Factors associated with aromatase inhibitor associated musculoskeletal symptoms in early stage breast cancer patients

Introduction: Aromatase Inhibitors (AI) are a mainstay of treatment for hormone receptor positive breast cancer (BC) in postmenopausal women. However, patients under AI treatment often suffer from Aromatase Inhibitor-Associated Musculoskeletal Symptoms (AIMSS), defined as myalgias, arthralgias, or joint stiffness in hands, fingers, knees, hips and feet, which may limit treatment and subsequently increase BC mortality. The depletion of estrogen following AI initiation has been postulated to cause AIMSS. However, it has not yet been fully established about the clinical significance of AIMSS and its risk factors and the underlying mechanisms. The aim of this study is to identify epidemiologic risk factors associated with the development of AIMSS in BC patients on adjuvant AI therapy. Methods: We conducted a retrospective review of medical records among 111 stages 0-III hormone receptor positive BC patients who received adjuvant AI therapy, including anastrozole, letrozole or exemestane, between January 2009 and June 2017, at the University of Maryland Greenebaum Comprehensive Cancer Center. To be eligible, women had to be either postmenopausal or premenopausal, on a GnRH analog for at least 3 months, and report of no AIMSS before the AI initiation. We collected patients’ data on demographics, lifestyle factors, reproductive histories, tumor characteristics, types of AI and cancer treatment, co-morbidities, use of medications, length of AI therapy, and onset and severity of AIMSS. We defined severe AIMSS as AIMSS requiring the change of AI therapy or discontinuation of AI. The demographics and clinicopathological characteristics of patients on AI therapy and frequencies of AIMSS onset during AI treatment was characterized with means (SDs) or percentages. To estimate the association of severe AIMSS with epidemiologic risk factors, odds ratios (ORs) and 95% confidence intervals were calculated using multivariable-adjusted logistic regression. Results: This study included 111 BC patients with a mean age of 64 years. Their mean BMI at time of BC diagnosis was 30.8 kg/m2, and 41% of patients were White, 39% were Black, 4% were Asian/Pacific Islander, and 16% were other. Majority of patients (77%) had no prior experience of tamoxifen use and used letrozole as an initial AI therapy (70.3%); 15.3% used anastrozole, and 14.4% used exemestane. We found that 52.6% of patients experienced any degree of AIMSS while on AI therapy. In particular, 19.8% of patients required change or holding AI therapy, and 3.6% permanently discontinued AI because of AIMSS. We observed that older age at AI therapy initiation and higher levels of circulating vitamin D-25OH were significantly associated with lower odds of severe AIMSS. Multivariate ORs (95% Cis) comparing the highest to the lowest tertile of age and vitamin D levels at AI initiation were 0.18 (0.05-0.71) and 0.10 (0.02-0.49), respectively (all P-trend: ≤ 0.04). There were no significant association between race, body mass index, smoking, alcohol use, reproductive factors, type of AI therapy, and tamoxifen use prior to AI therapy. Conclusions: In our study, nearly 52.6% of BC patients on adjuvant AI therapy experienced AIMSS. Of those, 23.4% changed or discontinued AI regimen due to severe AIMSS. Older age and higher circulating levels of vitamin D-25OH at the initiation of adjuvant AI therapy were associated with lower risk of developing severe AIMSS. The study results support the clinical significance of AIMSS in BC patients leading to decreased adherence to AI therapy. The replication of our association with age and vitamin D levels in a larger study is warranted as it may provide a greater insight into etiologies of AIMSS. Citation Format: Yamin Sun, Simran Elder, Seungyoun Jung, Candace Mainor, Shruti Murali, Paula Rosenblatt, Katherine Tkaczuk. Factors associated with aromatase inhibitor associated musculoskeletal symptoms in early stage breast cancer patients [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-12-13.