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Prevalence of testosterone deficiency is increasing in the adolescent and young adult male population. As the average paternal age rises, there is a significant population of men with hypogonadism seeking testosterone therapy wishing to achieve or maintain fertility potential. Identification of potential lifestyle modifications that may improve the testosterone deficiency is one of the initial interventions of the holistic strategy in treatment. This is followed by drug therapy; however, traditional testosterone therapy acts as a contraceptive by suppressing the hypothalamus-pituitary-gonadal (HPG) axis and therefore cannot be used as a treatment strategy. A solution has been the off-label use of selective estrogen receptor modulators, human chorionic gonadotropin (hCG), and anastrozole inhibitors to treat hypogonadal symptoms while increasing intratesticular testosterone, a necessity for spermatogenesis. Recently, a novel therapy, Natesto intranasal testosterone gel, has been shown to increase serum testosterone levels while maintaining semen parameters. This is hypothesized to be because of its short-acting properties having lesser effect on the HPG axis, in contrast to the long-acting properties of traditional testosterone therapy. It is important to differentiate hypogonadal men between those seeking to achieve or maintain fertility status because the drug therapy of choice differs. This can be accomplished by determining the levels of 17-hydroxyprogesterone (17-OHP), because it is a biomarker for intratesticular testosterone. Those with low 17-OHP may wish to initiate treatment with alternative therapies, whereas those with high 17-OHP may trial short-acting testosterone therapies. As the urologist's armamentarium continues to increase, better strategies to increase testosterone levels in men seeking fertility can be achieved.

In spite of their rarity when considered individually, the sum of all rare ovarian tumours (ROT) represent almost half of all ovarian malignancies. As such, their appropriate inclusion within dedicated clinical trials is essential for enhanced management.Supported by institutional expert national (e.g. TMRG) and international (e.g. ESGO) networks and owing to national (e.g. ARCAGY-GINECO) and international (e.g. ENGOT) collaborations dedicated to clinical research, the last few years have shown increased number of clinical trials dedicated to ROT. These either were based on specific molecular features of ROT (e.g. expression of oestrogen receptors for low-grade serous ovarian carcinomas and anastrazole evaluation in the PARAGON trial) or on the evaluation of innovative therapies (e.g. pembrolizumab within the ROT cohort from the AcSé Pembrolizumab multicentric basket trial). Furthermore, recent years have also shown the advent of randomized clinical trials. For instance, the ALIENOR trial positioned weekly paclitaxel as a new option for relapsed sex cord-stromal tumours, while the GOG281/LOGS trial raised trametinib as a new standard-of-care option for recurrent low-grade serous carcinomas.The last few years have exhibited a paradigm shift towards the possibility to develop dedicated trials for ROT, owing to international collaborations supported by institutional networks. Current trials, molecular-driven and based on innovative designs, are highly promising, as they may bring ROT management towards more personalized medicine.

We aimed to investigate the impact of anastrozole administration on the traditional components of the lipid profile (ie, total cholesterol [TC], LDL-C, HDL-C, and triglycerides [TGs]) by means of a systematic review and meta-analysis of randomized controlled trials.We searched the PubMed/Medline, Scopus, Embase, and Web of Science databases for relevant randomized controlled trials published in the English language until January 18, 2022. The weighted mean difference (WMD) and 95% CIs were calculated using a random-effects model (DerSimonian and Laird methods).Anastrozole administration significantly lowered TC concentrations when the treatment duration was ≤3 months (WMD = -2.73 mg/dL; 95% CI, -5.09 to -0.38 mg/dL; P = 0.02) and when the baseline TC concentration was ≥200 mg/dL (WMD = -3.64 mg/dL; 95% CI, -6.30 to -0.98 mg/dL; P = 0.007). HDL-C levels decreased after anastrozole administration when the treatment duration was3 months (WMD = -1.67 mg/dL; 95% CI, -3.24 to -0.10 mg/dL; P = 0.03). Anastrozole administration had no impact on TG or LDL-C values.Anastrozole administration in humans can decrease TC and HDL-C levels but has no effect on LDL-C or TG concentrations.

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.

(1) Background: This study aimed to conduct a NMA and CEA combined study to compare the effectiveness and cost-effectiveness of different CDK4/6 inhibitors (Abem, Palbo, and Ribo) plus NSAI with placebo plus NSAI in the first-line treatment of postmenopausal women with HR+/HER2− ABC from the perspective of payers in China. (2) Methods: Studies which evaluated CDK4/6 inhibitors plus NSAI for HR+/HER2− ABC were searched. A Bayesian NMA was carried out and the main outcomes were the hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS). The costs and efficacy of first-line therapies for HR+/HER2− ABC were evaluated using the Markov model. The main outcomes in the CEA were incremental cost–utility ratios (ICURs), incremental monetary benefit (INMB), and incremental net-health benefit (INHB). The robustness of the model was assessed by one-way, three-way, and probabilistic sensitivity analyses. Then, we further simulated the impact of different prices of CDK4/6 inhibitors on the results. (3) Results: Seven studies involving 5347 patients were included in the NMA. The three first-line CDK4/6 inhibitors plus NSAI groups provided significant PFS and OS superiority to NSAI alone. Abem + NSAI represented a significant statistical advantage onPFS (HR 0.74, 95% CI 0.61–0.90, p = 0.009) and indicated a trend of being the best OS benefit compared to the placebo + NSAI group (HR 0.89, 95% CI 0.72–1.08). The Abem + NSAI, Palbo + NSAI, and Ribo + NSAI groups resulted in additional costs of $12,602, $20,391, and $81,258, with additional effects of 0.38, 0.31, and 0.30 QALYs, respectively, leading to an ICUR of $33,163/QALY, $65,777/QALY, and $270,860/QALY. Additional pairwise comparisons showed that Abem + NSAI was the only cost-effective option in three CDK4/6 inhibitors plus NSAI groups at a willingness-to-pay (WTP) of $38,029/QALY. The sensitivity analyses showed that the proportion of receiving subsequent CDK4/6 inhibitors and the cost of Abem significantly influenced the results of Abem + NSAI compared with placebo + NSAI. (4) Conclusion: From the perspective of Chinese payers, Abem + NSAI was a cost-effective treatment option compared with placebo + NSAI at the WTP of $38,029/QALY, since only the ICUR of $33,163/QALY of Abem + NSAI was lower than the WTP of $38,029/QALY in China (2022). The Palbo + NSAI and Ribo + NSAI groups were not cost-effective unless drug prices were adjusted to 50% or 10% of current prices ($320.67 per cycle or $264.60 per cycle). (5) Others: We have prospectively registered the study with the PROSPERO, and the PROSPERO registration number is CRD42023399342.

Background: Estrogen receptor-positive (ER+) breast cancer is the most diagnosed subtype, with aromatase inhibitors (AIs) being one of the therapeutic drug types used in the clinic. However, endocrine resistance may develop after prolonged treatment, and different approaches, such as combining endocrine and targeted therapies, have been applied. Recently, we demonstrated that cannabidiol (CBD) induces anti-tumor actions in ER+ breast cancer cells by targeting aromatase and ERs. Considering this, we studied, in vitro, whether CBD when combined with AIs could improve their effectiveness. Methods: MCF-7aro cells were used and the effects on cell viability and on the modulation of specific targets were investigated. Results: CBD when combined with anastrozole (Ana) and letrozole (Let) caused no beneficial effect in comparison to the isolated AIs. In contrast, when combined with the AI exemestane (Exe), CBD potentiated its pro-cell death effects, abolished its estrogen-like effect, impaired ERα activation, and prevented its oncogenic role on the androgen receptor (AR). Moreover, this combination inhibited ERK1/2 activation, promoting apoptosis. The study of the hormonal microenvironment suggests that this combination should not be applied in early stages of ER+ breast tumors. Conclusions: Contrary to Ana and Let, this study highlights the potential benefits of combining CBD with Exe to improve breast cancer treatment and opens up the possibility of new therapeutic approaches comprising the use of cannabinoids.

In the revised diagnostic classification systems ICD-11 and DSM-5, secondary, organic forms of obsessive-compulsive disorder (OCD) are implemented as specific nosological entities. Therefore, the aim of this study was to clarify whether a comprehensive screening approach, such as the Freiburg-Diagnostic-Protocol for patients with OCD (FDP-OCD), is beneficial for detecting organic OCD forms. The FDP-OCD includes advanced laboratory tests, an expanded magnetic resonance imaging (MRI) protocol, and electroencephalography (EEG) investigations as well as automated MRI and EEG analyses. Cerebrospinal fluid (CSF), [18F]fluorodeoxyglucose positron emission tomography, and genetic analysis were added for patients with suspected organic OCD. The diagnostic findings of the first 61 consecutive OCD inpatients (32 female and 29 male; mean age: 32.7 ± 12.05 years) analyzed using our protocol were investigated. A probable organic cause was assumed in five patients (8%), which included three patients with autoimmune OCD (one patient with neurolupus and two with specific novel neuronal antibodies in CSF) and two patients with newly diagnosed genetic syndromes (both with matching MRI alterations). In another five patients (8%), possible organic OCD was detected (three autoimmune cases and two genetic cases). Immunological serum abnormalities were identified in the entire patient group, particularly with high rates of decreased “neurovitamin” levels (suboptimal vitamin D in 75% and folic acid in 21%) and increased streptococcal (in 46%) and antinuclear antibodies (ANAs; in 36%). In summary, the FDP-OCD screening led to the detection of probable or possible organic OCD forms in 16% of the patients with mostly autoimmune forms of OCD. The frequent presence of systemic autoantibodies such as ANAs further support the possible influence of autoimmune processes in subgroups of patients with OCD. Further research is needed to identify the prevalence of organic OCD forms and its treatment options.

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/m

Anastrozole (ANA), is an inhibitor of non-steroidal aromatase, widely employed for the treatment of breast cancer. However, ANA-associated liver injury cases have been documented in the application of the drug.The major purposes of the present study were to identify the structure of reactive metabolites derived from ANA and to study related metabolic pathways of ANA.We found ANA itself is an electrophilic species reactive to GSH. ANA can be metabolised to ANA

Molecular tests predicting the risk of distant recurrence (DR) can be used to assist therapy decision-making in oestrogen receptor-positive (ER+) and human epidermal growth factor receptor 2-negative (HER2-) breast cancer patients after considerations of standard clinical markers. The Oncotype DX Recurrence Score (RS) is a widespread tool used for this purpose. Here, we compared the RS with the StemPrintER Risk Score (SPRS), a novel genomic predictor with a unique biological basis in its ability to measure the expression of cancer stemness genes.We benchmarked the SPRS vs. RS, alone or in combination with clinicopathological variables expressed by the Clinical Treatment Score (CTS), for the prognostication of DR in a retrospective cohort of 776 postmenopausal patients with ER+/HER2-breast cancer enrolled in the translational arm of the randomised Arimidex, Tamoxifen, Alone or in Combination (ATAC) trial. Likelihood ratio (LR) with χIn all patients, the SPRS provided significantly more prognostic information than the RS for ten-year DR prognostication (C-index = 0.688, LR-χIn postmenopausal ER+/HER2- breast cancer patients, SPRS provided more prognostic information than RS for DR when used alone or in combination with the CTS. The SPRS could therefore potentially identify high-risk patients, who might benefit from aggressive treatments, from low-risk patients who might safely avoid adjuvant chemotherapy or prolongation of endocrine therapy.

