Premature ovarian failure is a devastating long-term toxic effect of chemotherapy for premenopausal women. The survival benefit of adjuvant chemotherapy in young women with operable hormone receptor–negative breast cancer is well known, but concern over becoming infertile may influence the choice of treatment for many women. A number of trials have investigated the combined use of a gonadotropin-releasing hormone (GnRH) agonist and adjuvant chemotherapy in an attempt to protect ovarian function in premenopausal women. Results of such studies were mixed, and there were few data on pregnancy outcomes.
The aim of this randomized trial was to determine whether administration of the GnRH agonist goserelin with chemotherapy would reduce the rate of ovarian failure after adjuvant or neoadjuvant treatment of hormone-receptor–negative early-stage breast cancer. A total of 257 premenopausal women with operable hormone receptor–negative breast cancer were randomized to receive standard chemotherapy with goserelin (goserelin group) or standard chemotherapy without goserelin (chemotherapy-alone group). The rate of ovarian failure at 2 years was the primary study end point. Ovarian failure was defined as the absence of menses for the preceding 6 months and follicle-stimulating hormone levels in the postmenopausal range at 2 years. Conditional logistic regression was used to compare rates. Secondary end points evaluated included pregnancy outcomes and disease-free and overall survival.
Of the 257 patients, 218 were eligible and could be evaluated: 113 in the chemotherapy-alone group and 105 in the goserelin group. Complete primary end-point data were available for 135 of the 218 patients who could be evaluated. Among these, the ovarian failure rate was 8% in the goserelin group and 22% in the chemotherapy-alone group; the odds ratio was 0.30, with a 95% confidence interval of 0.09 to 0.97; 2-sided P = 0.04. To determine the effect of the missing primary end-point data on the main study findings, sensitivity analyses were performed. The results of these analyses showed that the missing data had no significant effect on the association between treatment and stratification variables (age and planned chemotherapy regimen). Among the 218 patients who could be evaluated, more women became pregnant in the goserelin group than in the chemotherapy-alone group (21% vs 11%, P = 0.03). Kaplan-Meier curves showed that more women in the goserelin group had improved disease-free survival (P = 0.04) and overall survival (P = 0.05).
Consistent with the findings of previous randomized trials, these data suggest that administration of a GnRH agonist with chemotherapy protects ovarian function, reducing the risk of early menopause and improving prospects for fertility. Although missing primary-end-point data weaken interpretation of the findings, there is no evidence that the missing data influenced the relative comparison between randomized groups.
The Cleveland Clinic Foundation, Cleveland, OH (H.C.F.M.); SWOG Cancer Research Group Statistical Center, Fred Hutchinson Cancer Research Center (J.M.U., W.E.B.), and Seattle Cancer Care Alliance and University of Washington (J.G.), Seattle, WA; Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria (K.-A.P., P.A.F.); Australia and New Zealand Breast Cancer Trials Group (ANZBCTG) (K.-A.P., P.A.F., J.F.F.); Calvary Mater Hospital, Newcastle, New South Wales (F.B., J.M.L., J.F.F.); and University of Sydney, Sydney (F.B.), Australia; International Breast Cancer Study Group (IBCSG), Bern, Switzerland (K.-A.P., P.A.F.); National Institute of Oncology, Budapest, Hungary (E.H.); Auckland Regional Cancer and Blood Service, Auckland, New Zealand (D.P.); Fox Chase Cancer Center, Philadelphia, PA (L.J.G.); Instituto de Enfermedades Neoplasicas (H.L.G.) and Oncosalud SAC (C.S.V.), Lima, Peru; Dana-Farber Cancer Institute (A.H.P., R.D.G.) and IBCSG Statistical Center (R.D.G.), Boston, MA; Wichita Community Clinical Oncology Program, Wichita (S.R.D.), and University of Kansas, Westwood (C.J.F.), KS; University of Southern California Norris Cancer Center, Los Angeles (A.A.G.); the Angeles Clinic and Research Institute, Santa Monica (S.M.); and University of California at Irvine Chao Family Comprehensive Cancer Center, Orange (F.L.M), CA; National Cancer Institute, Division of Cancer Prevention, Bethesda, MD (L.M.); M. D. Anderson Cancer Center, Houston, TX (G.N.H.); and Loyola University Medical Center, Cardinal Bernardin Cancer Center, Maywood, IL (K.S.A.)