Months Of Aromatase Inhibitors Treatment Research Articles

Endothelial dysfunction in breast cancer survivors on aromatase inhibitors: changes over time

BackgroundBreast cancer is estimated to comprise about 290,560 new cases in 2022. Aromatase inhibitors (AIs) are recommended as adjuvant treatment for estrogen-receptor positive (ER+) breast carcinoma in postmenopausal women, which includes approximately two-thirds of all women with breast cancer. AIs inhibit the peripheral conversion of androgens to estrogen by deactivation of the aromatase enzyme, leading to a reduction in serum estrogen level in postmenopausal women with ER+ breast carcinoma. Estrogen is known for its cardiovascular (CV) protective properties through a variety of mechanisms including vasodilation of blood vessels and inhibition of vascular injury resulting in the prevention of atherosclerosis. In clinical trials and prospective cohorts, the long-term use of AIs can increase the risk for hypertension and hyperlipidemia. Studies demonstrate mixed results as to the impact of AIs on actual CV events and overall survival.MethodsA single arm longitudinal study of 14 postmenopausal women with ER+ breast cancer prescribed adjuvant AIs at the University of Minnesota (UMN). Subjects with a history of known tobacco use, hypertension, hyperlipidemia, and diabetes were excluded to eliminate potential confounding factors. Participants underwent routine labs, blood pressure assessments, and vascular testing at baseline (prior to starting AIs) and at six months. Vascular assessment was performed using the EndoPAT 2000 and HDI/PulseWave CR-2000 Cardiovascular Profiling System and pulse contour analysis on two occasions as previously described. Vascular measurements were conducted by one trained vascular technician. Assessments were performed in triplicate, and the mean indices were used for analyses. All subjects were on an AI at the follow-up visit. The protocol was approved by the UMN Institutional Review Board and all participants were provided written informed consent. Baseline and follow-up characteristics were compared using Wilcoxon signed-rank tests. Analyses were performed using R version 3.6.1 (R Foundation for Statistical Computing, Vienna, Austria).ResultsAfter six months of AI treatment, EndoPAT® ratio declined to a median 1.12 (Q1: 0.85, Q3: 1.86; p = 0.045; Figure 1) and median estradiol levels decreased to 2 pg/mL (Q1: 2, Q3: 3; p=0.052). There was no evidence of association between change in EndoPAT® and change in estradiol level (p = 0.91). There were no statistically significant changes in small or large arterial elasticity.ConclusionsWe hypothesize that long-term use of AI can lead to persistent endothelial dysfunction, and further investigation is necessary. In our study, patients were on AI for approximately 5-10 years. As a result, we do not have data on whether these changes, such as EndoPAT® ratio and the elasticity of small and large arterial, are reversible with discontinuation of AI. These findings set the stage for a larger study to more conclusively determine the association between AI exposure and cardiovascular outcomes. Further studies should evaluate for multivariate associations withmodifiable risk factors for CV disease.

CYP19A1 rs10046 Pharmacogenetics in Postmenopausal Breast Cancer Patients Treated with Aromatase Inhibitors: One-year Follow-up

Significant individual variation in bone loss associated with aromatase inhibitors (AIs) emphasizes the importance of identifying postmenopausal breast cancer patients at high risk for this adverse effect. The study explores the clinical relevance of genetic variation in the Cytochrome P450 19A1 (CYP19A1) gene in a subset of South African patients during the first year of taking AIs for estrogen receptor (ER)-positive breast cancer. The study population consisted of ER-positive breast cancer patients on AIs, followed in real-life clinical practice. Body mass index was measured and bone mineral density (BMD) was determined at baseline and at month 12. CYP19A1 genotyping was performed using real-time polymerase chain reaction analysis of rs10046, extended to Sanger sequencing and whole exome sequencing in 10 patients with more than 5% bone loss at month 12 at the lumbar spine. After 12 months of AI treatment, 72 patients had completed BMD and were successfully genotyped. Ten patients (14%) experienced more than 5% bone loss at the lumbar spine over the study period. Genotyping for CYP19A1 rs10046 revealed that patients with two copies of the A-allele were 10.79 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase at the lumbar spine, compared to patients with the GA or GG genotypes (CI of 1.771- 65.830, p=0.01). None of the 34 patients without lumbar spine bone loss at month 12 were homozygous for the functional CYP19A1 polymorphism. At the total hip region, patients with the AA genotype were 7. 37 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase (CI of 1.101- 49.336, p=0.04). Homozygosity for the CYP19A1 rs10046 A-allele may provide information, in addition to clinical and biochemical factors that may be considered in risk stratification to optimize bone health in postmenopausal breast cancer women on AIs. Further investigation is required to place the clinical effect observed for a single CYP19A1 gene variant in a genomic context.

