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. 2023 May 29:15:17588359231173180.
doi: 10.1177/17588359231173180. eCollection 2023.

Adjuvant denosumab in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials

Luca Mastrantoni  1 , Giovanna Garufi  2   3 , Elena Di Monte  2 , Noemi Maliziola  2 , Mariangela Pasqualoni  2 , Letizia Pontolillo  2 , Sergio Pannunzio  2 , Maria Chiara Cannizzaro  2 , Armando Di Bello  2 , Alessandra Fabi  4 , Antonella Palazzo  2   3 , Giampaolo Tortora  2   3 , Emilio Bria  2   3 , Armando Orlandi  2   3
Affiliations

Adjuvant denosumab in early breast cancer: a systematic review and meta-analysis of randomized controlled clinical trials

Luca Mastrantoni et al. Ther Adv Med Oncol. .

Abstract

Background: In early breast cancer (BC) the impact of denosumab on survival outcomes is still unclear. We undertook a systematic review and meta-analysis to assess efficacy and safety of adjuvant denosumab in addition to standard anticancer therapy.

Methods: PubMed, CENTRAL, Scopus, Embase, and oncological meetings websites were screened to identify potentially eligible randomized controlled trials (RCTs). Survival outcomes were disease-free survival (DFS), bone-metastasis-free survival (BMFS), and overall survival (OS). Fracture incidence and time to first fracture were bone-health outcomes. Osteonecrosis of the jaw (ONJ), atypical femur fractures (AFF), and other adverse events were also evaluated. Pooled hazard ratios (HRs) and risk ratios (RR) with respective 95% confidence interval (95% CI) were computed using a random-effects model. Exploratory subgroup analyses were performed.

Results: Two phase III RCTs were included, the Austrian Breast & Colorectal Cancer Study Group-18 (ABCSG-18) and the D-CARE trials, for a total of 7929 patients. In the ABCSG-18 trial, denosumab was administered every 6 months during endocrine therapy (for a median of seven cycles) while the D-CARE trial used an intensive schedule for a total treatment duration of 5 years. Adjuvant denosumab showed no difference in DFS (HR: 0.932; 95% CI: 0.748-1.162), BMFS (HR: 0.9896; 95% CI: 0.751-1.070), and OS (HR: 0.917; 95% CI: 0.718-1.171) compared to placebo in the overall population. In hormone receptor positive/human epidermal growth factor receptor 2 (HER2) negative BC patients, a DFS (HR: 0.883; 95% CI: 0.782-0.996) and BMFS (HR: 0.832; 95% CI: 0.714-0.970) benefit was observed and BMFS was prolonged in all hormone receptor positive patients (HR: 0.850; 95% CI: 0.735-0.983). Fracture incidence (RR: 0.787; 95% CI: 0.696-0.890) and time to first fracture (HR: 0.760; 95% CI: 0.665-0.869) were also improved. No increase in overall toxicity was seen with denosumab and no differences were observed for ONJ and AFF between the 60-mg every 6-month schedule and placebo.

Conclusion: Denosumab addition to anticancer treatment does not improve DFS, BMFS, or OS in the overall population, although a DFS improvement was observed in hormone receptor positive/HER2 negative BC patients and a BMFS improvement in all hormone receptor positive patients. Bone-health outcomes were improved with no added toxicity with the 60-mg schedule.

Registration: PROSPERO identifier: CRD42022332787.

Keywords: adjuvant therapy; bone-health; denosumab; early breast cancer; meta-analysis.

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Conflict of interest statement

LM, GG, EDM, NM, MP, LP, SP, MCC, and ADB declare no conflict of interest. AP has declared consulting fees/advisory role for Amgen, MSD, Novartis, travel and accommodation by Pfizer. AF has declared consulting fees/advisory role for AstraZeneca, Daiichi Sankyo, Eisai, Eli-Lilly. Epionpharma, exact science, MSD, Novartis, Pierre Fabre, Roche, Seagen. GT is supported by funds of Ministero della Salute (Ricerca Corrente 2022). EB is currently supported by the Associazione Italiana per la Ricerca sul Cancro (AIRC) under Investigator Grant (IG) No. IG20583. EB is supported by institutional funds of Università Cattolica del Sacro Cuore (UCSC-project D1). EB is supported by funds of Ministero della Salute (Ricerca Corrente 2022). EB received speakers’ and travels’ fee from MSD, AstraZeneca, Pfizer, Eli-Lilly, BMS, Novartis, and Roche. EB received institutional research grants from AstraZeneca, Roche. AO has declared consulting fees/advisory role for Novartis, Roche, Eli-Lilly, Amgen, Daiichi Sankyo and travel and accommodation by Daiichi Sankyo, Novartis, Roche, and Pfizer.

Figures

Figure 1.
Figure 1.
PRISMA flowchart. ASCO, American Society of Clinical Oncology; CENTRAL, Cochrane Central Register of Controlled Trials; ESMO, European Society for Medical Oncology; n, number; PRISMA, Preferred Reporting Items for Systematic reviews and Meta-Analyses; SABCS, San Antonio Breast Cancer Symposium.
Figure 2.
Figure 2.
Risk-of-bias assessment for survival outcomes. Traffic lights plot (a), bar plot (b).
Figure 3.
Figure 3.
Intention to treat analysis for DFS (a), BMFS (b), and OS (c). 95% CI, 95% confidence interval; BMFS, bone-metastasis-free survival; Den, denosumab; DFS, disease-free survival; HR, hazard ratio; OS, overall survival; Pla, placebo; seTE, treatment effect standard error; TE, treatment effect.
Figure 4.
Figure 4.
Subgroup analysis for DFS: menopausal status (a), concomitant therapy (b), hormone receptor status (c), HER2 status (d), molecular subtype (e). 95% CI, 95% confidence interval; CT, chemotherapy; Den, denosumab; DFS, disease-free survival; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; N, lymph nodes; Pla, placebo; seTE, treatment effect standard error; TE, treatment effect.
Figure 5.
Figure 5.
Subgroup analysis for BMFS: menopausal status (a), concomitant therapy (b), hormone receptor status (c), HER2 status (d), molecular subtype (e). 95% CI, 95% confidence interval; BMFS, bone-metastasis-free survival; CT, chemotherapy; Den, denosumab; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; N, lymph nodes; Pla, placebo; seTE, treatment effect standard error; TE, treatment effect.
Figure 6.
Figure 6.
Subgroup analysis for OS: menopausal status (a), concomitant therapy (b), hormone receptor status (c), HER2 status (d), molecular subtype (e). 95% CI, 95% confidence interval; CT, chemotherapy; Den, denosumab; HER2, human epidermal growth factor receptor 2; HR, hazard ratio; N, lymph nodes; OS, overall survival; Pla, placebo; seTE, treatment effect standard error; TE, treatment effect.
Figure 7.
Figure 7.
Fracture incidence in the overall population (a) and according to menopausal status (b). 95% CI, 95% confidence interval; Den, denosumab; Pla, placebo; RR, risk ratio.
Figure 8.
Figure 8.
Time to first fracture in the overall population (a) and according to menopausal status (b). 95% CI, 95% confidence interval; Den, denosumab; HR, hazard ratio; n, total number of patients; Pla, placebo.
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