Cancer Patients Receiving Aromatase Inhibitors Research Articles

Abstract PO2-12-10: Age-specific outcomes in breast cancer patients treated with aromatase inhibitors - A national inpatient sample database analysis

Abstract Background: This study aims to investigate the age-specific outcomes of breast cancer patients undergoing aromatase inhibitors therapy. Currently, no research exists on the age-specific differences in outcomes for this patient population. This study seeks to fill this knowledge gap and provide valuable insights into the various outcomes of these patients. Methods: This retrospective study analyzed hospitalization data from the National Inpatient Sample (NIS) between January 2016 and December 2019 using STATA/BE 17.0 for statistical analysis. It focused on breast cancer patients treated with aromatase inhibitors, evaluating outcomes like mortality, length of stay, charges, and clinical outcomes. We used univariate regression and logistic analysis, with ICD-10 codes utilized for data classification. Results: A total of 5,994 weighted hospitalizations were identified, consisting of breast cancer patients being treated with aromatase inhibitors. For patients aged below 65 (n=1,919), the inpatient mortality rate was 1.8% (n=35), while for patients aged 65 and above (n=4,075), it was slightly higher at 2.3% (n=94). However, there was no statistically significant difference in inpatient mortality between the two age groups (adjusted odds ratio [aOR] = 1.21 [0.82-1.78], p=0.339). The average length of stay (LOS) was similar for both age groups, with patients below 65 having a mean LOS of 4.75 days and those aged 65 and above having a mean LOS of 4.71 days. Total charges ($) in the younger population ( < 65) were incurred at a mean of $60,782.73 (56,764.18-64,801.27), compared to lesser charges in the elderly at a mean of $54,734.38 (52,339.83-57,128.94). The occurrence of pathological fractures was higher in patients below 65, with a rate of 1.6% (n=31), compared to 0.8% (n=33) in patients aged 65 and above (aOR = 0.47 [0.28-0.78], p=0.004). Regarding venous thromboembolism (VTE), the occurrence was 5.5% (n=105) in patients below 65 and 4.8% (n=195) in patients aged 65 and above. There was no significant difference between the two age groups (aOR = 0.86 [0.68-1.10], p=0.237). The occurrence of acute cerebrovascular accidents (CVA) was 0.6% (n=11) in patients below 65 and 1.6% (n=65) in patients aged 65 and above, with an aOR of 2.58 (1.38-4.80), indicating a significantly higher likelihood of CVA in the older age group (p=0.003). Patients aged 65 and above had a higher occurrence of myocardial infarction (MI) compared to patients below 65, with rates of 2.1% (n=85) and 0.1% (n=2), respectively. The aOR for MI was 2.35 (1.39-3.98), indicating a significantly higher likelihood of MI in the older age group (p=0.001). There was no statistically significant difference in the occurrence of hypertensive crisis (HTN crisis) between the two age groups (aOR=1.47 [0.93-2.34], p=0.09). Conclusion: Among breast cancer patients receiving aromatase inhibitors, there was no significant difference in in-patient mortality between those aged below 65 and those aged 65 and above. Both age groups had similar lengths of stay and charges incurred. There was no statistically significant difference in VTE and HTN crisis odds. However, patients below 65 had a higher occurrence of pathological fractures, while patients aged 65 and above had a higher likelihood of acute cerebrovascular accidents and myocardial infarction. Further guidelines must be established to improve inpatient morbidity and mortality in this patient population. Breast cancer patients on aromatase inhibitors therapy Citation Format: Rushin Patel, Akshit Chitkara, Zalak Patel, Mrunal Patel, Darshil Patel, Himanshu Kavani, FNU Anamika, Femina Patel. Age-specific outcomes in breast cancer patients treated with aromatase inhibitors - A national inpatient sample database analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-12-10.

Denosumab effect on bone mineral density and urinary-NTX in breast cancer patients receiving aromatase inhibitors.

Aromatase inhibitors are used post-surgical intervention in postmenopausal patients with breast cancer. However, these drugs accelerate decline in bone mineral density (BMD), which is countered by use of denosumab, and the efficacy of the drug can be assessed by bone turnover markers. We investigated the effects of denosumab administration for 2years on BMD and urinary N-telopeptide of type I collagen (u-NTX) levels in breast cancer patients treated with aromatase inhibitors. This was a single-center retrospective study. Postoperative hormone receptor-positive breast cancer patients with low T-scores biannually received denosumab from the time of initiation of aromatase inhibitor therapy for 2years. BMD was measured every 6months, and u-NTX levels were assessed after 1month and thereby every 3months. The median patient age of the 55 patients included in this study was 69 (range: 51-90) years. BMD gradually increased in the lumbar spine and femoral neck and u-NTX levels were lowest at 3months post-initiation of therapy. Patients were divided into two groups based on the change ratio of u-NTX 3months post-denosumab administration. Of these, the group with higher change ratio showed a higher degree of BMD restoration in the lumbar spine and femoral neck 6months post-denosumab treatment. Denosumab increased BMD in patients treated with aromatase inhibitors. The u-NTX level decreased soon after start of denosumab treatment, and its change ratio is predictive of improvement in BMD.

