AI-induced Arthralgia Research Articles

Current and future advances in practice: aromatase inhibitor-induced arthralgia.

Aromatase inhibitors (AIs) have shown great success as adjuvant therapy for post-menopausal women with hormone receptor-positive breast cancers. AI-induced arthralgia (AIA) is a frequent AI toxicity contributing to non-adherence and discontinuation. This review aims to understand current knowledge of AIA. The mean incidence of AIA was 39.1% and the mean discontinuation of AI therapy due to AIA was 9.3%. Most of the AIAs were non-inflammatory. A shorter time since the last menstrual period and pre-existing joint pain were risk factors. Vitamin D3 supplementation may be a preventative measure and treatment with duloxetine, acupuncture and/or exercise is supported by large randomized controlled trials. There was consistent improvement in AIAs with switching to an alternate AI, and this could additionally allow continuation of cancer treatment with AI. Further research is needed to identify predictive biomarkers, better characterize AIA subcategories and study more reliable therapeutic options.

Randomized placebo-controlled, double-blind clinical trial of nanoemulsion curcumin in women with aromatase inhibitor-induced arthropathy: an Alliance/NCORP pilot trial

PurposeAromatase inhibitor (AI) therapy reduces risk of recurrence and death for postmenopausal women with breast cancer (BC); however, AI-induced arthralgia (AIIA) can lead to discontinuation of treatment. Curcumin, a bioactive polyphenolic substance, may help ameliorate inflammation-related conditions including osteoarthritis and pain.MethodsWe conducted a multisite randomized placebo-controlled, double-blind pilot trial (Alliance A22_Pilot9) to evaluate the effects of nanoemulsion curcumin (NEC, 200 mg/day) in postmenopausal women experiencing AIIA for ≥ 3 months. The primary objective was to determine the feasibility of using Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) to detect changes from 0 (T0) to 3 months (T3) of NEC treatment in AI-induced symptoms and well-being; secondary objectives included evaluation of changes in Disabilities of the Shoulder, Arm, and Hand (DASH), Brief Pain Inventory-short form (BPI-SF), grip strength, and biomarkers at T0 and T3.ResultsForty-two patients were randomized to NEC or placebo; 34 women completed the 3-month study. Patient-reported outcome measures (PROMs: FACT-ES, DASH, BPI-SF) and biospecimens were collected at T0-T3 in > 80% of participants. Adherence was ≥ 90% for both arms. PROMs and grip strength did not differ significantly by treatment arm. Plasma curcumin was detected only in NEC arm participants. Serum estradiol and estrone levels were below detection or low on study agent. Gastrointestinal adverse effects were commonly reported in both arms.ConclusionNEC versus placebo in a multisite randomized trial is feasible and well-tolerated. Additional studies with larger sample size are needed to further evaluate the efficacy and safety of NEC in treatment of AIIA.ClinicalTrials.gov Identifier: NCT03865992, first posted March 7, 2019.

A Telehealth-Delivered Tai Chi Intervention (TaiChi4Joint) for Managing Aromatase Inhibitor-Induced Arthralgia in Patients With Breast Cancer During COVID-19: Longitudinal Pilot Study.

BackgroundEstrogen receptor–positive breast cancer is the most common type of breast cancer in postmenopausal women. Aromatase inhibitors (AIs) are the endocrine therapy of choice recommended for these patients. Up to 50% of those treated with an AI develop arthralgia, often resulting in poor adherence and decreased quality of life.ObjectiveThe study is a single-arm longitudinal pilot study aiming to evaluate the safety, feasibility, acceptability, and potential efficacy of TaiChi4Joint, a remotely delivered 12-week tai chi intervention designed to relieve AI-induced joint pain.MethodsWomen diagnosed with stage 0-III breast cancer who received an AI for at least 2 months and reported arthralgia with a ≥4 score on a 0 to 10 scale for joint pain were eligible for study enrollment. Participants were encouraged to join tai chi classes delivered over Zoom three times a week for 12 weeks. Program engagement strategies included using a private Facebook study group and a Box cloud for archiving live class recordings. The program uses SMS text messaging and emails with periodic positive quotes and evidence-based information on tai chi for facilitating community bonding and class attendance. Participants were invited to complete the following assessments at baseline and at 1-, 2-, and 3-month intervals from study enrollment: Brief Pain Inventory, Western Ontario and McMaster University Osteoarthritis Index (WOMAC), The Australian Canadian Osteoarthritis Hand Index (AUSCAN), Fatigue Symptom Inventory, Hot Flash Related Daily Interference Scale (HFRDIS), Pittsburgh Sleep Quality Index (PSQI), and Center for Epidemiological Studies–Depression (CES-D).ResultsA total of 55 eligible patients were invited to participate, and 39 (71%) consented and completed the baseline assessments. Participants attended 61% (median) of the suggested classes, with no tai chi–related adverse events reported. Of the 39 participants, 22 completed the 3-month follow-up assessment with a 56% retention rate. Study participants reported improvement from baseline compared to 3 months as follows (paired t test): Brief Pain Inventory (P<.001), AUSCAN pain subscale (P=.007), AUSCAN function subscale (P=.004), Fatigue Symptom Inventory (P=.004) and PSQI (P<.001), and HFRDIS (P=.02) and CES-D (P<.001). In particular, for our primary end point of interest, improvements in hip and knee symptoms, measured by WOMAC’s three subscales, were clinically meaningful and statistically significant when adjusted for multiple comparisons from baseline to 3 months post intervention.ConclusionsThe COVID-19 global pandemic has resulted in the need to rethink how mind-body therapies can be delivered. This study demonstrated the feasibility, acceptability, and potential efficacy of a telehealth-based tai chi intervention for reducing AI-induced arthralgia. The intervention decreased patient-reported pain and stiffness, and improved sleep quality and depressive symptoms. Fully powered, large, telehealth-based tai chi trials for AI-associated arthralgia are needed considering our promising findings.Trial RegistrationClinicalTrials.gov NCT04716920; https://www.clinicaltrials.gov/ct2/show/NCT04716920

