Drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method following mild COVID-19 in a patient under anastrozole therapy-A case report.

BACKGROUND: Anastrozole is a selective aromatase inhibitor used for the treatment of postmenopausal hormone-sensitive breast cancer. The major side effects include osteoporosis, hypercholesterolemia, and musculoskeletal events, such as arthralgia and myalgia. Other adverse events are rare, including symptoms of acne, masculinization, and drug-induced liver injury, with the latter reported in a few cases only. CASE: Here, we report on a patient under anastrozole therapy who developed drug-induced liver injury as assessed by the updated Roussel Uclaf Causality Assessment Method 5 weeks after a mild SARS-CoV-2 infection, which is, to the best of our knowledge, the first report of its kind involving anastrozole. Discontinuation of anastrozole resulted in a marked improvement of the alanine aminotransaminase, and aspartate aminotransaminase as well as normalized lactate dehydrogenase serum levels already seen after 26 days. Surprisingly, however, the cholestatic serum markers gamma-glutamyl transpeptidase and alkaline phosphatase showed a further rise, and took another 4 weeks to drop significantly. CONCLUSION: The presentation of this case is meant to alert physicians to a potential drug-induced liver injury following mild SARS-CoV-2 infection in patients under anastrozole medication.

Segmental Erythema Multiforme: An Unusual Drug Reaction to Anastrozole.

Erythema multiforme (EM) is an immune-mediated, mucocutaneous hypersensitivity syndrome that can occur as a result of various medications, including a wide range of antineoplastic and hormonal drugs. Anastrozole, a nonselective aromatase inhibitor used in breast cancer management has been associated with different cutaneous side effects, of which EM is rarely seen and usually in a minor or major form with typical target lesions. This is a short report of a patient who developed a rare cutaneous side effect after the use of aromatase inhibitor anastrozole - segmental erythema multiforme in cancer-affected area. Cutaneous adverse effects limited to cancer-affected breast are extremely rare but should be considered in everyday dermatological practice. We find this case instructive not only because of the rarity of the segmental EM, but also because, contrary to classical teaching, drug eruption due to anastrozole occurred months, not days after the initiation of therapy.

Optic Neuritis as a Consequence of Long-Term Medical Treatment Using Anastrozole: A Case Report.

BACKGROUND Vision loss secondary to optic neuritis is an uncommon adverse effect of nonsteroidal aromatase inhibitors. There have been few reports in the literature on visual disturbance in patients on long-term treatment with Anastrozole for breast cancer prevention; but none had symptoms worse than blurry vision and/or xerostomia. The present patient had acute onset of right-sided vision loss without other neurologic deficits while using the aromatase inhibitor Anastrozole for breast cancer treatment. CASE REPORT A 69-year-old woman presented to the Emergency Department with approximately 1 month of worsening right eye vision loss that was not associated with any other neurologic deficits or any acute symptoms. The symptom was constant and without alleviating or aggravating factors. After extensive workup with ophthalmologic evaluation, Infectious Disease evaluation, autoimmune tests, brain imaging, lumbar puncture with CSF analysis, and temporal artery biopsy reporting unremarkable results, it was determined that the patient was in an inflammatory state induced by long-term use of Anastrozole, an aromatase inhibitor. CONCLUSIONS The patient's long-term use of Anastrozole likely played a large part in developing right visual disturbance secondary to optic neuritis, as a patient of this age has little risk of developing conditions such as optic neuritis, unilateral loss of vision, and/or autoimmune conditions.

Variations in Incidence of Trigger Finger and Response to Corticosteroid Injection after Aromatase Inhibitor Therapy for Breast Cancer.

BACKGROUND: Aromatase inhibitors (AIs), such as letrozole and anastrozole, have been demonstrated to have significant musculoskeletal symptoms in patients. The purpose of this study was to evaluate the effect of specific AI medications on the incidence of trigger finger and independent factors affecting treatment outcomes within this population. METHODS: A retrospective chart review was performed at the authors' institution between the years 2014 and 2018 in patients with the diagnosis of breast cancer. This cohort was then sorted based on receiving medication regimens, trigger finger diagnosis, steroid injections, and need for surgical release of trigger finger. RESULTS: A total of 15,144 patients were included for initial review. The overall rate of trigger finger diagnosis was 2.75% in the entire breast cancer population and 4.5% for patients receiving AI therapy. Patients taking letrozole and anastrozole had an increased odds ratio of 2.0 and 1.7, respectively, for developing trigger finger. Patients who switched between letrozole and anastrozole during treatment had a higher rate of failed steroid injection treatment (45.2% versus 23.5%; P = 0.021). Among patients receiving AI treatment diagnosed with trigger finger, diabetes and hemoglobin A1c level greater than 6.5 were associated with significantly increased rates of failed steroid therapy. CONCLUSIONS: Patients receiving AI therapy have an increased incidence of trigger finger. The outcomes of treatment are equivalent between AI and non-AI trigger finger populations. However, steroid therapy is more likely to fail in patients who require switching of regimens because of significant musculoskeletal symptoms. Poorly controlled diabetes was also an independent factor for compromised steroid treatment of trigger finger. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Aromatase inhibition increases blood pressure and markers of renal injury in female rats.