Efficacy and Safety of Monthly Minodronate Therapy in Postmenopausal Breast Cancer Patients Receiving Aromatase Inhibitors.

Post-menopausal breast cancer (BC) patients who receive adjuvant aromatase inhibitor (AI) therapy may be at increased risk of bone loss, osteoporosis, and bone fracture. We aimed to evaluate the efficacy and safety of oral bisphosphonate minodronate in preventing bone loss complications. Patients receiving AI and 80% of those with suboptimal bone mineral density (BMD) were prescribed monthly oral minodronate 50 mg every 4 weeks for 72 weeks. BMD, bone metabolism markers, incidence of bone fractures, medication compliance, and other adverse events (AE) were examined every 24 weeks following administration. Fifty postmenopausal BC patients with a median age of 64.0 years were enrolled. The mean value of lumbar spine BMD was higher than that of the value before the minodronate administration at each observation point. Before and after the treatment, the median serum values of Tartrate-resistant Acid Phosphatase 5b (TRACP-5b) (mU/dl) and serum type I collagen cross-linked N-telopeptide (NTX) (nmolBCE/l) were decreased from 535.7 and 18.5 to 230.1 and 11.9, respectively. No adverse grade 2 or higher event was observed throughout this study. The combined administration of minodronate and AIs was safe and effective in preventing bone loss complications in postmenopausal BC patients.

Risk of cardiovascular disease in breast cancer patients receiving aromatase inhibitors vs. tamoxifen: A systematic review and meta-analysis.

Breast cancer is one of the leading causes of morbidity and mortality in women worldwide. In order to reduce the risks of its recurrence, endocrine therapies, such as tamoxifen and aromatase inhibitors are commonly administered. Despite having a similar efficacy in preventing breast cancer recurrence, these drugs differ in terms of instigating cardiovascular morbidities. Recent randomized controlled trials and cohort studies provide inconclusive evidence of the cardiovascular risks associated with the administration of these endocrine therapies. This present review and meta-analysis evaluates the comparative cardiovascular adverse event outcomes in breast cancer patients receiving tamoxifen and aromatase inhibitors. To evaluate the comparative cardiovascular adverse outcomes, such as venous thromboembolism, heart failure, angina, myocardial infarction and stroke in patients with breast cancer receiving tamoxifen and aromatase inhibitors. A systematic search of the academic literature was performed according to the PRISMA guidelines across five databases, including Web of Science, EMBASE, CENTRAL, Scopus, and MEDLINE. A random-effect meta-analysis was conducted to compare the cardiovascular adverse events (i.e. venous thromboembolism, heart failure, angina, myocardial infarction, stroke) in breast cancer patients treated with tamoxifen and aromatase inhibitors. From 993studies, 20 eligible studies were identified, with 174,142 female breast cancer patients (mean age: 67.4±3.8years). A meta-analysis revealed insignificantly (p>0.05) higher risks of venous thromboembolism (Odds ratio, 95% CI: 1.70, 0.91-3.18) in patients treated with tamoxifen as compared to aromatase inhibitors. We also observed insignificantly higher risks of stroke (0.93, 0.45-1.91), angina (0.77, 0.12-4.59), myocardial infarction (0.74, 0.30-1.79), and heart failure (0.81, 0.22-2.91) in patients receiving aromatase inhibitors as compared to tamoxifen. The study provides evidence regarding the comparative cardiovascular adverse outcomes between breast cancer patients consuming tamoxifen and aromatase inhibitors. The study reports an insignificant increase in the events of stroke, angina, myocardial infarction, and heart failure in breast cancer patients treated with aromatase inhibitors as compared to tamoxifen. The study also reports that tamoxifen treatment is associated with an insignificant increase in the events of venous thromboembolism as compared to treatment with aromatase inhibitors.

Musculoskeletal Pain and the Prevalence of Rheumatoid Arthritis in Breast Cancer Patients During Cancer Treatment: A Retrospective Study.

