Duration Of Aromatase Inhibitor Therapy Research Articles

Construction and validation of a risk prediction model for aromatase inhibitor-associated bone loss.

To establish a high-risk prediction model for aromatase inhibitor-associated bone loss (AIBL) in patients with hormone receptor-positive breast cancer. The study included breast cancer patients who received aromatase inhibitor (AI) treatment. Univariate analysis was performed to identify risk factors associated with AIBL. The dataset was randomly divided into a training set (70%) and a test set (30%). The identified risk factors were used to construct a prediction model using the eXtreme gradient boosting (XGBoost) machine learning method. Logistic regression and least absolute shrinkage and selection operator (LASSO) regression methods were used for comparison. The area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of the model in the test dataset. A total of 113 subjects were included in the study. Duration of breast cancer, duration of aromatase inhibitor therapy, hip fracture index, major osteoporotic fracture index, prolactin (PRL), and osteocalcin (OC) were found to be independent risk factors for AIBL (p < 0.05). The XGBoost model had a higher AUC compared to the logistic model and LASSO model (0.761 vs. 0.716, 0.691). The XGBoost model outperformed the logistic and LASSO models in predicting the occurrence of AIBL in patients with hormone receptor-positive breast cancer receiving aromatase inhibitors.

Adjuvant study of amcenestrant (SAR439859) versus tamoxifen for patients with hormone receptor-positive (HR+) early breast cancer (EBC), who have discontinued adjuvant aromatase inhibitor therapy due to treatment-related toxicity (AMEERA-6).

TPS607 Background: There are currently limited treatment options for patients with HR+ EBC who have discontinued adjuvant treatment with aromatase inhibitors (AIs) due to treatment-related toxicity. Amcenestrant is an optimized oral selective estrogen receptor degrader (SERD) with potent dual activity which antagonizes and degrades the ER resulting in inhibition of the ER signalling pathway. Preliminary clinical evidence from the phase 1/2 AMEERA-1 trial has demonstrated meaningful antitumour activity and a favourable safety profile of amcenestrant in the treatment of HR+ advanced breast cancer (Linden HM, Campone M, Bardia A, et al: Abstract PD8-08: A phase 1/2 study of SAR439859, an oral selective estrogen receptor (ER) degrader (SERD), as monotherapy and in combination with other anti-cancer therapies in postmenopausal women with ER-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic breast cancer (mBC): AMEERA-1. SABCS 2020 PD8-08). Methods: AMEERA-6 is a prospective, randomized, international, double-blind, double-dummy, phase 3 study. 3738 patients will be randomized 1:1 to receive either amcenestrant 200 mg daily or tamoxifen 20 mg daily. Eligible patients are pre-or postmenopausal women or men with HR+ EBC (stage IIB-III) who have received at least 6 months of adjuvant AIs (at least 3 months in the adjuvant setting if they have received prior neoadjuvant AI therapy) and discontinued them within 30 months of initiation due to treatment-related toxicity. Participants will be centrally assessed to have ER+ and/or PgR+ (≥10% positive stained cells) status by immunohistochemistry assay. Prior use of adjuvant CDK4/6 inhibitors are allowed. Patients are eligible irrespective of HER2 status; for patients with HER2-positive disease adjuvant anti-HER2 treatment and chemotherapy must be completed prior to randomization. Stratification factors include: duration of AI therapy, HER2 status, prior chemotherapy, prior CDK4/6 inhibitors, geographic region, and menopausal status. Planned treatment duration is 5 years. Patients will be followed-up for 10 years from randomization. The primary endpoint is invasive breast cancer-free survival (IBCFS). Invasive disease-free survival is a key secondary endpoint, while other secondary endpoints include distant relapse-free survival (RFS), locoregional RFS, overall survival, breast-cancer specific survival, safety, patient reported outcomes and pharmacokinetics. Adherence to treatment is an exploratory endpoint. AMEERA-6 opened for recruitment in January 2022. Clinical trial information: NCT05128773.

Evaluation of endocrine resistance using ESR1 genotyping of circulating tumor cells and plasma DNA.

