GLOBOCAN 2020 estimates that breast cancer is the most common cancer in the world, with an age standardized incidence rate of 47.8 cases per 100 000 women.1 As in most other countries, breast cancer has become a major health problem in China.2, 3 Adjuvant bisphosphonates and denosumab in early breast cancer have resulted in bone metastasis reduction and improved overall survival. Both of these drugs can prevent bone loss acceleration and reduce the risk of skeletal-related adverse events in breast cancer patients with treatment-induced estrogen level and/or bone density decrease.4 Previous studies have indicated that bisphosphonates also have more direct antitumor activity. This may be explained by the fact that bisphosphonates can modify the bone marrow microenvironment to prevent the activation of dormant tumor cells that have spread to the bone.5 Indeed, recent studies have demonstrated that circulating tumor cells (CTCs) in blood samples collected during routine follow-up of breast cancer patients 2 or 5 years after adjuvant chemotherapy were an independent prognostic factor.6-9 These studies suggest that bisphosphonates may improve the prognosis of breast cancer due to a direct adverse effect on CTCs.

Several studies have evaluated the effect of adding bisphosphonates to adjuvant treatment on survival of breast cancer patients, but the results are controversial and the conclusions reached are inconsistent.10, 11 Among them, two meta-analyses based on 18 766 cases collected by Early Breast Cancer Trialists Collaborative Group (EBCTCG) and 13 949 cases from the Cochrane Library showed that adjuvant bisphosphonate therapy significantly improved the survival of postmenopausal patients with breast cancer.12, 13 At present, the published treatment guidelines recommend that postmenopausal early breast cancer patients who have any indications for systemic treatment should be given adjuvant bisphosphonates for 3–5 years.14 However, the optimal treatment duration of adjuvant bisphosphonates for preventing recurrence and improving survival in early breast cancer patients is still unclear.

In a study recently published in JAMA Oncology, Friedl et al.15 analyzed the survival of early breast cancer patients who received 5- and 2-year adjuvant zoledronate treatment in a large randomized, multicenter, phase III clinical trial (SUCCESS A trial). Moreover, they compared the presence of CTCs in the blood samples of these two patient groups five years after adjuvant chemotherapy and assessed the frequency of adverse events related to zoledronate treatment. A total of 2987 patients with early breast cancer were enrolled in the study. Their ages ranged from 21 to 86 with a median age of 53 years old. Adjusted multivariate Cox proportional hazards regression models showed that overall survival (hazard ratio [HR] = 0.98; 95% confidence interval [CI] = 0.67–1.42; p = 0.90), disease-free survival (HR = 0.97; 95% CI = 0.75–1.25; p = 0.81), and distant disease-free survival (HR = 0.87; 95% CI = 0.65–1.18; p = 0.38) did not differ significantly between the 5- and 2-year treatment groups. Adverse events occurred more frequently in the 5-year zoledronate treatment group (46.2%) compared with the 2-year zoledronate treatment group (27.2%), especially bone pain (8.3% vs. 3.7%) and arthralgia (5.1% vs. 3.1%).

Although the subgroup analyses of EBCTCG revealed that ≥2 years of bisphosphonate treatment might not provide additional survival benefits,12 the results in these exploratory subgroup analyses are indirect evidence. The present study directly compared the effectiveness and safety of different adjuvant bisphosphonate treatment durations in early breast cancer patients for the first time. Additionally, the SUCCESS A trial is the first clinical trial to determine the optimal duration of adjuvant bisphosphonate treatment in early breast cancer. The results of this large randomized clinical trial showed that extending the adjuvant treatment of zoledronate to more than 2 years had no benefit in terms of overall, disease-free, and distant disease-free survival, regardless of menopausal status. Furthermore, with the extension of the zoledronate treatment duration, the incidence of adverse events (especially the skeletal-related events) increased.

This clinical trial has several limitations. First, this study used a variety of different zoledronate dosing schedules, which might have unpredictable effects on the experimental results. Moreover, this study only enrolled high-risk early breast cancer patients received adjuvant chemotherapy. Therefore, its results cannot be generalized and applied to all breast cancer patients. Last but not least, the number of adverse events involved in this study is relatively small, which limits the power of subgroup analysis.

Although this study still has the limitations mentioned above, it is the first direct evidence to prove that there is no statistically significant difference in prognosis between 2- and 5-years adjuvant zoledronate treatment following chemotherapy in high-risk early breast cancer patients. Therefore, the results in this study suggest that 3–5 years of adjuvant bisphosphonate treatment for high-risk early breast cancer patients which are recommended by current treatment guidelines could be reduced.

The authors declare no competing interests.