Breast cancer patients often develop musculoskeletal pain, resembling that experienced by patients with rheumatoid arthritis (RA), during cancer treatment. This study aimed to investigate the causes of musculoskeletal pain, including RA, among breast cancer patients. This retrospective study included breast cancer patients experiencing new-onset arthralgia during cancer treatment along with age- and sex-matched controls without breast cancer, who were evaluated at the Rheumatologic clinic between 2004 and 2017. The causes of musculoskeletal pain were compared between breast cancer patients and controls. The effects of cancer treatment on arthralgia and factors associated with RA were examined. A total of 146 breast cancer patients and 102 controls were included in the final analysis. The most common cause of arthralgia during breast cancer treatment was osteoarthritis (OA, 61.0%), followed by enthesopathy/tendinopathy (28.1%), which included tendinitis, adhesive capsulitis, and carpal tunnel syndrome. Overall, 50.0% of 72 breast cancer patients receiving aromatase inhibitors (AIs) satisfied the criteria of AI-induced musculoskeletal symptoms (AIMSS). The mean symptom duration (i.e., the time between pain onset and evaluation by a rheumatologist) was shorter in breast cancer patients than in controls (7.0 ± 12.1 vs. 14.8 ± 24.9 months, respectively; p = 0.004). RA was diagnosed in 3 (2.1%) breast cancer patients and 3 (2.9%) controls. All breast cancer patients with RA had an elevated erythrocyte sedimentation rate (ESR, 66.7 ± 25.0 mm/h), whereas those without RA had a normal ESR (20.4 ± 21.5 mm/h). Patients with breast cancer required more analgesics than the controls. OA and enthesopathy/tendinopathy are the most common causes of arthralgia in breast cancer patients, which may concurrently manifest as AIMSS. Patients with breast cancer did not have a higher prevalence of RA than those without breast cancer.

Statin use and breast cancer recurrence in postmenopausal women treated with adjuvant aromatase inhibitors: a Danish population-based cohort study

PurposeTo examine the association between statin use and risk of breast cancer recurrence in a national Danish cohort of postmenopausal breast cancer patients receiving aromatase inhibitors (AI) in the adjuvant setting.Patients and methodsWe enrolled all postmenopausal patients diagnosed with stage I–III estrogen receptor positive breast cancer during the years 2007–2017, assigned adjuvant AI treatment, and registered in both the Danish Breast Cancer Group database and the Danish Cancer Registry. We ascertained incident statin exposure (≥ 1 prescription post-diagnosis) from the Danish National Prescription Registry and modeled statins as a time-varying exposure lagged by 6 months. Follow-up began 7 months after diagnosis and continued to the first event of recurrence, death, emigration, 5 years elapsed, or 25th September 2018. We estimated incidence rates of recurrence at 5 years and used Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CI), comparing statin exposure with non-exposure.ResultsWe enrolled 14,773 eligible patients. During the 5 years of follow-up, there were 32 recurrences in 3163 person-years of follow-up among statin-exposed patients, and 612 recurrences in 45,655 person-years among unexposed patients (incidence rate per 1000 person-years: 10.12 [95% CI 6.92–14.28] and 13.40 [95% CI 12.36–14.51], respectively). In multivariable models, any statin exposure was associated with a reduced rate of 5-year breast cancer recurrence (adjusted HR 0.72 [95% CI 0.50–1.04]). Considering only lipophilic statins as exposure the results were similar (adjusted HR 0.70 [95% CI 0.48–1.02]).ConclusionsStatin use was associated with a reduced risk of breast cancer recurrence among postmenopausal patients diagnosed with early stage breast cancer who received adjuvant AI therapy.

Abstract P6-11-01: Adherence to guidelines for bone health in a predominantly Hispanic cohort of breast cancer patients receiving aromatase inhibitors

Abstract Introduction: Aromatase inhibitors (AI), by reducing estrogen levels, decrease the risk of recurrence of hormone receptor positive breast cancer but also lead to accelerated bone loss and increased fracture risk. This has led to guidelines for treating women on AIs with bone antiresorptive agents earlier in order to avoid fractures. The 2017 joint position statement from the International Osteoporosis Foundation, Cancer and Bone Society, European Calcified Tissue Society, International Expert Group for AI Bone Loss, European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Disease, International Menopause Society, and the International Society for Geriatric Oncology recommends treating patients on AI with either denosumab or bisphosphonates with BMD T-scores < -2.0, T-scores < -1.5 with one additional risk factor, or with ≥ 2 risk factors even without a BMD for the duration of AI therapy. The Garbar Breast Care Center at TTUHSC-El Paso serves a predominantly Hispanic patient population. As disparities in cancer care have been well documented amongst minorities, we sought to determine the adherence to the current guidelines for fracture prevention in this group. Methods: Post-menopausal women diagnosed with non-metastatic breast cancer and receiving adjuvant AIs who had a BMD done were included. Patients with pre-existing osteoporosis or already receiving antiresorptive therapy prior to cancer diagnosis were excluded. Electronic medical records of patients seen in clinic between 9/2015 and 3/2018 were reviewed to extract data regarding bone mineral density (T score, Z score), risk factors, and use of antiresorptive therapies. Study was approved by the institutional IRB. Results: A total of sixty patients were included. Median age was 65 years and 92% were Hispanic. Stage distribution was as follows: I, 40%, II, 43% and III, 17%. Thirty-eight (63%) met criteria to be treated with an antiresorptive agent. Thirty-two (53%) had T-scores < -2.0 and 6 (10%) had a T-score < -1.5 with at least 1 additional risk factor. Only 15 (39%) of the 38 patients who met guidelines for treatment were on antiresorptive therapy. Of the 15 patients who were on treatment, 10 had osteoporosis (T-score < -2.5), and 5 had osteopenia (T-score -2 to -2.5). Two additional patients were on antiresorptive therapy that did not meet the guidelines. Of the remaining 23 patients who met guidelines for treatment but were not treated, 6 had frank osteoporosis, 11 had a T-score between -2.0 and -2.5, and 6 had T-scores < -1.5 with at least one additional risk factor. Perceived barriers to appropriate institution of anti-resorptive therapy amongst oncologists were a) lack of timely dental evaluation and risk of osteonecrosis, b) cost of denosumab and zoledronic acid c) risk of myalgias and arthralgias with anti-resorptive agents potentially affecting compliance with AI therapy. Conclusion: In a predominantly Hispanic population, we found that only 39% of patients with indications for anti-resorptive therapy were on appropriate treatment. This has important implications for long term bone health amongst these cancer survivors. As adjuvant bisphosphonates have also been associated with a decrease in bone metastases and improvement of breast cancer specific survival, the low rate of adherence to guidelines can potentially contribute to inferior long-term survival. Timely access to dental services can potentially improve compliance rates. Citation Format: Tamis M. Bright, Meghan K. Mcalice, Abelardo Escriba-Omar, Sumit Gaur, Alexander V. Philipovskiy. Adherence to guidelines for bone health in a predominantly Hispanic cohort of breast cancer patients receiving aromatase inhibitors [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 P6-11-01.