Telehealth delivered Tai Chi intervention for managing aromatase inhibitor-induced arthralgia in breast cancer patients: TaiChi4Joint during the COVID-19 pandemic a Pilot study.

e12523 Background: Estrogen receptor positive breast cancer (BC) is the most common type of breast cancer in postmenopausal women and aromatase inhibitors (AI) are the endocrine therapy of choice recommended for these patients. Up to 50% of those treated with an AI develop Arthralgia often resulting in poor adherence and decreased quality of life. Methods: This is a single arm longitudinal pilot study aiming to evaluate the safety, feasibility, acceptability and potential efficacy of TaiChi4Joint, a remotely-delivered 12-week Tai Chi intervention designed for the relief of AI-induced joint pain. Women diagnosed with stage 0-III BC who have been receiving an AI for at least 2 months and reporting arthralgia with a ≥ 4 score on a 0-10 scale for joint pain were eligible for study enrollment. Participants were encouraged to join Tai Chi classes delivered over ZOOM three times a week for 12 weeks. Program engagement strategies include the use of a private Facebook study group and box.com cloud for archiving live class recordings. The program utilizes Text messaging and emails with periodic positive quotes and evidence based information on Tai Chi for facilitating community bonding and class attendance. Participants were invited to complete the following assessments online at baseline, 1, 2 and 3 months intervals from study enrollment: Brief Pain Inventory (BPI), Western Ontario and McMaster University Osteoarthritis index (WOMAC), The Australian Canadian Osteoarthritis Hand Index (AUSCAN), Fatigue Symptom Inventory (FSI), Hot Flash Related Daily Interference Scale (HFRDIS), Pittsburg Sleep Quality Index (PSQI) and Center for Epidemiological Studies Depression (CES-D). Results: 55 eligible patients were invited to participate and 39 consented and completed the baseline assessments. 61% (median) Participants attended the classes, with no Tai Chi related adverse events reported. 22 of the 39 participants completed the 3-month follow up assessments with a 56% retention rate. Study participants reported improvement from baseline compared to 3 month as follows: For BPI ( P = .000), AUSCAN pain subscale ( P =.000), AUSCAN function subscale for 35 patients ( P = .000), WOMAC ( P = .000), CES-D ( P = 0.001), FSI ( P = 0.00) and PSQI ( P = .000). However HFRDIS improved in 11 patients ( P = 0.00) for the other 22 patients (P = 0.154). Conclusions: The COVID-19 global pandemic has resulted in the need to rethink how mind-body therapies can be delivered. This study demonstrated the feasibility, acceptability, and potential efficacy of a Telehealth based Tai Chi intervention for reducing AI-induced arthralgia. The intervention decreased patient reported pain, stiffness and improved sleep quality and depressive symptoms. With our promising findings, larger telehealth based trials of Tai Chi for AI-associated arthralgia are needed. Clinical trial information: NCT04716920.

Genetic and clinical predictors of arthralgia during letrozole or anastrozole therapy in breast cancer patients.