Effects of SLCO1B1 polymorphisms on plasma estrogen concentrations in women with breast cancer receiving aromatase inhibitors exemestane and letrozole.

Aim: This study tested for associations between SLCO1B1 polymorphisms and circulating estrogen levels in women with breast cancer treated with letrozole or exemestane. Patients & methods: Postmenopausal women with hormone-receptor positive breast cancer were genotyped for SLCO1B1*5 (rs4149056) and rs10841753. Pretreatment and on-treatment plasma estrogens and aromatase inhibitor (AI) concentrations were measured. Regression analyses were performed to test for pharmacogenetic associations with estrogens and drug concentrations. Results:SLCO1B1*5 was associated with elevated pretreatment estrone sulfate and an increased risk of detectable estrone concentrations after 3months of AI treatment. Conclusion: These findings suggest SLCO1B1 polymorphisms may have an effect on estrogenic response to AI treatment, and therefore may adversely impact the anticancer effectiveness of these agents.

Association of a low-expression SLCO1B1 polymorphism with estrogen concentrations before and during aromatase inhibitor treatment for breast cancer.

543Background: Three aromatase inhibitors (AI), the steroid exemestane, and the azoles anastrozole and letrozole, are effective in the treatment of estrogen receptor positive (ER+) breast cancer by preventing biosynthesis of estrogens including estradiol (E2), estrone (E1), and estrone-sulfate (E1S) in postmenopausal women. OATP1B1, encoded by SLCO1B1, transports E1S into the liver for desulfation to active E1. Women carrying the low-expression SLCO1B1 rs4149056 single nucleotide polymorphism (SNP) have higher E1-conjugate levels (Dudenkov Breast Cancer Res Treat 2017). We hypothesized that patients carrying this SNP would have increased E1S at baseline, and this E1S reserve could resupply E1 and E2 resulting in detectable estrogen levels during AI treatment. Methods: Five hundred postmenopausal women with ER+ breast cancer were randomized 1:1 to either exemestane 25 mg/day or letrozole 2.5 mg/day. Plasma estrogen concentrations were measured prior to and after 3 months of AI treatment using LC/MS/MS (LLO...

Variable aromatase inhibitor plasma concentrations do not correlate with circulating estrogen concentrations in post-menopausal breast cancer patients.

The aromatase inhibitors (AI) exemestane (EXE), letrozole (LET), and anastrozole suppress estrogen biosynthesis, and are effective treatments for estrogen receptor (ER)-positive breast cancer. Prior work suggests that anastrozole blood concentrations are associated with the magnitude of estrogen suppression. The objective of this study was to determine whether the magnitude of estrogen suppression, as determined by plasma estradiol (E2) concentrations, in EXE or LET treated patients is associated with plasma AI concentrations. Five hundred post-menopausal women with ER-positive breast cancer were enrolled in the prospective Exemestane and Letrozole Pharmacogenetic (ELPh) Study conducted by the COnsortium on BReast cancer phArmacogomics (COBRA) and randomly assigned to either drug. Estrogen concentrations were measured at baseline and after 3months of AI treatment and drug concentrations were measured after 1 or 3months. EXE or LET concentrations were compared with 3-month E2 concentration or the change from baseline to 3months using several complementary statistical procedures. Four-hundred patients with on-treatment E2 and AI concentrations were evaluable (EXE n=200, LET n=200). Thirty (7.6%) patients (EXE n=13, LET n=17) had 3-month E2 concentrations above the lower limit of quantification (LLOQ) (median: 4.75; range: 1.42-63.8pg/mL). EXE and LET concentrations were not associated with on-treatment E2 concentrations or changes in E2 concentrations from baseline (all p>0.05). Steady-state plasma AI concentrations do not explain variability in E2 suppression in post-menopausal women receiving EXE or LET therapy, in contrast with prior evidence in anastrozole treated patients.