Therapeutic efficacy of hormonal therapies to target estrogen receptor (ER)-positive breast cancer is limited by the acquisition of ligand-independent ESR1 mutations, which confer treatment resistance to aromatase inhibitors (AIs). Monitoring for the emergence of such mutations may enable individualized therapy. We thus assessed CTC- and ctDNA-based detection of ESR1 mutations with the aim of evaluating non-invasive approaches for the determination of endocrine resistance. In a prospective cohort of 55 women with hormone receptor-positive metastatic breast cancer, we isolated circulating tumor cells (CTCs) and developed a high-sensitivity method for the detection of ESR1 mutations in these CTCs. In patients with sufficient plasma for the simultaneous extraction of circulating tumor DNA (ctDNA), we performed a parallel analysis of ESR1 mutations using multiplex droplet digital PCR (ddPCR) and examined the agreement between these two platforms. Finally, we isolated single CTCs from a subset of these patients and reviewed RNA expression to explore alternate methods of evaluating endocrine responsiveness. High-sensitivity ESR1 sequencing from CTCs revealed mono- and oligoclonal mutations in 22% of patients. These were concordant with plasma DNA sequencing in 95% of cases. Emergence of ESR1 mutations was correlated both with time to metastatic relapse and duration of AI therapy following such recurrence. The Presence of an ESR1 mutation, compared to ESR1 wild type, was associated with markedly shorter Progression-Free Survival on AI-based therapies (p = 0.0006), but unaltered to other non-AI-based therapies (p = 0.73). Compared with ESR1 mutant cases, AI-resistant CTCs with wild-type ESR1 showed an elevated ER-coactivator RNA signature, consistent with their predicted response to second-line hormonal therapies. Blood-based serial monitoring may guide the selection of precision therapeutics for women with AI-resistant ER-positive breast cancer.

Patient-reported Adherence to Adjuvant Aromatase Inhibitor Therapy Using the Morisky Medication Adherence Scale: An Evaluation of Predictors.

Endocrine therapy is part of standard adjuvant therapy for patients with hormone receptor-positive breast cancer and has been shown to improve recurrence-free and overall survival. However, adherence to endocrine therapy is suboptimal and is difficult to measure. In this study we evaluate the feasibility of using the Morisky Medication Adherence Scale (MMAS) to assess patient adherence to aromatase inhibitor (AI) therapy. Patients with stage 1 to 3, hormone receptor-positive breast cancer receiving adjuvant AI therapy were prospectively enrolled on an Institutional Review Board approved protocol. The MMAS questionnaire was administered to each patient and adherence was measured. Information on duration of AI therapy, patient and tumor characteristics, and treatment was collected. A multivariable logit model approach was utilized to evaluate potential barriers to adherence. Between 2011 and 2014, 100 patients were enrolled. The distribution of adherence levels was 13% low, 37% medium, and 50% high. High adherence was reported more frequently in white women (58%), patients with stage 2 and 3 disease (54%), and patients who did not receive chemotherapy (62%). Multivariable analysis demonstrated that higher adherence was more likely in white women compared with African American women (estimated odds ratio=2.8). Using the MMAS, only 50% of women with stage 1 to 3 breast cancer reported high adherence to AI therapy, consistent with other reports showing suboptimal adherence to adjuvant endocrine therapy. The MMAS allows for the rapid assessment of adherence to oral adjuvant endocrine therapy and is valuable in a busy clinical setting.

Abstract P5-12-03: Prevalence of bone loss among nonmetastatic breast cancer patients treated with aromatase inhibitors in the United States