Female patients with breast cancer frequently develop arthralgia when treated with aromatase inhibitors (AI). Although the mechanism of AI-induced arthralgia is unknown, potential biomarkers have been identified. The purpose of this study was to investigate the clinical and genetic predictors of AI-induced arthralgia in a prospective cohort of patients with estrogen receptor-positive breast cancer. One hundred and ninety-six patients were enrolled at initiation of AI therapy with either letrozole or anastrozole. Patients completed two validated self-report questionnaires assessing pain, stiffness, and physical function at baseline, and repeated the questionnaires at two and at six months after the initiation of treatment with an AI. Germline DNA of all patients was genotyped for seven single-nucleotide polymorphisms (SNPs) previously identified by genetic screens and genome-wide association studies as associated with AI-induced arthralgia. More than 50% of the study group experienced arthralgia symptoms. Genetic analysis revealed that four SNPs, in CYP19A1 (rs4775936) and ESR1 (rs9322336, rs2234693, rs9340799), were associated with the development of arthralgia (adjusted P = 0.016, 0.018, 0.017, 0.047). High body mass index (BMI) was also associated with the development of arthralgia symptoms (adjusted P = 0.001). Patients prescribed letrozole were significantly more likely to develop arthralgia than patients on anastrozole (P = 0.018), and also more likely to discontinue AI therapy due to arthralgia. The CYP19A1 (rs4775936) SNP was significantly associated with discontinuation of therapy due to intolerable arthralgia. Our results suggested that BMI and AI drug (letrozole versus anastrozole) were clinical predictors of arthralgia, while genetic variants rs4775936, rs9322336, rs2234693, and rs9340799 were genetic predictors of AI-induced arthralgia. Significantly, rs4775936 was also a predictor of discontinuation of therapy.

The effect of sukshma vyayama joint loosening yoga on aromatase inhibitor-induced arthralgia (AI) in breast cancer patients: A feasibility study conducted on Facebook.

e23129 Background: AI therapy causes joint pain in up to half of women, and up to 20% become non-compliant with treatment due to pain and discomfort. This pilot study investigated the efficacy of sukshma vyayama in improving AI-induced joint pain and evaluated the feasibility of delivering the intervention on Facebook. Methods: Breast cancer patients undergoing treatment with AI's with self-reported arthralgia were recruited via an IRB-approved announcement posted in two closed breast cancer support groups on Facebook to participate in a yoga study delivered on Facebook. Participants completed BPI, DASH, PRAI and WOMAC questionnaires before and after the study. Intervention consisted of 12 joint loosening exercises performed in a chair, once daily for 12 minutes, Monday-Friday for 4 weeks. Asynchronous video demonstrations were available in a secret Facebook group and viewing confirmed by typing "done" (time-stamped) in comments. Results: 200 women responded. 38 met the inclusion criteria/consent, 26 completed the online consent, interventions and pre/post questionnaires. Paired simple t tests results showed significant (P &lt; 0.05) improvement in all the pain measures and quality of life parameters after yoga intervention compared to baseline. Conclusions: This study provides the first evidence that it is feasible to teach sukshma vyayama to patients on Facebook and that the intervention significantly improves AI-induced arthralgia. Teaching yoga via social media may provide better access to this therapeutic modality to patients at all points in the cancer care continuum globally. [Table: see text]

Randomized, Double-Blind, Placebo-Controlled Phase II Clinical Trial on the Use of Uncaria tomentosa (Cat's Claw) for Aromatase Inhibitor-Induced Arthralgia: A Pilot Study

Introduction: Aromatase inhibitors (AI) are widely used in adjuvant breast cancer treatment, and diffuse articular pain secondary to AI use is the most common cause of treatment discontinuation. Uncaria tomentosa (cat’s claw) has antiinflammatory activity and is used to treat arthrosis and arthritis. Patients and Methods: This prospective, single-center, double-blind, randomized, placebo-controlled phase II study analyzed 70 patients with breast cancer undergoing AI therapy with complaints of arthralgia. The patients received 100 mg of the dry extract of Uncaria tomentosa three times daily for 4 weeks. At the beginning and end of the study, patients answered the Brief Pain Inventory (BPI), Disability Arm, Shoulder, and Hand (DASH), Lequesne, SF-36 Quality of Life questionnaires, completed a visual analog scale (VAS) for pain, and underwent laboratory testing. Results: U. tomentosa was not more effective than the placebo. No evidence of grade 3 or 4 toxicity was found. In addition, no significant differences were seen in laboratory results or inflammatory markers between the two study groups. Conclusion: Dry extract of U. tomentosa was safe but ineffective in reducing AI-induced arthralgia compared with the placebo. Furthermore, the plant extract had no detectable anti-inflammatory activity.

Abstract PD6-02: A randomized, controlled trial of high dose vs. standard dose vitamin D for aromatase inhibitor-induced arthralgia in breast cancer survivors

