The study involved 1,099 premenopausal women with estrogen or progestin receptor-positive, stage I or II breast cancer. Following surgery, the women were randomized to 1 of 2 treatment regimens: 1) ovarian suppression with 3.6 mg of goserelin (Zoladex) every 28 days for 3 years and 20 mg/day of tamoxifen for 5 years; 2) 6 cycles of chemotherapy consisting of cyclophosphamide (Cytoxan) 600 mg/m² combined with methotrexate 40 mg/m², and fluorouracil (Adrucil) 600 mg/m² intravenously on days 1 and 8.

All patients in the ovarian ablation group and 53.1% of those in the chemotherapy group developed treatment-related amenorrhea, defined as cessation of menstruation from treatment month 3 to month 6 or longer.

At a median follow-up of 11 years, 19.1% of the women overall had died and 28.4% had relapsed.

Further analysis showed that, overall, cessation of menstruation was associated with a significant 42% reduction in relapse risk (P = .0031), but not in mortality risk (P = .2342).

Similarly, among the 505 patients in the chemotherapy arm, treatment-related amenorrhea was associated with a significant 44% improvement in relapse-free survival (P = .0163) but not in overall survival.

Dr. Gnant said that women under the age of 40 years "accounted for basically the entire benefit in the chemotherapy group." Specifically, he reported, "there was a significant trend to improved relapse-free survival with treatment-related amenorrhea in women under 40 [P = .0965], but no association between menstruation and relapse-free survival in women ages 41 to 50 [P = .7585] or women over 50 [P = .3368]."

The results suggest that chemotherapy drugs may have a dual effect in some women -- they not only are cytotoxic, but also work indirectly by suppressing the ovaries, Dr. Gnant said.

"For younger patients who do not experience treatment-induced amenorrhea during chemotherapy, additional ovarian suppression may be advisable," Dr. Gnant said.

The question of whether drugs that suppress ovarian function benefit premenopausal patients with endocrine-responsive disease who continue to menstruate despite chemotherapy is the subject of several ongoing trials, he noted.

While awaiting results, Kathy S. Albain, MD, professor, department of medicine, hematology/oncology, Loyola University of Chicago Medical Center, Chicago, Illinois, said clinicians should discuss the treatment with patients on chemotherapy who do not experience treatment-induced amenorrhea.

"I already tell my younger patients with hormone receptor-positive breast cancer that there is probably a survival advantage to shutting down their menstrual cycles," she said.


[Presentation title: The Impact of Treatment-Induced Amenorrhea on Survival of Premenopausal Patients With Endocrine-Responsive Breast Cancer: 10-Year Results of ABCSG-05 (CMF Vs. Goserelin + Tamoxifen). Abstract 17]

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