Search Results (123)

Objectives: Obesity and the associated metabolic dysfunction influence fertility performance at molecular levels and ABC transporters are considered as potential molecular factors affecting fertility both in the testis and sperm; therefore, we aimed to examine the effect of a short-term diet-induced obesity on testicular and spermatic ABC transporters in a rat model focusing on the expressions of P-glycoprotein (P-gp, Abcb1) and breast cancer resistance protein (BCRP, Abcg2). The testicular androgen state involving aromatase enzyme (Cyp19a1), androgen receptor (Ar), and testosterone levels were also evaluated. Methods: Obesity was induced in male Sprague Dawley rats by feeding a high-fat, high-sugar diet (HFHSD) for 10 weeks, and metabolic status was evaluated using a glucose tolerance test. The weight and size of reproductive organs were measured, and Abcb1a/1b, Abcg2, Cyp19a1, and Ar expression in testes or sperm was determined by RT-PCR and Western blotting. At the same time, testosterone levels were measured by ELISA. Results: HFHSD successfully induced higher weight gain with glucose intolerance and reduced reproductive organ size. In obese rats, testicular Abcb1a and Abcb1b mRNA and P-gp protein expression were significantly higher, whereas testicular Abcg2 mRNA levels decreased. Spermatic Abcb1a, Abcb1b and Abcg2 mRNA expression also reduced in obesity. Neither testicular testosterone concentration nor Cyp19a1 and Ar mRNA expression levels changed after the 10-week obesogenic diet compared with controls. Conclusions: Overall, our study revealed infertility-related ABC transporter changes in obese male rats, suggesting that these alterations may predispose obese males to fertility impairments, even before the obesity-induced androgen dysregulation. Full article

This study investigated the application of six machine learning regression algorithms such as Random Forest, CatBoost, K-Nearest Neighbours, XGBoost, LightGBM, and Gradient Boosting, paired with Molecular ACCess System (MACCS) key fingerprints for the quantitative prediction of aromatase (CYP19A1) inhibitory potency, expressed as pIC₅₀. A dataset of 187 compounds was assembled from the ChEMBL database (version 33, Target ID: CHEMBL1978) following by systematic data curation workflow encompassing duplicate removal, pIC₅₀ transformation, and activity-based filtering. Model performance was rigorously evaluated using an 80/20 stratified train/test split, 5-fold cross-validation, and Y-randomisation testing to ensure unbiased assessment of predictive generalisation. Feature selection via CatBoost permutation importance on the held-out test set identified the top 20 predictive MACCS keys from an initial 166-bit space, substantially reducing dimensionality and improving generalisation across all models. Among the algorithms evaluated, CatBoost trained on the top 20 features achieved the strongest test-set performance (R² = 0.693, RMSE = 0.794, MAE = 0.659) with the most stable cross-validation R² (0.062 ± 0.304), outperforming all other algorithms. Y-randomisation testing returned an empirical p-value of <0.01, confirming that model performance reflects genuine structure–activity relationships rather than statistical chance. Permutation importance and SHAP analysis identified nitrogen-containing heterocyclic fragments (MACCS_41, MACCS_145) and halide-bearing substructures (MACCS_109) as the primary structural determinants of aromatase inhibitory potency, consistent with established CYP19A1 pharmacophoric requirements. Application of the model to ten representative plasticizers demonstrated that the refined applicability domain (h* = 0.423) accommodated eight of the ten compounds, enabling reliable potency predictions across phthalate esters and bisphenol analogues. These findings establish a transparent and reproducible QSAR framework for first-tier endocrine disruption risk screening of plasticizers and highlight the importance of permutation-based feature selection and applicability domain assessment in QSAR model development. Full article

Background: Fibroblast growth factor 21 (FGF21) is a peptide hormone that is synthesized by several organs and regulates energy homeostasis, including reducing fat mass and lowering hyperglycemia, insulin resistance and dyslipidemia. It also increased metabolic syndrome (MS) and cardiovascular risk in breast cancer (BC) survivors treated with aromatase inhibitors (AIs) aimed at reducing cancer recurrence. We evaluated whether blood FGF21 concentration is associated with MS and its five criteria in postmenopausal women treated with AIs, and whether this persists after multimodal interventions that reduce MS. Methods: A quasi-experimental longitudinal study in 31 postmenopausal women with localized BC on Ais, assessed via a 12-week multimodal program. Their MS was evaluated per the NCEP-ATP III guidelines (waist circumference, blood pressure, fasting glucose, triglycerides, HDL-cholesterol). Plasma FGF21 was measured pre/post-intervention via fasting blood samples, centrifugation, and ELISA assay. Results: Pre-intervention FGF21 median: 377.62 pg/mL (38.40–1616.42). Plasma FGF21 concentrations positively correlated with MS criteria number pre- and post-intervention (all p < 0.05). Linear regression confirmed pre-intervention MS criteria (β = 127.262, p = 0.006) and antihypertensive drugs as predictors of post-FGF21 levels. Analysis of individual MS criteria revealed significant associations with blood pressure (p = 0.028 and p = 0.022 for systolic and diastolic pressure, respectively) and fasting glucose changes (p = 0.008). Conclusions: Plasma FGF21 may act as a biomarker for monitoring exercise-based interventions which reduce MSs, particularly hypertension and hyperglycemia, in AI-treated BC survivors. Full article