Ovarian Function Recovery During Anastrozole in Breast Cancer Patients With Chemotherapy-Induced Ovarian Function Failure

Aromatase inhibitors (AIs) are given as adjuvant therapy for hormone receptor-positive breast cancer in postmenopausal women, also to those with chemotherapy-induced ovarian function failure. The current analysis reports on endocrine data of patients with chemotherapy-induced ovarian function failure who were included in the phase III DATA study assessing different durations of adjuvant anastrozole after tamoxifen. We identified all patients with chemotherapy-induced ovarian function failure. Women who underwent a bilateral ovariectomy or used luteinizing hormone-releasing hormone agonists before random assignment were excluded. Plasma estradiol and follicle-stimulating hormone levels were monitored until 30 months after random assignment at local laboratories. We aimed to determine the ovarian function recovery (OFR) rate during AI use by the cumulative incidence competing risk method and analyzed the trend of estradiol levels during AI use by a nested case-control approach in which a subset of control subjects were compared with the OFR patients excluding the value at OFR diagnosis. The 329 eligible patients had a median age of 50.0 years (range = 45-57 years) at random assignment. Thirty-nine patients developed OFR, corresponding with a 30-month recovery rate of 12.4%. Of these, 11 (28.2%) were age 50 years or older at AI initiation. The estradiol level decreased statistically significantly by 37.8% (95% CI = 27.4% to 46.7%) over the initial 30 months of AI treatment in both groups. However, the estradiol levels in the women who experienced OFR remained statistically significantly higher (difference = 20.6%, 95% CI = 2.0% to 42.7%) prior to OFR diagnosis compared with those who did not experience OFR. The risk of OFR during AI treatment in breast cancer patients with chemotherapy-induced ovarian function failure is relevant, even beyond 45 years. Furthermore, women experiencing OFR had statistically significant higher estradiol levels during AI treatment (before OFR) than those without, with potential consequences regarding efficacy.

A prospective study of aromatase inhibitor therapy initiation and self-reported side effects.

The objective of this study was to examine the associations between aromatase inhibitors (AIs) and side effects less frequently reported in the literature, including difficulty concentrating, forgetfulness, hair loss, and numbness in the extremities. Data were analyzed from a cohort of 146 breast cancer patients initiating AI therapy and followed for 1year and a cohort of 144 postmenopausal women without a history of cancer followed for 6months. At baseline (prior to AI therapy for breast cancer patients), and at 3months, 6months, and 1year (for breast cancer patients only), a comprehensive questionnaire was administered that ascertained data on symptoms. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated using logistic regression for new onset of symptoms among the breast cancer patients compared to the women without a history of cancer. Among thebreast cancer patients, 34.2% were treated with chemotherapy prior to AI treatment. Over the first 6months of AI treatment, breast cancer patients had significantly higher odds of reporting new onset of forgetfulness (OR 4.00; 95% CI 1.67, 9.59), difficulty concentrating (OR 2.73; 95% CI 1.29; 5.78), hair loss (OR 4.12; 95% CI 1.86, 9.17), and numbness/tingling in the extremities (OR 2.47; 95% CI 1.09, 5.62) compared to women without a history of cancer. Similar increases in odds were observed for the subgroup of women not treated with chemotherapy versus the comparison group. AI-related symptoms should be monitored and addressed so that adherence to therapy is maintained.

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 <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 <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 <0.05) and maximum activity over a 24 hour period (r=-0.61, p-value <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.