Abstract Background: Adjuvant endocrine therapy compromises bone health in patients (pts) with breast cancer, leading to osteopenia, osteoporosis, and fractures (Forbes 2008). For postmenopausal women with estrogen receptor (ER) positive (+ve) breast cancer, aromatase inhibitors (AI) have emerged as the standard of care because of superior efficacy over selective ER modulators such as tamoxifen, shown in several large clinical trials. As rates of utilization and duration of AI therapy are expected to continue to increase, we report estimates of the prevalence of women with nonmetastatic breast cancer treated with AI in the United States and examine evidence of bone loss before and after AI exposure. Methods: The Oncology Services Comprehensive Electronic Records (OSCER) database, an electronic medical record database on &amp;gt;500,000 cancer pts from oncology practices across the US, was used to identify women with breast cancer (ICD-9 174*), ≥1 clinic visit, and confirmed AI therapy (anastrozole, letrozole, or exemestane) in 2014, excluding pts with evidence of metastases (ICD-9 196-198, stage IV, or M1 disease). OSCER is projected nationally through methods of direct estimations utilizing claims data for 1-year period prevalence. Bone loss was defined by diagnosis of osteoporosis (ICD-9 733.0), osteopenia (ICD-9 733.90), or receipt of bone therapy in 2014. Bone therapies used as proxy for bone loss were intravenous (IV) (ibandronate, zoledronic acid), or oral bisphosphonates (BPs) (risedronate, ibandronate, etidronate, alendronate), or subcutaneous anti-RANK ligand antibody (denosumab [60 mg Q6M]). Results: It is nationally estimated that 538,630 (95% CI 519,839 - 557,422) women with nonmetastatic breast cancer were treated with an AI in 2014, representing a median of 6 prescriptions (mean 6.8). Of these, most (94%) were treated with anastrozole or letrozole, 55% were ≥65 years, and 11% took tamoxifen prior to first AI. Among women taking AI in 2014, 39% started in 2014, 24% started in 2013, and 37% have been on AI therapy since 2012 or earlier. Overall, 285,543 (53%) pts on AI therapy had evidence of bone loss, 30% of whom developed bone loss after exposure to AI therapy. Among the 338,784 women with no evidence of pre-existing bone loss, 25% (85,697) developed bone loss after initiating AI therapy (table), with 21% treated with oral and 1% IV BPs, or 9% with denosumab. 2014 prevalenceN (%)Nonmetastatic pts on AI therapy538,630At least 2 AI prescriptions in lifetime468,608 (87)Bone loss before starting AI199,846 (37)No bone loss before AI, with bone loss after AI85,697 (16) Conclusions: This study provides current estimates of the prevalence of nonmetastatic breast cancer treated with AI in the US using real-world data, indicating that more than 535,000 women were treated with AI in 2014. Considering that 37% of pts have been on endocrine therapy since 2012 or earlier, continued use of AI will likely lead to increased pts with bone loss. These women face an increased risk of fractures, highlighting the need for intervention with antiresorptive treatments (i.e., BPs have been studied, and denosumab has a labeled indication in this setting) that may help build bone mass and counteract detrimental effects on the bone. Citation Format: Pirolli M, Hernandez RK, Reich A, Liede A. Prevalence of bone loss among nonmetastatic breast cancer patients treated with aromatase inhibitors in the United States. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-12-03.

Effect of Aromatase Inhibitor Therapy on the Cardiovascular Health of Black and White Breast Cancer Patients

BackgroundThe present study examined racial differences in the cardiovascular health effects of aromatase inhibitors. Patients and MethodsData were analyzed from 77 white and 35 black patients with early-stage breast cancer initiating aromatase inhibitor therapy and subsequently followed for 1 year. At baseline and a 1-year follow-up clinic visit, a comprehensive cardiovascular health assessment was conducted, which included measurement of carotid intima-medial thickness and a blood draw to measure high-sensitivity C-reactive protein and cholesterol concentrations. A detailed questionnaire was also completed. The information collected was used to calculate each patient's 10-year risk of atherosclerotic cardiovascular disease events at both measurement points. Paired t tests were used to examine the changes in the continuous outcome variables within groups during the study period. Independent t tests were conducted to examine the changes over time between the 2 groups. ResultsNo statistically significant changes in carotid intima-medial thickness, atherosclerotic cardiovascular disease risk score, or the other cardiovascular-related outcomes (high-sensitivity C-reactive protein, cholesterol levels, blood pressure) during the first year of aromatase inhibitor therapy were observed among either the black or white breast cancer patients or between the 2 groups. Mean grip strength in the dominant hand decreased significantly and similarly during the 1-year period for the white and black breast cancer patients. ConclusionThe findings from the present study suggest no large adverse cardiovascular health effects from aromatase inhibitors during the first year of therapy among either black or white breast cancer patients. However, the results of the present study cannot rule out the potential for long-term adverse changes over the duration of aromatase inhibitor therapy or beyond.

Vascular toxicities of endocrine therapy in early-stage breast cancer: Encouraging observations in a nontrial setting.

