Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial

Abstract

The aim of the study is to analyse whether letrozole (L) and zoledronic acid plus L (ZL) are more effective than tamoxifen (T) as adjuvant endocrine treatment of premenopausal patients with breast cancer with hormone receptorepositive (HRþ) tumours. Patients and methods: In a phase 3 trial, 1065 premenopausal patients with HR þ early breast cancer received triptorelin to suppress ovarian function and were randomly assigned (1:1:1) to adjuvant T, L or ZL for 5 years. Cancer recurrence, second breast or non-breast cancer and death were considered events for the intention-to-treat disease-free survival (DFS) analysis. Results: With a 64-month median follow-up and 134 reported events, the disease-free rate at 5 years was 85.4%, 93.2% and 93.3% with T, L and ZL, respectively (overall P Z 0.008). The hazard ratio for a DFS event was 0.52 (95% confidence interval [CI], 0.34 to 0.80; P Z 0.003) with ZL vs T, 0.72 (95% CI, 0.48 to 1.07; P Z 0.06) with L vs T and 0.70 (95% CI, 0.44 to 1.12; P Z 0.22) with ZL vs L. With 36 deaths, there was no significant difference in overall survival (P Z 0.14). Treatment was stopped for toxicity or refusal in 7.3%, 7.3% and 16.6% patients, and in the safety population, grade 3e4 side-effects were reported in 4.2%, 6.9% and 9.1% patients treated with T, L or ZL, respectively. Conclusion: HOBOE study shows that in premenopausal patients with early breast cancer undergoing ovarian function suppression with triptorelin, ZL significantly improves DFS, while worsening compliance and toxicity, as compared with T. (NCT00412022)

Role of Bone Targeting Agents in the Prevention of Bone Metastases from Breast Cancer

“…In this regard, a multicenter phase III Italian clinical trial (HOrmonal BOne Effects, HOBOE) randomized 1065 premenopausal women with hormone-receptor-positive early BC to receive adjuvant triptorelin in addition to tamoxifen (TT), letrozole (TL) or letrozole + zoledronate (TLZ). Interestingly, at five years, the highest DFS was reached in TLZ arm (93.3%, 95% CI 89.8-95.6), and the comparison of TLZ versus TT reached statistical significance, with an absolute risk reduction of greater than 7% observed with TLZ from the fourth year on (p = 0.003) [67].…”

Current State of the Art in the Adjuvant Systemic Treatment of Premenopausal Patients With Early Breast Cancer

“…At a median follow-up of 5 years, a favorable but nonstatistically significant advantage for OFS plus letrozole as compared with OFS plus tamoxifen was observed in terms of DFS (HR: 0.72; 95% CI: 0.48-1.07) with no significant differences in OS (P = .14). 63 Taken together, the available evidence suggests that OFS (with tamoxifen or an AI) should be considered in patients with higher risk of disease recurrence, whereas tamoxifen alone is still a valid option for those with favorable clinicopathological features. 15,26,67 The higher the risk of recurrence, the larger is the expected benefit and thus the preference for the combination of OFS plus an AI.…”

“…Three trials compared the efficacy and safety of OFS combined with tamoxifen or an AI (Table 2). 62,63,65 In the ABCSG-12 trial, a total of 1803 premenopausal patients with hormone receptor-positive breast cancer were randomized to 3 years of OFS plus anastrozole or tamoxifen with or without zoledronic acid. 62 The patient population included in this trial had low risk of disease recurrence: median age was 45 years, 30% had nodal involvement, and 5% were previously exposed to chemotherapy.…”

“…In the HOBOE study, a total of 1065 premenopausal patients with hormone receptor-positive breast cancer were randomized to receive 5 years of treatment with OFS plus letrozole or OFS plus tamoxifen with or without zoledronic acid. 63 Median age at randomization was 45 years; about 45% of patients had nodal involvement and 62% were previously exposed to chemotherapy. At a median follow-up of 5 years, a favorable but nonstatistically significant advantage for OFS plus letrozole as compared with OFS plus tamoxifen was observed in terms of DFS (HR: 0.72; 95% CI: 0.48-1.07) with no significant differences in OS (P = .14).…”

“…26 Two trials evaluated the potential anticancer effect of bisphosphonates added to endocrine therapy in the specific cohort of premenopausal patients undergoing OFS. 62,63 In the ABCSG-12 trial, at a median follow-up of 8 years, the addition of zoledronic acid improved DFS compared with endocrine therapy alone (HR: 0.77; 95% CI: 0.60-0.99) with a trend in OS (HR: 0.66; 95% CI: 0.43-1.02). 62 In the HOBOE trial, a statistically significant benefit in DFS was observed for OFS plus letrozole plus zoledronic acid compared with OFS plus tamoxifen (HR: 0.52 95% CI: 0.34-0.80) without significant difference in OS.…”