Aromatase is a monooxygenase that catalyzes the rate-limiting step of estrogen biosynthesis from androgens. Aromatase inhibitors are widely used for the treatment of patients with hormone receptor-positive breast cancer. However, the effects of aromatase inhibitors on cardiovascular and renal health in females are understudied. Given that estrogen is protective against cardiovascular and kidney diseases, we hypothesized that aromatase inhibition elevates blood pressure and induces kidney injury in female Sprague-Dawley rats. Twelve-week-old female rats were implanted with radiotelemetry transmitters to continuously monitor blood pressure. After baseline blood pressure recording, rats were randomly assigned to treatment with the aromatase inhibitor anastrozole (ASZ) or vehicle (Veh) in drinking water. Twenty days after treatment initiation, rats were shifted from a normal-salt (NS) diet to a high-salt (HS) diet for an additional 40 days. Rats were euthanized 60 days after treatment initiation. Body weight increased in both groups over the study period, but the increase was greater in the ASZ-treated group than in the Veh-treated group. Mean arterial pressure increased in ASZ-treated rats during the NS and HS diet phases but remained unchanged in Veh-treated rats. In addition, urinary excretion of albumin and kidney injury marker-1 and plasma urea were increased in response to aromatase inhibition. Furthermore, histological assessment revealed that ASZ treatment increased morphological evidence of renal tubular injury and proximal tubular brush border loss. In conclusion, chronic aromatase inhibition in vivo with ASZ increases blood pressure and markers of renal proximal tubular injury in female Sprague-Dawley rats, suggesting an important role for aromatization in the maintenance cardiovascular and renal health in females.NEW & NOTEWORTHY Aromatase enzyme catalyzes the rate-limiting step in estrogen biosynthesis. Aromatase inhibitors are clinically used for the treatment of patients with breast cancer; however, the impact of inhibiting aromatization on blood pressure and renal function is incompletely understood. The present findings demonstrate that systemic anastrozole treatment increases blood pressure and renal tubular injury markers in female rats fed a high-salt diet, suggesting an important role for aromatization in preserving cardiovascular and renal health in females.

Efficacy and safety of letrozole or anastrozole in the treatment of male infertility with low testosterone-estradiol ratio: A meta-analysis and systematic review.

BACKGROUND: Aromatase inhibitors (AIs) have been used to treat male infertility for decades. However, due to the lack of large-scale randomized controlled studies and basic research, the efficacy and safety of AIs in the treatment of male infertility remain controversial. Therefore, it is necessary to conduct an evidence-based preliminary evaluation of the existing clinical trials of AIs in the treatment of male infertility. METHOD: A comprehensive literature search was performed in the PubMed, Embase, Cochrane, CNKI, VIP, CBM, and Wanfang databases through August 2021 for all studies. We conducted a systematic review with a meta-analysis of all available studies reporting sperm conventional parameters, gonadotropin and testosterone levels, and/or the pregnancy rate. RESULTS: A total of 10 studies involving 666 patients were included. Letrozole (LE) or anastrozole (AZ) administration significantly increased sperm concentration, total sperm count, serum luteinizing hormone (LH), follicle-stimulating hormone (FSH), testosterone (T) levels, and the testosterone-to-estradiol ratio (T/E2), but E2 levels were significantly reduced compared with baseline values. Compared with the control group, which included selective estrogen receptor modulators (SEMRs) or human chorionic gonadotropin (HCG), LE, or AZ did not have any significant effect on sperm concentration, motility, and morphology, except that AIs had less effect on sperm motility than the control group (weighted mean difference [WMD]: -2.55; 95% CI: -4.11 to -1.00; p = 0.001). CONCLUSION: AIs may be effective in the treatment of male infertility. For infertile male patients planning assisted reproduction, discontinuation of AIs for 2-7 days prior to sperm retrieval may increase the success rate of fertilization. Further studies with larger sample sizes are needed to validate these findings.

