Side Effects Of Aromatase Inhibitors Research Articles

Abstract P2-06-01: Improving the health of women on Aromatase Inhibitors: A pilot controlled dietary and exercise intervention trial

Abstract Background: In spite of aromatase inhibitors reducing risk of recurrence and mortality, painful side effects often cause women to discontinue use of the drug. Side effects of aromatase inhibitors include joint and muscle pain, loss of bone mineral density, and impairment of heart functioning. Discontinuation of aromatase inhibitors due to these side effects occur in up to 40% of breast cancer survivors, and consequently risks of recurrence and mortality increase. Objective: We developed two interventions designed to reduce inflammation, alleviate pain and stabilize bone mineral density. Methods: We are currently conducting a pilot parallel intervention trial that is targeted toward alleviating side effects from aromatase inhibitors through dietary and exercise controlled interventions lasting for three months. The dietary intervention is an anti-inflammatory Mediterranean diet designed to decrease inflammation and lessen joint and muscle pain. Participants randomized to the Mediterranean dietary intervention are exclusively consuming food provided by Territory Foods®, an outside food preparation and delivery service, local to Los Angeles. Our exercise intervention is designed to mobilize the joints, and strengthen and reduce bone loss. Participants are visiting the UCLA Kinross gym for three days per week and are undergoing tailored exercise sessions delivered from personal trainers following our bone strengthening intervention protocol. Anthropometric measures, muscle strength, DXA scanning of bone mineral density, peripheral arterial tonometry, pulse wave velocity and biomarkers of inflammation, bone turnover and heart functioning are conducted at baseline, mid- and end of intervention. Results: Our trial is targeted to accrue 20 participants. Thus far we enrolled six participants, with three participants completing the trial. Analysis is ongoing and preliminary results will be presented at the San Antonio Breast Cancer Symposium in December, 2022. Post intervention reports from participants have noted a reduction in pain symptoms, moderate weight loss and increase in muscle strength. Citation Format: Catherine L. Carpenter, Aashini K. Master, Olivia Julian, Dina Ben-Nissan, Michele Rakoff, Gail Thames, Zhaoping Li. Improving the health of women on Aromatase Inhibitors: A pilot controlled dietary and exercise intervention trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P2-06-01.

Most prevalent side effects of aromatase inhibitors in the treatment of hormone-positive breast cancer: a scoping review

Hormone-positive breast cancer is the most commonly diagnosed breast neoplasm among postmenopausal women and is strongly associated with the effects of estrogens on hormone receptors of breast cells. Aromatase inhibitors are especially prescribed for treatment, and are effective to reduce mortality rates and the development of a new contralateral breast tumor. However, even with the proven efficacy and safety in use of these medications, approximately 50% of the patients abandon treatment before the prescribed period due to their side effects. The study was carried out with the objective of mapping what national and international literature declare about the most prevalent side effects caused by aromatase inhibitors in the treatment of women with hormonepositive breast cancer. We used the guidelines from the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Extension for Scoping Review to elaborate this review. The methodology of choice was a scoping review aiming at synthetizing relevant information in an objective and clear manner about this drug class that is so common in breast cancer therapy, mainly benefitting women who are users of such drugs. According to the literature, reduced bone mineral density, arthralgia, hot flushes and dryness of the vaginal mucosa are the most reported symptoms, directly related with the absence of estrogen action on the body. These effects have a direct repercussion on the quality of life and on the discontinuation of treatment, leading to reduced functionality and high mortality rates.

Aromatase Inhibitors Induce Painful-like Musculoskeletal Symptoms in Mice: Behavioral, Molecular and Cellular Characterization

Breast cancer is the second most common cancer among women in the U.S. Most tumors are hormone-receptor positive, and patients receive adjuvant endocrine treatment with aromatase inhibitors (AI) to prolong disease-free survival and time-to-recurrence. Unfortunately, AI-associated musculoskeletal symptoms (AIMSS) such as joint pain and muscle stiffness/achiness is a common side-effect of AIs and approximately one-fourth of patients discontinue their therapy because of these side effects. The precise mechanisms of AIMSS are unknown and no clearly recognized therapies exist for prevention or treatment. We therefore characterized a mouse model of AI-induced AIMSS. C57BL/6J adult ovariectomized female mice received oral letrozole (0.5 mg/kg once/day for 15 days). Mice were then evaluated for multiple evoked and spontaneous nociceptive and pain-like behaviors. We also determined if supplementation of 17β-estradiol will reverse AIMSS behaviors. The effects of ketoprofen and duloxetine were tested in this model also. Female mice treated with letrozole show significant mechanical hypersensitivity, disruption of nesting behaviors and reduction of voluntary wheel running as well as rearing and burrowing behaviors. In addition, letrozole-treated DRG neurons showed enhanced excitability compared to vehicle-treated mice. Finally, a significant increase in expression levels of pro-inflammatory cytokines IL-1β, TNFα and IL-6 were observed in the DRGs of mice treated with letrozole. Administration of 17β-estradiol partially reversed these behavioral signs. Furthermore, contrary to ketoprofen, duloxetine showed effectiveness in the model and showed significant preference in the CPP test in letrozole-treated mice but not vehicle group. Our results suggest the AI letrozole induces painful AIMSS symptoms in mice that are partially mediated by estrogens. In addition, our results suggest peripheral neuronal hyperexcitability driven by proinflammatory cytokines at the DRG levels. These results enhance our understanding of AIMSS and facilitate development of novel therapies to treat AIMSS, thereby reducing discontinuation of this breast cancer therapy. Funds from VCU School of Medicine and Massey Cancer Center.

