Months Of Aromatase Inhibitor Therapy Research Articles

Variability of DNA Repair and Oxidative Stress Genes Associated with Worst Pain in Breast Cancer Survivors on Aromatase Inhibitors.

Pain is a problem affecting women with breast cancer (HR+BrCa) receiving aromatase inhibitor (AI) therapy. We investigated the relationship between single-nucleotide polymorphisms (SNPs) in DNA repair and oxidative stress genes and perceived worst pain after 6 months of AI therapy. We explored 39 SNPs in genes involved in DNA repair (ERCC2, ERCC3, ERCC5, and PARP1) and oxidative stress (CAT, GPX1, SEPP1, SOD1, and SOD2) in women with HR+BrCa receiving adjuvant therapy (AI ± chemotherapy; n = 138). Pain was assessed via the Brief Pain Inventory. Hurdle regression was used to evaluate the relationship between each associated allele and (1) the probability of pain and (2) the severity of worst pain. ERCC2rs50872 and ERCC5rs11069498 were associated with the probability of pain and had a significant genetic risk score (GRS) model (p = 0.003). ERCC2rs50872, ERCC5rs11069498, ERCC5rs4771436, ERCC5rs4150360, PARP1rs3219058, and SEPP1rs230819 were associated with the severity of worst pain, with a significant GRS model (conditional mean estimate = 0.45; 95% CI = 0.29, 0.60; p < 0.001). These results suggest DNA repair and oxidative stress pathways may play a role in the probability of pain and the severity of worst pain. As healthcare delivery moves towards the model of precision healthcare, nurses may, in the future, be able to use these results to tailor patient care based on GRS.

Effects of aromatase inhibitor therapy on visceral adipose tissue area and cardiometabolic health in postmenopausal women with early and locally advanced breast cancer.

Aromatase inhibitor (AI) therapy provides oncological benefits in postmenopausal women with oestrogen receptor-positive breast cancer. However, AI treatment has been associated with increased cardiovascular risk. In nonbreast cancer populations, experimentally induced low oestrogen states and natural transition to menopause have been associated with increases in visceral adipose tissue (VAT), a known surrogate marker for cardiometabolic risk. Given that AI treatment blocks oestradiol production, we hypothesized that AI treatment would increase VAT. We conducted a prospective 12-month cohort study of 52 postmenopausal women newly initiating AI treatment (median age: 64.5 years) and 52 women with breast pathology not requiring endocrine therapy (median age: 63.5 years). VAT area and other body composition parameters were measured at baseline, 6months and 12 months using dual X-ray absorptiometry. Other risk markers of cardiometabolic health were also assessed. In women initiating AI treatment, there was no statistically significant difference in VAT area after 12 months when compared to controls, with a mean adjusted difference of -5.00 cm2 (-16.9, 6.91), p = .55. Moreover, changes in total fat mass, lean mass, subcutaneous adipose tissue area, hepatic steatosis and measures in endothelial function were also not statistically different between groups after 12 months. Findings were similar after adjustments for activity levels and coronavirus disease 2019 lockdown duration. These data provide reassurance that over the initial 12 months of AI therapy, AI treatment is not associated with metabolically adverse changes in body composition, hepatic steatosis or vascular reactivity. The impact of extended AI therapy on cardiometabolic health requires further study.

Sleep disturbances and restless legs syndrome in postmenopausal women with early breast cancer given adjuvant aromatase inhibitor therapy

IntroductionWhether adjuvant therapy with aromatase inhibitors (AIs) causes sleep disturbances or not in postmenopausal women with early breast cancer (EBC) is still a controversial issue. MethodsBetween March 2014 and November 2017, validated questionnaires for assessing insomnia, anxiety, depression, quality of life (QoL) and restless legs syndrome (RLS) were administered to 160 EBC patients at baseline and after 3, 6, 12, and 24 months of AI therapy. ResultsAI therapy significantly decreased the patients’ QoL, but did not influence insomnia, anxiety or depression. However, it significantly increased the frequency and severity of RLS. Patients with RLS at baseline (19%) or who developed RLS during AI therapy (26.3%) reported statistically lower quality of sleep, higher anxiety and depression, and worse QoL compared to patients who never reported RLS (54.7%). ConclusionAlthough AI therapy does not affect sleep quality, it may increase RLS frequency. The presence of RLS could identify a group of EBC patients who may benefit from psychological support.