Abstract Background: Approximately half of women on aromatase inihbitor (AI) therapy develop AI-induced arthralgia (AIA), and many discontinue the medication because of this common side effect. While Vitamin D has been studied as a treatment for AIA, trial results have been conflicting thus far. Patients and Methods: All subjects were post menopausal women who were beginning adjuvant AI therapy for stage I-III hormone receptor positive breast cancer. Patients were randomized 1:1 to receive standard dose vitamin D3 (800 IU daily for 52 weeks) or high dose vitamin D3 (50,000 IU weekly for 12 weeks, followed by 2000 IU daily for 40 weeks). All patients also took oral calcium 600 mg daily. The primary endpoint was development of AIA, as defined by pre-specified changes in the Health Assessment Questionnaire II (HAQ-II). Secondary endpoints include compliance with AI therapy, and correlation between grip strength and development of AIA. Exploratory endpoint was measurement of inflammatory cytokine reduction in each arm. The trial was designed to enroll 184 patients, but this futility analysis was performed after 93 patients were enrolled. The futility boundary for stopping the trial early was calculated as p = 0.47. Results: All 93 patients (46 in the high dose arm, and 47 in the standard dose arm) enrolled in the study at the time of the interim analysis were evaluable. The HAQ-II was completed at 12 weeks in 76% on the high dose arm, and 68% in the standard dose arm. Subjects who did not complete the questionnaire were deemed as study failures (i.e. development of AIA was assumed). In the high dose arm, 25 patients (54%) developed AIA, compared to 27 patients (57%) in the standard dose arm. The one-tailed p value is 0.3818, and the Z-score is 0.3, yielding only a 38% conditional power that that study would find a significant difference between the two arms. Thus, the study was terminated early for futility. There was no significant difference between the two arms in adherence to AI therapy. The grip strength and inflammatory cytokine data are pending at this time. They will be ready by the time of the conference. Conclusions: There was no significant signal for benefit of high dose vitamin D supplementation, as compared to standard dose vitamin D, for AIA prevention in post menopausal women taking adjuvant AI therapy. These results further characterize the role of Vitamin D in AIA, and they inform future clinical trials in this arena. Further research is necessary, as this remains an important cause of non-adherence to this highly effective therapy. Citation Format: Niravath P, Wang T, Hilsenbeck SG, Lipscomb K, Pavlick A, Jiralerspong S, Nangia J, Ellis M, Ademuyiwa F, Cherian M, Frith A, Ma C, Park H, Rigden C, Suresh R, Osborne CK, Rimawi MF. A randomized, controlled trial of high dose vs. standard dose vitamin D for aromatase inhibitor-induced arthralgia in breast cancer survivors [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD6-02.

Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer.

The aromatase inhibitor (AI) letrozole is a first-line drug in the adjuvant treatment of breast cancer in postmenopausal women. Adherence to AI therapy, including letrozole, remains problematic due to the development of debilitating AI-induced arthralgia. Letrozole is metabolized in the liver by CYP2A6. It remains unknown if plasma letrozole levels or CYP2A6 genetic variation is associated with the development of arthralgia. We enrolled 126 female breast cancer patients initiated on letrozole therapy and prospectively collected blood samples at baseline and two follow-up time points to determine letrozole plasma concentrations and CYP2A6 genotype. At each visit, participants completed two validated questionnaires to assess the severity of arthralgia symptoms. More than half (55%) of patients experienced a significant increase in their arthralgia symptoms after initiation of treatment. The clinical variables of body mass index (P = 0.0003) and age (P = 0.0430) were negatively and positively associated with plasma letrozole concentrations, respectively. CYP2A6 genotype was significantly associated with letrozole levels (P < 0.0001), and increased plasma letrozole levels were observed in patients with CYP2A6 reduced-function genotypes. Plasma levels of letrozole and CYP2A6 genotype were not significantly associated with a change in pain score from baseline. CYP2A6 genotype was a significant predictor of letrozole plasma levels, but was not associated with the development of arthralgia.

Osteoporosis and musculoskeletal complications related to therapy of breast cancer

Aromatase inhibitors (AIs) are the treatment of choice for the majority of postmenopausal women with estrogen receptor (ER) positive breast cancers in early and advanced stage settings. One of most frequent side effects of AIs is bone loss that is of sufficient magnitude to increase risk of osteoporotic fractures. Osteoporosis is primarily a complex genetic disease with few modifiable risk factors. As the lifespan increases, and breast mortality decreases, more women with breast cancer will be at risk of osteoporotic fractures, or falls that result in fractures. The screening, prevention, and treatment of osteoporosis do not differ in women with or without breast cancer. Rather, breast cancer treatments, including AIs, chemotherapy-induced ovarian failure, and gonadotropin-releasing hormone (GnRH) agonists, all decrease estrogen, which causes net bone resorption, leading some women to experience fracture. Occurring in about fifty-percent of women, AI-induced arthralgia is one of the most common side effects, and causes of nonadherence and discontinuation. Registry studies show that nonadherence and discontinuation may contribute to higher breast cancer mortality. Thus, understanding the mechanisms, risk factors, and interventions to mitigate symptoms of AI-induced arthralgia is a high priority.