Evaluation of Pharmacokinetics and Safety With Bioequivalence of Anastrozole in Healthy Chinese Volunteers: Bioequivalence Study Findings.

Anastrozole is a third-generation aromatase inhibitor that exerts potent anti-breast cancer effects. This trial aimed to explore the pharmacokinetics (PK) and safety with bioequivalence of orally administered anastrozole provided by 2 sponsors in healthy volunteers.Two separate open-label, randomized, single-dose, crossover-design studies consisting of a fasting study (n = 23) and a fed study (n = 23, 1 participant withdrew before taking medication) were conducted. In each study, healthy volunteers were randomized to receive the test product (Haizheng Pharmaceutical Group) followed by the reference drug (AstraZeneca Pharmaceuticals LP), or vice versa. Each study subject received a 1-mg anastrozole tablet with a 21-day washout. The plasma concentrations of anastrozole were measured with liquid chromatography-tandem mass spectrometry, and PK parameters were determined by noncompartmental analysis. Forty-six healthy female volunteers were enrolled. For patients enrolled in the fasting study, the mean age was 55.0 years, mean weight was 57.1 kg, mean body mass index was 23.6 kg/m2 , and mean height was 155.5 cm. For patients enrolled in the fed study, the mean age was 54.2 years, mean weight was 55.9 kg, mean body mass index was 23.9 kg/m2, and mean height was 152.8 cm. All PK end points met the predefined criteria for PK equivalence. In fasting subjects, the median maximum plasma concentration was 23.4 and 22.6 at 1 hour for test and reference formulations, respectively. The maximum plasma concentration in fed subjects was 18.7 and 18.5 at 4 hours for test and reference formulations, respectively. Both fasting and fed studies achieved plausible bioequivalence. Anastrozole was well tolerated and exhibited a favorable safety profile at the prescribed doses. The severity of observed adverse events assessed according to the Common Terminology Criteria for Adverse Events (version CTCAE4.03) was mild, and some of the adverse events were not caused by anastrozole. Furthermore, the results of our study under fasting and fed conditions demonstrated bioequivalence of the test and reference products.

Eficacia y seguridad de fulvestrant en mujeres posmenopáusicas con cáncer de mama metastásico, RH positivo, HER2 negativo, sin crisis visceral, con intolerancia o progresión durante la terapia endocrina con anastrozol y exemestano / Efficacy and safety of fulvestrant in postmenopausal women with metastatic breast cancer, hr positive, her2 negative, without visceral crisis, with intolerance or progression during endocrine therapy with anastrozole and exemestane