Abstract 959: Aromatase inhibition shapes the clonal architecture of estrogen receptor-positive breast cancers

Abstract BACKGROUND: Aromatase inhibitors are routinely used to treat estrogen receptor (ER)-positive breast cancer in postmenopausal women. Yet, one-third of ER positive tumors are resistant to aromatase inhibitors with a further one-third developing resistance over time. The underlying mechanism conferring resistance to endocrine therapy is poorly understood. In the current work, we study the effect of aromatase inhibitor therapy on the clonal evolution of breast cancer and how it relates to therapy response. MATERIALS AND METHODS: We selected 12 aromatase inhibitor sensitive (post-treatment Ki67 < 10%) and 10 aromatase inhibitor resistant tumors (Ki67 > 10%) that had previously been whole genome sequenced (Ellis, et al. 2014). We obtained surgical samples of the same tumors after ∼4 months of aromatase inhibitor treatment, whole-genome sequenced them, and also obtained RNA-sequencing data for 19 of the pre-treatment and 18 of the post-treatment tumors. To better understand spatial heterogeneity we also whole-genome sequenced 11 secondary core biopsies taken from a subset of both the baseline and surgical tumors. RESULTS AND DISCUSSION: We classified each tumor based on its clonal heterogeneity, as inferred with the sciClone R package, and found 3 ‘simple’ tumors, comprised of only a founding clone, and 19 ‘complex’ tumors that contain one or more subclones. We further classified each tumor based on a stability metric, where ‘stable’ tumors (n = 4) showed little or no evidence of evolution between baseline and surgical intervention and ‘complex’ tumors (n = 18) exhibited a spectrum of clonal changes. These changes ranged from moderate shifts in subclonal frequencies to whole-scale remodeling, where minor subclonal populations gained near-complete dominance. In one extreme case, we observed co-occurring tumors of independent origin, with selection against an ER-positive population and relative expansion of an ER-negative tumor. Spatial heterogeneity was widespread as well, with 6 out of 11 secondary cores containing clonal architecture that differed from the primary. We find that the majority of tumors are both ‘complex’ and ‘dynamic’ in that they are made up of multiple subclones at baseline that undergo clonal selection following endocrine therapy. This clonal evolution may provide a path by which a tumor can bypass therapeutic intervention. Further study is needed to identify the genetic aberrations that underlie this differential response. Our results suggest that clonal heterogeneity is widespread in hormone positive breast cancer and has relevance to endocrine therapy response. Citation Format: Christopher A. Miller, Yevgeniy Gindin, Charles Lu, Obi Griffith, Malachi Griffith, Dong Shen, Jeremy Hoog, Mark Watson, Sherri R. Davies, Kelly Hunt, Jacqueline E. Snider, Katherine DeSchryver, Richard K. Wilson, Mathew J. Ellis, Elaine Mardis. Aromatase inhibition shapes the clonal architecture of estrogen receptor-positive breast cancers. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 959. doi:10.1158/1538-7445.AM2015-959

Impact of body mass index on estradiol depletion by aromatase inhibitors in postmenopausal women with early breast cancer

Background:Body mass index (BMI) has an impact on survival outcome in patients treated with aromatase inhibitors (AIs). Obesity is associated with an increased body aromatisation and may be a cause of insufficient estradiol depletion.Methods:Sixty-eight postmenopausal oestrogen receptor-positive patients with early breast cancer were prospectively included in this study. Follicle stimulating hormone (FSH), luteinizing hormone (LH) and estradiol were analysed immediately in the clinical routine lab and in a dedicated central lab before (T1) and 3 months after start with aromatase inhibitors (T2).Results:A total of 40 patients were normal or overweight (non-obese: BMI 18.5–29.9 kg m−2) and 28 were obese (BMI⩾30 kg m−2). Aromatase inhibitors significantly suppressed estradiol serum levels (T1: 19.5 pg ml−1, T2: 10.5 pg ml−1, P<0.01) and increased FSH serum levels (T1: 70.2 mIU ml−1, T2: 75.7 mIU ml−1, P<0.05). However, after 3 months of AI treatment, estradiol levels of obese patients were nonsignificantly higher compared with non-obese patients (12.5 pg ml−1 vs 9.0 pg ml−1, P=0.1). This difference was reflected by significantly lower FSH serum levels in obese compared with non-obese patients (65.5 mIU ml−1 vs 84.6 mIU ml−1, P<0.01). The significant effects of BMI on FSH serum levels could be detected both in the routine as well as in the dedicated central lab.Conclusion:Aromatase inhibitors are less efficient at suppressing estradiol serum levels in obese when compared with non-obese women.

