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Section 4
Optimal use of adjuvant tamoxifen and ovarian ablation

OVERVIEW

The International Breast Cancer Overview has clearly demonstrated that adjuvant ovarian ablation significantly reduces mortality in premenopausal patients and that 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 or without chemotherapy. While five years is the accepted current standard duration of adjuvant tamoxifen, randomized trials are evaluating more prolonged treatment or sequencing tamoxifen with aromatase inhibitors. Other SERMS are also being evaluated in various clinical settings including the STAR trial, which compares raloxifene to tamoxifen in high-risk women.

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 castration. This became standard treatment for premenopausal women with advanced breast cancer, and provided the first approach to trials of adjuvant systemic therapy 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.

15-YEAR BENEFITS OF TAMOXIFEN

In receptor-positive disease, the effects of five years of tamoxifen were very impressive in preventing approximately 40% of recurrences within the first 10 years. We now have 15-year follow - up on these trials, and these differences in recurrence and in survival are as big at year 15 as they we re at year 10. These are durable differences .

- Richard Peto, FRS

SUSTAINED ACTION OF TAMOXIFEN

The sustained biological action of tamoxifen seems to last for many years after it is no longer being administered. We have recently published a potential explanation. After tumor cells are retransplanted into animals for five years, tamoxifen stimulates growth, and no treatment results in sluggish tumor growth. But when you treat with estrogen, the tumors melt away. Physiological levels of estrogen attack the supersensitized tumors, creating an apoptotic mechanism killing these cells. This could explain how long-term adjuvant tamoxifenworks, because on stopping around five years, the woman's own estrogen now comes back and seeks out these supersensitized micrometastatic breast cancer cells consolidating the beneficial effects of tamoxifen with a second antitumor action.

-V Craig Jordan, PhD, DSc

OVERVIEW DATA ON OVARIAN ABLATION

The overview data is from older studies and the number of patients in the ovarian ablation trials are few, compared to the number in tamoxifen trials or chemotherapy trials. There were several thousand patients in the 60s and 70s, randomized to ovarian ablation or not, at first - mainly in the absence of any chemotherapy. In some of the later trials, chemotherapy plus ovarian ablation versus the same chemotherpy alone was studied.

And 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 chemotherapies of that day: CMF, AC and so on. And because the studies are so old, the receptor status wasn't known in many of the patients. In the later trials, you can see that added to chemotherapy, ovarian ablation isn't quite as clearly significantly effective, although it tends to add something to chemotherapy. It may be that with chemotherapy some of these patients become amenorrheic so that adding ovarian ablation doesn't do as much.

-Kathleen Pritchard, MD

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

NSABP P-2: THE STAR TRIAL

There is a great deal of enthusiasm for this trial, and an enormous amount of credit has to go to the NSABP members who are committed to moving the state-of-the-art forward. That's their primary commitment, and it was the primary commitment of the 13,388 selfless and courageous women who entered the P-1 trial. And I believe that there will be 22,000 more women out there who will enter P-2.

-Norman Wolmark, MD

RALOXIFENE

Raloxifene has been studied in a completely different population, namely older postmenopausal women selected for osteoporosis risk, and some data suggest that women with decreased bone density are at decreased breast cancer risk. The raloxifene data on breast cancer risk reduction is promising, but right now for postmenopausal women who are at increased risk, tamoxifen is clearly the drug of choice outside of a clinical trial. Also, raloxifene is only for postmenopausal women; there are no safety data in premenopausal women.

-Monica Morrow, MD

NSABP P-1: THE BREAST CANCER PREVENTION TRIAL

... we consider it highly inappropriate to not offer tamoxifen to women who are similar to those in the P-1 study and who may benefit from its use as a breast cancer preventive agent.

-Bernard Fisher, MD et al. J Natl Cancer Inst 1998;90(18):1371-1388.

In my view, both the certainty and the magnitude of the effect of tamoxifen on the prevention of breast cancer are remarkable aspects of the P-1 findings. In more than three decades of research, I have rarely, if ever, observed such a major response to a breast cancer therapeutic agent.

-Bernard Fisher, MD J Clin Oncol 1999;17(5):1632-1639.

NSABP P-1 PROVIDES PROOF OF PRINCIPLE FOR CHEMOPREVENTION

The BCPT has achieved an extraordinary advance for the control of breast cancer and has provided the proof of principle of the chemopre-vention approach. It is now established that human cancer can be prevented with a pharmacologic intervention. Why did the BCPT succeed, whereas many other phase III trials, particularly those involving ß-carotene, have not achieved positive results? The answer seems to relate largely to strength of rationale, which for the BCPT involved tamoxifen's therapeutic efficacy, secondary phase III clinical findings (involving contralateral breast cancer), and mechanistic/molecular-targeting study.

-Scott M Lippman, MD, Powel H Brown, MD, PhD J Natl Cancer Inst 1999;91(21):1809-1819.

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