Abstract P6-11-01: Final results of the randomized trial of exercise intervention vs. usual care for breast cancer patients with aromatase inhibitor to prevent and improve the aromatase inhibitor induced arthralgia

Abstract Aromatase inhibitors (AIs) have been used in the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer as a consequence of the significant benefit in DFS and OS when compared with tamoxifen. However the patients who receive AIs have an increased risk of arthralgia, at most 50% of patients did not take AIs and the 20% of the discontinued patients were within the first year of use. The HOPE study demonstrated that exercise was effective in improving AI-induced arthralgia. We conducted the AIAI (Arthralgia Improvement for the patients with Aromatase Inhibitors) study using wider eligibility criteria that the HOPE study to assess the impact on AI induced arthralgia in breast cancer patients. Patients were randomly assigned, in a 3:1 ratio, to exercise intervention or usual care. Following randomization participants could choose from 3 types of exercise including group 1 (120-150 minutes per week of walking or running), group 2 (daily NIPPON HOSO KYOKAI: NHK broadcast exercise in Japan) and group 3 (going up the stairs- frequency, etc). The primary endpoint was the arthralgia change at 6 and 12 months, which was assessed using the BPI (Brief Pain Inventory). Secondary endpoints included the BPI according to the completion rate of exercise (70% and more or less than 70%), the BPI change of the patients with arthralgia (the patients who had arthralgia at the time they enrolled this study; BPI worst pain 3≤), the BPI of the each exercise group, the BPI according to the duration of AIs therapy (24 months and more or less than 24 months), the correlation between the BMI change and the BPI change, adherence of AIs and safety. 102 were randomly assigned to exercise intervention group (22 patients dropped out of this study) and 37 to usual care group (9 patients dropped out of this study).Trends for differentiations of pain interference at 12 months was detected between exercise intervention group and usual care group, but the differences did not reach statistical significance (p = .067). There was statistically better pain interference of the 70% and more exercise completion group than the usual care group at 12 months (-0.29±1.22 for exercise intervention group and 0.33±0.88 for usual care group, p= .002). The change of pain interference was statistically better for the exercise intervention group than the usual care group at 12 months (p= .017, -0.61±0.69 for exercise intervention group and 1.14±1.56 for usual care group). There was statistically significant difference of pain interference between group 1 exercise intervention group and the usual care group at 12 months (-0.14±0.68 for group 1 exercise intervention group and 0.33±0.88 for the usual care group, p= .009). Tendencies were detected in the AIs therapy less than 24 months group. Trends for the correlation between BPI and BMI were detected in worst pain at 6 month, pain severity at 6 month and pain interference at 12 month. There was a statistically significant difference of AIs adherence between the exercise intervention group (99%) and the usual care group (92%) (P=0.03). Exercise may be effective in improving and preventing AI-induced arthralgia. Citation Format: Tamaki K, Takaesu M, Nagamine S, Terukina S, Kamada Y, Uehara K, Takigami N, Arakaki M, Yamashiro K, Miyashita M, Ishida T, McNamara KM, Tamaki N, Sasano H. Final results of the randomized trial of exercise intervention vs. usual care for breast cancer patients with aromatase inhibitor to prevent and improve the aromatase inhibitor induced arthralgia [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-11-01.

Vitamin D Levels, Vitamin D Receptor Polymorphisms, and Inflammatory Cytokines in Aromatase Inhibitor-Induced Arthralgias: An Analysis of CCTG MA.27

BackgroundApproximately half of women taking aromatase inhibitor (AI) therapy develop AI-induced arthralgia (AIA), and many might discontinue AI therapy because of the pain. Using plasma samples from the MA.27 study, we assessed several factors potentially associated with AIA. Patients and MethodsMA.27 is a phase III adjuvant trial comparing 2 AIs, exemestane versus anastrozole. Within an 893-participant nested case-control AIA genome-wide association study, we nested a 72 AIA case-144 control assessment of vitamin D plasma concentrations, corrected for seasonal and geographic variation. We also examined 9 baseline inflammatory cytokines: interleukin (IL)-1β, IL-6, tumor necrosis factor-α, interferon (IFN)γ, IL-10, IL-12p70, IL-17, IL-23, and chemokine ligand (CCL)-20. Finally, we analyzed the multivariate effects of baseline factors: vitamin D level, previously identified musculoskeletal single nucleotide polymorphisms, age, body mass index, and vitamin D receptor (VDR) Fok-I variant genotype on AIA development. ResultsChanges in vitamin D from baseline to 6 months were not significantly different between cases and controls. Elevated inflammatory cytokine levels were not associated with development of AIA. The multivariate model included no clinical factors associated with AIA. However, women with the VDR Fok-I variant genotype were more likely to have a lower IL-1β level (P = .0091) and less likely to develop AIA after 6 months of AI compared with those with the wild type VDR (P < .0001). ConclusionIn this nested case-control correlative study, vitamin D levels were not significantly associated with development of AIA; however, patients with the Fok-I VDR variant genotype were more likely to have a significant reduction in IL-1β level, and less likely to develop AIA.

