Molecular basis of aromatase inhibitor associated arthralgia: known and potential candidate genes and associated biomarkers

ABSTRACT

Introduction: Aromatase inhibitors (AIs) are routinely used for the adjuvant treatment of women with hormone receptor-positive early breast cancer. AIs are widely prescribed in the postmenopausal setting, as they are effective at preventing recurrence. However, their use is complicated by significant adverse effects, particularly arthralgia, noted in up to 50% of treated patients, and thereby affects quality of life and AI compliance. The mechanism by which AIs cause arthralgia is largely unknown, although there is a growing body of literature which suggests that there may be multiple intersecting mechanisms.

Areas covered: This review describes the evidence for the mechanistic basis of AI arthralgia as well as potential pathways that could contribute to the development of AI associated arthralgia.

Expert opinion: Interplay of multiple factors, such as interpatient variability in AI metabolism, possibly related to pharmacogenetic factors, the sudden decline of estrogen synthesis, vitamin D status, as well as upregulation of cytokines and inflammation pathways may precipitate or exacerbate muscle and joint pain are linked during AI therapy. However, much more research is needed in this area given the frequency and severity of AI-associated arthralgia.

KEYWORDS:

• Adverse drug reactions
• aromatase inhibitors
• arthralgia
• pharmacokinetics

Article highlights

• Breast cancer is the most common female cancer and is the second leading cause of death in women.

• Aromatase inhibitors (AIs) are the most commonly used first-line endocrine treatment for postmenopausal women with estrogen receptor-positive breast cancer.

• Significant adverse drug reactions (ADRs) are associated with AIs, the most common being arthralgia.

• The mechanism that causes AI-induced arthralgia is unknown, although the literature suggests there may be multiple intersecting mechanisms, including patient variability in AI metabolism and drug levels, the rate of estrogen decline during AI treatment, vitamin D deficiency, and increased muscle and joint inflammation have all been associated with arthralgia.

• Further studies are required to clarify the impact of genes on AI-induced ADRs. This research will help clinicians better manage AI therapy and may facilitate personalized medicine for women with breast cancer.

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Declaration of interest

The authors have no other 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 apart from those disclosed.

Additional information

Funding

The authors were supported by the Canadian Institutes of Health Research - DSEN (FRN-117588).