Abstract P5-18-11: Impact of supportive therapies on tolerance of aromatase inhibitors in patients with early-stage, hormone-positive breast cancer

Abstract Background: Aromatase inhibitors (AI) are standard of care in the treatment of early-stage hormone positive (HR+) breast cancer (BC). Commonly, these medications cause significant side effects which limit tolerability and often require a change in therapy. Supportive therapies are an essential part of treatment plans to improve adherence and quality of life. Studies in the last decade have demonstrated the critical role of supportive management in mitigating side effects from AI, such as the reduction in AI related joint pain with acupuncture or use of low dose oxybutynin for hot flashes. The aim of this study was to evaluate the real world use of supportive therapies for AI toxicities over the last decade and to determine if they were associated with patient adherence to initial AI treatment. Methods: We performed a retrospective chart review of all female patients at our academic institution with early-stage, HR+ BC who were initiated on adjuvant AI therapy between 2011-2020. From the electronic medical record, we collected information on patient demographics, AI side effects (hot flashes, vaginal dryness, joint pains, osteopenia/osteoporosis), use of supportive therapies, and duration of first AI therapy. Primary endpoint was the rate of discontinuation of AI at 1 year among those who used supportive therapies compared with those who did not. The Wilcoxon rank sum test, Fisher's exact test, Kruskal-Wallis rank sum test, and Pearson's Chi-squared test methods were used to compare rates of discontinuation of front-line AI therapy for each group. Results: We identified 990 patients (pts) with early-stage, HR+ BC who were started on adjuvant AI between 2011-2020. Of these patients, 97% (n= 963) had AI related side effects yet only 51% (n=504) received supportive therapies. The overall discontinuation rate within 1 year was 14.8% (147 of 990 pts). Patients who received at least 1 supportive therapy were more likely to remain on AI and had a lower 1 year discontinuation rate of 10% (51 of 504 pts) compared to 20% (96 of 486 pts) for those who did not receive any supportive therapy (p<0.001). The most commonly used supportive therapies were bone strengthening agents, with 35.6% (n=352) of patients receiving either denosumab or zoledronic acid, followed by acupuncture used in 11.2% (n=111) of patients. The use of acupuncture increased in 2018, compared to years prior (35 pts from 2011-2017, and 76 pts from 2018-2020). Similarly, oxybutynin use increased in 2019, compared to years prior (9 pts from 2011-2018, and 28 pts from 2019-2020). Upon further analysis, younger age was significantly associated with a higher 1 year discontinuation rate (median age 62 years in <1 year AI treatment group, and 64 years in >1 year AI treatment group, p=0.003). Race also appeared to have an impact on AI tolerance. Although only 31% (39 of 126 pts; p < 0.001) of Black patients received supportive therapy, this group had the lowest 1 year discontinuation rate at 8.7% (11 of 126 pts). Conversely, 56% (277 of 491 pts) of White patients received at least one supportive therapy, yet had the highest 1 year discontinuation rate at 17% (83 of 491 pts). Conclusions: Supportive therapies are essential to help patients mitigate side effects of AI. Patients who received at least one supportive therapy had increased rates of AI adherence beyond 1 year compared to those who did not receive any supportive treatment. The most commonly used therapies were bone strengthening agents and acupuncture. Use of acupuncture and low dose oxybutynin have increased in the past 3 years and 2 years, respectively, following publication of their efficacy. It is critical to further evaluate the impact that race and age have in relation to duration of treatment and use of supportive management. Further studies on how to improve patient tolerability and adherence to AI therapy are needed. Citation Format: Melanie W Kier, Zhiqiang Li, Brittney S Zimmerman, Rima Patel, Yunchen Yang, Mark Y Fink, Jason D Wells, Xiang Zhou, Scott Newman, Rong Chen, Eric Schadt, William Oh, Amy Tiersten. Impact of supportive therapies on tolerance of aromatase inhibitors in patients with early-stage, hormone-positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-11.

