Abstract P2-02-01: Benefit of adjuvant bisphosphonates in early breast cancer treated with contemporary systemic therapy: A meta-analysis of randomized control trials
Authors: Mittal Abhenil , Tamimi Faris , Valiente Consolacion Molto , Iorio Massimo Di , Amir Eitan 
Published: March 2023

Abstract
Introduction: Based on trials performed over a 25-year period, the Early Breast Cancer Trialists Collaborative Group (EBCTCG) identified a small but significant benefit of adjuvant bisphosphonates (BP) in reducing bone recurrence with a subsequent modest improvement in breast cancer-specific survival in post-menopausal women. Multiple studies show that contemporary event rates in early-stage breast cancer are much lower than those observed over a decade ago. This observation likely reflects the impact of modern adjuvant systemic therapy such as anthracycline and taxane chemotherapy and aromatase inhibitors. Therefore, re-evaluating the benefit of adjuvant bisphosphonate in the modern era is warranted.
Methods: We reviewed reports of randomized trials of adjuvant BP that accrued patients exclusively beyond 2000 and extracted 5-year disease free survival (DFS) and overall survival (OS) in BP and control group arm along with hazard ratios (HR) when reported. The mean 5-year DFS and OS weighted by study sample size was calculated for each group. HR for DFS and OS were pooled in a meta-analysis using generic inverse variance and random effects modelling. Trial level absolute differences in DFS and OS between BP and control arms were calculated. Meta-regression comprising linear regression weighted by sample size (mixed effects) was then performed to explore association between disease and treatment related factors and absolute differences in benefit from BP. Quantitative significance was explored using methods described by Burnand et al. Analyses were performed using SPSS version 28 (IBM Corp, Armonk NY) and Review manager v5.4.
Results: Twelve trials comprising 24109 patients were included in the analysis. Weighted mean DFS and OS in patients receiving BP were 85.8% and 91.7% respectively. For control group patients, these estimates respectively were 83.4% and 91.0%. For DFS, pooled HR across trials was 0.89 (0.81-0.97) with a 2.9% weighted mean difference favoring BP over control. Among patients receiving anthracycline and taxane based chemotherapy (n=3007), relative benefits were smaller; (HR DFS 0.94, 0.85-1.05). There was no significant OS benefit with BP (HR 0.92, 0.82-1.03) and this finding was observed irrespective of type of chemotherapy. The impact of BP on OS was smaller in both relative and absolute terms in studies with recruitment occurring more recently. Meta-regression results are shown in Table. There was lesser benefit in higher risk patients (node+, larger tumor size, ER-, grade 3 or those receiving chemotherapy). Overall, 1.13% patients experienced osteonecrosis related to BP therapy.
Conclusions: Compared to EBCTCG data, relative and absolute benefit from BP is similar or modestly lower among more recent trials. Benefit from adjuvant BP appears smaller in patients treated with more contemporary adjuvant systemic therapy especially anthracycline and taxane containing chemotherapy. It is uncertain if the impact of BP on OS (rather than breast-cancer specific survival) is of a clinically meaningful magnitude. Despite de-escalated dosing compared to metastatic disease, osteonecrosis was observed in &gt;1% of patients. It is possible that the benefits of BP are driven by patients with clinically low-risk disease rather than those with at high-risk. The balance between benefits and risks of adjuvant BP should be considered in individual patients.
Table 1: Metaregression Results
Citation Format: Abhenil Mittal, Faris Tamimi, Consolacion Molto Valiente, Massimo Di Iorio, Eitan Amir. Benefit of adjuvant bisphosphonates in early breast cancer treated with contemporary systemic therapy: A meta-analysis of randomized control trials [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-02-01.