Aromatase Inhibitor–Related Musculoskeletal Symptoms: Is Preventing Osteoporosis the Key to Eliminating These Symptoms?

Muslimani, Alaa; Spiro, Timothy; Chaudhry, Asif A.; Taylor, Harris C.; Jaiyesimi, Ishmael; Daw, Hamed

doi:10.3816/cbc.2009.n.006

Cited by 37 publications

(20 citation statements)

References 29 publications

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“…For both drugs, however, the primary reason for discontinuing drug therapy was the occurrence of musculoskeletal pain. We genotyped DNA samples from women enrolled in the MA.27 trial in an attempt to identify SNPs associated with musculoskeletal pain after AI therapy [17]. …”

Section: Resultsmentioning

confidence: 99%

Aromatase inhibitors, estrogens and musculoskeletal pain: estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression

et al. 2012

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IntroductionArthralgias and myalgias are major side effects associated with aromatase inhibitor (AI) therapy of breast cancer. In a recent genome-wide association study, we identified SNPs - including one that created an estrogen response element near the 3' end of the T-cell leukemia 1A (TCL1A) gene - that were associated with musculoskeletal pain in women on adjuvant AI therapy for breast cancer. We also showed estrogen-dependent, SNP-modulated variation in TCL1A expression and, in preliminary experiments, showed that TCL1A could induce IL-17RA expression. In the present study, we set out to determine whether these SNPs might influence cytokine expression and effect more widely, and, if so, to explore the mechanism of TCL1A-related AI-induced side effects.MethodsThe functional genomic experiments performed included determinations of TCL1A, cytokine and cytokine receptor expression in response to estrogen treatment of U2OS cells and lymphoblastoid cell lines that had been stably transfected with estrogen receptor alpha. Changes in mRNA and protein expression after gene knockdown and overexpression were also determined, as was NF-κB transcriptional activity.ResultsEstradiol (E2) increased TCL1A expression and, in a TCL1A SNP-dependent fashion, also altered the expression of IL-17, IL-17RA, IL-12, IL-12RB2 and IL-1R2. TCL1A expression was higher in E2-treated lymphoblastoid cell lines with variant SNP genotypes, and induction of the expression of cytokine and cytokine receptor genes was mediated by TCL1A. Finally, estrogen receptor alpha blockade with ICI-182,780 in the presence of E2 resulted in greatly increased NF-κB transcriptional activity, but only in cells that carried variant SNP genotypes. These results linked variant TCL1A SNP sequences that are associated with AI-dependent musculoskeletal pain with increased E2-dependent TCL1A expression and with downstream alterations in cytokine and cytokine receptor expression as well as NF-κB transcriptional activity.ConclusionsSNPs near the 3' terminus of TCL1A were associated with AI-dependent musculoskeletal pain. E2 induced SNP-dependent TCL1A expression, which in turn altered IL-17, IL-17RA, IL-12, IL-12RB2, and IL-1R2 expression as well as NF-κB transcriptional activity. These results provide a pharmacogenomic explanation for a clinically important adverse drug reaction as well as insights into a novel estrogen-dependent mechanism for the modulation of cytokine and cytokine receptor expression.

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Section: Resultsmentioning

confidence: 99%

Aromatase inhibitors, estrogens and musculoskeletal pain: estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression

et al. 2012

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“…Only six cohort studies had full-text available for assessment with the Newcastle Ottowa Scale. Of these six studies, two were assessed as high methodological quality (37,38); two studies were median methodological quality (17,39,40); and one study was of poor methodological quality (41).…”

Section: Methodological Quality Of Selected Studiesmentioning

confidence: 99%

Management of aromatase inhibitor induced musculoskeletal symptoms in postmenopausal early Breast cancer: A systematic review and meta-analysis

Roberts

Rickett

Greer

et al. 2017

Critical Reviews in Oncology/Hematology

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“…Cross-sectional studies have identified shorter length of time since menopause, 15 development of osteoporosis while on AI treatment, 17 obesity, and previous chemotherapy as risk factors. 19 One prospective study found that 45% of patients developed arthralgia, but the study failed to associate any pretreatment factors with its development.…”

Section: Introductionmentioning

confidence: 99%

Anastrozole-Associated Joint Pain and Other Symptoms in Patients With Breast Cancer

Shi¹,

Giordano²,

Lu³

et al. 2013

The Journal of Pain

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More than a third of breast cancer patients undergoing aromatase inhibitor (AI) treatment report joint pain. We conducted a longitudinal study to characterize the course of AI-induced joint pain and other symptoms and to identify potential predictors for developing these symptoms. Patients were recruited before AI initiation. The Brief Pain Inventory, M. D. Anderson Symptom Inventory, and a joint-pain questionnaire were administered at baseline and then biweekly for 1 year. Analysis included logistic regression, Cox models, and mixed-effects models. Of 47 patients assessed, 16 (34%) reported joint pain at least once. Median time to first report of joint pain was 7 weeks (range 1–38). Baseline pain was the only predictor for both incidence of joint pain and time to first event. In the first 6 weeks, emergence of joint pain was associated with increase in general pain, fatigue, disturbed sleep, hot flashes, vaginal dryness, and decreased sexual activity. After week 6, having joint pain was associated with increase in general pain and with persistently high fatigue. Having AI-associated joint pain correlated with increase in or persistence of other symptoms likely related to AI therapy. Further research is needed to validate predictors of AI-associated symptoms.

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Aromatase Inhibitor–Related Musculoskeletal Symptoms: Is Preventing Osteoporosis the Key to Eliminating These Symptoms?

Cited by 37 publications

References 29 publications

Aromatase inhibitors, estrogens and musculoskeletal pain: estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression

Aromatase inhibitors, estrogens and musculoskeletal pain: estrogen-dependent T-cell leukemia 1A (TCL1A) gene-mediated regulation of cytokine expression

Management of aromatase inhibitor induced musculoskeletal symptoms in postmenopausal early Breast cancer: A systematic review and meta-analysis

Anastrozole-Associated Joint Pain and Other Symptoms in Patients With Breast Cancer

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