Background: Oral progestogens, including megestrol acetate (MA) and medroxyprogesterone acetate (MPA), have largely been superseded by aromatase inhibitors, tamoxifen, and selective oestrogen receptor degraders (SERDs) in oestrogen receptor-positive (ER-positive) metastatic breast cancer. However, they remain an option as late-line therapy after failure of standard treatments. Contemporary data are limited, particularly in patients previously treated with CDK4/6 inhibitors. Methods: We conducted a multi-site retrospective analysis of patients with ER-positive metastatic breast cancer treated with MA or MPA between 2014 and 2024 at four hospital sites across London, United Kingdom. Patients were identified using pharmacy dispensing records. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan–Meier method and Cox regression. Subgroup analyses included prior CDK4/6 inhibitor exposure, histology and liver metastases. Results: A total of 116 patients were included. Median PFS was 2.4 months (95% CI 2.2–2.9), and median OS was 3.3 months (95% CI 2.7–4.9). Prior CDK4/6 inhibitor exposure was associated with shorter PFS (1.9 vs. 2.8 months; HR 1.59; 95% CI 1.08–2.35, p = 0.019) and a trend toward shorter OS (3.1 vs. 3.6 months; HR 1.18, 95% CI 0.80–1.75, p = 0.41). Similarly, liver metastases were associated with shorter PFS (2.3 vs. 2.8 months; HR 1.78, 95% CI 1.12–2.85, p = 0.015), with a trend toward worse OS (3.1 vs. 4.9 months; HR 1.45, 95% CI 0.93–2.25, p = 0.103). A subset of patients derived prolonged benefit, with a 6-month PFS rate of 16%. Toxicity was manageable; thromboembolic events and oedema occurred in 9% and 11% of patients respectively. Appetite improvement was reported in 10%. Conclusions: MA and MPA demonstrated modest but clinically relevant late-line activity in heavily pretreated, endocrine-refractory ER-positive metastatic breast cancer. While prior exposure to CDK4/6 inhibitors was associated with shorter PFS, patients without liver metastases appeared to derive the greatest benefit. These findings support a role for oral progestogens in selected patients who have exhausted standard therapeutic options. Full article

Background/Objectives: Previous studies have suggested that lifestyle intervention (LSI) therapies involving diet and exercise can modulate DNA methylation; however, whether this occurs in severely obese hypogonadal men undergoing weight loss from diet and exercise remains unclear. Methods: In this study, we investigated the effects of weight loss from diet and exercise on global DNA methylation as well as on the mRNA expression of specific demethylation enzymes, DNMT1, DNMT3A, and DNMT3B—in peripheral blood mononuclear cells (PBMCs) and DNA methylation markers in DNA of severely obese hypogonadal men. This is a secondary analysis of samples of severely obese (body mass index of ≥35 kg/m²) hypogonadal men undergoing weight loss from diet and exercise in addition to an aromatase inhibitor (anastrozole) or placebo for a total of 12 months. Results: LSI therapy significantly reduced global DNA methylation and 5-methylcytosine (5-mC) levels, decreased DNMT1, DNMT3A, and DNMT3B (p < 0.05) mRNA levels and markedly decreased CEBPα, FTO, and PPARγ mRNA expression. The reduction in global methylation was independent of aromatase inhibitor use. Conclusions: In summary, our findings suggest that LSI induces epigenetic modifications in leukocytes, possibly through the regulation of DNMT gene expression. Future studies are warranted to clarify the mechanistic pathways linking lifestyle-induced epigenetic alterations to metabolic health outcomes. Full article

Background: Follicle-stimulating hormone (FSH)-based vaccines show the potential to disrupt spermatogenesis without disturbing sexual function and libido in males. Herein, we developed a novel FSH vaccine based on the tandem of a conserved 13-amino acid receptor-binding epitope of FSHβ (FSHβ13AA-T) and tested its effect on reproductive physiology and function using the male mouse as a model. Methods: Serum reproductive hormone levels, testicular histology, daily sperm production, sperm motility, libido and fertility of male mice following FSH vaccination were determined. Results: Compared to placebo-immunized controls, FSH vaccination triggered (p < 0.05) marked antibody generation, inhibited spermatogenesis and reduced sperm motility (p < 0.05), without adverse effects on serum LH and testosterone levels as well as the libido of male mice. Mechanistically, FSH vaccination suppressed (p < 0.05) testicular local estrogen production by downregulated aromatase encoding gene Cyp19a1 expression and also downregulated (p < 0.05) expression of key spermatogenic genes in testes, including Creb, INHα, Wnt2, Aqp8, Cmtm2a and Spata19, thus disrupting and impairing spermatogenesis and sperm motility. Conclusions: These results demonstrate that immunization of male mice against FSHβ13AA could substantially inhibit spermatogenesis and reduce sperm motility. Thus, FSHβ13AA-based vaccines hold potential for development as male contraceptives that do not compromise libido in species including men in which FSH is essential for spermatogenesis. Full article