ANTECEDENTES: El presente dictamen preliminar expone la evaluación de la eficacia y seguridad de fulvestrant (monoterapia), en comparación con la quimioterapia, en el tratamiento de pacientes posmenopáusicas con cáncer de mama metastásico (CMM), receptor hormonal (RH) positivo, receptor 2 del factor de crecimiento epidérmico humano (HER2, por sus siglas en inglés) negativo, sin crisis visceral, con intolerancia o progresión a anastrozol y exemestano. SPECTOS GENERALES Los aspectos generales del cáncer de mama se han descrito previamente en los Dictámenes Preliminares N.° 022-DETS-IETSI-2021 (IETSI-EsSalud 2021a), N° 008- DETS-IETSI-2021 (IETSI-EsSalud 2021b) y N° 050-SDEPFyOTS-DETS-IETSI-2016 (IETSI-EsSalud 2016). Brevemente, el cáncer de mama es la primera causa de muerte por neoplasia maligna en mujeres en el mundo (Institute for Health Metrics and Evaluation 2021). En el 2019, en Perú se detectaron 4,743 casos nuevos de cáncer de mama en mujeres, y cerca de 1,840 muertes debido a esta condición clínica (Institute for Health Metrics and Evaluation 2021). El cáncer de mama con RH positivo es el tipo más común de cáncer de mama, y representa el 75 % de todos los cánceres de mama (Pritchard 2021). El tratamiento de elección del cáncer de mama con RH positivo es la terapia endocrina (Pritchard 2021; National Cancer Institute 2021). Específicamente, en las mujeres posmenopáusicas con CMM, RH positivo, HER2 negativo, la terapia endocrina de primera línea más utilizada son los IA, como el agente no esteroideo anastrozol y el agente esteroideo exemestano (National Cancer Institute 2021). Muchos de estos pacientes eventualmente presentan intolerancia o enfermedad progresiva durante la terapia endocrina con IA. En este contexto, las opciones de tratamiento son limitadas, e incluyen el uso de la quimioterapia (National Cancer Institute 2021; Ma and Sparano 2021). TECNOLOGÍA SANITARIA DE INTERÉS: FULVESTRANT: La información detallada sobre esta tecnología sanitaria se encuentra disponible en los Dictámenes Preliminares N.° 022-DETS-IETSI-2021 (IETSI-EsSalud 2021a) y N.° 050- SDEPFyOTS-DETS-IETSI-2016 (IETSI-EsSalud 2016). El fulvestrant es un antagonista competitivo del receptor del estrógeno que bloquea las acciones tróficas de los estrógenos sin poseer actividad agonista parcial (de tipo estrógeno). El mecanismo de acción está asociado con la regulación a la baja de los niveles de la proteína del receptor de estrógeno (U.S. Food and Drug Administration 2021; European Medicines Agency 2021). METODOLOGÍA: Se realizó una búsqueda sistemática de literatura con el objetivo de identificar evidencia sobre la eficacia y seguridad de fulvestrant (monoterapia) en comparación con la quimioterapia en pacientes posmenopáusicas con CMM, RH positivo, HER2 negativo, sin crisis visceral, con intolerancia o progresión durante la terapia endocrina con anastrozol y exemestano. Se utilizaron las bases de datos PubMed, Cochrane Library y LILACS. Asimismo, se realizó una búsqueda dentro de bases de datos pertenecientes a grupos que realizan evaluaciones de tecnologías sanitarias (ETS) y guías de práctica clínica (GPC), incluyendo el Scottish Medicines Consortium (SMC), el National Institute for Health and Care Excellence (NICE), la Canadian Agency for Drugs and Technologies in Health (CADTH), la Haute Autorité de Santé (HAS), el Institut für Qualitát und Wirtschaftlichkeit im Gesundheitswesen (IQWiG), el Instituto de Evaluación Tecnológica en Salud de Colombia (IETS), la Comissáo Nacional de Incorpornáo de Tecnologias no Sistema Único de Saúde (CONITEC), entre otros; además de la Base Regional de Informes de Evaluación de Tecnologías en Salud de las Américas (BRISA) y páginas web de sociedades especializadas en el manejo del cáncer de mama como National Comprehensive Cancer Network (NCCN), European Society for Medical Oncology (ESMO) y American Society of Clinical Oncology (ASCO). Se hizo una búsqueda adicional en la página web del registro de ensayos clínicos administrado por la Biblioteca Nacional de Medicina de los Estados Unidos (https://clinicaltrials.qov/)e International Clinical Trial Registry Platform (ICTRP) (https://apps.who.int/trialsearch/), para poder identificar ensayos clínicos en curso o cuyos resultados no hayan sido publicados para, de este modo, disminuir el riesgo de sesgo de publicación. RESULTADOS: Guías de práctica clínica Publicaciones incluidas en la evaluación de la evidencia: Cardoso et al., 2020. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5) (Cardoso et al. 2020). National Comprehensive Cancer Network (NCCN). NCCN Guidelines: Breast Cancer. Version 8.2021 - September 13, 2021 (NCCN 2021). Moy et al., 2021. Chemotherapy and Targeted Therapy for Patients With Human Epidermal Growth Factor Receptor 2­Negative Metastatic Breast Cancer That is Either Endocrine-Pretreated or Hormone Receptor­Negative: ASCO Guideline Update (Moy et al. 2021). El siguiente documento se excluyó por tratarse de un consenso de expertos. Pritchard et al., 2013. Endocrine therapy for postmenopausal women with hormone receptor-positive her2-negative advanced breast cancer after progression or recurrence on nonsteroidal aromatase inhibitor therapy: A Canadian consensus statement (Pritchard et al. 2013). CONCLUSIONES: El objetivo del presente dictamen preliminar fue evaluar la mejor evidencia científica sobre la eficacia y seguridad de fulvestrant (monoterapia) en comparación con la quimioterapia en pacientes posmenopáusicas con CMM, RH positivo, HER2 negativo, sin crisis visceral, con intolerancia o progresión durante la terapia endocrina con anastrozol y exemestano. La búsqueda de literatura permitió identificar tres GPC realizadas por la ESMO, la NCCN y la ASCO. En cuanto a las GPC identificadas, hubo discordancia entre las recomendaciones elaboradas para el tratamiento de mujeres posmenopáusicas con CMM, RH positivo, HER2 negativo, sin crisis visceral, con progresión durante la terapia endocrina. La NCCN recomienda el uso de la terapia endocrina, incluido fulvestrant, en el subgrupo de pacientes sin resistencia a la terapia endocrina, y la quimioterapia en el subgrupo con resistencia a la terapia endocrina. La ESMO recomienda el uso de la terapia endocrina, incluido fulvestrant, en la población objetivo, y no elabora recomendaciones sobre la quimioterapia. La ASCO recomienda el uso de la terapia endocrina con o sin terapia dirigida y la quimioterapia de un solo agente, sin preferencias entre una u otra. Sobre la evidencia utilizada para realizar las recomendaciones, la ESMO no citó evidencia alguna, mientras que la NCCN y la ASCO citaron evidencia que no respondía a la pregunta PICO establecida en el presente dictamen. En el momento actual no hay evidencia que compare la terapia endocrina con fulvestrant (monoterapia) versus la quimioterapia en mujeres posmenopáusicas con CMM, RH positivo, HER2 negativo, con intolerancia o progresión durante la terapia endocrina. En ese sentido, existe incertidumbre sobre el beneficio adicional del uso de fulvestrant sobre la quimioterapia en la población objetivo. La quimioterapia de agente único es una opción de tratamiento recomendada por la guía de la ASCO para la población objetivo de la presente evaluación. En EsSalud, hay varias opciones de quimioterapia disponibles en la Petitorio Farmacológico y existe una amplia experiencia en el uso de la quimioterapia en el tratamiento del CMM. Por lo expuesto, el IETSI no aprueba el uso de fulvestrant en pacientes posmenopáusicas con CMM, RH positivo, HER2 negativo, sin crisis visceral, con intolerancia o progresión durante la terapia endocrina con anastrozol y exemestano.

