Genetic Underpinnings of Musculoskeletal Pain During Treatment With Aromatase Inhibitors for Breast Cancer: A Biological Pathway Analysis

Abstract

Background: Musculoskeletal pain (MSKP) is the most reported symptom during treatment with aromatase inhibitors (AIs) for breast cancer. The mechanisms underlying MSKP are multidimensional and not well understood. The goals of this biological pathway analysis were to (1) gain an understanding of the genetic variation and biological mechanisms underlying MSKP with AI therapy and (2) identify plausible biological pathways and candidate genes for future investigation. Method: Genes associated with MSKP during AI therapy or genes involved in drug metabolism of and response to AIs were identified from the literature. Studies published through February 2019 were queried in PubMed®. The genes identified from the literature were entered into QIAGEN’s Ingenuity® Pathway Analysis (IPA) software to generate canonical pathways, upstream regulators, and networks through a core analysis. Results: The 17 genes identified were ABCB1, ABCG1, CYP17A1, CYP19A1, CYP27B1, CYP2A6, CYP3A4, CYP3A5, ESR1, OATP1B1, OPG, RANKL, SLCO3A1, TCL1A, UGT2A1, UGT2B17, and VDR. These genes are involved in encoding bone-remodeling regulators, drug-metabolizing enzymes (cytochrome P450 family, UDP-glucuronosyltransferases family), or drug transporters (ATP-binding cassette transporters, organic anion transporters). Multiple plausible biological pathways (e.g., nicotine degradation, melatonin degradation) and candidate genes (e.g., NFKB, HSP90, AKT, ERK1/2, FOXA2) are proposed for future investigation based on the IPA results. Conclusion: Multiple genes and molecular-level etiologies may contribute to MSKP with AI therapy in women with breast cancer. Our innovative combination of gene identification from the literature plus biological pathway analysis allowed for the emergence of novel candidate genes and biological pathways for future investigations.

Prevalence and correlates of joint pain among Chinese breast cancer survivors receiving aromatase inhibitor treatment

“…One possible explanation might be that the participants in this study were breast cancer survivors at an early stage and had completed the active anti-cancer treatments including chemotherapy, while pain is more frequent and severe for cancer patients who are at an advanced stage [37]. Besides, the ethnic difference and genetic variations between the two studies (the previous study [36] recruited participants in the USA) might also lead to different study ndings as genetic variation that involved in metabolism of AIs may contribute to the variations in the occurrence and severity of the side effects including joint pain [12].…”

“…Recent pharmacogenetics and pharmacogenomics suggested that the genetic and genomic variation at the population level is associated with the drug metabolism of and drug response to AIs, which may contribute to variability in the phenotype (e.g., occurrence, severity) of joint pain [12]. A full understanding of the phenotype and pre-treatment associates of AIs-induced joint pain in breast cancer survivors can contribute to enhanced symptom monitoring and management programmes, as well as more tailored and speci c healthcare services or interventions [13].…”

Aromatase inhibitor–associated musculoskeletal pain: An overview of pathophysiology and treatment modalities

“…Estrogen also helps to maintain the integrity of joints by inhibiting the breakdown of the cartilaginous extracellular matrix, as chondrocytes contain E2 receptors. 10 Estrogen also has an anti-inflammatory effect on the body by decreasing the synthesis of inflammatory cytokines such as tumor necrosis factor (TNF)-a and interleukin (IL)-1b, and increased levels of C-reactive protein (CRP), eotaxin, and monocyte chemoattraction protein 1 (MCP-1) have been detected in patients. 11 Magnetic resonance imaging (MRI) studies in women experiencing AIMSS have shown fluid surrounding the flexor sheaths, thickening of the flexor/extensor tendons in the hands, and fluid in the metacarpal joints, suggesting underlying inflammation caused by the medication.…”

Aromatase Inhibitors—Induced Musculoskeletal Disorders: Current Knowledge on Clinical and Molecular Aspects

“…Several risk factors, such as a period less than 5 years from menopause, previous menopausal hormone therapy and/or taxanes-based chemotherapy, obesity, pre-existing arthralgia or osteoarthritis (OA) at the beginning of AIs, were highlighted [4,10]. More recently, genetic factors primarily acting in estrogen pathways have been proposed as possibly linked with AIA [66][67][68][69]. Garcia-Giralt et al [67], in a study on 343 post-menopausal BC women starting AIs therapy, found several SNPs (rs4919686, rs4919683, rs4919687, rs3781287, rs10786712, rs6163) in the CYP17A1 (a gene encoding for the enzymes involved in the biosynthesis of androgens), as correlated with the onset of AIA after 12 months of therapy.…”