Background:: Anastrozole (ATZ) is a selective non-steroidal inhibitor widely used for the treatment of breast cancer in post-menopausal women. ATZ exerts its biological activity by inhibiting the enzyme aromatase, which is responsible for converting androgens to estrogens. Piperine (PIP), a natural alkaloid and the main component of black pepper, is used as a bioenhancer and for combating a variety of health issues ranging from upset stomach to dental problems. Introduction: ATZ has been reported to have poor water solubility and less bioavailability. The novel combination of ATZ and PIP was proposed to enhance the bioavailability of both the compounds. However, there are no reported studies on the simultaneous estimation of ATZ and PIP as well as stability studies to explore their potential interactions and degradation profiling. Method: A simple, accurate, precise, robust, sensitive, reliable, and economic analytical method for the simultaneous estimation of ATZ and PIP was developed using acetonitrile and water (60:40) as the mobile phase. Forced degradation studies and characterization of degradants were performed, and degradants were identified for molecular weight using LC-QTOF-ESI-MS; the structures of degradants were confirmed with mass accuracy measurements. The mechanism of each degradant has also been described in more detail in the manuscript. Result: A total of fourteen degradants were characterized. ATZ and PIP have shown synergistic anticancer effects in the 4T1 cell line and shown superior Pharmacokinetic and biodistribution with good oral absorption and high bioavailability. Results and Conclusion: A total of fourteen degradants were characterized and reported for their good human oral absorption. A precise, robust, accurate, cheap, and sensitive RP-HPLC-DAD simultaneous method for the estimation of ATZ and PIP has been developed. From the future point of view, there is huge scope to conduct pharmacological, pharmacodynamic, and drug-herb interaction studies based on this fruitful outcome. All the degradants may be screened against MDR-resistant breast cancer in the future to check their potential as a drug target.

Background: Short children face many problems throughout their lives. Consumption of growth hormone and the drugs such as Letrozole, Oxandrolone, and Anastrozole can increase the growth of children and adolescents. There is not an overall estimate of the effects of Letrozole, Oxandrolone, and Anastrozole on the growth of children and adolescents with Idiopathic Short Stature (ISS). There are different estimates of the effect of growth hormone and the drugs Letrozole, Oxandrolone, and Anastrozole on growth in children and adolescents with Idiopathic Short Stature. Therefore, the aim of this study was to compare the efficacy of growth hormone, Letrozole, Oxandrolone, Anastrozole, and a combination of growth hormone and aromatase inhibitors on height gain in children and adolescents with idiopathic short stature using meta-analysis method. Methods: Search was done in databases such as; Scopus, Web of Science(ISI), and PubMed using keywords: Idiopathic, Short Stature, Body Height, Aromatase Inhibitors, Growth hormone, Letrozole, Oxandrolone, Anastrozole. Randomized clinical trial studies ,that have investigated the efficacy of growth hormone and aromatase inhibitors on height gain in children and adolescents with short stature, were selected. Height standard deviation score (HSDS) before intervention and after treatment has been used to measure the rate of height increase in various studies. This study was written based on the PRISMA checklist and the heterogeneity of this study was evaluated using the Q statistic and I2 index. Results: Height increase index (HSDS) was obtained with the use of growth hormone combined with one of the aromatase inhibitors (0.38-3.58=95%CI) (SMD=0.98), with the use of growth hormone (0.62-1.14=95%CI) (SMD=0.88), with the use of Letrozole (0.51-16.51=95%CI) (SMD=0.83), with the use of Oxandrolone (0.99-0.99=95%CI) (SMD=0.56), and with the use of Anastrozole (0.00-0.63=95%CI) (SMD=0.31), which shows that all these drugs have a significant effect on height increase. (P

Purpose: Metastatic hormone receptor (HR)-positive, HER2-negative breast cancer is an important cause of cancer mortality. Endocrine treatment with or without additional targeted therapies has been the mainstay of treatment. This trial was designed to evaluate the combination of fulvestrant plus everolimus versus fulvestrant, everolimus, and anastrozole compared with fulvestrant alone in the first-line treatment of advanced HR-positive, HER2-negative breast cancer. Patients and Methods: This randomized placebo-controlled trial included postmenopausal women with HR-positive, HER2-negative advanced breast cancer who had received no prior systemic therapy for metastatic disease. Participants were randomized to one of three treatment arms and the primary outcome was progression-free survival (PFS), comparing combinations of fulvestrant and everolimus with or without anastrozole with fulvestrant alone. Circulating tumor cells (CTC), as measured with two different methods, and circulating tumor DNA (ctDNA) were evaluated serially prior to treatment and the beginning of the second cycle of therapy. Results: Due in part to changes in clinical practice, the study was closed after accruing only 37 participants. There was no evidence that everolimus-containing combination treatment improved PFS or overall survival relative to fulvestrant alone. When modeled continuously, an association was observed of baseline CTC and ctDNA with poorer survival. Conclusions: Although power of the study was limited, the findings were unable to support the routine use of everolimus combination endocrine therapy in the first-line treatment of advanced hormone-sensitive breast cancer. Prognostic impact of baseline ctDNA and copy-number variations in CTC was demonstrated.

Chemotherapy is often difficult to treat human epidermal growth factor receptor 2 (HER2)-positive metastatic recurrent breast cancer in the elderly, and no standard treatment has been established at this point. We experienced a case in which trastuzumab (Tmab) + anastrozole (ANA) was ineffective (progressive disease; PD) in elderly HER2-positive breast cancer with postoperative multiple liver metastases, but T-DM1 was significantly effective (complete response; CR), and treatment could be continued safely. An 82-year-old woman was referred to our department with a right breast mass. A close examination revealed right breast cancer cT1bN0M0 cStage I, and total mastectomy and sentinel lymph node biopsy were performed. The postoperative pathological result was pT1bN0M0 pStage I (luminal HER2 type). The patient was elderly and had no adjuvant treatment after the operation. Approximately 2 years after the operation, multiple liver metastases were observed, and treatment with ANA and Tmab was started. Four months later, MRI showed that the number of multiple liver metastases increased. The patient was diagnosed with PD, and the anti-HER2 drug was changed from trastuzumab to trastuzumab emtansine (T-DM1). The dose was reduced due to vomiting (grade 3). Two months later, MRI showed that the multiple liver metastases shrank and became obscure after 5 months. After that, T-DM1 was continued, and the disease did not worsen. In elderly people with difficulty in administering chemotherapy, T-DM1 may have a safe and sufficient therapeutic effect by adjusting the dose and managing side effects appropriately.

Purpose: In this study, a novel D-α-tocopheryl polyethylene glycol succinate (TPGS) modified bovine serum albumin (BSA) nanoparticles (NPs) were developed for delivery of Anastrozole (ANZ) which is optimized by Box-Behnken design (BBD). Fabricated TPGS-ANZ-BSA NPs were evaluated for their physicochemical and drug release characteristics. Methods: TPGS-ANZ-BSA NPs were prepared by desolvation thermal gelation method and the effects of critical process parameter (CPP) which are BSA amount, TPGS concentration and stirring speed on the critical quality attributes (CQA) such as % drug loading (%DL) and particle size were studied using BBD. TPGS-ANZ-BSA NPs were characterized using different spectroscopic techniques including UV-Visible and FTIR is used to confirm the entrapment of ANZ in BSA. DSC and PXRD revealed the amorphization of ANZ in the TPGS-ANZ-BSA NPs after freeze drying. Scanning electron microscopy (SEM) analysis was performed for the surface morphology analyses NPs. In vitro release studies were performed at pH 5.5 and pH 7.4 for 48h to mimic tumour microenvironment. Results: The BBD optimized TPGS-ANZ-BSA NPs showed 107 nm particle size with %DL 8.5± 0.5%. The spectroscopic and thermal characterizations revealed the successful encapsulation of ANZ inside the NPs. The TPGS-ANZ-BSA NPs were found to exhibit burst release at pH 5.5 and sustained release at pH 7.4. The short-term stability displayed no significant changes in physical properties TPGS-ANZ-BSA NPs at room temperature for a period one month. Conclusion: The BBD optimized TPGS-ANZ-BSA nanoparticles showed enhanced physiochemical properties for ANZ and potential candidates for anticancer agent drugs delivery.

Background Hormonal therapies are commonly prescribed to patients with metastatic granulosa cell tumours (GCT), based on high response rates in small retrospective studies. Aromatase inhibitors (AIs) are reported to have high response rates and an accepted treatment option. We report the results of a phase 2 trial of an AI in recurrent/metastatic GCTs. Methods 41 patients with recurrent ER/PR + ve GCT received anastrozole 1 mg daily until progression or unacceptable toxicity. The primary endpoint was clinical benefit rate (CBR) at 12 weeks, evaluated by RECIST1.1 criteria. Secondary endpoints included progression-free survival (PFS), CBR duration, quality of life and toxicity. Results The CBR at 12 weeks in 38 evaluable patients was 78.9%, which included one (2.6%; 95% CI: 0.5–13.5%) partial response and 76.3% stable disease. Two additional patients without measurable disease were stable, based on inhibin. Median PFS was 8.6 m (95% CI 5.5–13.5 m). There were delayed responses observed after 12 weeks with a total of 4 pts. (10.5%; 95% CI 4.2%–24.1%) with a RECIST partial response; 23 (59%) patients were progression-free at 6 months. The adverse effects were predominantly low grade. Conclusions This is the first prospective trial of hormonal therapy in GCTs. Although there was a high CBR, the objective response rate to anastrozole was much lower than the pooled response rates of >70% to AIs reported in most retrospective series and case reports. PARAGON demonstrates the importance of prospective trials in rare cancers and the need to reconsider the role of AIs as single agents in GCTs.

