy, if any, would you recommend for the following 43-year-old premenopausal women with ER-positive, HER2-positive breast cancer?

TUMOR SIZE/ NODAL STATUS		TAMOXIFEN	ANASTROZOLE*	LETROZOLE*	OVARIAN SUPPRESSION/ ABLATION	NONE
2.2 cm tumor 10+ nodes		80%	10%	5%	5%	-
0.8 cm tumor 2+ nodes neg nodes		70%	10%	5%	10%	5%

*Aromatase inhibitors are not recommended to premenopausal women without ovarian suppression.

HISTORY OF OVARIAN ABLATION

It is just over 100 years since George Beatson described the dramatic responses of three women with advanced breast cancer to surgical cast ration. This became standard treatment for premenopausal women with advanced breast cancer, and provided the first approach to trials of adjuvant systemic thera py by pioneers Dr Cole (Manchester ) and Dr Nissen-Meyer (Oslo). Unfortunately, they were underpowered statistically, and although they suggested that relapse-free survival could be prolonged, it was not until the first world overview that we could confidently conclude that such an approach improved survival.

—Michael Baum, ChM, FRCS; Joan Houghton, BSc
Br Med J 1999;319:568-571.

OVERVIEW DATA ON OVARIAN ABLATION

Since the ove rview data is from older studies, the number of patients in the ovarian ablation trials are few compared to the number in t a m oxifen or chemothera py trials. There were several thousand patients in the 1960s and 1970s, randomized to ovarian ablation or observation, at first — mainly in the absence of any chemothera py. In some of the later trials, chemothera py plus ovarian ablation versus the same chemothera py alone was studied.

In fact, there are very clear data that ovarian ablation is beneficial compared to no systemic treatment, with improvement much like what was seen with the chemotherapy regimens of that day: CMF, AC, etc. Because the studies are so old, the receptor status wasn't known in many of the patients. In the later trials, ovarian ablation added to chemotherapy isn't quite as significantly effective, although it tends to add something to chemothera py. It may be that some of these patients become amenorrheic with chemothera py, so that adding ovarian ablation doesn't do as much.

—Kathleen Pritchard, MD

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

COMBINATION ENDOCRINE THERAPY

Combination endocrine therapy is a conceptual change for us. We eliminated that approach a couple of decades ago. Perhaps because of small, inadequately powered trials that were unable to detect the type of differences we can identify today with larger studies. Combination endocrine therapy may be more effective than single agent treatment. With better tools now available, we are returning to the concept of complete estrogen blockade — a strategy that started several decades ago with hypophysectomy and adrenalectomy. Studies of chemical ovarian suppression plus tamoxifen suggest greater efficacy than either alone.

—Gabriel Hortobagyi, MD

STUDY OF GOSERELIN PLUS ANASTROZOLE IN METASTATIC DISEASE

Endocrine maneuvers are often limited in premenopausal women, however, we know that premenopausal patients with ER-positive tumors are just as likely to be sensitive to hormone therapy as postmenopausal women. We decided that, for patients on tamoxifen and goserelin, there was no reason why we shouldn't treat them in the same way as we would a postmenopausal woman who progresses on tamoxifen. You stop the tamoxifen and start an aromatase inhibitor. We had a series of women where that's what we did. We stopped the tamoxifen, continued the goserelin, and then substituted anastrozole for the tamoxifen. A significant percentage of those women responded.

—John F Robertson, MD, FRCS

AUSTRIAN TRIAL

A trial has been started in Austria that looks at goserelin plus anastrozole as an adjuvant therapy. The key randomization is to goserelin plus tamoxifen or goserelin plus anastrozole. The basis for that is there was a study presented at ASCO, whereby patients were randomized either to CMF or to goserelin plus tamoxifen.

This was in premenopausal, ER-positive patients. It showed that the early recurrence-free survival curves were in favor of the endocrine arm. Therefore they have taken that as the control arm for the next study. They're now comparing goserelin plus tamoxifen to goserelin plus anastrozole.

—John F Robertson, MD, FRCS

AROMATASE INHIBITORS IN WOMEN MADE MENOPAUSAL BY LHRH AGONISTS

There is one limited metastatic study in ER-positive patients demonstrating that goserelin plus anastrozole yielded similar responses to what has been seen in postmenopausal patients. We need to design appropriate trials to address this issue. It is very important to consider that aromatase inhibitors as monotherapy should not be used in premenopausal patients. But it would be a very interesting and logical approach to design trials of complete estrogen blockade in ER-positive premenopausal patients, using an LHRH agonist and anastrozole.

—Aman Buzdar, MD

ABCSG-12: OVARIAN SUPPRESSION PLUS ANASTROZOLE OR TAMOXIFEN IN HORMONE RECEPTOR-POSITIVE, NODE-NEGATIVE OR NODE-POSITIVE BREAST CANCER No Protocol Link

PROJECTED ACCRUAL: 1,250 patients will be accrued to this study.

All therapy given for 3 years.

STUDY CONTACT: Raimund Jakesz, Chair Austrian Breast & Colon Cancer Study Group Vienna, Austria

A PHASE II TRIAL OF ANASTROZOLE PLUS GOSERELIN IN THE TREATMENT OF HORMONE RECEPTOR-POSITIVE, METASTATIC CARCINOMA OF THE BREAST IN PREMENOPAUSAL WOMEN No Protocol Link

PROTOCOL: Goserelin q 4 weeks + anastrazole q day until disease progression.

Anastrazole starts 3 weeks after the initial administration of goserelin.

STUDY CONTACT: Robert W. Carlson, MD Christine Schurman, RN 650-723-8686

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

INTERGROUP 0101: DISEASE-FREE AND OVERALL SURVIVAL

7 year Disease-free Survival 7 year Survival CAF 58% 77% CAF/Zoladex 64% 78% CAF/Zoladex/Tamoxifen 73% 80%       Davidson NE. 2000 NIH Consensus Development Conference on Adjuvant Therapy for Breast Cancer; Abstract

INTERNATIONAL OVERVIEW RESULTS OF ADJUVANT OVARIAN ABLATION, TAMOXIFEN AND CHEMOTHERAPY

Adapted from Lancet 1996;348:1189-1196. Abstract Lancet 1998;353:930-942. Abstract

Derived from Klijn JGM 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(2):343-353. Abstract

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