Increased Fracture Risk in Women Treated With Aromatase Inhibitors Versus Tamoxifen: Beneficial Effect of Bisphosphonates.

Aromatase inhibitors have been associated with accelerated bone loss and an increased risk of osteoporotic fractures. Currently, bisphosphonates are recommended to reduce fracture risk in these patients. The aim of this study is to evaluate the fracture risk in breast cancer patients receiving aromatase inhibitors, compared to tamoxifen users, and to assess the effectiveness of oral bisphosphonates in reducing fracture risk. We performed an observational cohort study up to 10 years of follow-up. Data were extracted from primary care records in a population database. Women diagnosed with breast cancer between 2006 and 2015 and treated with tamoxifen or aromatase inhibitors (n = 36,472) were stratified according to low (without osteoporosis diagnosis nor bisphosphonates exposure) or high (with osteoporosis and/or treated with bisphosphonates) fracture risk. Cox models were used to calculate hazard ratios (HR [95% CI]) of fracture from the propensity score-matched patients. Sensitivity analyses account for competing risk of death were performed (subdistribution hazard ratio [SHR] [95% CI]). In postmenopausal women, fracture risk in aromatase inhibitor users showed an HR 1.40 [95% CI,1.05 to 1.87] and SHR 1.48 [95% CI, 1.11 to 1.98], compared to tamoxifen. Observing aromatase inhibitors patients at high risk of fracture, bisphosphonate-treated patients had an HR 0.73 [95% CI, 0.51 to 1.04] and SHR 0.69 [95% CI, 0.48 to 0.98] compared to nontreated. In conclusion, fracture risk in postmenopausal women during aromatase inhibitor treatment, in real-life conditions, was >40% compared to tamoxifen, corroborating previous randomized controlled trials results. In high-risk patients, bisphosphonate users had lower significant fracture incidence during aromatase inhibitor therapy than nonbisphosphonate users. Monitoring fracture risk and related risk factors in aromatase inhibitor patients is advisable. © 2019 American Society for Bone and Mineral Research.

Assessment of cardiotoxicity in hormone positive postmenopausal breast cancer patients receiving aromatase inhibitors

Background: Aromatase inhibitors (AIs) represent an effective endocrine treatment for hormone receptor-positive postmenopausal breast cancer patients with early stage or metastatic disease.Objective: Assessment of Cardiotoxicity in Hormone positive Postmenopausal Breast Cancer Patients receiving AIs (upfront orswitch therapy).Methods: This cross sectional study included 123 postmenopausal breast cancer patients presented to the Clinical Oncology Department, Ain Shams University (Cairo, Egypt) in the interval from August 2016 to June 2017 with hormone receptor positive receiving Aromatase Inhibitors, To assess cardiotoxicity in these patients, they were subjected to blood pressure and lipid profile measurement, electrocardiography (ECG), and electrocardiography (ECHO) and classified into patients had Nolvadex then A.I (arm 1) and others had upfront A.I (arm 2).Results: The age of patients ranged from 41 years to 85 years with mean age of 61 years. Seventy one patients (57.7%) showed cardiotoxicity as assessed by ECHO. They showed significant correlation with rising age above 62 years, IHD, history of HTN and DM (p value: .001, .001, .017 and 0.035 respectively). However, correlation between cardiotoxity and blood pressure changes, lipid profile changes and ECG findings and ECHO changes in switch therapy and upfront A.I were not statistically significant (p value = .275, .116, .081 and .761 respectively).Conclusion: Assessment of cardiotoxicity in hormone positive postmenopausal breast cancer patients receiving Aromatase Inhibitors showed evidence of cardiotoxicity in half the patients (57.7%) as detected by ECHO only. They showed statistically non significant correlations either recievied switch therapy or upfront A.I.