Abstract P5-12-01: Randomized trial of exercise intervention vs. usual care for breast cancer patients with aromatase inhibitor to prevent and improve the aromatase inhibitor induced arthralgia

Abstract Purpose: Arthralgia sometimes occurs in the breast cancer patients treated with aromatase inhibitors (AIs). It is one of the most important reasons for poor AIs adherence. Background; The HOPE study previously demonstrated that exercise was effective in improving AI-induced arthralgia in breast cancer patients. However, recruitment to this study was limited to severe cases (Criteria; physically inactive, &amp;gt;6 months AT treatment, &amp;gt;2 months arthralgia). To asses if these findings were more generalizable to all breast cancer contexts we conducted a randomized trial of exercise intervention using wider eligibility criteria that the hope study to assess the impact on AI induced arthralgia in breast cancer patients. Methods: We examined Japanese breast cancer patients operated at Nahanishi Clinic, Okinawa, Japan. Following the informed consent the patients were randomly assigned to a 3:1 ratio to exercise intervention or usual care, . Eligibility criteria included receiving an AI for 0-4 years, no metastases, any arthralgia level and any exercise habits. Following randomization participants could choose from 3 types of exercise including strong (120-150 minutes per week of walking or running), intermediate (gentle calisthenics (daily NIPPON HOSO KYOKAI: NHK broadcast exercise)) and weak (going up the stairs- frequency). Arthralgia was assessed using the Brief Pain Inventory (BPI), in which the patients completed a baseline, 6month and 12 month BPI assessment. Primary endpoint was BPI change at 12 months. Results: Among 227 women screened, we randomized 108 women, with 80 to exercise intervention (46 of strong, 19 of intermediate and 15 of weak) and 28 to usual care. Base line BPI were well balanced between exercise intervention and usual care. Overall exercise intervention reduced BPI scores relative to control. The BPI changes of worst pain, least pain, average pain and pain right now were 0.09, -0.25, -0.14 and 0 for exercise intervention group and 0.21, 0.46, 0.07 and 0.61 for usual care group, respectively. There was a statistically significant difference of AIs adherence between exercise intervention group (99%) and usual care group (92%) (P=0.03). Conclusion: Exercise intervention tends to improve the AI-induced arthralgia and has a positive effect on AIs adherence. Citation Format: Tajaesu M, Tamaki K, Nagamine S, Kamada Y, Uehara K, Arakaki M, Tamatsu Y, Yamashiro K, Miyashita M, Ishida T, Ohuchi N, McNamara K, Terukina S, Sasano H, Tamaki N. Randomized trial of exercise intervention vs. usual care for breast cancer patients with aromatase inhibitor to prevent and improve the aromatase inhibitor induced arthralgia [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-12-01.

Exercise adherence in a randomized trial of exercise on aromatase inhibitor arthralgias in breast cancer survivors: the Hormones and Physical Exercise (HOPE) study.

Up to 50% of postmenopausal breast cancer survivors taking aromatase inhibitors (AIs) experience AI-associated arthralgias, or joint pain, which causes many to stop taking AIs and may inhibit exercise, despite known health benefits. We thus evaluated exercise adherence and factors associated with better exercise adherence in breast cancer survivors experiencing AI-induced arthralgia in the (HOPE) year long randomized controlled trial. We included 61 HOPE women randomized to exercise (150min/week of moderate-intensity aerobic exercise and twice-weekly supervised strength training). Our main outcomes were aerobic exercise measured with daily activity logs, attendance at supervised exercise sessions, and changes in cardiorespiratory fitness, measured maximal oxygen consumption (VO2max). We examined means and standard deviations (SDs) for exercise adherence by demographic and medical characteristics and used the t test for mean differences. We also examined predictors of adherence using linear regression. On average, at the end of the year long trial, women reported 119 (SD 78) min/week of moderate-intensity aerobic exercise and participated in 70% of supervised exercise training sessions. After adjustment for other factors that influence adherence, at 6months postrandomization, only baseline VO2max was associated with higher aerobic exercise levels and at 12months, only older age predicted better supervised exercise training attendance. Breast cancer survivors taking AIs and experiencing arthralgia are able to initiate and maintain a year long exercise program, regardless of other factors that influence activity levels. Breast cancer survivors can exercise at levels that have been shown to improve AI-associated arthralgia.

Acupuncture for Aromatase Inhibitor-Induced Arthralgia: A Systematic Review.