Phase 2 study of anastrozole in rare cohorts of patients with estrogen receptor/progesterone receptor positive leiomyosarcomas and carcinosarcomas of the uterine corpus: The PARAGON trial (ANZGOG 0903).

BACKGROUND: Aromatase inhibitors have been used empirically to treat a subset of patients with hormone receptor positive uterine leiomyosarcomas(LMS) and carcinosarcomas (UCS) mainly supported by retrospective data. We evaluated the activity of anastrozole in two rare cohorts; patients with recurrent/metastatic LMS and UCS enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER+)/progesterone receptor positive (PR+) gynecological cancers. METHOD: An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER &/or PR + ve LMS or UCS with measurable disease, treated until progression or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity. RESULTS: 39 eligible patients were enrolled, 32 with LMS and 7 with UCS. For the LMS cohort CBR at 3 months was 35% (95% CI: 21-53%) with a median duration of clinical benefit of 5.8 months. Best response was a partial response in one patient. Two patients remained on treatment for more than one year. The median progression-free survival was 2.8 months (95% CI: 2.6-4.9). For the UCS cohort CBR at 3 months was 43% (95% CI: 16-75%) with a median duration of clinical benefit of 5.6 months. Stable disease was seen in 3 patients but no objective responses were seen. The median progression-free survival was 2.7 months (95% CI, 1.1-8.2). Safety was acceptable with 5/39 evaluable patients showing grade 3 toxicities. CONCLUSION: Whilst objective response rates with anastrozole are low, the clinical benefit rate and good tolerance suggests that aromatase inhibitor therapy may have a role in a subset of patients with metastatic LMS and UCS.

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer.

BACKGROUND: For postmenopausal women with hormone-receptor-positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear. METHODS: In this prospective, phase 3 trial, we randomly assigned postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years). The primary end point was disease-free survival. The primary analysis included all the patients who were still participating in the trial and who had no recurrence 2 years after randomization (i.e., when treatment in the 2-year group had ended). Secondary end points were overall survival, contralateral breast cancer, second primary cancer, and clinical bone fracture. RESULTS: Among the 3484 women who were enrolled in the trial, 3208 remained in the trial without disease progression after the first 2 years of extended anastrozole treatment following randomization. Among these women, disease progression or death occurred in 335 women in each treatment group in the primary-analysis set at 8 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.90). No between-group differences occurred in most secondary end points, and subgroup analyses did not indicate differences in any particular subgroup. The risk of clinical bone fracture was higher in the 5-year group than in the 2-year group (hazard ratio, 1.35; 95% CI, 1.00 to 1.84). CONCLUSIONS: In postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture. (Funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group; ABCSG-16/SALSA ClinicalTrials.gov number, NCT00295620.).