Whole Body Vibration Exposure on Markers of Bone Turnover, Body Composition, and Physical Functioning in Breast Cancer Patients Receiving Aromatase Inhibitor Therapy: A Randomized Controlled Trial.

Introduction: Women with breast cancer are often prescribed aromatase inhibitors, which can cause rapid loss of bone mass leading to significant potential for morbidity. Vibration training has been shown to be helpful in reducing bone turnover in postmenopausal women without cancer. Aim: To examine the effect of vibration stimulus on markers of bone turnover in breast cancer patients receiving aromatase inhibitors. Methods: Thirty-one breast cancer survivors undergoing treatment with aromatase inhibitors were randomized to vibration stimulus (n = 14) or usual care control (n = 17). Low-frequency and low-magnitude vibration stimulus (27-32 Hz, 0.3g) was delivered in supervised sessions via standing on a vibration platform for 20 minutes, 3 times per week for 12 weeks. The primary outcome was blood markers of bone resorption (serum N-telopeptide X/creatine) and formation (serum type 1 procollagen N-terminal propeptide; P1NP). Other study outcomes body composition as well as measures of physical functioning. Outcomes were compared between groups using analysis of covariance adjusted for baseline values as well as time on aromatase inhibitors. Outcomes: On average, participants were 61.5 years old and overweight (ie, body mass index = 28.5 kg/m2). Following vibration training, there was no significant difference between groups for bone resorption (adjusted group difference 0.5, P = .929) or formation (adjusted group difference 5.3, P = .286). There were also no changes in any measure of physical functioning body composition. Conclusions: Short-term low-magnitude vibration stimulus does not appear to be useful for reducing markers of bone turnover secondary to aromatase inhibitors in breast cancer patients; nor is it useful in improving physical function or symptoms. However, further investigations with larger samples and higher doses of vibration are warranted. Trial Registration: Australian and New Zealand Clinical Trials Registry (ACTRN12611001094965).

Effects of oral vitamin B12 for the treatment of aromatase inhibitors (AI)-related musculoskeletal symptoms in women with early stage breast cancer.

86 Background: Breast cancer patients receiving Aromatase Inhibitor (AI) therapy experience many side effects including arthralgias, myalgias and stiffness of joints. The objective of this study was to evaluate the effect of vitamin B12 supplements on pain related symptoms. Methods: In this study, patients taking AIs and experiencing pain at baseline were given 2500 mcg of vitamin B12 sublingually daily for 90 days. The validated Brief Pain Inventory-Short Form (BPI-SF) questionnaire using a 10 scale rating was evaluated prior and post- intervention. The BPI-SF asseses pain level and its interference with other daily life events on a scale from one to ten, one meaning pain does not interfere. Item 9 from the BPI assesses 7 important dimensions that are reported here. Results: 36 patients were recruited and scores were evaluated at baseline and at 90 days after taking vitamin B12 for general activity, mood, walking ability, normal work, relations with people, and for enjoyment of life post interventions as shown in the table. Conclusions: This study suggests that by taking a high dose of vitamin B12, significant improvement was observed in several dimensions related to pain scales in patients with AI -related musculoskeletal symptoms. Preliminary data confirms that vitamin B12 not only help improve pain, but it also aids in improving patient’s mood, well-being and relations with others. Larger randomized studies are warranted to confirm these promising findings. Clinical trial information: NCT03069313. [Table: see text]

Arthralgia- the principal side effect in Breast Cancer Patients Receiving Aromatase Inhibitors and its management

Arthralgia- the principal side effect in Breast Cancer Patients Receiving Aromatase Inhibitors and its management