This study evaluated the risk of major bleeding associated with concomitant use of direct oral anticoagulant (DOAC) and anticancer drugs (ACDs), which share metabolic pathways, in patients with atrial fibrillation (AF) and cancer. We performed a retrospective cohort study using Taiwan’s National Health Insurance database and included patients with AF and cancer who received DOAC prescriptions from 1 to 2012 to 31 December 2017. The incidence of major bleeding in person-quarters with concomitant use of DOAC and any of 15 ACDs with inhibitory or competitive effects of CYP3A4 or P-gp activity (docetaxel, vinorelbine, methotrexate, irinotecan, etoposide, doxorubicin, cyclophosphamide, imatinib, nilotinib, abiraterone, bicalutamide, tamoxifen, anastrozole, cyclosporine, tacrolimus) was compared with that in person-quarters with DOAC alone. Adjusted incidence-rate differences between DOAC use with and without concurrent ACDs were estimated using Poisson regression models weighted by the inverse probability of treatment. In 13,158 patients with AF and cancer (76.9 ± 8.9 years; male 60%), 1545 major bleeding events occurred during 90,540 DOAC-exposed person-quarters. Concurrent use of DOAC and any of 15 ACDs occurred in only 18% of patients. Compared with use of DOAC alone, concomitant use of DOAC and these ACDs was not associated with an increased risk of major bleeding. Co-medication with DOAC and ACDs with inhibitory or competitive effects on CYP3A4 or P-gp activity was not associated with a higher risk of major bleeding than DOAC alone. Our findings may provide clinicians with confidence regarding the safety of concurrent use of DOAC and ACDs in patients with AF and cancer.

A 49-year-old woman presented with abdominal pain. A computed tomography scan revealed a left breast mass with suspected peritoneal dissemination. She had no notable family history of the disease. Following a detailed examination, she was diagnosed with ovarian cancer(Stage ⅢC)and left breast cancer(Stage Ⅰ). After confirming the diagnosis of ovarian cancer with a laparoscopic biopsy, neoadjuvant chemotherapy was scheduled. Due to its efficiency in reducing tumor burden, debulking surgery was also performed. While receiving adjuvant chemotherapy for ovarian cancer, concomitant anastrozole was administered for breast cancer. A pathogenic variant of BRCA2 was subsequently identified. Once adjuvant chemotherapy for ovarian cancer had been completed, a left mastectomy and sentinel lymph node biopsy were performed as management for breast cancer. The patient will continue treatment with anastrozole for breast cancer and olaparib for ovarian cancer and will be followed up appropriately.

various operating parameters, such as current density (6.25 and 12.5 mA cm−2), pH (3–10), ANZ concentration (0.5–2 mg L−1), nature of supporting electrolytes, water composition, and water matrix, have been evaluated. ANZ removal of 82.4% was achieved at 1 mg L−1initial concentration after 90 min of reaction at 6.25 mA cm−2and 0.1 M Na2SO4. The degradation follows pseudo-first-order kinetics with the apparent rate constant, kapp, equal to 0.022 min−1. The kappincreases with increasing current density and decreasing solution pH. The addition of chloride in the range 0–250 mg L−1positively affects the removal of ANZ. However, chloride concentrations above 250 mg L−1have a detrimental effect. The presence of bicarbonate or organic matter has a slightly negative but not significant effect on the process. The EO of ANZ is compared to its degradation by solar photo-Fenton, and a preliminary economic analysis is also performed.

For postmenopausal women with hormone-receptor-positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear.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.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).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.).

Leptomeningeal carcinomatosis (LC) is defined as infiltration of the leptomeninges by metastatic carcinoma and often represents the end stage of cancer disease. In breast cancer, LC is associated with a median survival of approximately 6-8 weeks without specific treatment. It could increase by only few months with personalized treatment plans. Usually, the median time of onset of leptomeningeal spread is 18 months and it is diagnosed in up to 70% of patients with active and progressive systemic disease. We present an uncommon case of LC in a patient with history of breast cancer with a 10 year-disease-free condition and an overall survival after LC diagnosis of 10 months. Central Nervous System (CNS) Magnetic Resonance Imaging (MRI) showed contrast enhancement of medullary cone and cauda. Despite the negativity of cytological analysis of Cerebral-Spinal Fluid (CSF), the patient underwent meningeal and radicular biopsy in November 2019. The neuropathological examination confirmed the diagnosis of LC. The patient was started on the aromatase inhibitor anastrozole. A whole body contrast Computed Tomography (CT) scan at three months follow-up was negative for further disease dissemination. The patient is currently under oncological and radiological follow-up after more than 10 months from diagnosis. Although nowadays diagnosis of LC is prompted by cytological examination of CSF, its negativity should not halt the diagnostic process. In the presence of a high clinical suspicion of LC, we suggest the biopsy of lesion.

Objective To report the first case of secondary azoospermia after sleeve gastrectomy. Design Case report. Setting Academic male infertility clinic. Patient(s) A 33-year-old man with secondary azoospermia and primary testicular failure with testosterone deficiency after laparoscopic sleeve gastrectomy. Intervention(s) Hormonal therapy with anastrozole for 10 months and diagnostic testicular biopsy. Main Outcome Measure(s) Semen analyses and testicular histopathology. Result(s) Non-obstructive azoospermia persisted at 20 months after surgery despite hormonal therapy with anastrozole. Testicular histopathology revealed the presence of Sertoli cells only. Conclusion(s) Although further research is need to determine the relationship between sleeve gastrectomy and secondary infertility, men should be informed of the potentially deleterious effects of this surgery on semen parameters.

Zerko Wako,1 Daniel Mengistu,2 Negalign Getahun Dinegde,2 Tseganesh Asefa,1 Mulugeta Wassie1 1Department of Medical Nursing, School of Nursing, College of Medicine and Health Science, University of Gondar, Gondar, Ethiopia; 2School of Nursing and Midwifery, College of Health Science, Addis Ababa University, Addis Ababa, EthiopiaCorrespondence: Zerko Wako Tel +251918728268Email zerkowako1992@gmail.comBackground: In breast cancer patients, adherence to adjuvant hormone therapy (AHT) is uncertain. Seven in every 10 patients were hormone receptor positive and adjuvant hormone therapy (AHT) is prescribed for 5– 10 years for a woman with breast cancer. Therefore, the aim of this research was to examine adherence to adjuvant hormone therapy and related factors among women with breast cancer attending the Tikur Anbessa Specialized Hospital Oncology Center.Methods: An institutional-based cross-sectional study was conducted from March to April, 2019. Systematic random sampling technique was used to select participants. A semi-structured questionnaire was used. Medication possession ratio (MPR) was used where score ≥ 80% was adherence. Data were entered in EpiData version 4.4.2.1 and transferred to SPSS version 25, and analyzed using binary logistic regression.Results: Out of 216 women with breast cancer 209 participated in the study with a response rate of 97%. The overall adherence in this study was 77.5%. Getting social support (OR=3.959, 95%CI: 1.570– 9.980), being on anastrozole (OR=0.139, 95%CI: 0.040– 0.485), getting a thorough therapeutic communication about treatment (OR=4.590, 95%CI: 1.061– 19.863), undergoing mastectomy (OR=0.215, 95%CI: 0.059– 0.788), having side effects (OR=0.210, 95%CI: 0.085– 0.517) were found to be significantly associated with adherence to AHT.Conclusion: In general, the overall adherence to AHT was 77.5% for women with breast cancer. Factors such as types of adjuvant hormone therapy, lack of side effects, mastectomy, getting social support, and thorough therapeutic communication were strongly linked with adherence to them.Keywords: adherence, adjuvant hormone therapy, breast cancer, Ethiopia

Trastuzumab and lapatinib are drugs belonging to tyrosine kinase inhibitors family that are used in cancer treatment to prevent cell proliferation. Trastuzumab is an inhibitor of human epidermal growth factor receptor–2 (HER2) tyrosine kinase, and lapatinib is an inhibitor of epidermal growth factor receptor (EGFR). Tyrosine kinase inhibitors have also been investigated for treatment of endometriosis. In the present study, we aimed to investigate the effects of lapatinib and trastuzumab on rat endometriosis model. Endometriosis was surgically induced by the autologous transplantation of endometrial tissue and formation of endometriosis was confirmed via secondary laparotomy in 32 rats. Initially, 4 mg/kg dose of trastuzumab was applied intraperitoneally, and two additional doses of 2 mg/kg were applied 7 days and 14 days after the initial dose. Lapatinib was administered as 100 mg/kg daily doses for 14 days. Rats were randomly divided into four groups and were subjected to lapatinib, trastuzumab, anastrozole (0.004 mg/day, p.o.) and normal saline (0.1 ml, i.p.) treatments for 14 days. Then, endometriosis foci were excised, and endometriosis scores were calculated in a semi-quantitative manner. Immunohistochemical (IHC) examinations were also performed using VEGF, CD117 and Bax antibodies. Both anastrozole and tyrosine kinase inhibitors lowered endometriosis scores. Significant decreases in ovarian follicle numbers were observed in lapatinib and anastrozole groups but not trastuzumab group. Lapatinib and trastuzumab decreased endometriotic foci through suppressing cell proliferation and promoting programmed cell death.

Graphene and its derivatives are frequently used in cancer therapy, and there has been widespread interest in improving the therapeutic efficiency of targeted drugs. In this paper, the geometrical structure and electronic effects of anastrozole(Anas), camptothecin(CPT), gefitinib (Gefi), and resveratrol (Res) on graphene and graphene oxide(GO) were investigated by density functional theory (DFT) calculations and molecular dynamics (MD) simulation. Meanwhile, we explored and compared the adsorption process between graphene/GO and four drug molecules, as well as the adsorption sites between carriers and payloads. In addition, we calculated the interaction forces between four drug molecules and graphene. We believe that this work will contribute to deepening the understanding of the loading behaviors of anticancer drugs onto nanomaterials and their interaction.

GnRH-independent precocious puberty (GIPP) can be the presenting clinical picture experienced by patients with secreting germ cell tumor (GCT). Indeed, as luteinizing hormone (LH) and human chorionic gonadotropin (hCG) share identical α-subunits and similar β-subunits, an increased secretion of β-hCG may result in a precocious activation of Leydig cells. Though the co-occurrence of raised β-hCG levels and signs of precocious virilization usually prompts a complete oncological work-up, the diagnostic and therapeutic management of GCT-induced GIPP may be challenging. We report the case of a 6.2 year-old boy presenting with clinical and biochemical findings consistent with GIPP (discrepancy between overt virilization and pre-pubertal testicular volume, suppressed gonadotropins and remarkably raised testosterone). Brain imaging detected a bilobed cyst of the pineal gland, while serum and cerebrospinal baseline assessment initially ruled out raised alpha-fetoprotein or β-hCG levels. Nevertheless, a strict biochemical follow-up highlighted a fluctuant trend of tumor markers, with a more aggressive behavior and recurrent erections occurring as a result of unpredictable phases of raised testosterone and serum/cerebrospinal β-hCG, followed by sudden spontaneous decrease. Accordingly, a secreting pineal GCT was suspected. Given the fluctuating trend of tumor markers, surgery was initially kept on hold and a combined treatment with bicalutamide (androgen receptor blocker) and anastrozole (aromatase inhibitor) was undertaken in order to prevent the patient from experiencing further virilization and excessive bone age maturation. Subsequently, a progression in the size of the pineal tumor prompted surgical resection and a diagnosis of secreting GCT was histologically confirmed. Accordingly, the patient was started on adjuvant chemo- and radiotherapy. Antineoplastic treatment was followed by persistent and remarkable decrease of tumor markers and by a complete pubertal arrest. We reported the challenging diagnosis of a secreting pineal GCT in a patient with GIPP and a fluctuating trend of tumor markers, testosterone levels and associated clinical signs, hence prompting the indication for a systematic assessment and a strict monitoring whenever a patient with GnRH-independent precocious puberty shows clinical or radiological markers potentially consistent with a GCT.

