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Our goal was to evaluate the impact of level of androgen receptor (AR) expression on outcomes in women with estrogen receptor [alpha] (ER) positive breast cancer. We sought to corroborate our preclinical findings that AR-agonists were efficacious in patients with ER-positive tumors that also expressed high levels of AR. Tissue microarrays (TMAs) were prepared from primary tumor blocks from patients entered on a prospective randomized adjuvant trial of tamoxifen (Tam) alone or combined with fluoxymesterone (Flu), an AR-agonist, (NCCTG 89-30-52). TMAs were stained for ER and AR and expression examined in decile increments (0-100%) of positive invasive tumor nuclei. The primary endpoint was relapse-free survival (RFS). 301 (59%) of the 514 patients had sufficient tissue to determine ER and AR expression, where nuclear staining of > 70% was considered \"enriched\" and nuclear staining of [less than or equal to] 70% was considered \"poor/moderate\". Eleven (4%) of these patients had poor/moderate ER staining and were excluded from these analyses. The proportion of the ER-enriched tumors that also had AR-enriched expression levels was 56.3% in the Tam arm and 51.8% in the Tam + Flu arm. Within the AR-enriched patients, the cumulative incidence of RFS events showed an advantage for Tam + Flu over Tam alone that reached significance (Gray's test p = 0.0472). Our findings suggest that an AR-agonist may be of value in AR-enriched, ER-enriched breast cancers and should be studied in future trials because of the availability of new, more tolerable AR-agonists.

In this work, we studied the corrosion of Cu metal in 0.5 mol L−1 HCl and the inhibition effect of the expired Cefazolin drug. The inhibition efficiency (IE) of Cefazolin varied according to its concentration in solution. As the Cefazolin concentration increased to 300 ppm, the IE increased to 87% at 298 K and decreased to 78% as the temperature increased to 318 K. The expired drug functioned as a mixed–type inhibitor. The adsorption of the drug on the copper surface followed Temkin’s adsorption model. The magnitudes of the standard free energy change (ΔGoads) and adsorption equilibrium constant (Kads) indicated the spontaneous nature and exothermicity of the adsorption process. Energy dispersive X-ray (EDX) and scanning electron microscopy (SEM) techniques showed that the drug molecules were strongly attached to the Cu surface. The electrochemical frequency modulation (EFM), potentiodynamic polarization (PP), and electrochemical impedance spectroscopy (EIS) results were in good agreement with the results of the weight loss (WL) method. The density functional tight–binding (DFTB) and Monte Carlo (MC) simulation results indicated that the expired drug bound to the copper surface through the lone pair of electrons of the heteroatoms as well as the π-electrons of the tetrazole ring. The adsorption energy between the drug and copper metal was –459.38 kJ mol−1.

The androgen receptor (AR) is a steroid hormone receptor widely detected in breast cancer. Evidence suggests that the AR might be a tumor suppressor in estrogen receptor alpha-positive (ERα+ve) breast cancer but a tumor promoter in estrogen receptor alpha-negative (ERα-ve) breast cancer. Modulating AR activity could be a potential strategy for treating breast cancer. For ERα+ve breast cancer, activation of the AR had been demonstrated to suppress the disease. In contrast, for ERα-ve breast cancer, blocking the AR could confer better prognosis to patients. These studies support the feasibility of utilizing AR modulators as anti-cancer drugs for different subtypes of breast cancer patients. Nevertheless, several issues still need to be addressed, such as the lack of standardization in the determination of AR positivity and the presence of AR splice variants. In future, the inclusion of the AR status in the breast cancer report at the time of diagnosis might help improve disease classification and treatment decision, thereby providing additional treatment strategies for breast cancer.

Significant variation exists in the outcomes used in cancer cachexia trials, including measures of body composition, which are often selected as primary or secondary endpoints. To date, there has been no review of the most commonly selected measures or their potential sensitivity to detect changes resulting from the interventions being examined. The aim of this systematic review is to assess the frequency and diversity of body composition measures that have been used in cancer cachexia trials. MEDLINE, Embase and Cochrane Library databases were systematically searched between January 1990 and June 2021. Eligible trials examined adults (≥18 years) who had received an intervention aiming to treat or attenuate the effects of cancer cachexia for >14 days. Trials were also of a prospective controlled design and included body weight or at least one anthropometric, bioelectrical or radiological endpoint pertaining to body composition, irrespective of the modality of intervention (e.g., pharmacological, nutritional, physical exercise and behavioural) or comparator. Trials with a sample size of <40 patients were excluded. Data extraction used Covidence software, and reporting followed the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidance. This review was prospectively registered (PROSPERO: CRD42022276710). A total of 84 clinical trials, comprising 13 016 patients, were eligible for inclusion. Non‐small‐cell lung cancer and pancreatic cancer were studied most frequently. The majority of trial interventions were pharmacological (52%) or nutritional (34%) in nature. The most frequently reported endpoints were assessments of body weight (68 trials, n = 11 561) followed by bioimpedance analysis (BIA)‐based estimates (23 trials, n = 3140). Sixteen trials (n = 3052) included dual‐energy X‐ray absorptiometry (DEXA)‐based endpoints, and computed tomography (CT) body composition was included in eight trials (n = 841). Discrepancies were evident when comparing the efficacy of interventions using BIA‐based estimates of lean tissue mass against radiological assessment modalities. Body weight, BIA and DEXA‐based endpoints have been most frequently used in cancer cachexia trials. Although the optimal endpoints cannot be determined from this review, body weight, alongside measurements from radiological body composition analysis, would seem appropriate. The choice of radiological modality is likely to be dependent on the trial setting, population and intervention in question. CT and magnetic resonance imaging, which have the ability to accurately discriminate tissue types, are likely to be more sensitive and provide greater detail. Endpoints are of particular importance when aligned with the intervention's mechanism of action and/or intended patient benefit.