Antiplatelet Therapy Combined with Anastrozole Induces Features of Partial EMT in Breast Cancer Cells and Fails to Mitigate Breast-Cancer Induced Hypercoagulation.

Thromboembolic complications are a leading cause of morbidity and mortality in cancer patients. Cancer patients often present with an increased risk for thrombosis including hypercoagulation, so the application of antiplatelet strategies to oncology warrants further investigation. This study investigated the effects of anastrozole and antiplatelet therapy (aspirin/clopidogrel cocktail or atopaxar) treatment on the tumour responses of luminal phenotype breast cancer cells and induced hypercoagulation. Ethical clearance was obtained (M150263). Blood was co-cultured with breast cancer cell lines (MCF7 and T47D) pre-treated with anastrozole and/or antiplatelet drugs for 24 h. Hypercoagulation was indicated by thrombin production and platelet activation (morphological and molecular). Gene expression associated with the epithelial-to-mesenchymal transition (EMT) was assessed in breast cancer cells, and secreted cytokines associated with tumour progression were evaluated. Data were analysed with the PAST3 software. Our findings showed that antiplatelet therapies (aspirin/clopidogrel cocktail and atopaxar) combined with anastrozole failed to prevent hypercoagulation and induced evidence of a partial EMT. Differences in tumour responses that modulate tumour aggression were noted between breast cancer cell lines, and this may be an important consideration in the clinical management of subphenotypes of luminal phenotype breast cancer. Further investigation is needed before this treatment modality (combined hormone and antiplatelet therapy) can be considered for managing tumour associated-thromboembolic disorder.

Aromatase inhibitor anastrozole modifies cellular functions in gingival fibroblasts and endothelial cells: possible periodontal complications of aromatase inhibitor treatment.

BACKGROUND: Recent studies have shown that treatment with aromatase inhibitors contributes to an increased prevalence of periodontitis. OBJECTIVE: In this study, we assessed effects of the aromatase inhibitor anastrozole on cellular function of human gingival fibroblasts (HGFs) and endothelial cells. METHODS: Expression levels of collagen, extracellular matrix (ECM) proteins, matrix metalloproteinases (MMPs), and tissue inhibitors of metalloproteinases (TIMPs) were examined in HGFs exposed to anastrozole. Furthermore, inflammatory responses in HGFs cultured with anastrozole were evaluated in the presence of Porphyromonas gingivalis lipopolysaccharide. We also evaluated the vascular permeability and vascular endothelial (VE)-cadherin expression of endothelial cells exposed to anastrozole. RESULTS: Anastrozole enhanced expression levels of collagen, ECM proteins, TIMPs, and inflammatory cytokines in HGFs, as well as vascular permeability of endothelial cells. In addition, anastrozole reduced expression levels of MMPs in HGFs and VE-cadherin in endothelial cells. CONCLUSION: These results suggest that anastrozole modulates various cellular functions in HGFs and endothelial cells.

Abemaciclib in combination with endocrine therapy for East Asian patients with HR+, HER2- advanced breast cancer: MONARCH 2 & 3 trials.

This post hoc analysis of MONARCH 2 and MONARCH 3 assesses the efficacy, safety, and pharmacokinetics (PK) of abemaciclib in combination with endocrine therapy (ET) in East Asian patients with hormone receptor positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer. MONARCH 2 and MONARCH 3 are global, randomized, double-blind, phase 3 studies of abemaciclib/placebo + fulvestrant and abemaciclib/placebo + nonsteroidal aromatase inhibitor (NSAI, anastrozole or letrozole), respectively. The East Asian population comprised 212 (31.7%) of the 669 intent-to-treat (ITT) population in the MONARCH 2 trial and 144 (29.2%) of the 493 ITT patients in the MONARCH 3 trial. In the East Asian population, median progression-free survival (PFS) was significantly prolonged in the abemaciclib arm compared with placebo in both MONARCH 2 (hazard ratio [HR], 0.520; 95% confidence interval [CI], 0.362 to 0.747; P < .001; median: 21.2 vs 11.6 months) and MONARCH 3 (HR, 0.326; 95% CI, 0.200 to 0.531, P < .001; median: not reached vs 12.82 months). Diarrhea (MONARCH 2: 90%; MONARCH 3: 88%) and neutropenia (MONARCH 2: 68%; MONARCH 3: 58%) were the most frequent adverse events observed in the East Asian populations. Abemaciclib exposures and PK were similar in East Asians and the non-East Asian populations of both trials. Abemaciclib in combination with ET in the East Asian populations of MONARCH 2 and MONARCH 3 provided consistent results with the ITT populations, demonstrating improvements in efficacy with generally tolerable safety profiles for patients with HR+, HER2- advanced breast cancer.