68 Background: Endocrine therapy (ET) is the standard of care for postmenopausal (PM) women with early stage breast cancer (EBC). Studies suggest higher risk of vascular toxicities (VT) on aromatase inhibitor (AI) therapy. We report incidence/discontinuation rates of VTs in a cardiac clinic. Methods: PM women with hormone receptor positive EBC treated with ET (tamoxifen (T) ± AI) at Ottawa Hospital Cancer Center 01/99-2/06. Data included: demographics, vascular co-morbidities (VCM), ET, duration, VTs. Results: 626 pts, median age 59 years (r: 30-92), median follow-up 98 months (m), stage: I (196 pts), II (341 pts) III (89 pts) EBC. Majority (52.5%) pts had VCM at ET initiation; hypertension (HTN) (36%), hyperlipidemia (HYLP) (17%), coronary disease (12%), thrombosis (9%), angina (6%) TIA (6%). Treatment discontinued due to VT 3x more with T vs. AI. Most common VTs: edema, arrhythmias (ARR), cardiovascular (CVS) event, and HYLP. With Letrozole and T, previous VCM significantly increased risk of developing VT (chi-square: P=0.022 and 0.009). Time to develop VT shortest for T and exemestane. Previous VCM did not affect this interval. Longer exposure to T correlated with higher VT rate (t-test: p=0.046) not seen with AIs. Exposure to multiple AIs associated with higher VT rate (t-test: p=0.009). Conclusions: This cohort study reports similar VT rates with AI therapy as reported in the literature. T was associated with higher discontinuation rates (10.5%) due to VTs compared to AIs (2.8-3.3%). Longer duration of AI therapy was not associated with increased risk of VTs. These encouraging results reflect the real-life experience of women exposed to ET. [Table: see text]

Aromatase inhibitors and calcium absorption in early stage breast cancer

To investigate the effect of aromatase inhibitors (AI) on intestinal calcium absorption, measured using the gold-standard dual stable calcium isotope method. In this pilot study, we recruited 10 postmenopausal women with hormone receptor-positive breast cancer who planned to initiate AI therapy; women receiving chemotherapy were excluded. Women completed two 24 h inpatient calcium absorption study visits, the first prior to AI therapy and the second at least 6 weeks following onset of AI therapy. We calculated total fractional calcium absorption (TFCA) using the dose-corrected fractional recovery of two stable isotopes from 24 h urine collections. Ten postmenopausal women (mean±SD age, 66±7 years; 25(OH)D 40±7 ng/mL, and total calcium intake of 1,714±640 mg/day) exhibited no change in TFCA related to AI therapy (0.155±0.042 prior to and 0.160±0.064 following AI therapy, p=1.0). Subjects exhibited a surprisingly small decline in serum estradiol levels with AI therapy that was not statistically significant. However, there was a significant correlation between duration of AI therapy and the decline in serum estradiol levels (r=-0.65, p=0.040). In this pilot study, AI therapy did not decrease TFCA. Women with early stage breast cancer exhibited an unexpectedly low TFCA, most likely due to their high calcium intake. The null effect of AI therapy on TFCA might relate to the brief duration of AI therapy, the minimal effect of AI therapy on estradiol levels, subjects' high calcium intake or excellent vitamin D status.

P4-12-13: A Multi-Center Randomized Controlled Double Blind Trial Assessing the Effect of Acupuncture in Reducing Musculoskeletal Symptoms in Breast Cancer Patients Taking Aromatase Inhibitors: First Interim Analysis.

Abstract Background: Aromatase inhibitors (AIs) are recommended as first-line adjuvant hormonal therapy in postmenopausal women with hormone-receptor-positive breast cancer, as monotherapy or sequential therapy after tamoxifen. AI-associated musculoskeletal symptoms (AIMSS) occur in approximately 50% of women receiving AIs and in some may result in discontinuation of treatment. Symptom management is essential to ensure that breast cancer patients receive the full recommended duration of AI therapy. We conducted a randomized, placebo-controlled trial to evaluate the effect of acupuncture on AIMSS and report the first interim analysis. Method: Postmenopausal women with early stage breast cancer, experiencing AIMSS, who had not had acupuncture in the year prior to the study, were eligible. Patients were randomized to 8 weekly acupuncture or sham acupuncture. Health assessment questionnaire disability index (HAQ-DI ranging 0–3.0) and pain visual analog scale (VAS ranging 0–100) were used to assess clinical musculoskeletal disorder severity at weeks 0, 4, 8, and 12 or 24. Change in HAQ-DI (ΔHAQ-DI) and VAS scores (ΔVAS) from baseline were compared between patients receiving acupuncture versus sham acupuncture using exact Wilcoxon rank sum test. Serum samples were collected for measurements of estrogens and beta endorphin concentrations and cytokine profile before and after the intervention to evaluate the etiology of AIMSS and the mechanism of acupuncture in treating AIMSS. Results: Between May 2008 and June 2011, 48 patients were enrolled, 2 patients were not evaluable due to noncompliance to treatment and lost to follow up, 10 were still receiving treatment and therefore not evaluable. Thirty-six were evaluable, and were equally distributed between the real and sham acupuncture groups. Baseline characteristics were balanced between the two groups with regard to age, race, and body mass index (BMI) with the exception that baseline mean HAQ-DI was higher in the acupuncture group (0.9 vs 0.55, p=0.04). White/Black/Asian: 26/7/3, Median (range): age: 61 (45-82); BMI (kg/m2): 31.1 (22.9−59.6). At week 8, both groups showed a wide range of ΔHAQ-DI (ΔHAQ-DI =HAQ-DIweek8-HAQ-DIbaseline): from −1.38 to 0.5 in the acupuncture group versus from −1 to 0.12 in sham acupuncture group. There was no statistically significant difference in mean ΔHAQ-DI between the real and sham acupuncture groups (−0.33 vs −0.33, p=0.87). Eleven patients in each group (61%) reported decreased HAQ-DI scores, which correlated with improved function. There was no difference in mean ΔVAS between the real and sham acupuncture groups (−9.27 vs −13.82, p=0.67). No significant side effects were reported. Changes in other time points and in serum biomarkers will be presented at the meeting. Conclusions: The majority of breast cancer patients experiencing AIMSS who participated in our study reported a reduced HAQ-DI score both from acupuncture and sham acupuncture. We did not observe significant differences between responses to real versus sham acupuncture after 8 weekly treatments. The study remains open to accrual to reach 50 evaluable patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P4-12-13.