Clinical application of aromatase inhibitors to treat male infertility.

Infertility affects 15% of men and contributes to nearly half of all cases of infertility. Infertile men usually have impaired spermatogenesis, presenting as azoospermia or various degrees of asthenospermia and oligozoospermia. Spermatogenesis is a complex and coordinated process, which is under precise modulation by the hypothalamic-pituitary-gonadal (HPG) axis. An aberrant hormone profile, especially an imbalance between testosterone (T) and estradiol (E2), plays an essential role in male infertility. In the male, E2 is produced mainly from the conversion of T by the aromatase enzyme. Theoretically, reducing an abnormally elevated T:E2 ratio using aromatase inhibitors (AIs) could restore the balance between T and E2 and optimize the HPG axis to support spermatogenesis. For decades, AIs have been used to treat male infertility empirically. However, owing to the lack of large-scale randomized controlled studies and basic research, the treatment efficacy and safety of AIs in male infertility remain controversial. Therefore, there is a need to summarize the clinical trials and relevant basic research on the application of AIs in the treatment of male infertility. In this narrative review, we summarized the application of AIs in the treatment of male infertility, including the pharmacological mechanisms involved, clinical trials focused on patients with different types of infertility, factors affecting treatment efficacy and the side-effects. A literature search was performed using MEDLINE/PubMed and EMBASE, focusing on publications in the past four decades concerning the use of AIs for treating male infertility. The search terms included AI, male infertility, letrozole, anastrozole, testolactone, azoospermia, oligozoospermia, aromatase polymorphisms, obesity and antiestrogens, in various combinations. Clinical studies demonstrate that AIs, especially nonsteroidal letrozole and anastrozole, could significantly inhibit the production of E2 and its negative feedback on the HPG axis, resulting in increased T and FSH production as well as improved semen parameters in infertile men. Large-scale surveys suggest that obesity may result in symptoms of hypogonadism in both fertile and infertile males, such as decreased semen quality and attenuated sexual function, which can be improved by AIs treatment. Polymorphisms of the aromatase gene CYP19A1, including single nucleotide polymorphisms and tetranucleotide TTTA repeats polymorphism (TTTAn), also influence hormone profiles, semen quality and treatment efficacy of AIs in male hypogonadotropic hypogonadism and infertility. The side-effects of AIs in treating male infertility are various, but most are mild and well tolerated. The application of AIs in treating male infertility has been off-label and empirical for decades. This narrative review has summarized the target patients, dose, treatment duration and side-effects of AIs. Polymorphisms of CYP19A1 that may affect AIs treatment efficacy were also summarized, but a full understanding of the mechanisms involved in AIs action requires further study.

Long-term results from a randomized blinded sham- and waitlist-controlled trial of acupuncture for joint symptoms related to aromatase inhibitors in early stage breast cancer (S1200).

12018 Background: Musculoskeletal symptoms are the most common side effect of aromatase inhibitors (AIs) among breast cancer (BC) survivors. We previously reported that true acupuncture (TA) resulted in better pain outcomes than either sham acupuncture (SA) or wait-list controls (WC) at 6 weeks with durable effects through 24 weeks, with minimal toxicity. We now report the 52-week outcomes. Methods: We conducted a SWOG multicenter randomized controlled trial among postmenopausal women with early-stage BC. Patients taking an AI for ≥30 days and reporting a worst pain score of ≥3 out of 10 using the Brief Pain Inventory-Worst Pain (BPI-WP) were eligible. Subjects were randomized 2:1:1 to TA vs. SA vs. WC. Both the TA and SA protocols consisted of a 12-week intervention, with 2 sessions per week for 6 weeks, followed by 1 session per week for 6 additional weeks. At 24 weeks, all subjects remained blinded to intervention arm but were offered 10 sessions of true acupuncture. Endpoints included BPI scores, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for hips and knees, the Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH), PROMIS Pain Inventory Short Form (PI-SF), and Functional Assessment of Cancer therapy Endocrine Symptoms (FACT-ES). Results: Among 226 patients registered, 110 were randomized to TA, 59 to SA and 57 to WC. Baseline characteristics were similar among the arms. At 52 weeks, follow-up assessments were available for 91 (82.7%) TA, 53 (89.8%) SA, and 47 (82.5%) WC patients. In a linear regression adjusting for the baseline score and stratification factors, 52-week mean BPI-WP scores were 1.08 points lower (correlating with less pain) in the TA compared to SA arm (95% CI: 0.24-1.91, p =.01), and were 0.99 points lower in the TA compared to WC arm (95% CI: 0.12-1.86, p =.03). The proportion of patients experiencing a clinically meaningful (>2) reduction (i.e. improvement) in BPI-WP was 64% for TA compared to 45% on SA and 53% on WC. Patients randomized to TA had reduced BPI pain interference at 52 weeks compared to SA (adjusted difference = 0.58, 95% CI: 0.00-1.16, p =.05) but not compared to WC (adjusted difference = 0.33, 95% CI: -0.28-0.93, p =.29). Also, at 52 weeks, patients randomized to TA had improved PROMIS PI-SF T-scores compared to SA (adjusted difference = 2.35, 95% CI: 0.07-4.63, p =.04) but not compared to WC (adjusted difference = 1.28, 95% CI: -1.09-3.66, p =.29). No statistically significant differences were observed in other measures. Conclusions: Women with breast cancer receiving AI therapy and treated with 12 weeks of TA for joint symptoms had reduced levels of worst pain compared to control patients, an effect that was durable through one year despite completion of protocol acupuncture at 12 weeks, and the offering of acupuncture to all participants at 24 weeks. Clinical trial information: NCT01535066.