Aromatase inhibitors (AIs) are commonly used as adjunctive hormone treatment for early breast cancer patients. The major side effect of AIs is arthralgia, which affects adherence. Previous reviews suggested that acupuncture is effective in the management of cancer-related pain. The aim of this review is to evaluate the effects of acupuncture on arthralgia caused by AIs. This article examined randomized controlled trials (RCTs) measuring the effects of acupuncture on joint symptoms caused by AIs within 8 medical databases till May 2014. The quality of the articles was evaluated according to the Cochrane risk of bias (ROB) tool. Four RCTs were identified in medical journals. Two studies were conducted with manual acupuncture and 2 studies were electroacupuncture. The range of sample size was between 32 and 67. One RCT showed significant improvement in the acupuncture group compared with the sham control group and another RCT showed a statistical difference between the electroacupuncture and waitlist group. The other 2 studies showed no statistical differences between control and acupuncture groups. Two studies conducted blood analysis to elucidate the mechanism of efficacy of acupuncture for arthralgia. The 2 positive studies had a lower ROB and 2 studies had a high ROB. The systematic review suggests that acupuncture has potential benefits to improve arthralgia caused by AIs. However, further trials of adequate sample size, appropriate control group, and longer follow-up are necessary to investigate the efficacy of acupuncture in AI-induced arthralgia.

Abstract P5-15-03: Baseline joint pain predicts severity of subsequent joint symptoms in women initiating aromatase inhibitors for early stage breast cancer

Abstract Background: Aromatase inhibitors (AIs) are the standard adjuvant treatment of hormone-sensitive breast cancer (BC) in postmenopausal women. However, these therapies are associated with musculoskeletal complaints which may lead to non-adherence and early discontinuation. The aim of this study was to characterize the natural history of the AI-induced arthralgia. Methods: Postmenopausal women with stage I-III BC were prospectively enrolled at the onset of adjuvant AI therapy. Subjects completed the Brief Pain Inventory (BPI) questionnaire at baseline, 3, 6, 9, and 12 months. BPI worst pain scores were categorized as 0-3, 4-6 and 7-8. Multiple logistic regression analysis was used to evaluate the association between baseline factors and having a 2-point worsening in BPI worst pain score. A Cox-proportional hazards model was used to evaluate factors that influenced the time to first 2-point worsening in pain score. Clinically significant change was defined as ≥2-point increase from baseline. Those with a baseline BPI worst pain score of ≥9 were removed from analysis. Results: Among 180 consented subjects, 1 was found to be ineligible due to being perimenopausal, 42 subjects were lost to follow up, 17 subjects came off their AI and 8 subjects dropped out. Mean age was 61; 60% were white, 32% Black, 10%, Asian and 31% were Hispanic; 86% started on anastrazole; 24% had a change in AI. At baseline, 76 women had a BPI worst pain score between 0-3; 28 between 4-6; and 18 had 7+. Seventy subjects (64%) experienced at least a 2-point worsening of BPI from baseline and women who developed a 2-point worsening had a lower mean baseline BPI (2.57 vs. 3.75) compared to those who did not. Those experiencing an initial worsening in the first 6 months of therapy improved over time; while the patients experiencing BPI worsening at 9 months, continued to have progressive increase in BPI. In a multiple logistic regression model adjusting for AI switching, BMI, age, baseline score, prior chemotherapy, osteoarthritis, and prior hormone replacement therapy, those who had a baseline worst pain score between 4-6 (p=0.04) or 7+ (p=0.005) were less likely to develop a 2-point worsening in BPI at 12 months from baseline. Similarly, those with a baseline worst pain categorization of 7+ had a hazard ratio of 0.34 for time to 2-point worsening. Conclusions: Women with low baseline BPI score are more likely to develop worsening BPI score over time. Women who develop symptoms later in the course of their therapy are at greatest risk for persistent symptoms. This has implications for studies evaluating interventions for prevention of AI arthralgias. BPI mean scorePatients with &amp;gt;2 point increase in BPI at any timePatients with &amp;gt;2 point increase in BPI at 3 monthsPatients with &amp;gt;2 point increase in BPI at 6 monthsPatients with &amp;gt;2 point increase in BPI at 9 monthsPatients with &amp;gt;2 point increase in BPI at 12 monthsBaseline score3.752.57*2.592.302.11*1.85*Three month score4.254.526.08*4.684.133.87Six month score4.504.83*5.32*6.37*5.074.22Nine month score4.005.105.115.135.75*5.04Twelve month score4.255.37*5.484.865.666.21**p value &amp;lt;0.05 compared to baseline Citation Format: Lea Baer, Katherine D Crew, Danielle Awad, Kevin Kalinsky, Matt Maurer, Dawn L Hershman. Baseline joint pain predicts severity of subsequent joint symptoms in women initiating aromatase inhibitors for early stage breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-15-03.