PD01-04: Entinostat, a Novel Histone Deacetylase Inhibitor, Added to Exemestane Improves PFS in Advanced Breast Cancer in a Randomized, Phase II, Double-Blind Study.

Abstract Background: Entinostat is a novel, oral, class I-selective histone deacetylase inhibitor (HDACi) that has been shown pre-clinically to inhibit mechanisms of aromatase inhibitor (AI) resistance through epigenetically driven down-regulation of activated growth factor signaling pathways and normalization of estrogen receptor levels. This provided a strong rationale for the entinostat breast cancer (BC) program, which was designed to evaluate entinostat's ability to increase and/or restore sensitivity to treatment with an AI. Methods: Postmenopausal women with ER+ advanced BC who had ≤ 1 prior chemotherapy and had progressed on a non-steroidal AI were randomized 1:1 to exemestane 25 mg daily + entinostat 5 mg or placebo weekly. Progression free survival (PFS) was the primary endpoint; objective response rate and clinical benefit rate were secondary endpoints and overall survival (OS) was an exploratory endpoint. Prospectively defined subsets of interest included patients with “AI-sensitive and AI-resistant disease”. AI-sensitive was defined as having had a PR, CR or SD for ≥6 months (mos) in the metastatic setting or having completed and remained disease free for ≥12 months post adjuvant therapy. All others were considered AI-resistant. Treatment continued until disease progression or unacceptable toxicity. Response assessments were performed every 8 weeks. Results: 130 women were enrolled (64 exemestane+entinostat [E+E]; 66 exemestane+placebo [E+P]. All but 1 patient had Stage IV disease. 82% had measurable disease, of which 60% had visceral involvement. 42% had 1 prior line of hormonal therapy; 58% had &amp;gt;1. Analysis of the intent-to-treat (ITT) population showed significantly (defined prospectively as p&amp;lt;0.10) longer PFS with E+E than with E+P (median 4.28 vs 2.27 mos, respectively; hazard ratio [HR] = 0.73; p=0.06) (CI 0.49, 1.09). While not powered, results for pre-defined subsets were consistent with improved PFS in the E+E arm. Interestingly, the subset of patients identified as AI-resistant, demonstrated a HR of 0.61 (CI 0.30, 1.25) (median 3.72 vs. 1.78 mos). While OS is still early, at 18 mos median follow-up at time of abstract submission, the E+E arm demonstrated a median OS of 26.94 mos compared to the E+P arm of 20.33 mos (HR = 0.56) (CI 0.31, 1.02). Entinostat combined with exemestane was well tolerated. The most frequent adverse events (AEs) were fatigue, gastrointestinal disturbances, and hematologic abnormalities. AEs with a ≥ 20% higher incidence with E+E than E+P were fatigue (46% vs 26%) and uncomplicated neutropenia (25% vs 0%). Serious AE rate was similar for both arms (13% vs 12%). Conclusions: Adding entinostat to exemestane resulted in improved PFS, the study's primary endpoint. At a median follow-up of 18 mos, the exploratory endpoint of OS was also increased in the E+E arm. Importantly for a phase II study, the PFS benefit in all subsets evaluated was consistent with the overall improvement seen in the ITT. These data demonstrate that the addition of entinostat to AI therapy may prolong the duration of AI therapy, thereby delaying the initiation of subsequent therapies such as chemotherapy, a goal for many breast cancer patients. A phase III study is planned. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr PD01-04.