A prospective study of lifestyle factors and bone health in breast cancer patients who received aromatase inhibitors in an integrated healthcare setting.

Fracture and osteoporosis are known side effects of aromatase inhibitors (AIs) for postmenopausal hormone receptor positive (HR+) breast cancer (BC) patients. How modifiable lifestyle factors impact fracture risk in these patients is relatively unknown. We conducted a prospective cohort study to examine the association of lifestyle factors, focusing on physical activity, with risk of incident major osteoporotic fracture and osteoporosis in 2152 HR+ BC patients diagnosed from 2006 to 2013 at Kaiser Permanente Northern California and who received AIs. Patients self-reported lifestyle factors at study entry and at 6-month follow-up. Fracture and osteoporosis outcomes were prospectively ascertained by physician-adjudication and bone mineral density (BMD) values, respectively. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated from multivariable proportional hazards regression. Models were adjusted for age, menopausal status, race/ethnicity, body mass index (BMI), AJCC stage, breast cancer treatment, prior osteoporosis, and prior major fracture. Over a median 6.1 years of follow-up after AI initiation, 165 women experienced an incident osteoporotic fracture and 243 women had osteoporosis. No associations were found between overall moderate-vigorous physical activity and fracture risk, although < 150 min/week of aerobic exercise in the 6 months after BC diagnosis was associated with increased fracture risk (HR=2.42; 95% CI: 1.34, 4.37) compared with ≥ 150 min/week (meeting physical activity guidelines). Risk was also higher for never or infrequently engaging in aerobic exercise (HR=1.90; 95% CI: 1.05, 3.44). None or infrequent overall moderate-vigorous physical activity in the 6 months before BC diagnosis was associated with increased risk of osteoporosis (HR=1.94; 95% CI: 1.11; 3.37). Moderate-vigorous physical activity during the immediate period after BC diagnosis, particularly aerobic exercise, was associated with lower risk of major osteoporotic fractures in women on AI therapy. Findings may inform fracture prevention in women on AI therapy through non-pharmacologic lifestyle-based strategies.

Acupuncture for Arthralgia Induced by Aromatase Inhibitors in Patients with Breast Cancer: A Systematic Review and Meta-analysis.

Background:Aromatase inhibitor-induced arthralgia (AIA) is the most common side effect of aromatase inhibitors (AIs) used in breast cancer patients and is related to the rate of adherence to AIs. The clinical effects of acupuncture on AIA have been assessed by some randomized controlled trials (RCTs). However, some studies reported that acupuncture was effective, while others claimed that it was ineffective. To clarify the clinical and placebo effects of acupuncture in treating AIA, we conducted this meta-analysis.Methods:Two reviewers (XL and GW) independently searched for RCTs in 5 English databases (PubMed, Web of Science, Embase, Springer, Cochrane Library) and 4 Chinese databases (China National Knowledge Infrastructure Database (CNKI), SinoMed, VIP and Wanfang Database) from their inception to 30 November 2019. Following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, this meta-analysis was performed by fixed or random-effects models, and data were pooled with mean differences (MDs).Results:Seven trials involving 603 patients were reviewed. The primary outcome, the Brief Pain Inventory (BPI) score, significantly differed between the acupuncture and control groups [pain-related interference: MD = −1.89, 95% confidence interval (CI) [−2.99, −0.79], Z = 3.36 (P = .008 < .05), pain severity: MD = −1.57, 95% CI [−2.46, −0.68], Z = 3.45 (P = .0006 < .05), worst pain: MD = −2.31, 95% CI [−3.15, −1.48], Z = 5.47 (P < .0001 < .05)]. No severe adverse events were reported in any study.Conclusion:This meta-analysis showed that acupuncture is a safe and effective treatment for breast cancer patients with AIA. Additional research with improved blinding methods is warranted to further explore the nature of non-specific and placebo effects in true and sham acupuncture.

