Repurposing denosumab in breast cancer beyond prevention of skeletal related events: Could nonclinical data be translated into clinical practice?

ABSTRACT

Introduction

Denosumab is a human monoclonal antibody inhibiting the receptor activator of nuclear factor kappa-B ligand (RANKL). Initially approved as antiosteοporotic agent, denosumab is being currently pursued as a candidate for drug repurposing in oncology, especially breast cancer.

Areas covered

The present review provides an overview of the therapeutic potential of denosumab in breast cancer beyond prevention of skeletal-related events (SREs), with focus on prevention of carcinogenesis in BRCA mutation carriers and on adjuvant treatment in early breast cancer patients. Study search was conducted on the following electronic databases: PubMed, Google scholar, Scopus.com, ClinicalTrials.gov, and European Union Clinical Trials Register from 2008 until June 2020.

Expert opinion

Nonclinical data have established links between RANKL signaling and breast cancer initiation and progression, rationalizing exploring the potential bone-independent anticancer role of denosumab beyond SREs prevention. Preclinical and preliminary clinical data show that denosumab may inhibit carcinogenesis in BRCA mutation carriers. Denosumab adjuvant in early breast cancer has been shown, though inconsistently, to provide a disease-free survival benefit for a subgroup of patients. Despite promising results, the incorporation of denosumab in preventive and therapeutic protocols of breast cancer beyond prevention of SREs cannot be endorsed until further research consolidates its efficacy.

KEYWORDS:

• BRCA mutation carriers
• breast cancer
• denosumab
• drug repurposing
• early breast cancer
• metastasis
• RANKL
• RANK

Article highlights

• Denosumab ‒ a fully human monoclonal antibody blocking the receptor activator nuclear factor-kB ligand (RANKL) ‒ is indicated for prevention of SREs in patients with solid tumors, including breast cancer.

• Direct inhibitory effects of denosumab on initiation and progression of breast cancer are increasingly being reported.

• Preclinical data show that denosumab may restore the dysregulated interplay among progesterone, RANKL acting as downstream effector of progesterone, and OPG, which is known to exert a procarcinogenic effect on breast tissue.

• Nonclinical and preliminary clinical data suggest that denosumab may attenuate the breast carcinogenesis in BRCA mutation carriers.

• Clinical data indicate, though inconsistently, that denosumab adjuvant in early breast cancer yield a disease-free survival benefit for postmenopausal women.

• The potential therapeutic efficacy of denosumab in breast cancer beyond SREs prevention cannot be embraced in the Clinics, pending its further evaluation.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

A reviewer has declared personal fees/travel support from Amgen, DaiichiSankyo, AstraZeneca, EliLilly, LifeBrain, Nanostring, Novartis, TLC Biopharmaceuticals; also they have declared an immediate family member is employed by Sandoz. Peer reviewers on this manuscript have no other relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.