Protocol for Exercise Program in Cancer and Cognition (EPICC): A randomized controlled trial of the effects of aerobic exercise on cognitive function in postmenopausal women with breast cancer receiving aromatase inhibitor therapy

The Exercise Program in Cancer and Cognition (EPICC) Study is a randomized controlled trial designed to test the effects of moderate-intensity aerobic exercise on cognitive function in postmenopausal women with early-stage breast cancer during the first six months of aromatase inhibitor therapy. It is estimated that up to 75% of survivors of breast cancer experience cognitive impairment related to disease and treatment. At present, there are no known interventions to improve or manage cognitive function for women with breast cancer. Here, we describe a single-blinded, randomized controlled trial with allocation of 254 postmenopausal women with early-stage breast cancer to a supervised six-month aerobic exercise intervention or usual care. Prior to beginning aromatase inhibitor (AI) therapy, participants complete baseline assessments of cognitive function, cardiorespiratory fitness, blood-based biomarkers, physical activity and sleep, and symptoms (fatigue, sleep problems, depressive symptoms, anxiety). A random subset of participants (n = 150) undergoes neuroimaging procedures that include structural and functional magnetic resonance imaging assessments. All participants maintain an activity diary; physical activity and sleep monitoring is repeated three and seven months post-randomization. The remaining baseline assessments are repeated seven months post-randomization. If successful, exercise could be a low-cost method to improve cognitive function in women with breast cancer that is easily adaptable to the home or community.Trial registration: Clinicaltrials.govNCT02793921. Registered 20 May 2016.

Effect of Aromatase Inhibitor Therapy on Sleep and Activity Patterns in Early-stage Breast Cancer

IntroductionAdherence to aromatase inhibitor (AI) therapy is poor, often because of treatment-emergent side effects, including musculoskeletal symptoms, fatigue, and insomnia. In the present analysis, we examined the sleep patterns and daytime function both objectively using actigraphy and subjectively using validated questionnaires in women initiating AI therapy. Patients and MethodsPostmenopausal women with stage 0-III hormone receptor-positive breast cancer who were initiating AI therapy were eligible. The patients wore actigraphy devices for 10 consecutive days and completed questionnaires at baseline before the initiation of AI and after 3 months of AI therapy. Associations between the baseline demographics and symptoms, changes in patient-reported outcomes and actigraphy measures from baseline to 3 months of AI therapy and discontinuation of AI therapy were examined using sign tests, logistic regression models, Spearman's correlation, and linear mixed models. ResultsForty-two patients (86%) completed the baseline assessments and 23 patients (47%) completed both the baseline and the 3-month assessments. Objectively measured daytime function as measured by total daytime activity decreased during the 3 months after starting AI (232,566 activity count vs. 204,205 activity count; P = .023), and the decrease was more evident in women with higher baseline physical function. Reduced daytime activity correlated with increased fatigue (ρ = −0.49; P = .017). ConclusionDaytime function decreased after initiation of AI therapy and correlated moderately with increased fatigue, although no association was identified with changes in pain or sleep quality. Additional studies are required to understand why function is reduced, which could have implications for interventions to improve patient tolerance of, and persistence with, AI therapy.

Abstract P5-13-05: Effect of aromatase inhibitor (AI) therapy on sleep and activity patterns in early stage breast cancer

