Importance Whether the administration of luteinizing hormone-releasing hormone analogues (LHRHa) during chemotherapy is a reliable strategy to preserve ovarian function is controversial owing to both the lack of data on long-term ovarian function and pregnancies and the safety concerns about the potential negative interactions between endocrine therapy and chemotherapy. Objective To evaluate long-term results of LHRHa-induced ovarian suppression during breast cancer chemotherapy. Design, Setting, and Participants Parallel, randomized, open-label, phase 3 superiority trial conducted at 16 Italian sites. Between October 2003 and January 2008, 281 premenopausal women with stage I to III hormone receptor-positive or hormone receptor-negative breast cancer were enrolled. Last annual follow-up was June 3, 2014. Interventions Patients were randomized to receive adjuvant or neoadjuvant chemotherapy alone (control group) or chemotherapy plus triptorelin (LHRHa group). Main Outcomes and Measures The primary planned end pointwas incidence of chemotherapy-induced early menopause. Post hoc end points were long-term ovarian function (evaluated by yearly assessment of menstrual activity and defined as resumed by the occurrence of at least 1 menstrual cycle), pregnancies, and disease-free survival (DFS). Results A total of 281 women (median age, 39 [range, 24-45] years) were randomized. Median follow-up was 7.3 years (interquartile range, 6.3-8.2 years). The 5-year cumulative incidence estimate of menstrual resumption was 72.6%(95%CI, 65.7%-80.3%) among the 148 patients in the LHRHa group and 64.0%(95%CI, 56.2%-72.8%) among the 133 patients in the control group (hazard ratio [HR], 1.28 [95%CI, 0.98-1.68]; P =.07; age-adjusted HR, 1.48 [95%CI, 1.12-1.95]; P =.006). Eight pregnancies (5-year cumulative incidence estimate of pregnancy, 2.1% [95%CI, 0.7%-6.3%]) occurred in the LHRHa group and 3 (5-year cumulative incidence estimate of pregnancy, 1.6%[95%CI, 0.4%-6.2%]) in the control group (HR, 2.56 [95%CI, 0.68-9.60]; P =.14; age-adjusted HR, 2.40 [95%CI, 0.62-9.22]; P =.20). Five-year DFS was 80.5%(95%CI, 73.1%-86.1%) in the LHRHa group and 83.7%(95%CI, 76.1%-89.1%) in the control group (LHRHa vs control: HR, 1.17 [95%CI, 0.72-1.92]; P =.52). Conclusions and Relevance Among premenopausalwomenwith either hormone receptor- positive or hormone receptor-negative breast cancer, concurrent administration of triptorelin and chemotherapy, compared with chemotherapy alone,was associated with higher long-term probability of ovarian function recovery, without a statistically significant difference in pregnancy rate. Therewas no statistically significant difference in DFS forwomen assigned to triptorelin and those assigned to chemotherapy alone, although study powerwas limited.
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