New Roles Forecast for Endocrine Therapy

PARIS, France--New ideas and applications for endocrine therapyin early breast cancer may provide a revolution in our thinkingabout the nature of the disease, said Dr. M. Baum, of The RoyalMarsden Hospital, London. The efficacy of adjuvant tamoxifen (Nolvadex)therapy in prolonging disease-free survival in postmenopausalwomen with early breast cancer has been securely established,he said at the Fifth International Congress on Anti-Cancer Chemotherapy.

The next generation of trials, he stressed, must explore the utilityof tamoxifen therapy in premenopausal women and in those withnegative estrogen-receptor (ER) status, the interaction of tamoxifenwith estrogen replacement therapy, the optimum duration of tamoxifentherapy, and the role of tamoxifen in primary therapy.

The conclusion that tamoxifen is effective only in postmenopausalwomen may well be flawed, Dr. Baum said. The problem, he suggested,may stem from comparisons of chemotherapy plus tamoxifen versuschemotherapy alone, in which the benefits of tamoxifen may beovershadowed or diluted by the effects of chemotherapy.

He challenged the idea that tamoxifen, which causes a paradoxicalincrease in estradiol levels prior to menopause, is a biologicallyimplausible therapy for premenopausal women. "If you believethat there's a simple interaction between estrogen and micrometastases,then you would assume that tamoxifen would make things worse inthe premenopausal woman--but that is just not the case,"he said.

In fact, he pointed out, the United Kingdom Cancer Research Campaign(CRC) Adjuvant Breast Cancer Trial documented similar 10-yearfollow-up results in 300 premenopausal women and 660 postmenopausalwomen who had received tamoxifen.

"The joker in the pack is the unexpected results of the oldtrials of ovarian ablation," Dr. Baum said. He noted thatthe Scottish Cancer Trials Group found "superimpossible"15-year survival curves in premenopausal women who underwent ovarianablation and in those who received adjuvant chemotherapy.

The question of whether ovarian suppression is equivalent to chemotherapyis particularly important, he stressed, now that currently availableluteinizing hormone-releasing hormone (LHRH) analogs offer a reversiblealternative to surgical castration or radiation menopause.

An ongoing CRC-European collaborative trial has randomized nearly2,000 women under 50 with operable breast cancer to receive tamoxifen,an LHRH analog, both agents, or no therapy. In this trial, adjuvantchemotherapy is being reserved only for those patients with apoor prognosis.

Although the Scottish Cancer Trials Group also reported that ovarianablation was more effective in ER-positive patients, Dr. Baumargued that the trial was too small to permit subgroup analysisand that a modest advantage for ER-negative patients may wellhave been overlooked.

In light of the current recognition that tamoxifen works not onlyas an antiestrogen but also via induction of TGF-beta and suppressionof insulin-like growth factor (IGF), he advised clinicians toignore the patient's ER status when using tamoxifen alone.

ERT and All-Cause Mortality

Dr. Baum also questioned the conventional wisdom that estrogenreplacement therapy (ERT) be withheld from women with breast cancer,even in the absence of evidence that it worsens breast cancerprognosis.

"There's a tragic irony that many patients who may not evenbe benefiting from systemic anticancer therapy may be experiencinga seriously impaired quality of life from ovarian suppression,"he commented.

In response to grassroots demand, he said, a feasibility pilotstudy is now being conducted at The Royal Marsden in which perimenopausalwomen with breast cancer who either complain of menopausal symptomsor have a family history of osteoporosis or ischemic heart diseaseare being randomized to hormone replacement therapy or placebo.

"It's all-cause mortality we're interested in, because wemay indeed be saving a few patients from breast cancer only tohave them die of ischemic heart disease," he noted.

Open-Ended Prescriptions?

The optimum duration of tamoxifen therapy also has yet to be resolved,Dr. Baum said. "I find it quite extraordinary that womenare left on adjuvant tamoxifen as an open-ended prescription,"he noted. "This is taking the results of clinical trialsand extrapolating them way beyond what we know."

Although the long-term treatment strategy is based on the assumptionthat tamoxifen acts as a cytostatic agent, Dr. Baum emphasizedthat some cell lines may, in fact, become dependent on tamoxifen.Moreover, he noted, long-term therapy with high-dose tamoxifenmay be associated with an increased risk of endometrial cancer.

Dr. Baum cited an overview of five trials involving 2,300 womenthat showed equivalent survival with short-duration and long-durationtamoxifen. A more definitive answer, he said, may be forthcomingfrom a CRC trial in which several thousand women who had receivedtamoxifen for 2 years were randomized to either continue therapyfor another 3 years or to stop therapy.

Dr. Baum reviewed recent evidence suggesting that surgical removalof the primary tumor might result in the loss of angiogenesis-inhibitingand apoptosis-stimulating factors and thereby kick-start the growthof dormant micrometastases. This cascade of events might be interrupted,he proposed, by priming the patient with antihormones, progestins,or antiangiogenic agents prior to surgery.

Based on this theoretical rationale, Dr. Baum and his colleaguesare piloting a study of primary adjuvant tamoxifen therapy thatwill serve as a prelude to large-scale CRC trials comparing primarytamoxifen with or without aromatase inhibitors versus conventionallytimed medical therapy.