This clinical trial evaluated the addition of fluoxymesterone (Flu) to tamoxifen (Tam) in women with resected early stage breast cancer and attempted to corroborate the findings of superiority for the combination over Tam alone seen in a previous randomized trial in metastatic disease. Postmenopausal women with early stage breast cancer that was known to be estrogen receptor (ER) positive were randomized to treatment with Tam (20 mg per day orally for 5 years) alone or combined with Flu (10 mg orally twice per day for 1 year). The primary endpoint was relapse-free survival (RFS) defined as local-regional or distant recurrence including ductal carcinoma in situ of the ipsilateral, but not contralateral breast, and death from any cause. There were 541 eligible patients entered between 1991 and 1995 and the treatment arms were balanced with respect to patient characteristics. The median follow up of patients still alive was 11.4 years. No significant difference was found between Tam plus Flu and Tam alone in terms of RFS or overall survival. The adjusted hazard ratio (Tam+Flu/Tam) for relapse or death without relapse was estimated to be 0.84 (95% CI: 0.64-1.10) and that for death was 0.89 (95% CI: 0.67-1.18). As expected there was more virilization in women who received Flu. This clinical trial did not demonstrate superiority of Tam plus Flu over Tam alone as adjuvant therapy for postmenopausal women with resected early breast cancer known to be ER positive.

Breast cancer subtypes expressing hormone receptors (HR+ BCa) have a good prognosis and respond to first-line endocrine therapy (ET). However, the majority of HR+ BCa patients exhibit intrinsic or acquired ET resistance (ET-R) and rapid onset of incurable metastatic BCa. With the failure of conventional ET, limited targeted therapy exists for ET-R HR+ BCa patients. The androgen receptor (AR) in HR-negative BCa subtypes is emerging as an attractive alternative target for therapy. The AR drives Luminal AR (LAR) triple-negative breast cancer progression, and LAR patients consistently exhibit positive clinical benefits with AR antagonists in clinical trials. In contrast, the function of the AR in HR+ BCa is more conflicting. AR in HR+ BCa correlates with a favorable prognosis, and yet, the AR supports the development of ET-R BCa. While AR antagonists were ineffective, ongoing clinical trials with a selective AR modulator have shown promise for HR+ BCa patients. To understand the incongruent actions of ARs in HR+ BCa, the current review discusses how the structure and post-translational modification impact AR function. Additionally, completed and ongoing clinical trials with FDA-approved AR-targeting agents for BCa are presented. Finally, we identify promising investigational small molecules and chimera drugs for future HR+ BCa therapy.

There is no consensus on the optimal endpoint(s) in cancer cachexia trials. Endpoint variation is an obstacle when comparing interventions and their clinical value. The aim of this systematic review was to summarize and evaluate endpoints used to assess appetite and dietary intake in cancer cachexia clinical trials. A search for studies published from 1 January 1990 until 2 June 2021 was conducted using MEDLINE, Embase and Cochrane Central Register of Controlled Trials. Eligible studies examined cancer cachexia treatment versus a comparator in adults with assessments of appetite and/or dietary intake as study endpoints, a sample size ≥40 and an intervention lasting ≥14 days. Reporting was in line with PRISMA guidance, and a protocol was published in PROSPERO (2022 CRD42022276710). This review is part of a series of systematic reviews examining cachexia endpoints. Of the 5975 articles identified, 116 were eligible for the wider review series and 80 specifically examined endpoints of appetite (65 studies) and/or dietary intake (21 studies). Six trials assessed both appetite and dietary intake. Appetite was the primary outcome in 15 trials and dietary intake in 7 trials. Median sample size was 101 patients (range 40–628). Forty‐nine studies included multiple primary tumour sites, while 31 studies involved single primary tumour sites (15 gastrointestinal, 7 lung, 7 head and neck and 2 female reproductive organs). The most frequently reported appetite endpoints were visual analogue scale (VAS) and numerical rating scale (NRS) (40%). The appetite item from the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ) C30/C15 PAL (38%) and the appetite question from North Central Cancer Treatment Group anorexia questionnaire (17%) were also frequently applied. Of the studies that assessed dietary intake, 13 (62%) used food records (prospective registrations) and 10 (48%) used retrospective methods (24‐h recall or dietary history). For VAS/NRS, a mean change of 1.3 corresponded to Hedge's g of 0.5 and can be considered a moderate change. For food records, a mean change of 231 kcal/day or 11 g of protein/day corresponded to a moderate change. Choice of endpoint in cachexia trials will depend on factors pertinent to the trial to be conducted. Nevertheless, from trials assessed and available literature, NRS or EORTC QLQ C30/C15 PAL seems suitable for appetite assessments. Appetite and dietary intake endpoints are rarely used as primary outcomes in cancer cachexia. Dietary intake assessments were used mainly to monitor compliance and are not validated in cachexia populations. Given the importance to cachexia studies, dietary intake endpoints must be validated before they are used as endpoints in clinical trials.