The impact of estrogen depletion by aromatase inhibitors on adiponectin serum levels in postmenopausal patients with breast cancer.

e11601 Background: Adiponectin impacts on breast cancer risk and prognosis. Obesity and insulin resistance are correlated with low adiponectin serum levels, which increase breast cancer risk and lead to a worse outcome regarding breast cancer. Additionally a cross talk between the adiponectin and estrogen signaling system has been suggested. Here we prospectively investigated the impact of estrogen depletion via aromatase inhibitors (AI) on adiponectin serum levels in postmenopausal patients with breast cancer. Methods: 68 postmenopausal ER positive patients with breast cancer, scheduled to receive anastrozole or letrozole as adjuvant endocrine treatment were prospectively included in this study. Serum was taken before (T1) and 3 months after start with aromatase inhibitors (T2). Non-fasting serum levels of adiponectin, FSH, LH, E2, glucose and insulin were analyzed immediately in the clinical routine lab and in a dedicated central lab able to measure E2 in serum at low concentrations with high sensitivity. Results: At baseline, a strong significant negative correlation between adiponectin and body mass index (BMI) as well as a positive correlation between adiponectin and FSH serum levels could be observed (r=-0.43, p=0.01 and r=0.38, p=0.03, respectively). Taking the previously proposed cut off of 15.5μg/ml, patients with low adiponectin serum levels had a significantly higher BMI and significant lower FSH serum levels. No interaction between adiponectin and estradiol serum levels could be detected. As previously shown, AI treatment significantly decreased estradiol serum levels and consequently increased FSH serum levels. However, 3 months of AI treatment did not alter adiponectin, insulin and c-peptide serum levels, respectively. Conclusions: Short term estrogen depletion via aromatase inhibitors does not impact on non-fasting adiponectin, insulin and c-peptide serum levels in postmenopausal patients with breast cancer.

Insulin-like growth factor 1 and musculoskeletal pain among breast cancer patients on aromatase inhibitor therapy and women without a history of cancer

Musculoskeletal pain is a common side effect of aromatase inhibitors (AIs), the adjuvant hormonal treatment of choice for postmenopausal estrogen-receptor-positive breast cancer. Although the pain is usually attributed to the estrogen depletion associated with AIs, not all women on AIs experience these symptoms. Thus, the goal of this study was to examine whether changes in the insulin-like growth factor (IGF) axis were associated with pain among women initiating AI therapy or a comparison group of women without a history of cancer. Data were analyzed from a cohort study of 52 breast cancer patients for whom AI therapy was planned and 88 women without a history of cancer. Questionnaire data on pain symptoms were collected, and blood was drawn at baseline (prior to AI therapy for patients) and 6 months after baseline. The blood samples were assayed for IGF-1 and IGF-binding protein-3 (IGFBP-3). While results showed no statistically significant changes in any of the measures across time for either the breast cancer or the comparison group, increases in both IGF-1 concentrations and the IGF-1/IGFBP-3 ratio over the first 6 months of AI treatment were significantly associated with the onset or increase in musculoskeletal pain among the breast cancer patients. Associations between IGF-1, IGFBP-3, and the IGF-1/IGFBP-3 ratio and pain were not observed in the comparison group. Although preliminary, findings from this study implicate the IGF axis in the development of AI-associated musculoskeletal pain and represent a first step in developing effective interventions to alleviate this side effect.