Pembrolizumab is a monoclonal antibody. Anastrozole is an infertility inhibitor of aromatase. Resveratrol is an antioxidant polyphenol in the reproductive system. This study was planned to demonstrate the protective effects of anastrozole and resveratrol against pembrolizumab-induced reproductive damage. Forty-two Sprague–Dawley rats were used in the study. Groups: The control, Pembrolizumab (PEMB), PEMB + Anastrazol (ANAST), PEMB + Resveratrol (RES), RES, and ANAST groups. At the end of the experiment, rats were euthanased under anaesthesia. Tissue samples were taken from rats for biochemical, histological, and ELISA evaluations. Tissues were subjected to routine tissue follow-up for histological analysis. Biochemically, thiobarbituric acid reactive substance (TBARS), glutathione (GSH), catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GSH-Px) levels were measured. Sperm motility, abnormal sperm rate, and epididymal sperm concentration were examined spermatologically. Serum testosterone and programmed cell death-1 (PD-1) levels were measured using the ELISA. TBARS levels were significantly increased and GSH, SOD, GPx, and CAT levels were mitigated in PEMB-treated rats. Histologically; Control, ANAST, and RES groups testis samples were observed with normal histological appearance. Histological damage was detected in seminiferous tubule structures in testicular tissue in the PEMB group. In treatment groups, this damage was decreased. In addition, PD-1 and testosterone levels were evaluated by the ELISA method. ANAST and RES have therapeutic effects against reproductive damage caused by PEMB. © 2022 Wiley-VCH GmbH.

Dysregulated brain cholesterol metabolism is one of the characteristics of Alzheimer’s disease (AD). 27-Hydroxycholesterol (27-OHC) is a cholesterol metabolite that plays an essential role in regulating cholesterol metabolism and it is suggested that it contributes to AD-related cognitive deficits. However, the link between 27-OHC and cholesterol homeostasis, and how this relationship relates to AD pathogenesis, remain elusive. Here, 12-month-old ApoE ε4 transgenic mice were injected with saline, 27-OHC, 27-OHC synthetase inhibitor (anastrozole, ANS), and 27-OHC+ANS for 21 consecutive days. C57BL/6J mice injected with saline were used as wild-type controls. The indicators of cholesterol metabolism, synaptic structure, amyloid β 1-42 (Aβ1-42), and learning and memory abilities were measured. Compared with the wild-type mice, ApoE ε4 mice had poor memory and dysregulated cholesterol metabolism. Additionally, damaged brain tissue and synaptic structure, cognitive decline, and higher Aβ1-42 levels were observed in the 27-OHC group. Moreover, cholesterol transport proteins such as ATP-binding cassette transporter A1 (ABCA1), apolipoprotein E (ApoE), low-density lipoprotein receptor (LDLR), and low-density lipoprotein receptor-related protein1 (LRP1) were up-regulated in the cortex after the 27-OHC treatment. The levels of cholesterol metabolism-related indicators in the hippocampus were not consistent with those in the cortex. Additionally, higher serum apolipoprotein A1 (ApoA1) levels and lower serum ApoE levels were observed in the 27-OHC group. Notably, ANS partially reversed the effects of 27-OHC. In conclusion, the altered cholesterol metabolism induced by 27-OHC was involved in Aβ1-42 deposition and abnormalities in both the brain tissue and synaptic structure, ultimately leading to memory loss in the ApoE ε4 transgenic mice.

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, Abemaciclib in combination with endocrine therapy (ET) in the East Asian populations of MONARCH 2 and MONARCH 3 improved efficacy for patients with HR+, HER2− advanced breast cancer.

The population pharmacokinetics (popPK) of ribociclib and population pharmacokinetic/pharmacodynamic (PK/PD) relationship between ribociclib and absolute neutrophil count (ANC) were characterized in patients with cancer. PopPK and ANC PK/PD modeling were both conducted in 2 rounds per data availability. Initial models were developed based on data sets from early-phase trials and qualified using external data from the phase III MONALEESA-2 trial. The second round of analyses was performed using updated data sets that included 2 more phase III trials (MONALEESA-3 and -7). The popPK and ANC PK/PD models adequately described the data and demonstrated reasonable predictive ability. Covariate analysis showed that ribociclib PK were not affected by age, sex, race, baseline Eastern Cooperative Oncology Group (ECOG) status (grade 1), mild/moderate renal impairment, mild hepatic impairment, or concomitant use of combination partners, including aromatase inhibitors (letrozole, anastrozole) or fulvestrant, proton-pump inhibitors, or weak cytochrome P450 3A4/5 inhibitors. Body weight had no impact on ribociclib clearance to warrant dose adjustment. The ANC PK/PD relationship was not affected by age, weight, sex, race, baseline ECOG status (grade 1), or concomitant use of letrozole, anastrozole, or fulvestrant. The PK/PD analysis confirmed reversibility of ribociclib's effect on ANC; it also suggested that lowering the dose of ribociclib would mitigate ANC decrease and neutropenia risk. The popPK and ANC PK/PD analyses support the use of ribociclib in combination with an aromatase inhibitor or fulvestrant in patients with hormone receptor-positive, human epidermal growth factor receptor-2-negative advanced or metastatic breast cancer without dose adjustment in subpopulations, and the use of dose interruption/reduction to mitigate potential treatment-emergent neutropenia.

Importance Findings in this work might provide certain guidance for current clinical work. Objective This study aimed to evaluate the efficacy and safety of these drugs based on the Bayesian network meta-analysis. Evidence review Two researchers systematically and comprehensively searched PubMed, Embase, and the central databases of the Cochrane Library from inception to September 15, 2020. The number of specific events and sample size were extracted from each of the included studies. This Bayesian theory-based network meta-analysis included indirect comparisons and mixed treatment analysis. Indirect comparisons compare the efficacy of at least three interventions simultaneously and are mostly used when there are few direct comparison studies. In addition, indirect comparisons are conducted on the basis of direct comparisons through mixed treatment analysis, which can thus improve the accuracy of analysis. Findings A total of nine randomized controlled trials involving 60,732 participants were included. As a result, compared with placebo in high-risk pre- or postmenopausal women, endocrine therapy (ET) decreased the risks of total breast cancer (TBC, odds ratio [OR] 0.69, 95% confidence interval [CI] 0.56-0.85), invasive breast cancer (IBC, OR 0.69, 95% CI 0.53-0.89), estrogen receptor-positive breast cancer (ER+BC) (OR 0.49, 95% CI 0.38-0.64), and ductal carcinoma in situ (OR 0.74, 95% CI 0.56-0.98), but increased the risks of pulmonary embolism (OR 1.33, 95% CI 1.05-1.69), total venous thrombosis (OR 1.75, 95% CI 1.28-2.38), and endometrial carcinoma (EC, OR 1.84, 95% CI 1.17-2.88). In further network stratification analyses, anastrozole, exemestane, and tamoxifen were found to decrease the risks of TBC, IBC, and ER + BC relative to placebo. Similarly, raloxifene decreased the risk of IBC (OR 0.65, 95% CI 0.48-0.85), while tamoxifen increased the risk of EC (OR 2.42, 95% CI 1.10-7.35). Conclusions and relevance To sum up, ET decreased the risks of TBC, IBC, ER + BC, and ductal carcinoma in situ, while increasing the risks of pulmonary embolism, total venous thrombosis, and EC in high-risk pre- or postmenopausal women. Meanwhile, anastrozole, exemestane, and tamoxifen possibly exerted potential protective effects on TBC, IBC and ER + BC. Typically, raloxifene might be effective on IBC, while tamoxifen might increase the risk of EC. Therefore, clinicians should fully weigh the benefits and risks of ET to develop a rational individualized treatment.

BackgroundAromatase 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.MethodAn 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.Results15 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.ConclusionThe 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.KeywordsAromatase inhibitorsAnastrazoleEndometrial stromalsarcomasUterine sarcoma

Background Adjuvant endocrine therapy is recommended for the treatment of hormone-receptor-positive breast cancer. Aromatase inhibitors are associated with significant musculoskeletal adverse effects, likely through growth hormone/insulin-like growth factor 1 modulation, while tamoxifen reduces insulin-like growth factor 1 production. We describe the case of a patient who was treated successfully with tamoxifen for her hormone-receptor-positive breast cancer and acromegaly. Case presentation A 57-year old White female with hormone-receptor-positive breast cancer was diagnosed with acromegaly. She received adjuvant endocrine therapy with anastrozole but could not tolerate this medication because of severe arthralgia, so she was switched to tamoxifen. Shortly after starting tamoxifen, the patient’s musculoskeletal symptoms resolved and her insulin-like growth factor 1 levels normalized. She has remained in remission of her acromegaly and breast cancer since initiating tamoxifen. Conclusion This case highlights the dual benefit of tamoxifen therapy in the treatment of hormone-receptor-positive breast cancer and acromegaly. Unlike anastrozole, tamoxifen has the benefit of lowering insulin-like growth factor 1 levels, which underscores its advantage in reducing adverse musculoskeletal symptoms during the treatment of hormone-receptor-positive breast cancer. We offer the first reported use of tamoxifen monotherapy for the successful treatment of acromegaly and hormone-receptor-positive breast cancer. While tamoxifen may offer an additional, oral option for acromegaly patients who do not respond to or tolerate conventional growth-hormone-lowering therapy, additional studies are necessary.

Breast cancer remains the most common cancer in women in the United States. For certain women at high risk for breast cancer, endocrine therapy (ET) can greatly decrease the risk. Tools such as the Breast Cancer Risk Assessment Tool (or Gail Model) and the International Breast Cancer Intervention Study risk calculator are available to help identify women at increased risk for breast cancer. Physician awareness of family history, reproductive and lifestyle factors, dense breast tissue, and history of benign proliferative breast disease are important when identifying high-risk women. The updated US Preventive Services Task Force and American Society of Clinical Oncology guidelines encourage primary care providers to identify at-risk women and offer risk-reducing medications. Among the various ETs, which include tamoxifen, raloxifene, anastrozole, and exemestane, tamoxifen is the only one available for premenopausal women aged 35 years and older. A shared decision-making process should be used to increase the usage of ET and must be individualized. This individualized approach must account for each woman's medical history and weigh the benefits and risks of ET in combination with the personal values of the patient.