Abstract Background: AIs are commonly used for treatment of postmenopausal women with hormone receptor-positive breast cancer for 5-10 years. However, women often experience side effects including musculoskeletal pain and sleep disturbances that lead to treatment discontinuation and worse healthcare-related outcomes. There is a need to understand the impact of adjuvant AI therapy on sleep and activity patterns in treated patients and associations with treatment adherence. This study examines objective and subjective changes in sleep patterns and daytime function in patients starting AI therapy using actigraphy and questionnaires. Methods: 49 postmenopausal women with hormone receptor-positive breast cancer who completed local surgery and chemotherapy and were planning to start AI therapy were enrolled. Patients completed 10 consecutive days of actigraphy and validated questionnaires to assess pain, sleep quality, fatigue and physical function at baseline and after three months of AI therapy. Changes in actigraphy parameters after 3 months of AI therapy were examined using paired T-tests and associations between actigraphy measures and patient-reported outcomes were examined using Pearson's correlations. Results: 42 patients completed the baseline assessment and 22 patients completed the 3 month assessment. 20 patients were excluded due to incomplete actigraphy data (n=3), discontinuation of AI therapy (n=5) or withdrawal from the study per patient preference (n=12) prior to the 3 month assessment. Total 24 hour activity, average activity per minute and maximum activity over a 24 hour period worsened after 3 months of AI therapy (all p-values &amp;lt;0.05). There was a trend towards worse sleep efficiency after 3 months. Patient-reported physical function also decreased after 3 months of AI therapy (p-value &amp;lt;0.05), but pain severity remained unchanged. Worsening patient-reported fatigue after 3 months of AI treatment correlated to a decrease in average activity per minute (r=-0.55, p-value &amp;lt;0.05) and maximum activity over a 24 hour period (r=-0.61, p-value &amp;lt;0.05). Changes in actigraphy variables and questionnaires after 3 months of AI therapyMean actigraphy sleep and activity variablesBaseline assessment3 month assessmentP-value*24 hour total activity2125901881040.01924 hour average activity per minute (AC)157.6141.00.03724 hour maximum activity (AC)10359030.012Total sleep time (min)456.1469.10.17Sleep efficiency (%)77.274.60.068Wake after sleep onset (min)72.982.00.52Total activity at night (AC)595367050.13PROMIS Physical Function52.148.30.001Brief Pain Inventory Severity0.601.10.10*p-value from t-test Conclusions: Daytime activity and sleep patterns are negatively affected by AI therapy and are associated with worsening fatigue. Future research is needed to better understand the relationship between fatigue and daytime activity, which may lead to interventions to improve tolerance and adherence to AI therapy. Citation Format: Bhave MA, Kidwell K, Lyden AK, Alsamarraie C, Henry NL. Effect of aromatase inhibitor (AI) therapy on sleep and activity patterns in early stage 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 P5-13-05.

Impact of chemotherapy followed by aromatase inhibitors on bone health of women with ER-positive early breast cancer in real world clinical settings in Greece: Results of the POCHARBI trial conducted by the Hellenic Society of Breast Surgeons

IntroductionThe aim of this observational study was to assess the combined impact of chemotherapy (CT) and aromatase inhibitors (AI) therapy on bone mineral density (BMD) in postmenopausal women with estrogen receptor (ER)-positive early breast cancer. MethodsPatients were treated with a third generation AI, either as adjuvant therapy (HT cohort, n = 166) or as subsequent endocrine therapy after initial treatment with chemotherapy (CT cohort, n = 124), and were followed up for a 12-month period. BMD was evaluated at lumbar spine (LS) and total hip (HP) before CT, before AI therapy and after 12 months of AI therapy. The primary study objective was changes in LS BMD between pre CT treatment and post 12 months AI therapy in the CT cohort. ResultsThere were no statistically significant changes in LS BMD, either within CT or HT cohort. In the CT cohort, the mean LS BMD change was −0.72% (95% CI: −2.97%, +1.53%, p = 0.5526) between CT start and month 12 of AI therapy, while it was −0.19% (95% CI: −2.12%, +1.74%, p = 0.8309) and −0.59% (95% CI: −3.18%, +2.00%, p = 0.4759) between CT start and AI start and AI start and month 12 of AI therapy respectively. The mean change in LS BMD in the HT cohort (i.e. after 12 months of AI treatment) was +1.51% (95% CI: −0.96%, +3.98%, p = 0.7420). ConclusionsThe results of this study indicate that, under routine clinical practice, most postmenopausal patients who receive CT before AI therapy do not experience debilitating BMD consequences during the first year of AI treatment.Trial registration: ClinicalTrials.gov Identifier NCT01298362.

Association of Variants in Candidate Genes with Lipid Profiles in Women with Early Breast Cancer on Adjuvant Aromatase Inhibitor Therapy

Aromatase inhibitors can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant aromatase inhibitors. We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and aromatase inhibitor metabolism pathways with fasting lipid profiles during the first 3 months of aromatase inhibitor therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models. A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides by 20.2 mg/dL and 39.3 mg/dL (P < 0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (P < 0.00053). Variants in CYP19A1 are associated with decreases in triglycerides and variable changes in HDL-C in postmenopausal women on adjuvant aromatase inhibitors. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with aromatase inhibitor therapy.

Bone turnover markers at 3 months of aromatase inhibitor therapy for prediction of 1-year bone mineral density loss: The B-ABLE cohort.