Enhancing Health for the Growing Number of Older Cancer Survivors: Designing Innovative Behavioral Interventions

By 2040, there will be an estimated 26.1 million cancer survivors in the United States, with 73% over age 65. Compared to younger survivors and those without cancer, older adult cancer survivors have an elevated comorbidity burden. Lifestyle interventions can play a key role in preventing and managing chronic health conditions and promoting quality of life during and after cancer treatment. Yet, behavioral interventions for maximizing health are under-utilized in older adults with cancer. At times, older adults may have unique needs that require tailoring to increase accessibility, optimization, and uptake of behavioral interventions.This symposium will showcase innovative approaches for enhancing health among older adult cancer survivors during and after cancer treatment. Dr. Bluethmann will discuss design considerations for using geriatric assessment in an ongoing exercise trial to manage side effects of aromatase inhibitors. Dr. Gell will present data on older survivors’ preferences regarding text messaging to support physical activity maintenance from an intervention study. Dr. Leach will discuss the use of technology to facilitate lifestyle change in older cancer survivors, presenting data on older adults’ user preferences and benefits from an eHealth tool. The discussant, Dr. Trevino, will summarize how these interventions can be leveraged to promote engagement in managing older survivors’ health and to inform next steps in intervention development. Collectively, this multidisciplinary group of speakers will provide practical information and “lessons learned” from designing behavioral and technology-based interventions, and highlight the promise that these approaches hold for improving quality of life in aging cancer survivors. Cancer and Aging Interest Group Sponsored Symposium.

A phase II RCT of high-dose vitamin D supplementation and exercise for cancer treatment-induced bone loss in breast cancer patients on aromatase inhibitors.

11500 Background: Cancer-treatment-induced bone loss (CTIBL) is a side effect of aromatase inhibitors (AIs) and can result in osteoporotic fractures. Vitamin D (VITD) protects against postmenopausal bone loss but it is unclear if the recommended daily allowance (RDA: 600 IU/day) of VITD is sufficient to prevent CTIBL. This phase II RCT aimed to assess the feasibility, safety, and preliminary efficacy of high-dose VITD (with and without exercise) on bone mineral density (BMD) compared to the RDA. Methods: Non-metastatic breast cancer patients starting AIs with low VITD (&lt;32 ng/ml) were randomized 1:1:1 into 3 arms: 1) placebo 2) high-dose VITD (50,000 IU/week) or 3) high-dose VITD + Exercise for Cancer Patients (EXCAP): a home-based, personalized walking and resistance band training program for 24 weeks. All subjects received the RDA of VITD 600 IU/day. Serum VITD and calcium levels were assessed at baseline, weeks 6, 12, 18, and 24. BMD was assessed at the hip via DXA at baseline and week 24. Results: Of the 116 subjects randomized (mean age = 60; 94% white; mean baseline VITD = 24.6 ng/mL), 90 provided fully evaluable data. Compliance (≥ 80% of instructed doses) exceeded 95% in all 3 arms with no between-group difference. ANCOVA showed significant differences between groups on final VITD levels (high-dose = 63.6 vs high-dose + EXCAP = 60.3 vs placebo = 32.0 ng/mL; p&lt;0.001) without severe calcium toxicities, as indicated by final calcium level (high-dose = 9.4 vs high-dose + EXCAP = 9.5 vs placebo = 9.4 ng/mL; p = 0.78). The placebo group lost a significant amount of hip BMD (−1.7%; p &lt; 0.01) while hip BMD was maintained in the high-dose (−0.1%; p = 0.77) and high-dose + EXCAP (−0.2%; p = 0.74) resulting in significant between-group differences for high-dose + EXCAP vs placebo (p = 0.04) and high-dose vs placebo (p = 0.05). Conclusions: This is one of the first studies to show our novel high-dose VITD intervention, with and without exercise, significantly reduced hip BMD loss in breast cancer patients on AIs. Moreover, high-dose VITD supplementation is safe and feasible in this population. A phase III RCT is needed to confirm these findings. Funding: K07CA168911. Clinical trial information: NCT01419730.