Purpose of review The introduction of synthetic glucocorticoids 70 years ago made survival possible in classic 21-hydroxylase deficiency (21OHD). The currently used glucocorticoid therapy may lead to unphysiological dosing with negative consequencies on health in addition to the problems that may arise due to androgen over-exposure. Recent findings Fertility in females with 21OHD seemed to be impaired, especially in the salt-wasting (SW) phenotype but when pregnancies did occur there was a higher risk for gestational diabetes and cesearean section. Increased fat mass, body mass index, insulin resistance and frequency of autoimmune disorders as well as impaired echocardiographic parameters and lower bone mineral density were found in 21OHD compared to controls. Negative effects on cognitive functions have been identified. Adrenal tumors, especially myelolipomas, were prevalent. Increased knowledge on steroid metabolism in 21OHD and urine steroid profiling may improve assessment of treatment efficacy. Nevanimibe, abiraterone acetate and anastrozole may have a place in the future management of 21OHD. Long-acting glucocorticoids may be a less favorable, especially dexamethasone. Summary The various clinical outcomes need regular monitoring. Negative consequencies are to large extent the result of the unphysiological glucocorticoid replacement. Modern management with improved follow-up and future addition of new drugs may improve outcomes.

Background Anastrozole is a non-steroidal fourth generation aromatase inhibitor that stops the conversion of testosterone to estradiol and has been used as empiric medical therapy for the treatment of male infertility in men with an abnormal testosterone-to-estradiol ratio

Background We investigated the association between body mass index (BMI) and breast cancer risk in women at increased risk of breast cancer receiving tamoxifen or anastrozole compared with placebo using data from the International Breast Cancer Intervention Studies [IBIS-I (tamoxifen) and IBIS-II (anastrozole)]. Methods Baseline BMI was calculated from nurse assessed height and weight measurements for premenopausal (n = 3138) and postmenopausal (n = 3731) women in IBIS-I and postmenopausal women in IBIS-II (n = 3787). The primary endpoint was any breast cancer event (invasive and ductal carcinoma in situ). We used Cox proportional hazards regression to calculate hazard ratios (HRs) for risk after adjustment for covariates. Results There were 582 (IBIS-I) and 248 (IBIS-II) breast cancer events [median follow-up = 16.2 years (IQR 14.4–17.7) and 10.9 years (IQR 8.8–13.0), respectively]. In adjusted analysis, women with a higher BMI had an increased breast cancer risk in both IBIS-I [HR = 1.06 per 5 kg/m2 (0.99–1.15), p = 0.114] and in IBIS-II [HR per 5 kg/m2 = 1.21 (1.09–1.35), p 2 = 1.14 (1.03–1.26), p = 0.01] but not premenopausal women [adjusted HR per 5 kg/m2 = 0.97 (0.86–1.09), p = 0.628]. There was no interaction between BMI and treatment group for breast cancer risk in either IBIS-I (p = 0.62) or IBIS-II (p = 0.55). Conclusions Higher BMI is associated with greater breast cancer risk in postmenopausal women at increased risk of the disease, but no effect was observed in premenopausal women. The lack of interaction between BMI and treatment group on breast cancer risk suggests women are likely to experience benefit from preventive therapy regardless of their BMI. Trial registration Both trials were registered [IBIS-I: ISRCTN91879928 on 24/02/2006, retrospectively registered (http://www.isrctn.com/ISRCTN91879928); IBIS-II: ISRCTN31488319 on 07/01/2005, retrospectively registered (http://www.isrctn.com/ISRCTN31488319)]

Angiosarcoma is a malignant mesenchymal tumor characterized by the presence of vascular endothelial cells. Although rare, angiosarcoma developing in the mammary glands has a poor prognosis. We report a case of breast angiosarcoma with a preoperative diagnosis of late recurrence of breast cancer. A 78-year-old woman noticed a tumor in her right breast and visited our hospital. The patient had undergone breast-conserving surgery and axillary lymph node dissection from the right breast 12 years before the visit. The tumor was diagnosed as T4bN0M0, stage IIIB. Anastrozole was administered as postoperative adjuvant therapy for 5 years; the patient also received 50-Gy whole-breast radiation therapy after surgery. Physical examination during her visit revealed an elevated lesion with blue purpura around the nipple in the right breast. We performed breast ultrasound and detected a well-defined 19.6 × 16.4 × 10.7 mm hypoechoic tumor in the left subareolar area. The patient underwent core needle biopsy (CNB). Based on the CNB specimen findings, she was suspected to experience late local recurrence after surgery. Therefore, she underwent total mastectomy after breast-conserving surgery. A dark-red tumor sized 18 × 12 mm was found in a specimen from the nipple. The pathological diagnosis of the specimen revealed short spindle-shaped tumor cells with strong nuclear pleomorphism and a significant interstitial fibrosis. Immunohistochemistry using D2-40 and CD31 antibodies showed irregular luminal proliferation at the anastomosis, infiltration into the surrounding tissue, and massive necrosis, thereby leading to the diagnosis of breast angiosarcoma. We have reported a case of breast angiosarcoma with a preoperative diagnosis of late recurrence of breast cancer.

Glioblastoma Multiforme (GBM) is a tumor that infiltrates several brain structures. GBM is associated with abnormal motor activities resulting in impaired mobility, producing a loss of functional motor independence. We used a GBM xenograft implanted in the striatum to analyze the changes in Y (vertical) and X (horizontal) axis displacement of the metatarsus, ankle, and knee. We analyzed the steps dissimilarity factor between control and GBM mice with and without anastrozole. The body weight of the untreated animals decreased compared to treated mice. Anastrozole reduced the malignant cells and decreased GPR30 and ERα receptor expression. In addition, we observed a partial recovery in metatarsus and knee joint displacement (dissimilarity factor). The vertical axis displacement of the GBM+anastrozole group showed a difference in the right metatarsus, right knee, and left ankle compared to the GBM group. In the horizontal axis displacement of the right metatarsus, ankle, and knee, the GBM+anastrozole group exhibited a difference at the last third of the step cycle compared to the GBM group. Thus, anastrozole partially modified joint displacement. The dissimilarity factor and the vertical and horizontal displacements study will be of interest in GBM patients with locomotion alterations. Hindlimb displacement and gait locomotion analysis could be a valuable methodological tool in experimental and clinical studies to help diagnose locomotive deficits related to GBM.

Background The aim of this study was to investigate whether the PAM-50-based 46-gene assay carries prognostic value for risk of local recurrence of breast cancer. Methods The Austrian Breast and Colorectal Cancer Study Group (ABCSG) 8 RCT compared 5 years of tamoxifen with tamoxifen for 2 years followed by anastrozole for 3 years in postmenopausal women with endocrine receptor-positive breast cancer. This study included patients from the trial who had breast-conserving surgery for whom tumour blocks were available for PAM-50 analysis. Results Tumour blocks from 1204 patients who had breast-conserving surgery were available for the PAM-50 analysis, and 1034 of these received radiotherapy. After a median follow-up of 10.8 years, 23 local events had been observed, corresponding to an overall local recurrence risk of 2.2 per cent. Univariable competing-risk analysis demonstrated that patients at low risk according to PAM-50 analysis (risk-of-recurrence (ROR) score less than 57) had a significantly lower incidence of local recurrence than those in the high-risk group at 5 years (0.1 (95 per cent c.i. 0 to 0.7) versus 2.2 (0.9 to 4.6) per cent respectively; subhazard ratio (SHR) 17.18, 95 per cent c.i. 2.06 to 142.88; P = 0.009) and 10 years (0.9 (0.4 to 2.0) versus 3.8 (1.9 to 6.6) per cent; SHR 4.76, 1.72 to 13.17; P = 0.003). Multivariable analyses that included ROR score, age, tumour size, nodal status, type of surgery, tumor grade, and trial-specific endocrine therapy confirmed that ROR score was an independent prognostic factor for risk of local recurrence. Analysis of the women randomized to radiotherapy or control after breast conservation showed that PAM-50 was not predictive of radiotherapy effect. Conclusion PAM-50 can be used as a prognostic tool for local recurrence risk in postmenopausal women with hormone receptor-positive breast cancer treated with endocrine therapy. The test was not predictive for the benefit of radiotherapy.

Introduction: Given the recent advances in early detection, improving access to care and the introduction of more effective anti-cancer medications including endocrine therapy, targeted and immunotherapy, more women with breast cancer survive their disease. Majority of patients with breast cancer express hormone receptors (estrogen and or progesterone receptors) on cancer cells. Aromatase inhibitors (AI) are the gold standard treatment of hormone-sensitive postmenopausal women with breast cancer. Several studies had documented the accelerated bone loss associated with AI. The use of bone modifying agents like bisphosphonates and denosumab had resulted in significant improvement in bone mineral density among females treated with AI. In this paper, we study the efficacy of implementing a comprehensive program on bone health for such patients. Patients and Methods: Postmenopausal women with hormone-sensitive early-stage breast cancer treated with endocrine therapy (ET) were included. A comprehensive bone health program was implemented. The program includes extensive counselling by medical oncologist, calcium and vitamin-D supplements, increase milk intake and exercise. Patients with baseline lumbar spine or total hip T-scores ≥ -2 were given short intravenous bisphosphonate infusion every 6 months. Patients with osteoporosis are referred to and followed in a specially designed “osteoporosis clinic”. Results: Between 2013 and 2019, a total of 210 patients fulfilled the eligibility criteria and were enrolled. All were female, median (range) age 67 (43-86) years. All patients had a pathologically confirmed diagnosis of breast cancer, treated and followed up at our institution. High risk patients (n=103, 49.0%) were treated with 6-8 cycles of chemotherapy, including anthracyclines and taxanes. Following the completion of chemotherapy, all patients were treated with endocrine therapy. Patients with low-risk disease (n=107, 51.0%) were treated with upfront endocrine therapy-alone. Aromatase inhibitors, letrozole or anastrozole, were the endocrine therapy of choice in all patients. At baseline, and prior to start of AI, the median T-scores at the hip and lumber spines were -1.0 (range: -3.6, 1.9) and -1.4 (range: -3.9, 2.6), respectively. Osteoporosis was documented in 38 (18.1%) patients while 101 (48.1%) others had osteopenia; none were on any treatment or even aware of their BMD. 46 (25.3%) patients had vitamin-D deficiency while 74 (40.7%) others had vitamin-D insufficiency and none were on prior active replacement therapy or even aware of this problem. Following at least 12-months of endocrine therapy, 32 (84.2%) of patients with osteoporosis and 69 (68.3%) of those with osteopenia had a stable or higher BMD. Thus, the number of patients with osteoporosis declined to 27, 12.9% of the total cohort. On the other hand, 41 (57.7%) of those with normal baseline BMD had a drop in their follow up BMD. Vertebral fractures, presented with back pain and documented by imaging studies, were reported in 3 (11.1%) patients with osteoporosis compared to none in patients with normal BMD, p=0.021. Rib fracture and hip fracture were reported in one patient each and both had normal BMD before and after AI therapy. Conclusions: Postmenopausal women with breast cancer are at risk of osteopenia and osteoporosis. Such risk increases significantly with the use of AI. However, early interventions with modifiable risk factors, Vitamin-D supplements and use of bone-modifying agents can lower this risk. Citation Format: Razan Mansour, Ula Al-Rasheed, Akram Al-Ibraheem, Shereen Abu Jaradeh, Rashid Abdel-Razeq, Rayan Bater, Noor Mashahdani, Shrouq Tbayshat, Hikmat Abdel-Razeq. The efficacy of a comprehensive bone health program in maintaining bone mineral density in postmenopausal women with early-stage breast cancer treated with endocrine therapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS9-30.