581 Background: Most guidelines recommend bone mineral density (BMD) monitoring at 1-2 years of aromatase inhibitor (AI) therapy for women who do not need bisphosphonate therapy according to baseli...

Feasibility and promise of a 6-week program to encourage physical activity and reduce joint symptoms among elderly breast cancer survivors on aromatase inhibitor therapy

National guidelines suggest that women with hormone receptor positive breast cancer be considered for adjuvant endocrine treatment with an aromatase inhibitor (AI). Joint symptoms (arthralgia) are a common AI side-effect. There is a need for effective approaches to arthralgia management that enable survivors to remain on AI therapy while optimizing as pain-free a life as possible. This feasibility study investigates a 6-week self-directed walking program in a sample of elderly female breast cancer survivors on AIs reporting joint pain. Walk With Ease (WWE) goal--minimum 30 min of walking 5 days a week (150 min per week). Eligibility: age >65; Stage I-III breast cancer; ≥3 months of AI therapy; self-reported joint pain/stiffness. (1) walking--number of days/week and number of minutes/walk, (2) visual analog scales (VAS) for joint pain, fatigue and stiffness, and (3) arthritis self-efficacy (ASE) to manage joint pain and fatigue. t-tests, correlation coefficients and effect sizes. Sample target of 20 was achieved--mean age 71 (65-87), 85% Caucasian, mean BMI 29. Proportion walking 150 min/week increased from 21% at baseline to 50% at 6 weeks (p < 0.001). Mean joint pain at baseline (39.7 + 26.9) decreased 10% (p = 0.63), fatigue (37.4+33.3) decreased 19% (p = 0.31), joint stiffness (46.1 + 27.2) decreased 32% (p = 0.07). A self-directed walking program among elderly breast cancer survivors on AI therapy significantly increased total time of walking per week over a 6 week period. Joint pain, stiffness, and fatigue also decreased, although not significantly. Testing within a larger sample is warranted.

Association between musculoskeletal symptoms and serum vitamin D levels in women receiving aromatase inhibitor treatment.

e20560 Background: Up to 40% of women with estrogen positive (ER+) breast cancer treated with aromatase inhibitors (AIs) experience musculoskeletal symptoms (AIMSS) such as bone pain, joint pain, joint stiffness, and muscle weakness that negatively impact functional ability. Previous reports indicate that vitamin D insufficiency is common in this patient population and that D supplementation might attenuate AIMSS by affecting muscle, bone and/or nerve metabolism. To test the association between AIMSS and serum 25(OH)D levels, we analyzed data collected as part of a pilot prospective study assessing instrument effect sizes to measure AIMSS. Methods: Data were analyzed from 58 women, age 61 ± 10 y with a history of ER+ breast cancer stage I-IIIa. AIMSS symptoms were measured at baseline (pre AI) and 6 mo using the Breast Cancer Prevention Trial Musculoskeletal Subscale (BCPT-MS), the Western Ontario and McMaster Universities Arthritis Index (WOMAC), and the Australian-Canadian Hand Osteoarthritis Index (AUSCAN). Serum 25(OH)D was measured by radioimmunoassay (Diasorin liaison, Stillwater, MN). Linear regression analysis was used to determine the association between changes in AIMSS scores (dependent variables) and changes in serum 25(OH)D from baseline to 6 mo, adjusting for age and season. Results: From baseline to 6 mo there were significant increases on all AIMSS measures (BCPT-MS, WOMAC and AUSCAN p&lt;0.02). These increases in AIMSS measures were not associated with the change in serum 25(OH)D from baseline to 6 mo (Δ =11 ng/ml ± 12; p&lt;0.001). Conclusions: Worsening of symptoms during the initial 6 months of AI therapy was not associated with changes in serum 25(OH)D levels. These results suggest that short-term supplementation with 25(OH)D does not attenuate the symptoms of AIMSS in post-menopausal women with ER+ breast cancer during the first 6 mo of AI therapy. However vitamin D insufficiency was uncommon in this study population (mean 25(OH)D at baseline 31 ng/ml ± 10 and 42± 13 ng/ml at 6 mo). Well controlled clinical trials are needed to further our understanding of these relationships. Clinical trial information: NCT01074320.