Incidence of arthralgia syndrome (AS) related to aromatase inhibitors (AIs) in postmenopausal women with early breast cancer (EBC)

e11603 Background: Anastozole (A) and letrozole (L) are standard drugs in up-front adjuvant endocrine therapy in postmenopausal hormone positive EBC. AIs have a higher incidence of osteoporosis, bone fractures and musculoskeletal symptoms, particularly joint pain and stiffness (AS) respect to tamoxifen. The real incidence of AS can be underestimated respect to data derived from clinical trials. Methods: From 1/07 to 12/07 we registered all patients (pts) taking A or L as adjuvant therapy for at least 3 months. We screened 47 pts, 3 pts refused to participate at the study and 2 resulted metastatic. A total of 42 pts were enrolled. The median age was 67 yrs (range 51–89), the median time since menopause was 11 yrs (range 1–48). 30 pts had natural menopause, 7 surgical menopause and 5 reported chemo-induced menopause. 25 pts took A and 17 pts took L. The median duration on therapy was 19 months (range 3–68) and 31 pts had received chemotherapy (9 CMF, 17 anthra-based, 5 anthra-taxane based). Results: 11 pts (26%) did not report AS, 19 pts (45%) had new-onset AS and 12 (29%) had worsening of prior joint pain after starting adjuvant AIs therapy. Most pts reported moderate to severe AS requiring occasional use of nonsteroidal anti-inflammatory drugs (75%), 15% used oral supplements and 10% used opiates, only 4 women used exercise to relieve joint stiffness. 17 pts interrupted the therapy from 7 to 20 days in order to reduce the symptoms and 7 obtained a partial improvement. 11 pts (35%) suffered from AS declared the worsening of quality of life. In univariate analysis presence of AS was not associated with age, entry into menopause, years since menopause, duration of AI therapy or previous chemotherapy. Conclusions: Our data show a higher incidence of AS in clinical practice respect to literature data, which caused worsening of quality of life and could be reason of discontinuation of effective therapy. The exact mechanism of AIs-related arthralgia is unclear, but is believed to be related to estrogen deprivation, however further studies are needed to define the pathogenesis in order to find an effective therapy. No significant financial relationships to disclose.

Modalities of prescription of aromatase inhibitors (AI) in adjuvant therapy for postmenopausal women with HR+ breast cancer: Analysis of daily practices in France

e11619 Background: Aromatase inhibitors (AIs) are widely used as adjuvant therapy for HR+ breast cancer. This survey is an overview of clinical daily practices in France Methods: Multicentric survey conducted in October 2008 by Internet among a sample of 293 physicians specialized in breast cancer management (oncologists, radiotherapists, surgeons) prescribing adjuvant AIs in post-menopausal patients with HR+ breast cancer Results: When started upfront, 87% of physicians expressed that the optimal duration of AIs treatment is 5 years, and 7 % more than 5 years. Nevertheless only, 33% of physicians inform their patients of a total duration of AIs therapy of 5 years, and 66% of a possible adjustment according to the evolution of the scientific knowledge during the five years. AIs are prescribed after the end of chemotherapy by 97% of physicians, after the end of radiotherapy by 83%, and during radiotherapy by 15%. When started after two years of tamoxifen, 71 % of physicians expressed that the optimal duration of AIs treatment is 3 years, 22% 5 years, and 3% more than five years. When started after five years of tamoxifen, 48% of physicians expressed that the optimal duration of AIs treatment is less than three years, 15% 3 years, 15% 5 years, and 2% more than five years. The optimal duration of treatment with aromatase inhibitors is still subject to question for 73% of the physicians interviewed Conclusions: In France, most physicians declared an optimal duration of treatment with aromatase inhibitors in adjuvant setting in HR+ breast cancer in line with guidelines and/or approved indications. However, the optimal duration of treatment is still subject to question for many physicians No significant financial relationships to disclose.

