This application entitled, """"""""Estrogen deprivation and Aromatase Inhibitor associated Arthralgia,"""""""" seeks to apply pharmacogenetic epidemiology, appropriate biomarkers, and validated patient-reported outcomes to define the role of estrogen deprivation in arthralgia (joint pain) occurrence, severity, and functional interference among postmenopausal women receiving aromatase inhibitors (AIs) as adjuvant therapy for early stage breast cancer. AIs are a class of medications that block the conversion of androgens to estrogens inhibiting aromatase enzyme, thereby resulting in significant estrogen depletion. Nearly 50 percent of breast cancer patients taking AIs report AI-associated arthralgia (AIAA). AIAA impairs functional status and quality of life, leading to premature medication discontinuation in 10-20percent of patients. The mechanisms underlying AIAA are not well understood, making it difficult to identify individuals at risk for developing such symptoms and hampering efforts to devise effective interventions. The etiology of AIAA is likely to be complex. Based upon basic science literature, clinical experience, and our preliminary results, we hypothesize that estrogen withdrawal induced by AIs may result in an increase in pain sensitivity, leading to the subjective experience of AIAA. Recently, we have identified polymorphisms in CYP19A1 (encoding the aromatase enzyme) that were associated with patient-reported AIAA occurrence, demonstrating that genetic variations in the genes encoding certain enzymes of the estrogen pathways may predict the risk of AIAA. To extend this work, we will bring together a multidisciplinary team of researchers and clinicians in pain and symptom management, genetic epidemiology and biostatistics, reproductive endocrinology, breast oncology, and nursing to address the following aims:
Specific Aim 1 : To determine the associations between genetic variants related to estrogen pathways and patient-reported AIAA occurrence. We will conduct a cross-sectional study of 1,000 stage I-III breast cancer survivors currently receiving AIs to determine relationships between specific genetic variants and patient-reported outcomes of arthralgia.
Specific Aim 2 : To determine whether estrogen levels mediate the association between CYP19A1 genetic polymorphism and AIAA. To answer this aim, we will conduct a prospective cohort study among 450 breast cancer patients who are due to initiate AIs;we will follow them before AIs (Baseline), and at one, three, and six months after initiation of AI therapy. Exploratory Aim: To explore the role of AI-related estrogen deprivation in pain sensitivity. To answer this aim, we will perform multimodal sensory testing in a subset of eligible and consenting participants from the above prospective cohort (N=100). The proposed study will increase our understanding of the mechanisms underlying AIAA. This increased understanding will facilitate the development and translation of new therapeutics and preventative strategies for this important problem affecting hundreds of thousands of breast cancer patients.
More than 2.5 million women in the United States have survived breast cancer as a result of early diagnosis and effective therapies, such as aromatase inhibitors. However, aromatase inhibitor-associated arthralgia (joint pain) impairs functional status and leads to non-optimal adherence that seriously affects both the quality of life and survival. The proposed study will help create more effective diagnosis and tailored interventions to manage this painful condition affecting hundreds of thousands of women with breast cancer each year.
|Sansone, Pasquale; Ceccarelli, Claudio; Berishaj, Marjan et al. (2016) Self-renewal of CD133(hi) cells by IL6/Notch3 signalling regulates endocrine resistance in metastatic breast cancer. Nat Commun 7:10442|
|Dean, Lorraine T; DeMichele, Angela; LeBlanc, Mously et al. (2015) Black breast cancer survivors experience greater upper extremity disability. Breast Cancer Res Treat 154:117-25|
|Garland, Sheila N; Stainken, Cameron; Ahluwalia, Karan et al. (2015) Cancer-related search for meaning increases willingness to participate in mindfulness-based stress reduction. Integr Cancer Ther 14:231-9|
|Bauml, Joshua; Chen, Lu; Chen, Jinbo et al. (2015) Arthralgia among women taking aromatase inhibitors: is there a shared inflammatory mechanism with co-morbid fatigue and insomnia? Breast Cancer Res 17:89|
|Brier, Moriah J; Chambless, Dianne; Gross, Robert et al. (2015) Association between self-report adherence measures and oestrogen suppression among breast cancer survivors on aromatase inhibitors. Eur J Cancer 51:1890-6|
|Brier, Moriah J; Chambless, Dianne L; Lee, Laura et al. (2015) Development and validation of the Penn Arthralgia Aging Scale among breast cancer survivors. Cancer 121:2808-13|
|LeBlanc, Mously; Stineman, Margaret; DeMichele, Angela et al. (2014) Validation of QuickDASH outcome measure in breast cancer survivors for upper extremity disability. Arch Phys Med Rehabil 95:493-8|
|Brown, Justin C; Mao, Jun J; Stricker, Carrie et al. (2014) Aromatase inhibitor associated musculoskeletal symptoms are associated with reduced physical activity among breast cancer survivors. Breast J 20:22-8|
|Garland, Sheila N; Johnson, Brad; Palmer, Christina et al. (2014) Physical activity and telomere length in early stage breast cancer survivors. Breast Cancer Res 16:413|
|Garland, Sheila N; Palmer, Christina; Donelson, Michelle et al. (2014) A nested case-controlled comparison of telomere length and psychological functioning in breast cancer survivors with and without insomnia symptoms. Rejuvenation Res 17:453-7|
Showing the most recent 10 out of 11 publications