Purpose: The purpose of this study is to evaluate survival outcome in patients with hormone receptor (HR)-positive (+) metastatic breast cancer (MBC) who received fluoxymesterone after disease progression while receiving contemporary hormonal therapy, as well as the association between estrogen receptor (ER)/androgen receptor (AR) status and survival outcome in these patients. Methods: We retrospectively identified 103 patients treated with fluoxymesterone for HR + MBC from 2000 to 2014 and with at least one previous hormonal therapy in a metastatic setting. Results: A median of 3 (range 1–10) hormonal therapies (aromatase inhibitors, tamoxifen, and/or fulvestrant) were received before fluoxymesterone; 33 patients discontinued fluoxymesterone before progression because of physician decision or adverse events including toxicity in 14 patients. Of the remaining 70 patients, 2 (3 %) had complete response, 7 (10 %) partial response, and 21 (30 %) stable disease for at least 6 months, yielding a clinical benefit rate of 43 %. The median PFS was 3.9 months (95 % CI 3.2–5.3 months). Multivariate analysis revealed no significant association between PFS and the type or number of prior systemic treatments. All 39 patients who had archived tumor slides available for AR staining had ER + carcinoma; 10 had ≥1 % but <10 %, 18 had ≥10 %, and 11 had no AR nuclear expression. AR positivity with various cutoffs (i.e. any AR + cells, ≥1 % AR + cells, or ≥10 % AR + cells) was not significantly associated with survival outcome. Conclusions: Fluoxymesterone can be considered for patients whose ER + MBC progresses on contemporary hormonal therapy, regardless of the level of AR expression.

Background Our goal was to evaluate the impact of level of androgen receptor (AR) expression on outcomes in women with estrogen receptor α (ER) positive breast cancer. We sought to corroborate our preclinical findings that AR-agonists were efficacious in patients with ER-positive tumors that also expressed high levels of AR. Methods Tissue microarrays (TMAs) were prepared from primary tumor blocks from patients entered on a prospective randomized adjuvant trial of tamoxifen (Tam) alone or combined with fluoxymesterone (Flu), an AR-agonist, (NCCTG 89-30-52). TMAs were stained for ER and AR and expression examined in decile increments (0–100%) of positive invasive tumor nuclei. The primary endpoint was relapse-free survival (RFS). Results 301 (59%) of the 514 patients had sufficient tissue to determine ER and AR expression, where nuclear staining of > 70% was considered “enriched” and nuclear staining of ≤ 70% was considered “poor/moderate”. Eleven (4%) of these patients had poor/moderate ER staining and were excluded from these analyses. The proportion of the ER-enriched tumors that also had AR-enriched expression levels was 56.3% in the Tam arm and 51.8% in the Tam + Flu arm . Within the AR-enriched patients, the cumulative incidence of RFS events showed an advantage for Tam + Flu over Tam alone that reached significance (Gray’s test p  = 0.0472). Conclusions Our findings suggest that an AR-agonist may be of value in AR-enriched, ER-enriched breast cancers and should be studied in future trials because of the availability of new, more tolerable AR-agonists.

Purpose When conducting trials aimed at the improvement of cancer-related and/or cancer treatment-related toxicities, it is important to determine the best means of measuring patients’ symptoms. Methods The authors of this current manuscript have an extensive experience with the conduct of symptom-control clinical trials. This experience is utilized to provide insight into the best means of measuring symptoms caused by cancer and/or cancer therapy. Results Patient-reported outcome data are preferable for measuring bothersome symptoms, for determining toxicities caused by treatment approaches, and offer more accurate and detailed information compared with health care practitioners recording their impressions of patient experiences. Well-validated patient friendly measures are recommended when they are available. When such are not readily available, face-valid, single-item numerical rating scales are effective instruments to document both treatment trial outcomes and cancer treatment side effects/toxicities. Conclusion The use of numerical rating scales are effective means of measuring symptoms caused by cancer, by cancer treatments, and/or alleviated by symptom control treatment approaches.