Background: POLARIS is an ongoing, prospective, real world, noninterventional study in patients (pts) with HR+/HER2– ABC receiving PAL. This interim report describes real-world PAL use in preMeno pts. Methods: POLARIS has a targeted enrollment of 1500 pts from ~110 sites in the United States and Canada. Using patient data collected from medical charts and physician surveys, baseline demographics, clinical characteristics, and treatment patterns were analyzed descriptively in self-reported preMeno pts with ABC. Results: At the data cutoff of May 20, 2020, 1208 pts were enrolled; 134 (11.1%) from 61 sites were preMeno, of whom 14.2% completed ≥6 months of PAL treatment. Among 134 preMeno pts (74.6%) who received first-line (1L) therapy, 69.0% received PAL+letrozole (LET) or anastrozole, 28.0% PAL+fulvestrant, and 3.0% PAL+exemestane. Median disease-free interval was 39.3 (range: 0 to 236) months; median treatment-free interval was 14.8 (-3 to 134) months. Of 34 pts (25.4%) who received PAL as second or later line (≥2L), 23.8% previously received hormonal therapy, 28.6% chemotherapy, and 14.3% both. The majority of pts (96.27%) initiated PAL at 125 mg regardless of line of therapy (Table). During the first PAL treatment cycle, 2.9% of all preMeno pts, 1% of 1L pts, and 8.8% of ≥2L pts had a dose reduction; 8.2%, 9%, and 5.9%, respectively, had an interruption. Dose reductions/interruptions peaked in cycle 2 (11.9%/15.7%); 56.67% of these modifications were due to adverse events. Conclusions: PAL is routinely prescribed in clinical practice for preMeno women with HR+/HER2- ABC. The majority of preMeno pts in this real-world dataset received PAL+LET as 1L ABC treatment; PAL was primarily initiated at the recommended dose (125 mg) and was well tolerated with few dose modifications required. Clinical trial identification: Pfizer (NCT03280303) Table.CharacteristicFirst-Line Pre/Perimenopausal Patients (n=100)Second or Later Line Pre/Perimenopausal Patients (n=34)Pre/Perimenopausal Patients (N=134)Age at study enrollment, yMedian (range)44 (22-61)42.5 (27-58)44 (22-61)Distribution, n (%) Citation Format: Meghan S Karuturi, Adnan Garrett, Joanne L Blum, Jay Anderson, Erin Jepsen, Timothy Pluard, Thomas Stanton, Kenneth Manning, Joseph C Cappelleri, Faith Beery, Yao Wang, Debu Tripathy. Pre/perimenopausal (preMeno) women receiving palbociclib (PAL) for hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2–) advanced breast cancer (ABC) in a real-world setting: Treatment patterns from POLARIS [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS7-19.

Background: NET is offered to postmenopausal patients (pts) with clinical stage 2/3 ER+/HER2- BC to promote breast-conserving surgery. Also limited surgical accessibility during the COVID19 pandemic has increased NET utility. Inability to identify ET-resistant disease at diagnosis risks disease progression (PD) and delays more effective treatments. Dowsett et al. recently demonstrated that baseline levels of ER, progesterone receptor (PR), Ki67 (>15% vs ≤15%), and Ki67 (>10% vs ≤10%) 2-4 weeks (wks) after starting NET may improve appropriate patient (pt) selection for NET (PMC7280290). The ER, PR and Ki67-based prediction model divides pts with primary ER+/HER2- BC into 3 groups for appropriateness for NET: (Group 1) NET is likely to be inappropriate (Allred ER 10% has been associated with worse outcome (PMC5455353), or (Group 3) NET is appropriate (ER 8 and PgR ≥6). The ALTERNATE trial (NCT01953588) randomized postmenopausal women with clinical stage II or III, ER+ (Allred score 6-8)/HER2- BC to receive anastrozole (ANA), fulvestrant (FUL), or ANA + FUL for 6 months, unless Ki67 was >10% on wk 4 or 12 biopsy, in which case pts were triaged to receive neoadjuvant chemotherapy (NCT) or surgery. As previously reported, the ET-sensitive disease (mPEPI 0 plus pCR) rates were similar across the treatment arms and overall 22% (286 of 1,299) pts had Ki67 >10% at wk 4 or 12. The ALTERNATE trial therefore provides a large independent data set to evaluate the NET appropriateness model. Results: Among 1,299 eligible pts randomized to receive 6 months of NET, 214 were excluded due to absent HR Allred score (n=41) or absence of pre-treatment and wk 4 Ki67 determinations (n=173). The proportions of the remaining 1,085 pts in Group 1, 2 and 3 were 1% (n=10), 43% (n= 468), and 56% (n=607), respectively. On-study Ki67 >10% prompting conversion from NET to NCT/Surgery occurred in: Group 1 90% (9 of 10), Group 2 30% (141 of 468), and Group 3 17% (104 of 607) (Table 1). Among the 1,075 pts in Groups 2 and 3, 260 (24%) pts had Ki67 ≤15% at baseline (BL), among whom only 14 (5.4%) had Ki67 >10% at wk 4, compared to 231 of the 815 (28.3%) who had BL Ki67 >15% and subsequent Ki67 >10% at wk 4. 2% of pts who remained on NET due to on-treatment Ki67 Conclusion: ALTERNATE trial data support a model whereby levels of ER, PR and Ki67 at diagnosis can be used for the identification of postmenopausal pts with primary ER+/HER2- BC who are appropriate for NET. When baseline ER Allred scores are >6 and Ki67 ≤15%, there is a low likelihood of ET-resistant disease. When BL Ki67 is >15%, ET sensitivity is variable, and on-treatment biopsy for Ki67 may assist in triaging regarding NET appropriateness, particularly given the extremely low local PD rates seen in ALTERNATE when on-treatment Ki67 was Table 1 Baseline levels of ER, PR, and Ki67 in Relation to Wk 4 Ki67 (N=1,085)BaselineWeek 4GroupNERAllred ScorePRAllred ScoreKi67Ki67 ≤10%N (%)Ki67 >10%N (%)1N=2615%1 (12.5%)7 (87.5%)2AN=647 or 815%148 (63%)87 (37%)2BN=466 or 7≥6≤15%42 (91.3%)4 (8.7%)51 (30.2)N=1236 or 7≥6>15%76 (61.8%)47 (38.2%)3N=1508≥6≤15%143 (95.3%)7 (4.7%)104 (17.1)N=4578≥6>15%360 (78.8%)97 (21.2%) Citation Format: Matthew J Ellis, Vera Suman, A. Marilyn Leitch, Souzan Sanati, Kiran Vij, Gary W Unzeitig, Jeremy Hoog, Mark Watson, Olwen Hahn, Joseph Guenther, Abigail Caudle, Erika Crouch, Horacio Maluf, Mitch Dowsett, Amy Tiersten, Monica Mita, Wajeeha Razaq, Tina J Hieken, Yang Wang, Travis Dockter, Jo Anne Zujewski, Anna Weiss, Clifford Hudis, Eric P Winer, Kelly Hunt, Ann H Partridge, Cynthia X Ma, Lisa A Carey. Validation of a predictive model for potential response to neoadjuvant endocrine therapy (NET) in postmenopausal women with clinical stage II or III estrogen receptor positive (ER+) and HER2 negative (HER2-) breast cancer (BC): An ALTERNATE trial analysis (Alliance A011106) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-10.

Background: CTCs are detectable in approximately 50% of pts with metastatic breast cancer, and elevated CTC levels are an independent negative prognostic factor. CTCs have been shown to play a valuable role in predicting outcomes in pts with ABC treated with chemotherapy or endocrine therapy. This phase II trial was conducted to evaluate the clinical benefit (CB) of pazopanib, a VEGF receptor tyrosine kinase inhibitor (TKI) combined with nonsteroidal aromatase inhibitors (NSAIs) in pts with ABC resistant to NSAIs. As an exploratory analysis, we hypothesized that CTC levels might be correlated with response to pazopanib plus endocrine therapy. Methods: Eligibility included postmenopausal women with hormone receptor positive (HR+) ABC and progressive disease after at least one month of NSAIs. Treatment was pazopanib 800 mg/day plus either letrozole or anastrozole. The primary endpoint was clinical benefit rate at 12 weeks (CBR12, wks). Secondary endpoints included progression free survival (PFS), safety, and the impact of pazopanib and NSAI on CTCs. A CBR of 20% was considered a clinically meaningful comparison to the expected CBR of Results: 32 pts were enrolled; 28 are evaluable for study endpoints. The median age was 58 years (range: 41-77). Pts were heavily pre-treated, with a median of 2 prior hormone therapies (range 1-6) and 1 prior chemotherapy (range 0-8). 8 pts (28.6%) stopped treatment due to adverse events, and 6 pts progressed before wk 12. CBR12 was 46.4% (12 SD, 1 PR), and CBR24 was 25% (5 SD, 2 PR). Safety has been presented (ASCO 2020). Median PFS was 20 wks, and median PFS for pts with CBR12 was 24 wks. Five (22%) of 23 pts with CTC data were CTC-positive (5 CTC/7.5 mL). There was no significant association between CBR12 and CTC status at baseline, or between CBR12 and change in CTC status (baseline to 4 wks after initiation of treatment). 7 pts had non-CBR12 and CTC data; 4 pts (n=4/7; 57%) were CTC positive at either baseline, week 4 or both. 11 pts had CBR12 and CTC data; all patients were CTC negative at baseline and remained negative at 4 wks. 7 pts had PFS >6 months (24, 32, 36, 36, 48, 184 and 274 wks), and 6 had CTC data: all were CTC-negative at baseline and 4 wks, then remained negative at 12 wks. Based on baseline values only, CTC-positive pts had a shorter median PFS compared to CTC-negative pts, but the difference was not statistically significant (11 wks vs 14 wks, p=0.18). Persistently CTC negative patients had significantly longer PFS compared to patients who were CTC positive at any time during study treatment (36 wks vs 11 wks, p=0.01). Conclusions: The addition of pazopanib to NSAIs resulted in a CBR12 of 46.4%, and a CBR24 of 25% in pts with heavily pre-treated ABC resistant to NSAIs. These results support clinical efficacy of antiangiogenic TKI in HR+ ABC and suggest benefit in hormone resistant disease. Consistently negative CTCs correlated with response and response duration. PFS was significantly longer in patients who were consistently CTC negative, further defining the prognostic role of CTCs in HR+ ABC. (NCT01466972) Citation Format: Ozge Gumusay, Mark Jesus M. Magbanua, Melanie C. Majure, Travis Deal, Jonathan R. Renslo, Chiara A. Wabl, Michelle E. Melisko, A. Jo Chien, Andrei Goga, Mark M. Moasser, John W. Park, Jimmy Hwang, Hope S. Rugo. Circulating tumor cell (CTC) enumeration in a phase II trial of pazopanib in addition to endocrine therapy in patients with hormone resistant advanced breast cancer (ABC) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS2-19.