Phase 2 study of anastrozole in patients with estrogen receptor/progesterone receptor positive recurrent low-grade endometrial stromal sarcomas: The PARAGON trial (ANZGOG 0903).

BACKGROUND: Aromatase inhibitors are standard of care for low-grade endometrial stromal sarcomas (LGESS), based on very high response rates reported in retrospective studies. We evaluated the activity of anastrozole in recurrent/metastatic LGESS patients enrolled in PARAGON, a basket trial of anastrozole in estrogen receptor (ER±)/progesterone receptor (PR+) gynecological cancers. METHOD: An investigator-initiated, single-arm, prospective open-label trial of anastrozole 1 mg/day in patients with ER ± PR + ve LGESS with measurable disease, treated until progressive disease or unacceptable toxicity. Primary endpoint was clinical benefit (complete/partial response + stable disease) rate (CBR) at 3 months. Secondary endpoints include progression-free survival (PFS), quality of life and toxicity. RESULTS: 15 eligible patients were enrolled. CBR at 3 months was 73% (95% CI: 48-89.1%); unchanged at 6 months. Best response was 26.7%, including complete response in one (6.7%; 95% CI 1.2-29.8%), partial response in three (20%, 95% CI 7.1-45.2%) and stable disease in seven (46.7%). Four patients ceased treatment by 3 months due to progression. Median PFS was not reached (25th percentile: 2.9 months (95% CI: 1.2-NR)). PFS was 73.3%, 73.3% and 66% at 6, 12, and 18 months, respectively. Six patients remained on treatment for an average of 44.2 months (range 34.5-63.6) up until data cut. Toxicity was as expected, with 3 patients stopping due to adverse effects. CONCLUSION: The 26.7% objective response rate with anastrozole is lower than reported in retrospective series, but the CBR was high and durable. The results underscore the importance of prospective trials in rare cancers.

Switching of Hormone Therapies in Breast Cancer Women.

OBJECTIVE: The objective of the present study was to analyze the reasons that led to hormone therapies (HTs) regimen changes in women with breast cancer. METHODS: This was a retrospective cross-sectional study from a single-institution Brazilian cancer center with patient records diagnosed with breast cancer between January 2012 and January 2017. RESULTS: From 1,555 women who were in treatment with HT, 213 (13.7%) women had HT switched, either tamoxifen to anastrozole or vice-versa. Most women included in the present study who switched HT were > 50 years old, postmenopausal, Caucasian, and had at least one comorbidity. From the group with therapy change, 'disease progression' was reason of change in 124 (58.2%) cases, and in 65 (30.5%) patients, 'presence of side effects' was the reason. From those women who suffered with side effects, 24 (36.9%) had comorbidities. CONCLUSION: The present study demonstrated a low rate of HT switch of tamoxifen to anastrozole. Among the reasons for changing therapy, the most common was disease progression, which includes cancer recurrence, metastasis or increased tumor. Side effects were second; furthermore, age and comorbidities are risk factors for side effects.

OBJETIVO: O objetivo do presente estudo foi analisar os motivos que levaram às mudanças no esquema hormonioterápico (HT) em mulheres com câncer de mama. MéTODOS: Estudo transversal retrospectivo realizado no Hospital da Mulher de Campinas e consequente pesquisa de prontuários de mulheres diagnosticados com câncer de mama entre janeiro de 2012 e janeiro de 2017. RESULTADOS: De 1.555 mulheres em tratamento com HT, 213 (13,7%) mulheres tiveram HT alterado, tamoxifeno para anastrozol ou vice-versa. A maioria das mulheres incluídas no presente estudo que tiveram mudança de HT tinha > 50 anos, estava na pós-menopausa, era caucasiana e tinha pelo menos uma comorbidade. Os principais motivos de troca de HT foram devido a 'progressão da doença', ocorrendo em 124 (58,2%) casos e a 'presença de efeitos colaterais' (n = 65; 30,5%). Das mulheres que sofreram efeitos colaterais, 24 (36,9%) apresentaram comorbidades. CONCLUSãO: O presente estudo demonstrou uma baixa taxa na alteração de tamoxifeno para anastrozol. Entre as razões mais comuns para alterar a HT estava a progressão da doença, que inclui recorrência do câncer, metástase ou aumento do tumor. Os efeitos colaterais foram a segunda causa e, além disso, a idade e as comorbidades foram fatores de risco para efeitos colaterais.