Mammographic Breast Density Response to Aromatase Inhibition

Mammographic breast density (MBD) is decreased by tamoxifen, but the effect of aromatase inhibitors is less clear. We enrolled early-stage postmenopausal patients with breast cancer initiating adjuvant aromatase inhibitor therapy and ascertained mammograms before and at an average 10 months of aromatase inhibitor therapy. We matched cases to healthy postmenopausal women (controls) from a large mammography screening cohort on age, baseline body mass index, baseline MBD, and interval between mammograms. We estimated change in MBD using a computer-assisted thresholding program (Cumulus) and compared differences between cases and matched controls. In predominantly White women (96%), we found 14% of the 387 eligible cases had a MBD reduction of at least 5% after an average of 10 months of aromatase inhibitor therapy. MBD reductions were associated with higher baseline MBD, aromatase inhibitor use for more than 12 months, and prior postmenopausal hormone use. Comparing each case with her matched control, there was no evidence of an association of change in MBD with aromatase inhibitor therapy [median case-control difference among 369 pairs was -0.1% (10th and 90th percentile: -5.9%, 5.2%) P = 0.51]. Case-control differences were similar by type of aromatase inhibitor (P's 0.41 and 0.56); prior use of postmenopausal hormones (P = 0.85); baseline MBD (P = 0.55); and length of aromatase inhibitor therapy (P = 0.08). In postmenopausal women treated with aromatase inhibitors, 14% of cases had a MBD reduction of more than 5%, but these decreases did not differ from matched controls. These data suggest that MBD is not a clinically useful biomarker for predicting the value of aromatase inhibitor therapy in White postmenopausal women.

Prospective study to assess fluid accumulation and tenosynovial changes in the aromatase inhibitor-induced musculoskeletal syndrome: 2-year follow-up data

Aromatase inhibitors (AIs) frequently lead to the AI-induced musculoskeletal syndrome (AIMSS). Looking into its pathophysiology, 6 months of AI therapy thickens the tendon sheath with intra-articular fluid (IAF) retention and loss of grip strength. We here report 24-month follow-up data. A prospective cohort study of 33 postmenopausal breast cancer patients received adjuvant endocrine therapy; 27 received an AI and 6 received tamoxifen. At baseline, 6 and 24 months patients had a rheumatologic examination, including a grip strength test, and magnetic resonance imaging of both hands and wrists. The primary end point was tenosynovial changes; secondary end points were changes in morning stiffness, grip strength and IAF. Twenty-three AI and 5 tamoxifen patients completed all investigations. Between month 6 and 24, IAF further increased in AI users (P = 0.04) but not in tamoxifen users, and grip strength further decreased in both groups. The worsened tenosynovial changes were strongly correlated with a decrease in grip strength. At 24 months, morning stiffness continued to be present in over a third of AI users. AIMSS represents a substantial problem in breast cancer patients. It is associated with tenosynovial changes, IAF retention, joint stiffness and loss of grip strength that do not improve with prolonged use.

S6-2: Patient-Reported Predictors of Early Treatment Discontinuation: NCIC JMA.27/E1Z03 Quality of Life Study of Postmenopausal Women with Primary Breast Cancer Randomized to Exemestane or Anastrozole.