Background: In the phase III MONARCH plus study (NCT02763566) the cyclin-dependent kinase (CDK) 4&6 inhibitor abemaciclib in combination with non-steroidal aromatase inhibitors (NSAI) or with fulvestrant compared with placebo demonstrated its efficacy and acceptable safety profile at interim analysis in postmenopausal women with hormone receptor-positive, human epidermal growth factor receptor 2-negative (HR+/HER2-) locoregionally recurrent or metastatic breast cancer. One of the most common treatment-emergent adverse event (TEAE) was diarrhea, typically low grade and of early onset. We will further characterize abemaciclib-associated diarrhea and describe its management in MONARCH plus trial. Methods: MONARCH plus study included two cohorts of patients. Cohort A enrolled patients with initial treatment of endocrine therapy, received abemaciclib or placebo plus NSAI (anastrozole or letrozole); Cohort B enrolled patients who progressed on prior endocrine therapy, receiving abemaciclib or placebo plus fulvestrant. The relative dose intensity was defined as the percentage of actual dose received relative to the planned dose. The severity of diarrhea was reported by investigators and graded according to Common Terminology Criteria for Adverse Events Version 4.0 (CTCAE v4.0). Further analysis on diarrhea included time to onset, duration, supportive medication and dose modifications. Progression-free survival (PFS) was defined as time from randomization to death or progression (RECIST v1.1), and a stratified Cox proportional hazard model was used to estimate the hazard ratio (HR) between study intervention arm and placebo arm. Results: The median relative dose intensity of abemaciclib in abemaciclib plus NSAI arm and abemaciclib plus fulvestrant arm were 96.77% and 96.30% respectively. In abemaciclib plus NSAI arm and abemaciclib plus fulvestrant arm, the median time to onset of first reported diarrhea was 7 and 6 days and majority of diarrhea events occurred early (66.3% and 71.2% of patients reported diarrhea in Cycle 1 respectively). Diarrhea was typically of low grade (3.9% and 1.9% of patients reported Grade 3 in abemaciclib plus NSAI arm and abemaciclib plus fulvestrant arm, no Grade 4 diarrhea was reported in either arm). Median duration of grade ≥ 3 diarrhea was 2.5 and 3.5 days. Diarrhea was managed by dose adjustments and/or supportive medication (Table 1). Dose reductions were present in 2.0% and 2.9% of patients, and anti-diarrhea therapy was received in 30.2% and 32.7% of patients with abemaciclib plus NSAI and abemaciclib plus fulvestrant arm, respectively. As data cutoff, most diarrhea events were reported as resolved, and the incidence dropped below 10% (Grade 2) and 1% (Grade 3) by Cycle 2 in both arms and kept low incidence over time. Compared to the placebo arm, patients treated with abemaciclib combination who reported diarrhea within the first 7 days (abemaciclib + NSAI, HR [95% CI]: 0.289 [0.166, 0.502]; abemaciclib + fulvestrant, HR [95% CI]: 0.371 [0.213, 0.647]) had significant improvement in PFS. Conclusion: Majority of diarrhea events were of low grade in severity and well managed by anti-diarrheal medications, dose omissions or/and dose reductions in MONARCH plus patients. Table 1. Summary of dose adjustments and supportive medications in patients experiencing diarrheaCohort ACohort BAbemaciclib + NSAIAbemaciclib + FulvestrantN = 205N = 104Diarrhea (any grade), n (%)164 (80.0)82 (78.8)1105 (51.2)52 (50.0)251 (24.9)28 (26.9)38 (3.9)2 (1.9)Outcome, number of events, n796333Recovered/resolved, n (%)757 (95.1)318 (95.5)Not recovered/resolved, n (%)17 (2.1)7 (2.1)Treatment change, n (%)Dose reduction4 (2.0)3 (2.9)Dose omission3 (1.5)3 (2.9)Treatment discontinuation00Anti-diarrhea therapies, n (%)62 (30.2)34 (32.7)loperamide48 (23.4)21 (20.2)berberine6 (2.9)6 (5.8) Citation Format: Zefei Jiang, Xichun Hu, Qingyuan Zhang, Tao Sun, Yongmei Yin, Huiping Li, Min Yan, Zhongsheng Tong, Christina Pimentel Oppermann, Yunpeng Liu, Romulo Costa, Man Li, Xi Chen, Ying Cheng, Quchang Ouyang, Ning Liao, Xiaojia Wang, Xinhong Wu, Jifeng Feng, Roberto Hegg, Govindbabu Kanaka Setty, Amit Agarwal, Jyoti Bajpai, Jing Cheng, Gustavo Girotto, Chanchal Goswami, Wenjing Hu, Jian Huang, MA Coccia Portugal, Jin Yang, Rongsheng Zheng, Fabio Andre Franke, Qiang Liu, Yunjiang Liu, Yongkui Lu, Cristiano Souza, Shiying Yu, Nalini Kilara, Harsha Panchal, Ashish Singh, Shona Nag, Jian Liu, Bernardo Rapoport, Neonyana Keorapetse Rebecca Tabane, Hongxia Wang, Ning Wang, Rubing Han, Wanli Zhang. Management of abemaciclib associated diarrhea in patients with hormone receptor-positive/human epidermal growth factor receptor 2-negative advanced breast cancer: Analysis of the MONARCH plus study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-25.

Background: In MONALEESA-3 and MONALEESA-7 trials, ribociclib (RIB, a selective CDK4/6 inhibitor) in combination with endocrine therapy (aromatase inhibitor [AI] or fulvestrant [FUL]) demonstrated a significant prolongation of overall survival among patients with breast cancer (BC), regardless of menopausal status and treatment-line. In the premenopausal or perimenopausal women, RIB + AI/FUL should be combined with a luteinizing hormone-releasing hormone agonist. The real-world evidence for the effectiveness, safety, and tolerability of RIB + AI/FUL in the routine clinical practice is needed to support the use of this combination. Methods: RIBANNA is a prospective, non-interventional study ongoing in Germany since October 2017. Pre-, peri- and postmenopausal women (planned, n = 3020) treated with RIB + AI/FUL, or endocrine monotherapy (ET), or chemotherapy (CT) as the first-line treatment for HR+/HER2- aBC in accordance with German guidelines were included. Data from routine clinical practice in all 3 cohorts, including further lines of sequential therapy, were collected. Updated data on baseline demographics and safety analysis will be presented. Additionally, first experience with CANKADO, an innovative digital and patient-friendly application for electrocardiogram (ECG) measurement, are described. By combining this app to Kardia mobile (AliveCor’s single lead device), single-lead ECG can be recorded and sent via the CANKADO app for a cardiologist to read over. The cardiologist reviews the measurements, and reports the corrected QT interval by Fredericia (QTcF) results towards the trial site. Impact of the use of CANKADO onto the clinical routine will be analyzed. Results: For the second interim analysis, 1141 patients were enrolled until July 12th, 2019, while the full analysis set comprised 813 patients (Table 1). Median duration of RIB exposure in patients on RIB + AI/FUL vs total population was 151 vs 150 days respectively. At cut-off date, patients received first-line (89%, n = 1016), second-line (7%, n = 82), and third-line treatments (1%, n = 11). A starting dose of 600 mg per day for RIB in the first-line setting was seen in most of the patients (85%); data of second-line patients will be reported later. The first-line mean daily dose of RIB was 451.6 mg/day RIB was prescribed mainly in combination with letrozole (75%), fulvestrant (12%), anastrozole (7%), and exemestane (6%). A total of 62% of patients in the study were documented as therapy-naïve for ET. Of 424 patients with early breast cancer, 129 (30%) had documented prior CT without ET. The most common all-grade adverse events frequently noted in RIB + AI/FUL cohort in comparison with other cohorts were nausea (RIB [19%] vs ET [9%] vs CT [11%]), neutropenia (19% vs 1% vs 10%), fatigue (17% vs 9% vs 14%), and leukopenia (14% vs 4% vs 12%). The usage of CANKADO application to assess QTcF was initiated in the year 2019 and first data will be presented. Conclusion: RIBANNA study showed diverse population characteristics among the patients who received RIB treatment in a real-world setting. The third interim analysis is planned in October 2020, and the updated baseline data, information on safety, digital ECG measurement using CANKADO application will be presented. Baseline Demographic Characteristics as of Second Interim AnalysisDemographic VariableRIB + AI/FUL (n = 658)Endocrine Therapy (n = 78)Chemotherapy (n = 77)Mean age, years (SD)67 (11)72 (12)62 (10)Mean time since initial diagnosis, years6.17.23.6T stage at baseline*, n (%)TX204 (31)28 (36)18 (23)T0+T1132 (20)12 (15)11 (14)T2-T4302 (46)35 (45)42 (54)N stage at baseline*, n (%)NX212 (32)29 (37)28 (36)N0+N1317 (48)36 (46)35 (46)N2+N3108 (16)10 (13)8 (10)M stage at baseline*, n (%)MX6 (1)0 (0)0 (0)M018 (3)1 (1)1 (1)M1616 (94)75 (96)71 (92)Metastatic location at baseline*, n (%)CNS, liver, lungs258 (39)14 (18)42 (54)Bone only181 (28)42 (54)11 (14)Skin, lymph nodes, other149 (23)16 (20)14 (18)*Remaining cases are missing.CNS, central nervous system. Citation Format: Achim Wöckel, Cosima Brucker, Thomas Decker, Jörg Falbrede, Helmut Forstbauer, Thomas Göhler, Oliver Hoffmann, Christian Jackisch, Jan Janssen, Andreas Köhler, Kerstin Lüdtke-Heckenkamp, Diana Lüftner, Frederik Marmé, Arnd Nusch, Toralf Reimer, Christian Roos, Marcus Schmidt, Rudolf Weide, Peter Fasching. Real-world efficacy of ribociclib + aromatase inhibitor/fulvestrant, or endocrine monotherapy, or chemotherapy as first-line treatment in women with HR-positive, HER2-negative locally advanced or metastatic breast cancer: Third interim analysis from the RIBANNA study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS10-16.