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 GS4-04: Randomized blinded sham- and waitlist-controlled trial of acupuncture for joint symptoms related to aromatase inhibitors in women with early stage breast cancer (S1200)

Abstract Background: Musculoskeletal symptoms are the most common side effect of aromatase inhibitors (AIs) and can result in decreased quality of life and discontinuation of therapy. Pilot data from two prior single institution studies showed that acupuncture decreased AI-induced joint symptoms in breast cancer (BC) patients. Methods: We conducted a SWOG multicenter randomized controlled trial among postmenopausal women with early stage BC. Patients taking an AI for ≥30 days and having a worst pain score of ≥3 out of 10 using the Brief Pain Inventory (BPI-WP) were eligible. Subjects were randomized at a 2:1:1 ratio to true acupuncture (TA) vs. sham acupuncture (SA) vs. waitlist control (WC). The TA protocol used a standardized protocol of body and auricular acupoints tailored to joint symptoms. The similarly standardized SA protocol utilized superficial needling of non-acupoints. Both the TA and SA protocols consisted of a 12 week intervention, with 12 sessions administered over 6 weeks, followed by 1 session per week for 6 additional weeks. The primary endpoint was change in the BPI-WP (worst pain) score at 6 weeks. Secondary outcomes included other BPI scores, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) for the hips and knees, the Modified Score for the Assessment of Chronic Rheumatoid Affections of the Hands (M-SACRAH), and functional testing with grip strength and "Timed Get Up and Go" (TGUG). The design specified alpha=.025 two-sided tests to account for two independent comparisons (TA vs. SA and TA vs. WC). Results: Among 226 patients registered, 110 were randomized to TA, 59 to SA and 57 to WC. Baseline characteristics were similar between the groups. In a linear regression adjusting for the baseline score and stratification factors, 6-week mean BPI-WP scores were 0.92 points lower (correlating with less pain) in the TA compared to SA arm (95% CI: 0.20-1.65, p=.01), and were 0.96 points lower in the TA compared to WC arm (95% CI: 0.24-1.67, p=.01). The proportion of patients experiencing a clinically meaningful (&amp;gt;2) reduction (i.e. improvement) in BPI-WP was 58% for TA compared to 33% on SA and 31% on WC. Patients randomized to TA had improved symptoms compared to SA at week 6 according to all other BPI pain measures (average pain, p=.04; pain interference, p=.02; pain severity, p=.05; worst stiffness, p=.02). Results were similar compared to WC. Patients randomized to TA compared to SA or WC had statistically significant or marginally statistically significant improvements in BPI pain measures at week 12. Patients randomized to TA had generally improved symptoms compared to SA or WC at week 6 and at week 12 according to the M-SACRAH and WOMAC measures (p&amp;lt;0.05). With regard to adverse events, more patients on the TA arm experienced Grade 1 bruising compared to SA (47% vs. 25%, p=.01). No other differences by arm for selected adverse events were observed. Conclusions: This study was the first large multicenter trial to investigate the effect of acupuncture in treating AI-induced joint symptoms in BC patients. According to multiple measures, TA generated better outcomes than either SA or WC with minimal toxicity. Citation Format: Hershman DL, Unger JM, Greenlee H, Capodice J, Lew DL, Kengla AT, Melnik MK, Jorgensen CW, Kreisle WH, Minasian LM, Fisch MJ, Henry L, Crew KD. Randomized blinded sham- and waitlist-controlled trial of acupuncture for joint symptoms related to aromatase inhibitors in women with early stage breast cancer (S1200) [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 GS4-04.

Joint symptoms associated with anastrozole and letrozole in patients with breast cancer: a retrospective comparative study

BackgroundJoint symptoms are a common side effect of aromatase inhibitors. However, it is not known if the risk of these symptoms varies between the members of this drug class. The aim of this study was to compare the frequency of joint symptoms associated with anastrozole and that associated with letrozole.MethodsWe retrospectively reviewed patients with breast cancer who were treated with anastrozole or letrozole at Tsukiji Breast Clinic, Japan, between April 2008 and July 2014. Joint symptoms were deemed to include both joint pain and painless joint symptoms. The time to onset of joint symptoms in the anastrozole group was compared with that in the letrozole group using Kaplan–Meier curves and the log-rank test.ResultsOf 141 patients identified to have received aromatase inhibitors, 70 had been treated with anastrozole and 71 with letrozole. Joint symptoms occurred in 60.3% of the 141 patients (60.0% in the anastrozole group and 60.6% in the letrozole group; p = 1). Median time to appearance of joint symptoms was 583 days, with no significant difference between the anastrozole and letrozole groups (p = 0.962). There was no significant difference in time to onset of joint pain (p = 0.139); however, time to onset of painless joint symptoms was significantly shorter in the anastrozole group (p = 0.022). The sites at which joint symptoms occurred were similar in the two groups.ConclusionsThe results of this study indicate that there is no difference in the pattern of occurrence of joint symptoms caused by anastrozole and those caused by letrozole.Trial registrationTrial registration was not required for this study because of its retrospective nature and lack of intervention.

