Long-Term Outcome Results Of The Phase Iii Promise-Gim6 Study Evaluating The Role Of Lhrh Analog (Lhrha) During Chemotherapy As A Strategy To Reduce Ovarian Failure In Early Breast Cancer Patients

Background: The administration of LHRHa during chemotherapy (CT) is still considered an experimental strategy to preserve ovarian function and fertility mainly due to the lack of data on long-term ovarian function and pregnancy rate, and because of the concerns about the safety of the procedure in hormone-receptor positive breast cancer. The present analysis reports long-term outcome results of the phase 3 PROMISE-GIM6 study aiming to evaluate the role of LHRHa as a strategy to protect ovarian function during CT.Material and methods: In this multicenter, randomized, phase 3 study, premenopausal women with stage I to III breast cancer candidates for (neo)adjuvant CT were randomly allocated (1:1) with a centralized system to receive CT alone or combined with LHRHa triptorelin. The primary aim was to compare the incidence of CT-induced early menopause between treatment arms (Del Mastro et al. JAMA 2011). The present analysis focuses on long-term ovarian function, pregnancies, and disease-free survival (DFS) events.Results: From October 24, 2003 through January 14, 2008, 281 patients entered the study. Median follow-up was 7.3 years (6.3-8.2 years). A total of 226 patients (80.4%) had hormone receptor positive disease. The 5-year cumulative incidence estimate of menstrual resumption was 72.6% (95% Confidence Intervals [CI] 65.7-80.3) in the CT plus LHRHa arm and 64.0% (95% CI 56.2-72.8) in the control group (hazard ratio [HR] 1.28, 95% CI 0.98-1.68; p = 0.071). The age-adjusted estimate of HR was 1.48 (95% CI 1.12-1.95; p = 0.006). A total of 8 pregnancies occurred in the CT plus triptorelin group and 3 pregnancies in the CT alone group (HR 2.56, 95% CI 0.68-9.6; p = 0.142; age-adjusted HR 2.40, 95% CI 0.62-9.22; p = 0.204). Thirty-six DFS events were observed among the 148 patients allocated to CT plus triptorelin and 29 among the 133 patients allocated to CT alone. The estimated rates of DFS at 5 years were 80.5% (95% CI 73.1-86.1) and 83.7% (95% CI 76.1-89.1) in the CT plus triptorelin and CT alone arms, respectively (HR 1.17, 95% CI 0.72-1.92; p = 0.519).Conclusions: In premenopausal, young breast cancer patients, the concurrent administration of LHRHa triptorelin and CT increases the probability of long-term ovarian function maintenance, with no negative effect on prognosis. The higher number of pregnancies in the CT plus triptorelin arm as compared to the CT alone arm suggests a possible benefit in terms of fertility preservation (ClinicalTrial.gov: NCT00311636). Background: The administration of LHRHa during chemotherapy (CT) is still considered an experimental strategy to preserve ovarian function and fertility mainly due to the lack of data on long-term ovarian function and pregnancy rate, and because of the concerns about the safety of the procedure in hormone-receptor positive breast cancer. The present analysis reports long-term outcome results of the phase 3 PROMISE-GIM6 study aiming to evaluate the role of LHRHa as a strategy to protect ovarian function during CT. Material and methods: In this multicenter, randomized, phase 3 study, premenopausal women with stage I to III breast cancer candidates for (neo)adjuvant CT were randomly allocated (1:1) with a centralized system to receive CT alone or combined with LHRHa triptorelin. The primary aim was to compare the incidence of CT-induced early menopause between treatment arms (Del Mastro et al. JAMA 2011). The present analysis focuses on long-term ovarian function, pregnancies, and disease-free survival (DFS) events. Results: From October 24, 2003 through January 14, 2008, 281 patients entered the study. Median follow-up was 7.3 years (6.3-8.2 years). A total of 226 patients (80.4%) had hormone receptor positive disease. The 5-year cumulative incidence estimate of menstrual resumption was 72.6% (95% Confidence Intervals [CI] 65.7-80.3) in the CT plus LHRHa arm and 64.0% (95% CI 56.2-72.8) in the control group (hazard ratio [HR] 1.28, 95% CI 0.98-1.68; p = 0.071). The age-adjusted estimate of HR was 1.48 (95% CI 1.12-1.95; p = 0.006). A total of 8 pregnancies occurred in the CT plus triptorelin group and 3 pregnancies in the CT alone group (HR 2.56, 95% CI 0.68-9.6; p = 0.142; age-adjusted HR 2.40, 95% CI 0.62-9.22; p = 0.204). Thirty-six DFS events were observed among the 148 patients allocated to CT plus triptorelin and 29 among the 133 patients allocated to CT alone. The estimated rates of DFS at 5 years were 80.5% (95% CI 73.1-86.1) and 83.7% (95% CI 76.1-89.1) in the CT plus triptorelin and CT alone arms, respectively (HR 1.17, 95% CI 0.72-1.92; p = 0.519). Conclusions: In premenopausal, young breast cancer patients, the concurrent administration of LHRHa triptorelin and CT increases the probability of long-term ovarian function maintenance, with no negative effect on prognosis. The higher number of pregnancies in the CT plus triptorelin arm as compared to the CT alone arm suggests a possible benefit in terms of fertility preservation (ClinicalTrial.gov: NCT00311636).