A follow-up study of a randomized controlled study evaluating safety and efficacy of leuprorelin acetate every-3-month depot for 2 versus 3 or more years with tamoxifen for 5 years as adjuvant treatment in premenopausal patients with endocrine-responsive breast cancer

Abstract

Background: Previously, we conducted the 5-year open-label, randomized controlled trial (RCT) of leuprorelin adjuvant therapy in post-operative premenopausal patients with endocrine-responsive breast cancer, which was a pilot study to investigate the optimal duration of leuprorelin treatment. Since, however, long-term outcomes became required for the adjuvant endocrine therapy, we performed this follow-up observation study.

Methods: Follow-up observation study was performed up to 10th year after randomization, continuing RCT to evaluate the efficacy and safety of leuprorelin every 3 months for ≥ 3 versus 2 years, with daily tamoxifen for 5 years. Primary endpoints were disease-free survival (DFS) and 2-year landmark DFS.

Results: Eligible patients (N = 222) were randomly assigned to receive leuprorelin for either 2 years (N = 112) or ≥ 3 years (N = 110) with tamoxifen. Leuprorelin treatment for ≥ 3 years versus 2 years provided no significant difference in DFS (HR 0.944, 95% CI 0.486-1.8392) or 2-year landmark DFS (N = 99 and 102 in 2-year and ≥ 3-year groups, HR 0.834, 0.397-1.753). In small, higher-risk subgroup (n = 17); however, 2-year landmark DFS in ≥ 3-year group was significantly longer (HR 0.095, 0.011-0.850) than that in 2-year group. The incidence of bone-related adverse events was around 5% in both groups.

Conclusions: Adjuvant leuprorelin treatment for ≥ 3 years with tamoxifen only showed similar efficacy and safety profiles to those for 2 years in analyses among all patients but suggested greater benefit in higher-risk patients. No new safety signal was identified for long-term leuprorelin treatment.

Trial registration number: Not applicable. This was an observational study.

Keywords: Adjuvant endocrine therapy; Endocrine-responsive breast cancer; LH-RH agonist; Ovarian function suppression; Premenopausal patient.

Fig. 1

Study design and timeline

Fig. 2

Patient disposition. FAS full analysis set, IC informed consent, RCT randomized controlled trial

Fig. 3

OR comparing incidence rates of OS, DFS and bone-related adverse events in 3-or-more-year treatment group with those in 2-year treatment group. OR of incidences of death and DFS events in patients treated with leuprorelin for 3 or more years versus those treated with it for 2 years a in FAS and b in mFAS. c OR of incidences of bone-related adverse events between these two groups. P value was calculated using 2-sided Fisher’s exact test. Other SMNs esophageal carcinoma (n = 1 in 2-year treatment group), and rectal carcinoma, cervical carcinoma and cutaneous lymphoma (each n = 1 in ≥ 3-year treatment group), modified FAS dataset from patients who were available to continue the study from 2 years (96 weeks) after the randomization. CI confidence interval, DFS disease-free survival, FAS full analysis set, LRR local–regional recurrence, mFAS modified FAS, MTS metastasis, OR odds ratio, OS overall survival, SMNs Secondary malignant neoplasms

Fig. 4

DFS and OS compared between 2-year and 3-or-more-year treatment groups in FAS and mFAS. a DFS in FAS. b 2-year landmark DFS in mFAS. c OS in FAS. d 2-year landmark OS in mFAS. 2-year landmark DFS/OS, defined as the time from the second year after randomization to DFS or OS events, modified FAS dataset from patients who were available to continue the study from 2 years (96 weeks) after the randomization. DFS disease-free survival, FAS full analysis set, mFAS modified FAS, OS overall survival

Fig. 5

2-year landmark DFS compared between 2-year and 3-or-more-year treatment groups in higher- and low-risk patient subgroups. a DFS subgroup analysis to verify clinical risk factors in 2-year treatment groups using univariate Cox regression analysis. P value was determined by a two-sided log-rank test. ^aRisk was classified into low- and higher-risk based on the breast cancer stage considering lymph node status and patient age as shown below. b 2-year landmark DFS, defined as the time from the second year after randomization to DFS events. The interaction between treatment (3-or-more versus 2-year treatment) and risk level (higher and low) was analysed using the multivariate Cox proportional-hazard model. Interaction p-value was determined using a 2-sided Wald test. Higher-risk patients patients who had ≥ stage IIb or who were aged under 35 years in stage IIa, low-risk patients patients who had stage I or who were aged ≥ 35 in stage IIa, modified FAS dataset from patients who were available to continue the study from 2 years (96 weeks) after the randomization. DFS disease-free survival, mFAS modified full analysis set