Treatments for Breast Cancer That Affect Cognitive Function in Postmenopausal Women

About one of every eight women will develop breast cancer during her lifetime. Approximately a quarter of a million new cancer cases are expected in 2017. Of those breast cancers, 60% to 75% will have characteristics suggesting that estrogens are likely to promote growth of those tumors. Consequently, inhibiting estrogen synthesis is one of the main treatments of choice. Therefore, women must understand the potential adverse effects of those treatments on quality of life. This review discusses (a) the role of estrogens locally synthesized in the brain in laboratory animals and women, (b) the effects of estrogens and blockers of estrogen synthesis on cognitive function, and (c) the limitations in experiments on women taking inhibitors. This article aims to provide women and oncologists with information that will encourage them to consider side effects of aromatase inhibitors (AIs) treatment on the brain.

Patterns and reasons for switching classes of hormonal therapy among women with early-stage breast cancer.

Breast cancer patients can switch hormonal therapy (HT) regimens due to treatment side effects or menopausal status change. We describe HT class switching from aromatase inhibitor (AI) to tamoxifen (TAM), and vice versa. In a cohort of 3,265 women diagnosed with hormone-receptor-positive breast cancer at Kaiser Permanente Northern California from 2005 to 2013, we analyzed prescription records, switching reasons, and treatment adherence post-switch by chart review, through 31 December 2014. There were 290 women who switched from AI to TAM (AI switchers), including 130 (45%) switchers during the first year of treatment; and 446 women who switched from TAM to AI (TAM switchers), including 120 (27%) switchers within the first year. After the switch, 136 (47%) AI switchers and 260 (58%) TAM switchers finished or remained on the planned therapy; 69 (24%) AI switchers and 99 (22%) TAM switchers discontinued therapy. AI side effects (73%), specifically joint pain/arthralgia and bone health issues, were the most common reasons for switching from AI to TAM, whereas from TAM to AI, it was menopausal status change (42%). Study findings highlight the need for better ways to control patient symptoms from HT to prevent discontinuation, and thus ensure best prognosis.

Abstract P5-12-02: Can a supervised exercise program compared to usual care prevent aromatase inhibitor-induced musculoskeletal pain in women with breast cancer?

Abstract Background: Aromatase Inhibitors (AIs) are commonly prescribed as hormone therapy for post-menopausal women with estrogen receptor-positive breast cancer. A number of authors have reported AI side effects that include increased risk for developing osteoporosis, joint pain, weight gain and depression. For example, 30-40% of post-menopausal women treated with AIs experience mild to severe joint pain. Although the exact causes of AI-induced joint pain are unknown, the side-effects are most likely due to low estrogen levels in the body. . Denysschen et al. (2014) reported a significantly lower number of painful joints, reduced depressive symptoms, increased muscle strength, and improvement in quality of life in patients with AI-induced joint pain after an 8 week upper and lower body resistance exercise program. Objective: To investigate whether a supervised exercise program could reduce or prevent musculoskeletal pain in patients with breast cancer undergoing AI therapy. Methods: Twenty participants with breast cancer have thus far been randomised to either: (a) usual care and advice regarding benefits of regular exercise; or (b) usual care + 12 week supervised and home-based exercise program consisting of upper and lower body resistance exercises with self-selected aerobic exercises. Participants accrued 150 mins / week of moderate intensity aerobic exercise at 60-70% HRmax on 5 or more days of each week including 2 supervised sessions / week. Initial exercise intensity is individualized and generally begins at 55% to 60% of HRmax (15 to 30 minutes per session) and progresses to 60% - 70% of HRmax by week 6. Strength training consisted of 2 supervised sessions per week, of two sets of 10 to 12 repetitions of eight different strength exercises at 60% to 75% of estimated one repetition maximum. On at least 3 other days, using the same dosing principles participants executed 4 lower and 4 upper body resistance exercises at home using resistance bands. The primary outcome measures were pain (brief pain inventory; BPI) scores and grip strength (JAMAR dynamometer (kg)) measured at baseline, 3, 6 and 12 months. Two-way repeated ANOVAs were undertaken to evaluate differences between groups and factors. Results: Mean pain scores across 12 months were largely maintained (p&amp;gt;0.05) for participants undertaking the exercise program compared to control participants whose mean BPI scores progressively increased from baseline through to 12 month follow-up. In the exercise group, mean pain scores increased by one BPI unit between baseline and 12 month follow-up. In the control group, mean pain scores increased by five BPI units between baseline and 12 month follow-up. A clinically significant difference in BPI scores is a change of two or more BPI units (Mease et al, 2011). Grip strength measures were significantly different (P&amp;lt;0.001) between groups at each time point with a trend towards improved grip strength between baseline and 6 months in the exercise group. Grip strength decreased in both groups between 6 and 12 months. Conclusion: By managing physical performance and pain as side effects of AIs, a 12 week supervised exercise program may contribute to preventing non-adherence with or withdrawal from AI therapy. Citation Format: Sanmugarajah J, Allan S, Bagchi R, Laakso E-L. Can a supervised exercise program compared to usual care prevent aromatase inhibitor-induced musculoskeletal pain in women with breast cancer? [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 P5-12-02.