Abstract Background: Patient-reported outcomes (PRO) assess symptom burden and health-related quality of life (HRQL) more accurately than clinical report. We previously found that treatment-emergent adverse events (CTCAE V3.0) did not impact efficacy in the main NCIC MA.27 trial, although many women discontinued treatment early. The purpose of this substudy was to obtain PROs in MA.27/E1Z03 participants to evaluate treatment-related side effects and HRQL between exemestane and anastrozole and to identify predictors of treatment discontinuation. Methods: The Eastern Cooperative Oncology Group trial (E1Z03) assessed PROs in a sample of MA.27 patients (N=686; 99.3% participation rate). Participants completed the 56-item Functional Assessment of Cancer Therapy-Endocrine Symptoms (FACT-ES) pre-treatment and at months 3, 6, 12 and 24 to assess breast-cancer specific concerns, side effects of hormonal treatments and HRQL. We used 1) Wilcoxon rank sum test to compare treatment-related symptoms and HRQL between trial arms; 2) linear mixed effect models to test differences in changes of treatment-related symptoms and HRQL between trial arms; 3) linear regression to examine the effects of symptoms on HRQL and 4) adjusted Cox regression to assess predictors of treatment duration. Results: Participants included 371 women randomized to anastrozole and 315 randomized to exemestane. Demographic and disease characteristics were balanced between trial arms. Participants were a mean age of 65.6 yrs (SD=9.2), White (95.9%), ECOG PS of 0 (87.2%), stage T1 (75.5%) or T2 (22.7%), and stage N0 (73.9%) or N1 (16.3%). Prior treatments included partial mastectomy (65.7%), chemotherapy (27.8%) and radiotherapy (51.7%). Treatment-related symptoms measured by 23 items from the FACT-ES did not differ between treatment arms at months 3, 6, 12 and 24 and the timeline change of treatment-related symptoms was similar between treatment arms (p = ns). HRQL was significantly impacted by decreased libido, weight gain, feeling bloated, breast sensitivity, mood swings, irritability, join pain, nausea and bother by treatment side effects (p &amp;lt; 0.001). 248 participants were off-treatment by 4.1 yrs. A Cox model adjusted for other symptoms, demographic and disease characteristics indicated the hazard of discontinuing treatment early increased by 29% when the severity of being bothered by side effects at baseline increased by 1 point (HR=1.29, 95% CI:1.09−1.54). At baseline, patients with prior treatments or taking more medicines reported more bother by side effects (p &amp;lt; 0.001). Increased joint pain in the first 3 months after treatment was also associated with increased hazard of discontinuing treatment early (HR=1.13, 95% CI: 1.01−1.28). Conclusions: PRO assessment indicated comparable symptom burden and HRQL among postmenopausal women randomized to anastrozole or exemestane, with increasing symptom burden over time negatively affecting HRQL. Patients who 1) initiate an aromatase inhibitor (AI) with bother by side effects from prior treatment and concomitant medications and 2) experience increased joint pain during the first 3 months of AI therapy are at risk for early discontinuation of AI therapy. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr S6-2.

Abstract P2-14-09: Prospective Evaluation of Change in 2-Point Discrimination of Index Finger as a Potential Early Predictive Marker for Carpal Tunnel Syndrome among Women Receiving Adjuvant Aromatase Inhibitor Therapy for Postmenospausal Breast Cancer in the Exemestane and Letrozole Pharmacogenomics (ELPh) Trial

Abstract Introduction: Third generation aromatase inhibitors (AIs) represent an integral part of hormonal therapy in postmenopausal women with hormone receptor (HR)-positive breast cancer. AIs are associated with musculoskeletal symptoms in up to 50% of women. Post-hoc analyses of adjuvant AI trials (ATAC and IES) have suggested that AIs might be associated with carpal tunnel syndrome (CTS), a pressure-induced neuropathy disorder caused by compression on the median nerve. The clinical diagnosis of CTS is made with typical symptoms of pain, weakness, and paresthesias in affected arm. A variety of tests, including change in 2-point discrimination (2PD) can be used to aid in diagnosis. However, the actual incidence of CTS and clinical utility of diagnostic tests such as 2PD have not been prospectively examined among women receiving AIs. Methods: Postmenopausal women with stage 0-III HR-positive breast cancer, who had completed local therapy and, if indicated, adjuvant chemotherapy, and who were enrolled in the multi-center Exemestane and Letrozole Pharmacogenetics (ELPh) trial underwent prospective evaluation of 2PD with the Disc-criminator™ (sliding aesthesiometer) at baseline, and 3 months, following initiation of the AI. The end of the Disc-criminator™ was applied at the two points at same time to the skin on the volar tip pulp of the index fingers, and the threshold value (in mm) was determined as the shortest distance between the two points a woman was able to differentiate. The exercise was repeated thrice at each point. Abnormal 2PD thresholds were defined using standard criteria (outside 95 percentile for age). The differences in mean 2PD from baseline to 3 months were analyzed using a multivariate mixed effects model where the correlations from repeated measures were accounted for by assuming an unstructured covariance structure. A p value &amp;lt; 0.05 was considered statistically significant. Results: A total of 104 women underwent baseline 2PD testing. The mean age was 59 years, 55.8% had stage I disease, and 42.3% received adjuvant chemotherapy. We observed abnormal 2PD thresholds in 1.9% and 3.5% of women at baseline and 3 months respectively. There was a significant worsening in the adjusted mean 2PD from baseline (3.4 mm) to 3 months (4 mm, p=0.01). The increase in mean 2PD following 3 months of AI therapy was higher among women with age &amp;gt; 55 (p=0.02), BMI &amp;gt; 25 (p=0.002), African Americans (p=0.02), and those who received adjuvant chemotherapy (p=0.05), as compared to their counterparts. Conclusion: Adjuvant AI therapy was associated with a significant worsening of 2PD at 3 months, particularly among older women, overweight women, and those receiving adjuvant chemotherapy. Correlation with CTS symptoms and need for surgical release will be presented at the meeting. Our results suggest that 2PD is a non-invasive method that may potentially allow for early detection of CTS. If confirmed, change in 2PD could serve as an objective early predictor for subsequent CTS in postmenopausal women with breast cancer initiating AI therapy. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-14-09.