Abstract S2-02: The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial

Abstract Background: Adjuvant endocrine therapy compromises bone health in pre- and postmenopausal breast cancer (BC) patients. Bisphosphonates have been shown to prevent and counteract these side effects of endocrine therapy, and to improve disease-free and overall survival outcomes in postmenopausal (natural or induced) BC patients (EBCTCG meta-analysis, Lancet 2015). The aim of ABCSG-18 was to investigate the effects of adjuvant anti-RANK-ligand Denosumab on bone health and disease outcomes in postmenopausal patients with early hormone receptor+ (HR+) BC receiving AI treatment. Patients and Methods: 3,425 postmenopausal patients with HR+ BC receiving AI were recruited in 58 trial sites into this prospective, randomized, double-blind, placebo-controlled, phase-III trial. Patients were randomized 1:1 to either Denosumab 60mg or placebo q6mo s.c. Bone end point results showed that adjuvant denosumab significantly reduced clinical fractures (primary endpoint, HR=0.5, p<0.0001), improved bone mineral density, and reduced vertebral fractures without relevant toxicity (Gnant et al., Lancet 2015). Disease-free survival (DFS) is a secondary endpoint. Following an IDMC recommendation based on the results of a protocol-specified interim analysis, a DFS analysis took place in September 2015, before a patients' choice unblinding option will be provided to trial patients in the year 2016. Additional disease outcome related end points (BMFS, OS) will be analysed during further study follow up. Results: With a median follow-up of 4 years, 370 DFS events were recorded. 203 DFS events occurred in the placebo group, and 167 in the Denosumab group (HR 0.816, p=0.051). Subgroup analyses indicate that the Denosumab benefit (overall absolute 2.1% at 5 years) may be particularly driven by tumors larger than 2cm (HR=0.66, p=0.016), ductal breast cancer histology type (HR=0.79, p=0.048), and tumors with both ER and PR positive (HR=0.75, p=0.013). Summary and conclusion: Adjuvant Denosumab 60mg q6mo s.c. improves disease-free survival of HR+ breast cancer patients receiving aromatase inhibitors. Numerically, this benefit of adjuvant Denosumab is at least comparable to the DFS-benefit of adjuvant bisphosphonates. Bases on these results and the previously reported dramatic reduction of fractures, adjuvant Denosumab should be offered to all postmenopausal HR+ breast cancer patients on AI. Citation Format: Gnant M, Pfeiler G, Dubsky PC, Hubalek M, Greil R, Jakesz R, Wette V, Balic M, Haslbauer F, Melbinger-Zeinitzer E, Bjelic-Radisic V, Artner-Matuschek S, Fitzal F, Marth C, Sevelda P, Mlineritsch B, Steger GG, Manfreda D, Exner R, Egle D, Bergh J, Kainberger F, Talbot S, Warner D, Fesl C, Singer CF, On behalf of the Austrian Breast and Colorectal Cancer Study Group. The impact of adjuvant denosumab on disease-free survival: Results from 3,425 postmenopausal patients of the ABCSG-18 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-02.

P037 Ki67 assessment using a 5-grade scale revealed high reproducibility for luminal type breast cancer

Goals: Local application of estradiol (E2) to treat vulvovaginal atrophy in postmenopausal breast cancer patients receiving aromatase inhibitors is known to elevate serum estradiol levels and thereby might counteract breast cancer therapy. Thus, vaginal application of estriol (E3) has been recommended for these patients. However, it is unclear to what extent E3 stimulates breast cancer cell growth. In this study, we examined the effect of E3 on growth and gene expression of two human breast cancer cell lines. Methods: We used an established in vitro cell culture assay and compared the effect of E2 and E3 on growth of the estrogen receptor alpha-positive breast cancer cell lines MCF-7 and T-47D testing a wide range of hormone concentrations of 10–10M. E3 effects on gene expression were examined by means of reporter gene assays, RT-qPCR and Western blot analysis. Results: E3 acted as a potent estrogen and exerted a mitogenic effect on T-47D and MCF-7 cells at concentrations of 10M (288 pg/ml) and higher. With regard to activation of an estrogen response element (ERE) in breast cancer cells, effects of E3 were visible at 10M. The same concentrations of E3 activated expression of the estrogen-responsive gene PR and of the proliferation genes cyclin A2, cyclin B1, Ki-67, c-myc and b-myb, providing molecular mechanisms underlying the observed growth increase. Conclusion: Like E2, low levels of E3 were able to trigger a robust estrogenic response in breast cancer cells. Thus, our data suggest caution regarding use of E3 by breast cancer survivors. Disclosure of Interest: No significant relationships.

Effects of estriol on growth, gene expression and estrogen response element activation in human breast cancer cell lines

ObjectiveLocal application of estradiol (E2) to treat vulvovaginal atrophy in postmenopausal breast cancer patients receiving aromatase inhibitors is known to elevate serum estradiol levels and thereby might counteract breast cancer therapy. Thus, vaginal application of estriol (E3) has been recommended for these patients. However, it is unclear to what extent E3 stimulates breast cancer cell growth. In this study, we examined the effect of E3 on growth and gene expression of two human breast cancer cell lines. MethodsWe used an established in vitro cell culture assay and compared the effect of E2 and E3 on growth of the estrogen receptor alpha-positive breast cancer cell lines MCF-7 and T-47D testing a wide range of hormone concentrations of 10−12–10−7M. E3 effects on gene expression were examined by means of reporter gene assays, RT-qPCR and Western blot analysis. ResultsE3 acted as a potent estrogen and exerted a mitogenic effect on T-47D and MCF-7 cells at concentrations of 10−9M (288pg/ml) and higher. With regard to activation of an estrogen response element (ERE) in breast cancer cells, effects of E3 were visible at 10−10M. The same concentrations of E3 activated expression of the estrogen-responsive gene PR and of the proliferation genes cyclin A2, cyclin B1, Ki-67, c-myc and b-myb, providing molecular mechanisms underlying the observed growth increase. ConclusionsLike E2, low levels of E3 were able to trigger a robust estrogenic response in breast cancer cells. Thus, our data suggest caution regarding use of E3 by breast cancer survivors.