Randomized Exercise Trial of Aromatase Inhibitor–Induced Arthralgia in Breast Cancer Survivors

Arthralgia occurs in up to 50% of breast cancer survivors treated with aromatase inhibitors (AIs) and is the most common reason for poor AI adherence. We conducted, in 121 breast cancer survivors receiving an AI and reporting arthralgia, a yearlong randomized trial of the impact of exercise versus usual care on arthralgia severity. Eligibility criteria included receiving an AI for at least 6 months, reporting ≥ 3 of 10 for worst joint pain on the Brief Pain Inventory (BPI), and reporting < 90 minutes per week of aerobic exercise and no strength training. Participants were randomly assigned to exercise (150 minutes per week of aerobic exercise and supervised strength training twice per week) or usual care. The BPI, Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index, and Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire were completed at baseline and at 3, 6, 9, and 12 months. Intervention effects were evaluated using mixed-model repeated measures analysis, with change at 12 months as the primary end point. Over 12 months, women randomly assigned to exercise (n = 61) attended 70% (± standard deviation [SD], 28%) of resistance training sessions and increased their exercise by 159 (± SD, 136) minutes per week. Worst joint pain scores decreased by 1.6 points (29%) at 12 months among women randomly assigned to exercise versus a 0.2-point increase (3%) among those receiving usual care (n = 60; P < .001). Pain severity and interference, as well as DASH and WOMAC pain scores, also decreased significantly at 12 months in women randomly assigned to exercise, compared with increases for those receiving usual care (all P < .001). Exercise led to improvement in AI-induced arthralgia in previously inactive breast cancer survivors.

Clinical and genetic risk factors for AI-induced arthralgia.

e20601 Background: Aromatase Inhibitors (AIs) are associated with arthralgia development, leading to therapy non-adherence and premature discontinuation. Clinical and genetic risk factors have been...

Acupuncture for Treatment of Arthralgia Secondary to Aromatase Inhibitor Therapy in Women with Early Breast Cancer: Pilot Study

Aromatase inhibitors (AIs) are recommended as adjuvant hormone treatment for postmenopausal women with early breast cancer. A substantial proportion of women taking AIs experience joint pain and stiffness. Studies have suggested that acupuncture may be effective in treating joint pain. A pilot study was conducted to evaluate the feasibility, safety and efficacy of using acupuncture to treat AI-induced arthralgia. A total of 32 patients were randomised to receive either sham or real electroacupuncture (EA) twice weekly for 6 weeks. Outcomes of joint pain, stiffness and physical function were measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), overall pain severity and interference with the BPI-SF and quality of life (QOL) with the Functional Assessment of Cancer Therapy-General (FACT-G) instrument. Hand strength was assessed by a grip test, and a serum marker of inflammation (C reactive protein (CRP)) was also measured. All assessments were performed at baseline, 6 weeks and 12 weeks, except for blood samples at baseline and 6 weeks only. No serious adverse events were reported during or after acupuncture treatments. There were no significant differences in outcome measures. However, positive trends were observed in stiffness and physical function at week 12 in favour of real EA. Findings suggest that acupuncture is feasible and safe in patients with breast cancer with joint pain caused by AI. A larger study with adequately powered to confirm these results and detect clinically relevant effects is needed.

Abstract P2-12-01: Prospective Evaluation of Joint Symptoms in Postmenopausal Women Initiating Aromatase Inhibitors for Early Stage Breast Cancer

Abstract Background: Aromatase inhibitors (AIs) are widely prescribed to postmenopausal women for the adjuvant treatment of hormone-sensitive breast cancer (BC). However, musculoskeletal complaints can lead to nonadherence and early discontinuation. The aim of this study was to characterize the natural history of the AI-induced arthralgia syndrome and determine predictors of worsening symptoms. Methods: Postmenopausal women with stage I-III BC initiating adjuvant AI therapy were enrolled. All patients completed the following questionnaires at baseline and every 3 months for a year: Modified Brief Pain Inventory-Short Form (BPI-SF), Western Ontario and McMaster Universities Osteoarthritis (WOMAC) index and the Modified Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH). Higher scores reflect worse symptoms. Quality of life was assessed using the Functional Assessment of Cancer Therapy-Endocrine Subscale (FACT-ES). Hand grip strength was measured at each visit with a Martin dynamometer. Paired t-tests were performed to compare follow-up evaluations to baseline. Linear Regression was performed to evaluate the association between baseline symptoms and change in symptoms. Results: A total of 169 patients have been consented, 3-month data is available on 102; 6-month data on 85. Median age: 63 (42–89); White/Black/Asian/Hispanic: 61.48/30.33/3.28/25.6; median BMI (kg/m2): 28 (12–50). Compared to baseline, there was a statistically significant increase in BPI pain severity and endocrine related symptoms on the FACT-ES at 3 and 6 months. Significant changes in the BPI pain interference, M-SACRAH pain and stiffness, WOMAC function, physical well-being on the FACT-ES, trial outcome index and pinch grip strength were seen at 3 months; however these changes did not remain significant at 6 months. Logistic regression models evaluating predictors of patient reported outcome measures and grip strength were performed. Baseline score was the strongest predictor of worsening symptoms (p &amp;lt; 0.01) after correcting for age, prior chemotherapy and baseline joint conditions. Conclusions: Treatment with adjuvant AI therapy is associated with significant worsening of joint pain and stiffness which is most prominent at the 3 months evaluation. Patients with baseline joint symptoms are at greatest risk for worsening symptoms on AIs. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-12-01.