Aromatase inhibitor treatment limits progression of peritoneal endometriosis in baboons

To determine the effect of inhibiting aromatase activity on endometrial lesion growth and aromatase expression in a baboon model of induced endometriosis. Prospective study. Primate research institute. Sixteen olive baboons. Sixteen olive baboons with induced endometriosis were examined with laparoscopy 10 months after disease inoculation. Animals in group 1 (n = 10) were treated with 1.25 mg/d of the aromatase inhibitor (AI) letrozole, and animals in group 2 (n = 6) were given a placebo for a total of 6 months. Total number of endometriotic lesions, morphology, and volume of lesions, as well as semiquantitative reverse transcription-polymerase chain reaction and quantitative polymerase chain reaction for levels of aromatase cytochrome messenger RNA were measured. Ovarian volumes were evaluated before treatment initiation and every 2 months during the study. Treatment of group 1 animals with an AI significantly decreased lesion volume from baseline measurements, whereas the placebo-treated animals showed an increase in lesion volume. Aromatase messenger RNA levels in lesions in the AI-treated animals were significantly lower compared with the placebo-treated animals. Ovarian volumes were significantly increased at 6 months of AI treatment compared with pretreatment volumes. These findings suggest that suppression of aromatase cytochrome P450 may inhibit the invivo growth of endometriotic lesions in baboons.

Abstract P2-13-01: Impact of Body Mass Index (BMI) on the efficacy of aromatase inhibitors to suppress estradiol serum levels in postmenopausal patients with early breast cancer: a prospective proof of principle

Abstract Background: BMI impacts on the efficacy of aromatase inhibitors (AIs) regarding disease outcome in patients with early breast cancer. We hypothesized that this clinical impact of BMI is driven by the inability of AIs to suppress estradiol (E2) serum levels to the same low level in obese compared to non-obese patients. Methods: 68 postmenopausal ER positive patients with breast cancer, scheduled to receive anastrozole or letrozole as adjuvant endocrine treatment were prospectively included in this study. Serum was taken before (T1) and 3 months after start with aromatase inhibitors (T2). Serum levels of FSH, LH, E2, glucose and insulin were analyzed immediately in the clinical routine lab and in a dedicated central lab able to measure E2 in serum at low concentrations with high sensitivity. Results: 40 patients were normal - or overweight (non-obese; BMI 18.5–29.9 kg/m2) and 28 patients were obese (BMI ≥ 30 kg/m2). A weak non-significant correlation between BMI and baseline E2 serum levels (r = 0.2, p = 0.2) translated into a strong negative, highly significant correlation between BMI and baseline FSH (r = −0.6, p &amp;lt; 0.01). After 3 months of AI treatment, a moderate correlation between BMI and E2 serum levels (r = 0.35, p = 0.05) and a moderate negative correlation between BMI and FSH (r = −0.34, p = 0.05) could be observed. Aromatase inhibitors significantly suppressed E2 serum levels in non-obese (T1: 18.9 pg/ml, T2: 9.0 pg/ml, p &amp;lt; 0.01) as well as in obese patients (T1: 20.2 pg/ml, T2: 12.5 pg/ml, p &amp;lt; 0.05). In addition an increase in FSH serum levels was observed in obese (T1: 50.0 mIU/ml, T2: 65.5 mIU/ml, p &amp;lt; 0.01) but not in non-obese (T1: 84.0 mIU/ml, T2: 84.6 mIU/ml) patients. However, after 3 months of AI treatment, E2 levels of obese patients were not at the same low level when compared to non-obese patients (E2 obese: 12.5 pg/ml vs. E2 non-obese: 9.0 pg/ml, p = 0.1). This difference translated into significantly lower FSH serum levels in obese compared to non-obese patients (FSH obese: 65.5 mIU/ml vs. FSH: 84.6 mIU/ml, p &amp;lt; 0.01). The significant effects of BMI on FSH serum levels could be detected both in the routine - as well as in the dedicated central lab. Conclusion: AIs are less efficient at suppressing E2 serum levels in obese when compared to non-obese women. The observed effect may contribute to the survival disadvantage of obese patients in adjuvant AI trials. FSH serum levels should be validated as high sensitive surrogate parameters for estradiol serum level suppression by aromatase inhibitors in postmenopausal patients with breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-13-01.