Survival benefit of zoledronic Acid in postmenopausal breast cancer patients receiving aromatase inhibitors.

PurposeA growing body of evidence indicates that zoledronic acid (ZA) can improve the clinical outcome in patients with breast cancer and low estrogen levels. In the present study, we aimed to investigate the survival benefit of ZA administration in postmenopausal Korean women with breast cancer who were also receiving aromatase inhibitors.MethodsBetween January 2004 and December 2010, 235 postmenopausal breast cancer patients undergoing aromatase inhibitor therapy were investigated. All patients were postmenopausal, as confirmed by laboratory tests. Of these patients, 77 received adjuvant upfront ZA for at least 1 year in addition to conventional adjuvant treatment. The remaining 158 patients never received ZA and were treated according to the St. Gallen guidelines.ResultsThe baseline characteristics for ZA treatment were not different between the two groups. The median follow-up time was 62 months, and the patients who received ZA in addition to aromatase inhibitors showed a better recurrence-free survival compared to those who received aromatase inhibitors alone (p=0.035). On multivariate analysis, the patients who received ZA showed a better recurrence-free survival independent of the tumor size, nodal status, progesterone receptor, and histological grade. For this model, Harrell c index was 0.743. The hazard ratio of ZA use for recurrence-free survival was 0.12 (95% confidence interval, 0.01-0.99).ConclusionOur findings suggest that upfront use of ZA as part of adjuvant treatment can offer a survival benefit to postmenopausal breast cancer patients receiving aromatase inhibitor treatment.

A randomised trial of electro-acupuncture for arthralgia related to aromatase inhibitor use

BackgroundArthralgia is a common and debilitating side-effect experienced by breast cancer patients receiving aromatase inhibitors (AIs) and often results in premature drug discontinuation. MethodsWe conducted a randomised controlled trial of electro-acupuncture (EA) as compared to waitlist control (WLC) and sham acupuncture (SA) in postmenopausal women with breast cancer who self-reported arthralgia attributable to AIs. Acupuncturists performed 10 EA/SA treatments over 8weeks using a manualised protocol with 2Hz electro-stimulation delivered by a TENS unit. Acupuncturists administered SA using Streitberger (non-penetrating) needles at non-traditional acupuncture points without electro-stimulation. The primary end-point was pain severity by Brief Pain Inventory (BPI) between EA and WLC at Week 8; durability of response at Week 12 and comparison of EA to SA were secondary aims. FindingsOf the 67 randomly assigned patients, mean reduction in pain severity was greater in the EA group than in the WLC group at Week 8 (−2.2 versus −0.2, p=0.0004) and at Week 12 (−2.4 versus −0.2, p<0.0001). Pain-related interference measured by BPI also improved in the EA group compared to the WLC group at both Week 8 (−2.0 versus 0.2, p=0.0006) and Week 12 (−2.1 versus −0.1, p=0.0034). SA produced a magnitude of change in pain severity and pain-related interference at Week 8 (−2.3, −1.5 respectively) and Week 12 (−1.7, −1.3 respectively) similar to that of EA. Participants in both EA and SA groups reported few minor adverse events. InterpretationsCompared to usual care, EA produced clinically important and durable improvement in arthralgia related to AIs in breast cancer patients, and SA had a similar effect. Both EA and SA were safe.

Electro-acupuncture for joint pain related to aromatase inhibitors among breast cancer survivors: A randomized placebo-controlled trial.