SSRI could relieve aromatase inhibitor side effects

SSRI could relieve aromatase inhibitor side effects

The effect of exercise on body composition and bone mineral density in breast cancer survivors taking aromatase inhibitors.

This study examined the effect of 12 months of aerobic and resistance exercise versus usual care on changes in body composition in postmenopausal breast cancer survivors taking aromatase inhibitors (AIs). The Hormones and Physical Exercise study enrolled 121 breast cancer survivors and randomized them to either supervised twice-weekly resistance exercise training and 150 min/wk of aerobic exercise (N = 61) or a usual care (N = 60) group. Dual-energy X-ray absorptiometry scans were conducted at baseline, 6 months, and 12 months to assess changes in body mass index, percent body fat, lean body mass, and bone mineral density. At 12 months, the exercise group relative to the usual care group had a significant increase in lean body mass (0.32 vs. -0.88 kg, P = 0.03), a decrease in percent body fat (-1.4% vs. 0.48%, P = 0.03), and a decrease in body mass index (-0.73 vs. 0.17 kg/m2 , P = 0.03). Change in bone mineral density was not significantly different between groups at 12 months (0.001 vs. -0.006 g/cm2 , P = 0.37). A combined resistance and aerobic exercise intervention improved body composition in breast cancer survivors taking AIs. Exercise interventions may help to mitigate the negative side effects of AIs and improve health outcomes in breast cancer survivors.

Treatment with Aromatase Inhibitors in Postmenopausal Women with Breast Cancer and the Possibility of Influencing Side Effects

The third generation aromatase inhibitors (anastrozole, letrozole, exemestane) have become standard endocrine treatment for postmenopausal estrogen receptor - positive breast cancers in all settings (neoadjuvant, adjuvant, metastatic breast cancer), based on superiority to tamoxifen. Aromatase inhibitors interfere with the conversion of androgens into estrogens by blocking the enzyme aromatase resulting in low estradiol levels. Aromatase inhibitors are contraindicated in women with functional ovaries. Many premenopausal women develop amenorrhea after adjuvant chemoterapy. Aromatase inhibitors may promote recovery of ovarian function which could lead to therapeutic failure or even to unexpected pregnancy. Currently available measures to determine the menopausal status are conflicting. This paper focuses primarily on adverse effects of aromatase inhibitors which can lead to non-compliance or to discontinuation of treatment. Many side effects of aromatase inhibitors are related to estrogen deprivation. On the other hand as aromatase inhibitors lack estrogenic activity, they are not associated with serious adverse events typical for tamoxifen, such as endometrial cancer and thromboembolic disease. Aromatase inhibitors therapy is often associated with vasomotor symptoms (hot flashes), vaginal dryness, dyspareunia, bone loss, arthralgias and myalgias (musculoskeletal symptoms). Management of these side effects can lead to improved adherence and persistence with therapy.Key words: breast cancer - menopause - aromatase inhibitors - ovarian function recovery - adverse effectsThis work was supported by Czech Ministry of Health - RVO (MOÚ, 00209805).The author declares she has no potential conflicts of interest concerning drugs, products, or services used in the study.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers.Submitted: 10. 7. 2016Accepted: 3. 8. 2016.

Meme Kanseri Tanılı Hastada Letrozol ile İndüklenen Lineer Likenoid Erüpsiyon

Letrozole which acts as an aromatase inhibitor is used in the treatment strategy for oestrogen receptor-positive breast cancer. Cutaneous adverse effects including vasculitis and erythema nodosum of letrozole have been rarely described in literature. Recently reported eczematous skin eruption due to letrozole is one of the side effects that known to be developed by this drug. To our knowledge letrozole induced linear drug eruption has not been described in previous reports. We report 52-year-old woman who had unilateral pruritic lichenoid eruption over left tight following Blaschko lines after using letrozole. Cutaneous side effects of aromatase inhibitors can be serious as progressive cutaneous vasculitis or can be presented with mild cutaneous side effects as in our case. The physicians should be aware of this benign clinical condition. The decision to discontinue medication is dependent to the knowledge of severity of the side effects.