Randomized Trial of Denosumab in Patients Receiving Adjuvant Aromatase Inhibitors for Nonmetastatic Breast Cancer

Adjuvant aromatase inhibitor therapy is well established in postmenopausal women with hormone receptor-positive breast cancer, but such therapy is complicated by accelerated bone loss and increased fracture risk. We investigated the ability of denosumab, a fully human monoclonal antibody against receptor activator of nuclear factor-kappaB ligand, to protect against aromatase inhibitor-induced bone loss. Eligible women with hormone receptor-positive nonmetastatic breast cancer treated with adjuvant aromatase inhibitor therapy were stratified by duration of aromatase inhibitor therapy (< or = 6 v > 6 months), received supplemental calcium and vitamin D, and were randomly assigned to receive placebo (n = 125) or subcutaneous denosumab 60 mg (n = 127) every 6 months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary end point was percentage change from baseline at month 12 in lumbar spine bone mineral density (BMD). At 12 and 24 months, lumbar spine BMD increased by 5.5% and 7.6%, respectively, in the denosumab group versus placebo (P < .0001 at both time points). Increases were observed as early as 1 month and were not influenced by duration of aromatase inhibitor therapy. Increases in BMD were also observed at the total hip, total body, femoral neck, and the predominantly cortical one-third radius. Bone turnover markers decreased with denosumab treatment. Overall incidence of treatment-emergent adverse events (AEs) was similar between treatment groups. In women with nonmetastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy, twice-yearly administration of denosumab led to significant increases in BMD over 24 months at trabecular and cortical bone, with overall AE rates similar to those of placebo.

Endocrine Therapy and Bone Loss in Breast Cancer: Time to Close in the RANK(L)?

Endocrine Therapy and Bone Loss in Breast Cancer: Time to Close in the RANK(L)?

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.

Optimal Use of Aromatase Inhibitors: To Lead or to Follow?

Optimal Use of Aromatase Inhibitors: To Lead or to Follow?

Adjuvant endocrine therapy for postmenopausal breast cancer in the era of aromatase inhibitors: an update

There is overwhelming evidence that optimal adjuvant endocrine therapy for hormone sensitive breast cancer in postmenopausal women should include a third generation aromatase inhibitor (AI). On current evidence, adjuvant anstrozole or letrozole should be used upfront in such patients especially in those with high risk disease (node positive and/or tumours > 2 cm). The sequential approach of tamoxifen for 2–3 years followed by exemestane or anastrozole for 2–3 years is a reasonable alternative to 5 years of AI monotherapy in patients with low risk disease (node negative and tumour smaller than 2 cm) especially if the tumour is positive for estrogen and progesterone receptors.Node-positive patients completing 5 years of adjuvant tamoxifen should be offered letrozole for up 48 months. Further research is required to establish the long-term cardiovascular safety of AIs especially that of letrozole and exmestane, the optimal AI to use, duration of AI therapy and whether monotherapy with an AI for 5 years is superior to sequencing an AI after 2–3 years of tamoxifen.The bone mineral density (BMD) should be measured at baseline and monitored during therapy in women being treated with AIs. Anti-osteoporosis agents should such as bisphosphonates should be considered in patients at high risk of bone fractures.

Aromatase inhibitors in the early adjuvant setting – the latest evidence

In early breast cancer, adjuvant therapy significantly reduces the risk of recurrence after complete surgical resection of the tumor mass. For over a decade, 5 years of adjuvant endocrine therapy with the selective estrogen receptor modulator tamoxifen has been the gold standard in hormone-receptor-positive (HR+) disease. Despite therapy with tamoxifen, relapses still occur, and the rate of relapse is particularly high in the first 2–3 years after surgery. More effective therapies are urgently required to prevent these relapses, particularly in patients with higher-risk disease. The third-generation aromatase inhibitors (AIs), letrozole , anastrozole and exemestane , have shown greater efficacy than tamoxifen, with comparable tolerability, in large, randomized, phase III trials in the early adjuvant setting. On the basis of these findings, AIs are now displacing tamoxifen as the preferred adjuvant endocrine therapy for HR+ early breast cancer in postmenopausal women . Two treatment strategies have been used to investigate AI efficacy in the early adjuvant setting, both with 5 years’ tamoxifen as the comparator: upfront AI for 5 years, or switching to an AI after completing between 2 and 3 years of tamoxifen. When given upfront, anastrozole (ATAC trial) and letrozole (BIG 1-98 trial) have been shown to significantly improve disease-free survival compared with tamoxifen. Letrozole also significantly reduced the risk of distant recurrence, a well-recognized predictor of breast cancer death. Indirect comparisons suggest that these two AIs may not be clinically equivalent, but a direct comparison of letrozole and anastrozole in a prospective, randomized trial is required to prove whether these two AIs do differ clinically. Switching to exemestane or anastrozole therapy after 2–3 years of tamoxifen has also been shown to significantly reduce the risk of relapse compared with 5 years of tamoxifen therapy. However, in these trials, randomization and/or analyses were initiated at the time of switching therapy, including only patients who remained disease-free at this time, thus excluding patients with higher-risk disease who had experienced early relapse, and selecting a more favorable patient population. Trials comparing upfront AIs with the sequential approaches are ongoing: BIG 1-98 and amended TEAM. Of note BIG 1-98 is the only trial to include both switching strategies: tamoxifen followed by letrozole and letrozole followed by tamoxifen. Trials in the early adjuvant setting have revealed that AIs are generally well tolerated: side effects are predictable and manageable. Although further studies are required to determine the optimum treatment strategy and duration of AI therapy, the third-generation AIs are proving highly effective agents in the treatment of HR+ early breast cancer, and bring into question the validity of tamoxifen as the gold standard for adjuvant therapy. Recently updated international guidelines now recommend that early adjuvant therapy should include an AI.