9639 Background: Arthralgia is a common and debilitating symptom in a significant proportion of breast cancer patients receiving aromatase inhibitors (AIs). Methods: We conducted a randomized, placebo-controlled trial of electro-acupuncture compared to waitlist control (WLC) and sham acupuncture in postmenopausal women with breast cancer who self-attributed their arthralgia to taking AIs. Acupuncturists delivered ten treatments of tailored acupuncture with 2 Hz electro-stimulation via a TENS unit. Sham acupuncture used non-penetrating Streitberger needles at non-traditional acupuncture points and lacked electro-stimulation. The primary endpoint was pain severity measured by the Brief Pain Inventory (BPI) between electro-acupuncture and WLC at Week 8; durability of response at Week 12 and comparison of electro to sham acupuncture were secondary aims. Results: Sixty-seven patients were randomized to the three arms. The mean reduction in BPI pain severity was significantly greater in the electro-acupuncture group than WLC group at both Week 8 (-2.2 vs. -0.2 p=0.0004) and Week 12 (-2.4 vs. -0.2, p&lt;0.0001). The BPI pain-related interference also improved significantly in the electro-acupuncture group compared to WLC group at Weeks 8 (-2.0 vs. +0.2, p=0.0006) and 12 (-2.1 vs. -0.1, p=0.0034). Sham acupuncture reduced pain severity (-2.3) and pain-related interference (-1.5) at Week 8 similar to electro-acupuncture (p= non-significant); however, the effect of sham acupuncture appeared to decrease at Week 12 for pain severity (-1.7) and pain-related inference (-1.3). Conclusions: Electro-acupuncture significantly improved AI-related arthralgia over “usual care” with clinically important and durable changes in symptoms. Treatment effects were similar between the electro and sham groups at Week 8, suggesting that a large component of acupuncture effect is mediated through the process of acupuncture delivery rather than the specificity of needle placement or needle penetration of skin. Research is needed to evaluate the long term effects of electro-acupuncture to improve AI-related arthralgia. Clinical trial information: NCT01013337.

Aromatase inhibitor-associated musculoskeletal symptoms: incidence and associated factors

PurposeArthralgia is the most common side effect in breast cancer patients receiving aromatase inhibitor (AI) therapy. Few studies have evaluated the risk factors, onset, and incidence of musculoskeletal pain in these patients. This study identifies the risk factors of AI-related severe arthralgia and their prevalence.MethodsAll the clinical and pathological records of postmenopausal patients diagnosed with invasive breast cancer using AI at Samsung Medical Center from January 2005 to November 2007 were reviewed. Multivariate logistic regression analyses were performed to evaluate the risk factors of AI-associated musculoskeletal symptoms (AIMSS) and factors associated with AI discontinuance.ResultsAmong 299 patients, 69 patients (23%) experienced musculoskeletal symptoms attributed to AI use. In multivariate logistic regression analysis, no statistically significant outcome was found to confirm the risk factors for the development of AIMSS. Among the 69 patients who experienced AI-associated musculoskeletal symptoms, 29 (39.7%) discontinued AI use. Multivariate logistic regression analyses revealed an association of prior tamoxifen use with discontinuance of AI (P < 0.01; odds ratio, 4.27; 95% confidence interval, 1.74 to 10.50).ConclusionPrior use of tamoxifen is related to discontinuation of AI due to AI-associated severe arthralgia. Special monitoring and proper pain control for these patients should be considered during the treatment period.

YOCAS yoga for musculoskeletal symptoms in breast cancer patients receiving aromatase inhibitors: A URCC CCOP randomized, controlled clinical trial.

9028 Background: Up to 50% of breast cancer patients on aromatase inhibitor therapy report significant musculoskeletal symptoms such as joint and muscle pain, which decreases treatment adherence. We conducted a secondary data analysis of a multi-site, phase III randomized, controlled, clinical trial examining the efficacy of yoga for improving musculoskeletal symptoms among breast cancer patients currently receiving hormone therapy (aromatase inhibitors [AI] or tamoxifen [TAM]) through the University of Rochester Cancer Center Community Clinical Oncology Program (CCOP). Methods: The original RCT randomized patients with any type of non-metastatic cancer without previous yoga participation into 2 arms: 1) standard care monitoring [controls] or 2) 4-week yoga intervention (2x/wk; 75 min/session) plus standard care. The yoga intervention utilized the UR Yoga for Cancer Survivors (YOCAS) program consisting of breathing exercises, 18 Hatha and Restorative yoga postures, and meditation. Only breast cancer patients currently receiving AI (N=95) or TAM (N=72) were included in this secondary analysis. Changes in musculoskeletal symptoms were assessed using ANCOVA with baseline values as covariates between the yoga and control groups. Results: Compared to TAM users at baseline, AI users reported higher levels of general pain (1-5 score: AI=2.65 vs. TAM=2.17; p=0.01), muscle aches (0-4 score: AI=2.14 vs. TAM=1.65; p=0.01), and total physical discomfort (0-24: AI=8.03 vs. TAM=5.92; p=0.01). Among AI users only, participants in the yoga group demonstrated greater reductions in general pain (CS=change score; Yoga CS= -0.37 vs. Control CS= +0.02; p=0.02), muscle aches (Yoga CS= -0.58 vs. Control CS= -0.15; p=0.03) and total physical discomfort (Yoga CS= -2.07 vs. Control CS= -0.58; p=0.04) from pre- to post-intervention than the control group. Conclusions: The severity of musculoskeletal symptoms was higher for AI users than for TAM users. Among breast cancer patients on AI therapy, the community-based YOCAS intervention significantly reduced general pain, muscle aches, and physical discomfort. Funding: NCI U10CA37420, KL2RR024136-05, K07CA120025.