Effect of Aromatase Inhibitors on Background Parenchymal Enhancement and Amount of Fibroglandular Tissue at Breast MR Imaging

To evaluate whether treatment with an aromatase inhibitor (AI) influences background parenchymal enhancement (BPE) or amount of fibroglandular tissue (FGT) at breast magnetic resonance (MR) imaging in postmenopausal women with prior history of breast cancer. A waiver of authorization and patient consent was granted by the institutional review board for this HIPAA-compliant retrospective study. Postmenopausal women with breast cancer and MR imaging findings of the contralateral unaffected breast, before and during 6-12 months of AI treatment (anastrozole, letrozole, or exemestane), between August 1999 and June 2010 were retrospectively identified (n = 149). Two readers performed blinded side-by-side comparison of BPE and MR imaging-depicted FGT before and during treatment. BPE and FGT were classified as the same or greater on one of the two MR studies and by using categorical scales: minimal, mild, moderate, or marked for BPE and fatty, scattered, heterogeneously dense, or dense for FGT. Consensus was reached in cases of disagreement. The sign test was used to conduct a side-by-side comparison of BPE and FGT before and during AI treatment. A decrease in BPE occurred in 33.9% (37 of 109) of women during anastrozole treatment, while an increase occurred in only one (P < .0001); 28 of 37 decreases resulted in a category change of BPE. A decrease in MR imaging-depicted FGT occurred in 5.5% (six of 109) of women, while no increases occurred (P = .031). During letrozole treatment, a decrease in BPE occurred in 46% (15 of 33), while an increase occurred in one woman (P = .0003); a decrease in FGT occurred in only one woman, and no increases occurred. Similar results were seen when women also undergoing chemotherapy were excluded. Only seven women were treated with exemestane. Treatment with 6-12 months of anastrozole or letrozole was associated with decreases in BPE, which occurred in a greater proportion of women than decreases in FGT.

P2-08-01: Impact of Aromatase Inhibitors on Background Parenchymal Enhancement and Amount of Fibroglandular Tissue on Breast MRI.

Abstract Background: On breast MRI, background parenchymal enhancement (BPE) and volume of fibroglandular tissue (FGT) have been shown to reflect a patient's hormonal status. Tamoxifen has been shown to reduce mammographic breast density and may serve as an early predictor of response in the prevention setting (Cuzick, JNCI 2011). We have shown that adjuvant tamoxifen can reduce BPE in the unaffected breast in women with breast cancer. We hypothesize that aromatase inhibitor (AI) induced endocrine changes in breast tissue should also be evident and therefore we performed a study to evaluate whether adjuvant AI therapy influences BPE or amount of FGT in the contralateral breast. Methods: An electronic medical record review identified 856 postmenopausal women with stage I-III breast cancer who had at least two breast MRIs and took adjuvant AI treatment. A retrospective chart review was conducted to select those patients without a history of prior tamoxifen or raloxifene treatment who had a MRI of the contralateral breast both before and during 6 to 12 months of AI treatment. After exclusion of all irradiated breasts, 168 women were eligible. MRIs were performed between August 1999 and June 2010. Two radiologists who were blind to AI treatment status, independently rated level of BPE and amount of FGT using categorical scales: BPE — Minimal, Mild, Moderate, Marked; FGT — Fatty, Scattered, Heterogeneously Dense, Dense (based on proposed BIRADS criteria for BPE and on ACR criteria for FGT). Blinded side-by-side direct comparison evaluated whether there was a category change between the two MRIs. A consensus was reached in cases of disagreement. The Wilcoxon signed-rank test was used to assess changes in rating categories for BPE and FGT between before and during AI breast MRIs. A waiver of authorization was granted by the institutional review board for this study. Results: In this study 127/168 (76%) women were treated with anastrozole, 33/168 (20%) with letrozole and 8/168 (5%) with exemestane. Based on the blinded side-by-side comparison, a category (or more) decrease in BPE occurred during treatment with AIs (p&amp;lt;0.0001). There was an overall shift from higher to lower degree of BPE in 35% (45/127) of the women taking anastrozole while a category increase occurred in only one woman (1%; p &amp;lt;0.0001). A similar result was seen in the women taking letrozole [45% (15/33) had a decrease versus 3% (1/33) an increase; p=0.0003] and exemestane [25% (2/8) had a decrease versus 12.5% (1/8) an increase; p=0.50]. For FGT a category decrease occurred in 5% (6/127) of anastrozole users while no increase occurred [0% (0/127), p=0.016]. The respective numbers for letrozole were 3% (1/33) and 0% (0/33), and nobody on exemestane had a change in FGT. Conclusions: After 6 to 12 months of treatment with adjuvant AIs, there was a statistically significant category (or more) decrease in BPE. BPE is more sensitive than FGT to changes in normal breast stroma that occur during adjuvant treatment with AIs and BPE may be a marker of anti-hormonal activity in the breasts. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-08-01.