Off-treatment bone mineral density changes in postmenopausal women receiving anastrozole for 5 years: 7-year results from the IBIS-II prevention trial.

BACKGROUND: Anastrozole has been associated with substantial accelerated bone mineral density (BMD) loss during active treatment. METHODS: One thousand four hundred and ten women were included in a BMD substudy and stratified into three strata according to their baseline T-score at spine or femoral neck. The primary objective of this analysis was to investigate whether DXA BMD at the spine and hip changed two years after treatment cessation (between years 5 and 7) in those who did not receive risedronate. RESULTS: Five- and seven-year BMD data were available for a total of 528 women who did not receive risedronate. In women with normal BMD at baseline, an increase in BMD at the lumbar spine after anastrozole withdrawal was observed 1.25% (95% CI 0.73 to 1.77) (P = 0.0004), which was larger than in those on placebo (0.14% (-0.29 to 0.56))). At the hip, BMD remained unchanged between years 5 and 7 for those previously on anastrozole but continued to a decrease in those who had been randomised to placebo (-1.35% (-1.70 to -0.98)). CONCLUSIONS: These are the first results reporting BMD changes after stopping anastrozole in a breast cancer prevention setting. Our results show that the negative effects of anastrozole on BMD in the preventive setting are partially reversible.

Single-nucleotide polymorphism biomarkers of adjuvant anastrozole-induced estrogen suppression in early breast cancer.

OBJECTIVES: Based on our previous findings that postmenopausal women with estrone (E1) and estradiol (E2) concentrations at or above 1.3 pg/ml and 0.5 pg/ml, respectively, after 6 months of adjuvant anastrozole therapy had a three-fold risk of recurrence, we aimed to identify a single-nucleotide polymorphism (SNP)-based model that would predict elevated E1 and E2 and then validate it in an independent dataset. PATIENTS AND METHODS: The test set consisted of 322 women from the M3 study and the validation set consisted of 152 patients from MA.27. All patients were treated with adjuvant anastrozole, had on-anastrozole E1 and E2 concentrations and genome-wide genotyping. RESULTS: SNPs were identified from the M3 genome-wide association study. The best model to predict the E1-E2 phenotype with high balanced accuracy was a support vector machine model using clinical factors plus 46 SNPs. We did not have an independent cohort that is similar to the M3 study with clinical, E1-E2 phenotypes and genotype data to test our model. Hence, we chose a nested matched case-control cohort (MA.27 study) for testing. Our E1-E2 model was not validated but we found the MA.27 validation cohort was both clinically and genomically different. CONCLUSIONS: We identified a SNP-based model that had excellent performance characteristics for predicting the phenotype of elevated E1 and E2 in women treated with anastrozole. This model was not validated in an independent dataset but that dataset was clinically and genomically substantially different. The model will need validation in a prospective study.

Changes in serum estradiol levels with Estring in postmenopausal women with breast cancer treated with aromatase inhibitors.

BACKGROUND: Anti-estrogen therapy is an effective intervention for preventing reoccurrence of hormone receptor-positive breast cancer in women. However, the side effects of anti-estrogen therapy, including urogenital symptoms, have been reported to cause significant morbidity. There is controversial data, mainly due to small sample sizes, reporting on the safety and efficacy of using vaginal estrogen to treat urogenital symptoms in patients on aromatase inhibitor therapy. METHODS: We proposed a prospective trial to measure the change in blood estradiol levels in postmenopausal women with hormone receptor-positive breast cancer undergoing treatment with aromatase inhibitors when treated with vaginal estrogen preparation, Estring, for their urogenital symptoms. Only 8 prospective patients were enrolled, and the study was amended to include 6 retrospective patients who were treated similarly. Blood estradiol levels were measured at baseline and at week 16 for all patients. RESULTS: The median age for all patients was 55 years, and the majority of them were treated with anastrozole. There was no significant difference between baseline and week 16 estradiol levels (p = 0.81). In addition, patients in the prospective group reported subjective improvement in their vaginal dryness symptoms questionnaires. CONCLUSIONS: The vaginal estrogen preparation, Estring, did not cause persistent elevations in serum estradiol levels and might be a safer option for women with significant urogenital symptoms requiring estrogen therapy. IMPLICATIONS FOR CANCER SURVIVORS: Vaginal estrogen preparation, Estring, might be an option for women with hormone receptor positive breast cancer who have persistent urogenital symptoms.