A prospective study of aromatase inhibitor‐associated musculoskeletal symptoms and abnormalities on serial high‐resolution wrist ultrasonography

Nearly half of women treated with aromatase inhibitors (AI) develop AI-associated musculoskeletal symptoms (AIMSS) such as arthralgias, but to the authors' knowledge the etiology is unclear. The upper extremities are frequently affected, especially the wrists, hands, and fingers. AI use may also increase the risk of developing carpal tunnel syndrome. Tendon sheath fluid and tenosynovial changes have been demonstrated by imaging symptomatic patients who were treated with AIs. The authors hypothesized that these abnormalities are correlated with AIMSS. Thirty consecutive patients in whom adjuvant therapy with letrozole or exemestane was initiated on a prospective clinical trial enrolled in a pilot study evaluating tendon and joint abnormalities at baseline and after 3 months of AI therapy. Patients underwent high-resolution ultrasonography of the wrists bilaterally and completed the Health Assessment Questionnaire (HAQ) and pain Visual Analog Scale (VAS). AIMSS were defined as an increase in the HAQ or VAS score during AI therapy that exceeded a predefined cutoff. Twenty-five patients completed both the baseline and 3-month assessments. During the first 12 months of AI therapy, 15 patients developed AIMSS, and 13 discontinued therapy because of musculoskeletal symptoms. There was a trend toward an association between the presence of tendon sheath abnormalities on wrist ultrasound at baseline and the development of AIMSS (P = .06). Clinically relevant musculoskeletal symptoms develop in women treated with AIs, leading to treatment discontinuation in a substantial percentage of these patients. However, in the current study, patient-reported symptoms were not found to be associated with changes visible on wrist ultrasonography.

Long-term “protective” effect of aromatase inhibitors on the endometrium of postmenopausal breast cancer patients

Decrement of endometrial thickness was recorded following short-term aromatase inhibitor treatment in breast cancer patients previously treated with tamoxifen. It is necessary to verify if long-term aromatase inhibitor treatment can maintain this phenomenon. Prospective long-term comparison of the last ultrasonographic endometrial thickness measurement taken before discontinuation of long-term tamoxifen treatment in 64 postmenopausal breast cancer patients, with further repeated measurements, performed following administration of aromatase inhibitors. There was a significant decrement of endometrial thickness, following 36.5 +/- 15.7 months of tamoxifen treatment, from a mean value of 8.7 +/- 5.2 mm, measured at the last ultrasonographic measurement performed before discontinuation of tamoxifen treatment, down to a mean value of 6.2 +/- 4.6 mm, measured following 5.3 +/- 4.8 months of aromatase inhibitor therapy (P < 0.001). Further ultrasonographic studies revealed the same significant trend. In the first ultrasonographic study performed during aromatase inhibitor treatment, five (7.8%) patients demonstrated a significant increase of endometrial thickness. Hysteroscopy revealed a benign endometrial polyp in three patients and atrophic endometrium in the other 2. In 35 patients (54.7%), endometrial thickness was reduced following the administration of aromatase inhibitors and in 24 patients (37.5%) there was no change in endometrial thickness. With longer duration of aromatase inhibitor therapy, more patients showed decrement of endometrial thickness. Reversal of endometrial thickening induced by long-term tamoxifen treatment in postmenopausal breast cancer patients is maintained throughout long-term aromatase inhibitor treatment.