Bone Health in Postmenopausal Women Treated with Adjuvant Aromatase Inhibitors for Early Breast Cancer: 12 Months Follow-Up.

Abstract Background:The use of aromatase inhibitors (AI) in the adjuvant setting for postmenopausal women with receptor-positive breast cancer is well established. The AI treatment has been associated with decline in bone mineral density (BMD), and increased bone turnover markers. We designed a prospective study to evaluate the effect of oral bisphosphonates (BP) on vertebral and non vertebral fractures (VF), bone turnover markers (bTM), BMD, and quality of life (QoL) in postmenopausal women receiving adjuvant AI for hormone receptor positive early breast cancer.Material and methods:Postmenopausal, receptor-positive breast cancer women treated with AI as initial therapy [Letrozol (LET)] or after 2 or 5 years of tamoxifen [switched to exemestane (EXE)] were included. Patients were stratified by lumbar spine, femoral neck and total hip BMD to receive open-label treatment with BP, alendronate or risedronate, (if osteoporosis [T-score&amp;lt;-2,5] or osteopenia [T-score&amp;lt;-2.0] and 1 major risk factor, defined as group of high risk of fracture) or calcium and vitamin D supplementation (if normal BMD or T-score&amp;gt;-2.0 and no major risk factor). Levels of 25-OH vitamin D, N-telopeptide (NTx), bone alkaline phosphatase (bALP) and osteocalcin (OC) were measured at baseline, 3, 12 and 24 moths, and BMD and thoracic and lumbar spine X-rays were assesed at baseline, 1 and 2 years. QoL was evaluated by ECOS-16 questionnaire and a visual analogue scale used to evaluate arthralgia. Results:from 03/2006 to 03/2009, 261 patients have been included and 117 have completed &amp;gt;12 month follow up. All the bTM increased after 12 months of AI treatment and a significant decrease on BMD was also observed (Table 1). This effect is reverted with oral BP treatment, maintaining the BMD level and reducing the bTM. With the AI introduction QoL of patients became worse, and the BP treatment did not improve neither arthralgia nor bone pain. Osteoporotic fractures were recorded at baseline in 12.3% of women (4.2% VF and 7.7% non VF).Conclusions:AI treatment increased bone turnover, decreased BMD and QoL. Of note, BP use decreased bone turnover, has neutral effect in BMD and does not improve QoL. This study suggests that the current recommendation of the use of BP should be revisited to consider including all postmenopausal women treated with adjuvant AI to avoid increased bone turnover and bone mass decrease.Table 1. BMD at baseline, 12 months and changes Without BP (n=76) With BP (n=41) BMD value (g/cm2)AIBasal12 month% change / pBasal12 month% change / pFemoral NeckLET0.7650.751- 1.96 / 0.020.6480.657+ 1.61 / NS EXE0.7560.749- 0.6 / NS0.6260.644+ 2.63 / 0.013Lumbar spineLET0.9900.969- 2.36 / 0.00010.8150.813- 0.17 / NS EXE0.9570.940- 1.57 / 0.0430.8110.814+ 0.86 / NS Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3175.

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.