Adjuvant Endocrine Therapy for Postmenopausal Women with Early Breast Cancer

Results from multiple clinical trials involving aromatase inhibitors have added to the knowledge base relating to endocrine therapy of postmenopausal women with hormone receptor-positive early breast cancer. In the extended adjuvant setting, data from the Austrian Breast and Colorectal Cancer Study Group 6a trial showed an advantage for anastrozole following 5 years of tamoxifen treatment, consistent with the more robust MA.17 trial that examined letrozole versus placebo following 5 years of tamoxifen treatment. The combined analysis of the Austrian Breast and Colorectal Cancer Study Group 8 trial and the German Arimidex Nolvadex 95 trial, plus the Italian Tamoxifen Anastrozole trial, have shown the advantage of switching to anastrozole over continuing the tamoxifen to complete the full 5 years of adjuvant therapy. These trials support the previously reported larger and double-blind Intergroup Exemestane Study. The Arimidex, Tamoxifen, Alone or in Combination trial now has data out to 68 months of median follow-up showing the maintenance of a significant advantage of anastrozole over tamoxifen for disease-free survival. In this initial treatment setting, the Breast International Group 1-98 trial recently showed a significant advantage for letrozole over tamoxifen. The current debate is centered on whether the optimal strategy is to give an aromatase inhibitor initially or after several years of tamoxifen treatment. Multiple important questions remain, including the predictive value of molecular markers such as progesterone receptor, the optimal duration of aromatase inhibitor therapy, the long-term adverse effects, and the relative efficacy and toxicity of the different aromatase inhibitors.

American Society of Clinical Oncology Technology Assessment on the Use of Aromatase Inhibitors As Adjuvant Therapy for Postmenopausal Women With Hormone Receptor–Positive Breast Cancer: Status Report 2004

To update the 2003 American Society of Clinical Oncology technology assessment on adjuvant use of aromatase inhibitors. Based on results from multiple large randomized trials, adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer should include an aromatase inhibitor in order to lower the risk of tumor recurrence. Neither the optimal timing nor duration of aromatase inhibitor therapy is established. Aromatase inhibitors are appropriate as initial treatment for women with contraindications to tamoxifen. For all other postmenopausal women, treatment options include 5 years of aromatase inhibitors treatment or sequential therapy consisting of tamoxifen (for either 2 to 3 years or 5 years) followed by aromatase inhibitors for 2 to 3, or 5 years. Patients intolerant of aromatase inhibitors should receive tamoxifen. There are no data on the use of tamoxifen after an aromatase inhibitor in the adjuvant setting. Women with hormone receptor-negative tumors should not receive adjuvant endocrine therapy. The role of other biomarkers such as progesterone receptor and HER2 status in selecting optimal endocrine therapy remains controversial. Aromatase inhibitors are contraindicated in premenopausal women; there are limited data concerning their role in women with treatment-related amenorrhea. The side effect profiles of tamoxifen and aromatase inhibitors differ. The late consequences of aromatase inhibitor therapy, including osteoporosis, are not well characterized. The Panel believes that optimal adjuvant hormonal therapy for a postmenopausal woman with receptor-positive breast cancer includes an aromatase inhibitor as initial therapy or after treatment with tamoxifen. Women with breast cancer and their physicians must weigh the risks and benefits of all therapeutic options.