Aromatase inhibitors reverse tamoxifen induced endometrial ultrasonographic changes in postmenopausal breast cancer patients

Aromatase inhibitors may decrease endometrial thickness in breast cancer patients previously having short-term tamoxifen treatment. There is a necessity to find out if aromatase inhibitors can also decrease endometrial thickness in patients previously treated with long-term tamoxifen treatment. Prospective comparison of the last ultrasonographic endometrial thickness measurement taken before discontinuation of long-term tamoxifen treatment in 36 postmenopausal breast cancer patients, with further measurements, performed following aromatase inhibitors administration. There was a significant decrement of endometrial thickness, following 36.2 +/- 16.8 months of tamoxifen treatment, from a mean value of 9.1 +/- 5.8 mm, measured at the last ultrasonographic measurement performed before discontinuation of tamoxifen treatment, down to a mean value of 6.0 +/- 5.0 mm, measured following 5.8 +/- 5.8 months of aromatase inhibitors therapy (P = 0.001). A second ultrasonographic measurement performed in 8 patients following of additional 7.5 +/- 4.0 months of aromatase inhibitors treatment revealed further decrement of mean endometrial thickness to 4.8 +/- 2.1 mm (P = 0.002 compared to baseline). In 28 patients (77.8%), endometrial thickness was reduced following the administration of aromatase inhibitors, in four patients (11.1%) there was no change in endometrial thickness and four (11.1%) patients demonstrated an increase of endometrial thickness. Aromatase inhibitors may reverse endometrial thickening induced by long-term tamoxifen treatment in postmenopausal breast cancer patients.

Prospective endometrial assessment of breast cancer patients treated with third generation aromatase inhibitors

Objective. A prospective evaluation of the effects on endometrium of third generation aromatase inhibitors (AIs), administered as adjuvant up-front therapy or switched therapy in menopausal patients suffering from breast cancer. Methods. Forty-five patients suffering from estrogen-receptor positive breast cancer were treated with AIs as adjuvant endocrine therapy; 27 patients switched from tamoxifen to AIs (group 1) due to adverse medical events related to tamoxifen intake (22 patients) or to an extended endocrine treatment after 60 months of tamoxifen therapy (5 patients); whereas 18 patients received AIs as up-front adjuvant therapy (group 2). All patients underwent endometrial investigation before the start of AIs therapy and, thereafter, at 12 month intervals. Endometrial assessment was based on Transvaginal Ultrasonography (TU), followed by hysteroscopy and endometrial biopsy when a double layered endometrial stripe above 4 mm was measured on the longitudinal plane of uterine scanning. Six patients, showing endometrial hyperplasia before the start of AIs therapy, underwent hysteroscopy on a yearly basis, disregarding the endometrial thickness measured by TU. Histopathologic results on endometrial biopsies represented the reference test in order to estimate the prevalence of endometrial morbidity. Results. Demographic and clinical variables evaluated (age, parity, age at menarche and menopause, Body Mass Index, previous chemotherapy and radiotherapy) did not differ in groups 1 and 2. The average period of endometrial surveillance after the start of AIs therapy was 24.8 ±10.8 months for group 1 and 21.4 ± 11.5 months for group 2. A progressive decrease of endometrial thickness, from 8.2 ± 5.0 to 3.0 ± 1.2 in group 1 and from 4.7 ± 4.3 to 1.9 ± 0.3 in group 2, was found before the start and after 36–48 months of AIs therapy. The second line endometrial investigations' rate dropped from 70.3% to 12.5% in group 1 and from 27.7% to 0.0% in group 2, at baseline and after 36–48 months of AIs therapy, respectively. We found baseline endometrial abnormalities in 25.9% and in 22.2% of patients in groups 1 and 2 ( P = 0.4), respectively. During AIs administration, an endometrial pathology was found in 1 patient of group 1 and in 3 patients of group 2. In 3 patients, the abnormality consisted of simple hyperplasias and in all these patients an abnormal endometrium (1 complex atypical hyperplasia and 2 simple hyperplasias) was already detected at baseline assessment. Only in 1 patient (2.2%) of group 2 did we find an emerging pathology, consisting of adenosarcoma harbored within an endometrial polyp, detected after 12 months of therapy with letrozole. In 3 out of 5 patients showing simple hyperplasia and in 1 patient showing atypical hyperplasia before the start of AIs therapy, we observed a reversal to normal endometrium and to simple hyperplasia, respectively, after 12 months of therapy with anastrozole. Conclusions. AIs delivered as up-front therapy for breast cancer have no effects on unspecific endometrial thickening. When administered as switched therapy after tamoxifen withdrawal, AIs may reverse tamoxifen-associated endometrial thickening. As a consequence, we reduced unnecessary second-line endometrial investigations. A low rate of emerging endometrial pathology was found during AIs therapy.

Aromatase regulation and breast cancer.

Aromatase regulation and breast cancer.