Background: Adjuvant aromatase inhibitors (AI) reduce recurrence and mortality after early stage hormone receptor-positive (HR+) breast cancer (BC). Treatment-related toxicities, including AI-induced musculoskeletal symptoms (AIMSS), are common during adjuvant AI therapy. Prior work suggests the risk of AIMSS is associated with inherited germline genetic polymorphisms in several genes, such as TCL1A, CYP19A1, OPG, and VDR. These pharmacogenetic associations require replication in independent cohorts prior to clinical translation to identify patients at risk for AIMSS. The objective of this retrospective pharmacogenetic analysis was to replicate previously reported associations for candidate germline genetic polymorphisms with AIMSS. Methods: Women with stage 0-III HR+ BC initiating adjuvant endocrine therapy (ET) with tamoxifen or an AI were enrolled in a prospective clinic-based observational cohort. The type of ET was selected by the provider. A baseline (BL) blood sample was collected for isolation of germline DNA for pharmacogenetic analysis. AIMSS were assessed by patient-reported outcomes (PRO). Participants completed PROMIS pain interference (PI), PROMIS physical function (PF) and Functional Assessment of Cancer Therapy - Endocrine Symptoms (FACT-ES) measures at BL and after 3, 6, 9, 12, 24, 48 and 60 months (mo). The FACT-ES includes one question about joint pain, rated on a 5-point scale (“not at all” to “very much”). This secondary retrospective pharmacogenetic analysis was conducted in participants receiving AI therapy for whom blood samples and PRO scores at BL and 3 and/or 6 mo were available. For the primary analysis, we defined AIMSS as a ≥4 point increase in PI T score from BL to 3 and/or 6 mo. For secondary analyses, we evaluated alternate definitions of AIMSS including a ≥4 point decrease in PF T score and a ≥1 category increase on the FACT-ES joint pain question from BL to 3 and/or 6 mo. The primary hypothesis was that TCL1A rs11849538 is associated with AIMSS. Twelve other germline variants in CYP19A1, VDR, PIRC66, OPG, ESR1, CYP27B1, CYP17A1, and RANKL previously reported to be associated with AIMSS were also analyzed. We assumed a dominant genetic effect and pre-specified the direction of effect on AIMSS for each variant. We conducted univariate logistic regression to evaluate associations between each definition of AIMSS and candidate polymorphism using an unadjusted α=0.05. Significant univariate associations in the expected direction were adjusted for age, race, body mass index (BMI), prior taxane and type of AI using multivariable logistic regression. Results: Of 182 participants on AI, 143 with PRO and genetic data available were included in this analysis. Median age was 67, 85% were white, median BMI was 27.8 and 27% had prior taxane. 78% received anastrozole, 20% letrozole and 2% exemestane. On primary analysis, participants carrying TCL1A rs11849538 were not more likely to develop AIMSS as defined by increase in PI T score by ≥4 (OR=1.29, 95% CI: 0.55-3.07, p=0.56). None of the other polymorphisms was associated with increase in PI T score by ≥4. On secondary analysis, OPG rs2073618 was associated with AIMSS, as defined by an increase on the FACT-ES joint pain question ≥1 (OR=3.33, 95% CI: 1.48-7.49, p=0.004) and this association maintained significance after covariate adjustment (OR=3.98, 95% CI: 1.61-9.84, p=0.003). Age, race, BMI, prior taxane and type of AI were not associated with AIMSS on multivariate analysis. No other polymorphisms were associated with AIMSS on secondary analyses. Conclusions: Carriers of OPG rs2073618 may be at increased risk of AIMSS. If confirmed in other cohorts, OPG genotyping may be able to identify individuals with HR+ early BC at increased risk for AIMSS during AI therapy. Alternate ET or interventions to reduce musculoskeletal symptoms may be needed for this population. Citation Format: Daniel L Hertz, Karen Lisa Smith, Yuhua Zong, Christina L Gersch, Andrea Pesch, Arti Patel, Jennifer Lehman, N. Lynn Henry, Kelley M Kidwell, James M Rae, Vered Stearns. Association of OPG rs2073618 and aromatase inhibitor induced musculoskeletal symptoms [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-25.

Background: The combination of anastrozole and fulvestrant (A+F) is associated with improvement in overall survival (OS) as compared to anastrozole (A) in patients (pts) with hormone receptor-positive (HR+) breast cancer (BC), specifically in pts with endocrine naïve disease or in pts with long disease-free interval (Mehta et al. NEJM 2019). We performed an IRB-approved retrospective assessment of the time-to-treatment failure (TTF) and overall survival (OS) outcomes in pts treated at our institution with A+F, and assessed the impact of A+F in various molecularly defined subsets of pts. Methods: We reviewed charts of 118 pts with advanced HR+ BC who received A+F. Pts with brain metastases were not excluded. Performance status (PS) ranged from 0-3. We compared TTF and OS outcomes in pts with and without molecular aberrations including HER2 overexpression/amplification, or mutations in PIK3CA, ESR1 or BRCA1/2. HER2 status was tested through tumor. PIK3CA and ESR1 were tested on tumor or ctDNA by next generation sequencing. Germline/somatic BRCA1/2 status was assessed either through ctDNA or germline testing. Kaplan-Meir survival curves were constructed. Primary statistical analysis was log-rank test, followed by Cox regression to estimate the hazard ratio and 95% confidence intervals. All p values are 2-sided. Results: Overall 68 patients had endocrine-sensitive (ES) disease and 50 patients had acquired endocrine-resistant (ER) disease. Median TTF was 26 months in the ES group vs. 10 months in the ER group (HR: 0.47;95% Cl: 0.30 - 0.75, p= 0.001). Median OS was 57 months in the ES group vs. 38 months in the ER group (HR: 0.51; 95% Cl: 0.30 - 0.86, p= 0.01). Among the 31 pts tested for PIK3CA mutation, 21 pts were negative (control) and 10 pts were positive (PIK3CA mutant). Median TTF was 23 months for control vs.14 months for PIK3CA mutant (HR: 0.89; 95% CI: 0.40 -1.95, p = 0.76). Median OS was not reached for control vs. 44 months for PIK3CA mutant (HR: 0.50; 95% Cl: 0.16 - 1.56, p = 0.23). Among the 35 pts tested for ESR1 mutation, 27 pts were negative (control) and 8 patients were positive (ESR1 mutant). Median TTF was 26 months for control vs. 10 months for ESR1 mutant (HR: 0.59; 95% CI: 0.23 - 1.52, p = 0.20). Median OS was 66 months for control vs. 65 months for ESR1 mutant (HR: 1.63; 95% Cl: 0.44 - 5.95, p = 0.46). In the 17 pts tested for BRCA mutation (germline or somatic), 6 of them were positive (BRCA mutant) and 11 of them were negative (control). Median TTF was 36 months for control vs. 10 months for BRCA mutant (HR: 0.40; 95% CI: 0.12 - 1.40, p = 0.09). Median OS was 35 months for control but has not been reached in the BRCA mutant group (HR: 1.16; 95% Cl: 0.23 - 5.88, p = 0.93). Of 118 patients, 92 pts were HER2 negative (control) and 26 patients were HER2 positive. Median TTF was 23 months for control vs. 14 months for HER2+ group (HR: 0.80; 95% CI: 0.46 - 1.39, p = 0.42). Median OS was 52 months for control vs. 40 months for HER2+ group (HR: 0.87; 95% Cl: 0.47 - 1.64, p = 0.67). Conclusions: The time-to-treatment failure and overall survival in the endocrine-sensitive disease are 2-fold higher compared to the endocrine-resistant disease. Patients with PIK3CA, ESR1 or BRCA1/2 mutation or with HER2 overexpression/amplification historically have poor survival outcomes, but in hypothesis-generating analysis, we showed statistically similar overall survival outcomes in these patients treated with anastrozole plus fulvestrant, compared to controls without these poor prognostic features. We suggest that anastrozole plus fulvestrant should be the preferred partner with molecularly targeted agents. Citation Format: Tianyi Tang, Yu Cheng, Ritesh Parajuli, Neha Patel, Min-Ying Su, Chaitali Nangia, Rita S Mehta. Overall survival outcomes of combination anastrozole and fulvestrant in molecular subsets of hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-32.

Background: Chemopreventive agents such as selective estrogen receptor modulators (SERMs; tamoxifen and raloxifene) and aromatase inhibitors (AIs; exemestane and anastrozole) have proven efficacy in reducing breast cancer risk by 41%-79% in high risk women. Women at high risk of developing breast cancer face the complex decision of whether to take SERMs or AIs for breast cancer chemoprevention. Underserved racial/ethnic minority women are less likely to take chemoprevention, contributing to higher rates of advanced tumors, and poorer clinical outcomes compared to non-Hispanic whites, which could exacerbate health disparities. RealRisks is a patient-centered web-based decision aid (DA) that was designed to promote understanding of breast cancer risk and to engage diverse women in planning a preference-sensitive course of decision-making about taking chemoprevention. We aimed to understand perceptions of women at high-risk for developing breast cancer regarding their use of RealRisks. Methods: We completed enrollment to a randomized controlled trial (RCT) among 300 racially/ethnically diverse high-risk women assigned to standard educational materials alone or in combination with RealRisks, with the primary endpoint of chemoprevention uptake at 6 months. We conducted a qualitative study using semi-structured interviews with a subset of 27 high-risk women enrolled in the intervention arm of the RCT to understand how they interact with the DA. All interviews were audio-recorded, transcribed verbatim, and compared against the digital recordings to ensure accuracy of the content. Content analysis was used as a method to analyze the data and to generate themes. Results: The mean age of the participants was 60.9 years (SD, 10.3). Our sample was racially and ethnically diverse with 59.3% non-Hispanic white, 18.5% non-Hispanic black, 14.8% Hispanic/Latina, and 3.7% Asian. Most participants had a family history of breast cancer (70.4%) and most (78%) reported using RealRisks after being granted access to the DA. Three overarching themes emerged from the qualitative analyses: (1) acceptability of the intervention, (2) usability of the intervention, (3) and information needs. RealRisks was found to be acceptable among the women who used the DA (n=21/27). Most women (n=18/21) felt that RealRisks improved their knowledge about breast cancer risk and chemoprevention options and informed their decision-making about whether or not taking chemoprevention was the right choice for them (n=17/21). Most women reported that RealRisks was easy to navigate, user-friendly, and easily accessible online. Alternatively, a subset of women (n=9/21) shared challenges with using the DA, as they wanted more tailoring based on user characteristics; felt that the DA was specifically targeting multi-ethnic populations that did not reflect them; used difficult terminology; and had a strong emphasis on chemoprevention drugs. Participants offered recommendations for improving the DA and shared their information needs, which mainly focused on wanting to learn about guidelines for mammography screening and lifestyle modification. Conclusions: With this qualitative study, we demonstrated the acceptability of the RealRisks web-based DA among diverse high-risk women with a few caveats and recommendations for improvement. These results emphasize the need for more tailoring of the DA based on user characteristics and a holistic approach to reducing breast cancer risk, to include information on breast cancer screening, as well as lifestyle risk factors. Next steps include incorporating feedback from this study to further enhance the DA and to optimize the modular architecture within RealRisks to include additional modules to meet the needs of diverse high-risk women. Citation Format: Ashlee Guzman, Thomas Silverman, Jennie Mata, Rita Kukafka, Katherine D Crew, Tarsha Jones. Use of a web-based decision aid to promote chemoprevention uptake among racially/ethnically diverse women at high-risk for developing breast cancer: A qualitative study [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS8-35.

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. Resumo 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 razõesmais 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.