Background: Breast cancer survivors often experience long-term endocrine- and chemotherapy-related side effects, including sleep disorders, anxiety, and depression. Sleep disorders are particularly prevalent and affect patient adherence and quality of life. This study examined the prevalence and risk factors for sleep disorders in patients with breast cancer based on treatment exposure. Methods: Patients with breast cancer (2009–2015) were identified from the Health Insurance Review and Assessment database. They were categorized by chemotherapy exposure and further by endocrine or taxane use. Sleep disorders, anxiety, and depression were assessed using diagnostic and prescription codes. Propensity score matching and Cox proportional hazard models were applied to adjust confounders and evaluate risk factors. Results: Among the 62,714 patients, those receiving endocrine therapy had a higher risk of sleep disorders (hazard ratio [HR], 1.276; 95% confidence interval [CI], 1.087–1.497; p = 0.003), irrespective of tamoxifen or aromatase inhibitor use. In chemotherapy-treated patients, taxane exposure significantly increased sleep disorder risk (HR, 1.268; 95% CI, 1.159–1.389; p < 0.001). The cumulative incidence of sleep disorders peaked within two years post treatment and remained elevated over time. Anxiety and depression rates did not differ significantly between the treatment groups. Conclusions: Endocrine therapy and taxane chemotherapy are independent risk factors for sleep disorders in patients with breast cancer. Screening and interventions are essential for improving long-term well-being. Future studies should explore personalized approaches for managing treatment-related sleep disturbance. Full article

Background/Objectives: Kidney cancer (RC) is a significant global health burden. Renal cell carcinoma (RCC) is the most common form of kidney cancer. Its predominant histological subtype is clear cell renal cell carcinoma (ccRCC), which is frequently diagnosed at an advanced local stage or with metastases. Detecting cancer at an early stage significantly increases the likelihood of a cure; therefore, research on new markers and a thorough understanding of tumor biology are essential. This study investigated the significance of aromatase (ARO), cathepsin S (CTSS), and matrix metalloproteinase 1 (MMP-1) as potential biomarkers in ccRCC. Methods: ARO, CTSS, and MMP-1 concentrations in plasma were determined using SPRi biosensors. Appropriate antibodies were used as biorecognition molecules in the biosensors. The samples analyzed came from 60 patients with histopathologically confirmed clear cell renal cell carcinoma (ccRCC) and from 26 patients diagnosed with chronic cystitis or benign prostatic hyperplasia (BPH). Results: A statistically significant increase (p < 0.00001) in the concentration of all proteins compared with the control samples was observed at the T3–T4 stage. The ARO concentration was already statistically significantly higher at the T1–T2 stage (p < 0.00001). The ROC curve for aromatase demonstrated high sensitivity and specificity for detecting ccRCC, with a cut-off point of 7.53 ng mL⁻¹. A moderate positive correlation was also found between the concentrations of the three tested substances in renal cancer, which may indicate potential interactions in the tumor’s pathogenesis. Conclusions: SPRI testing has been shown to be an alternative to standard methods for detecting potential ccRCC markers. The biosensors used in the study can simultaneously determine ARO, CTSS, and MMP-1. The results obtained suggest the potential importance of these proteins in the development of ccRCC, and our work proposes a new diagnostic technique that may aid in the diagnosis of ccRCC. Full article

Background/Objectives: Despite initial sensitivity to ET, most patients with HR+/HER2− breast cancer develop resistance. A key molecular mechanism of endocrine resistance in HR+ breast cancer involves dysregulation of the cyclin D–CDK4/6–Rb signaling axis, which controls the transition from the G1 to S phase of the cell cycle. Introducing cyclin-dependent kinase 4 and 6 inhibitors (CDK4/6i) has changed therapeutic paradigms in HR+/HER2− breast cancer, as their synergistic use with endocrine therapy significantly prolongs progression-free survival (PFS) and effectively mitigates clinically relevant endocrine resistance in this patient population compared to ET alone. The aim of our study was to evaluate patients’ clinical characteristics, the clinical effectiveness of treatment, measured by progression-free survival (PFS), and the safety profile of combined ribociclib (CDK4/6i) and standard endocrine therapy (aromatase inhibitor) as a first-line treatment for patients with HR+/HER2− advanced or metastatic breast cancer at the Clinic of Oncology, University Clinical Centre Nis, Serbia. Methods: In this study, we present a retrospective prospective analysis of all patients with metastatic HR+/HER2− breast cancer treated with a combination of ribociclib and aromatase inhibitors in the first-line treatment of metastatic HR+/HER2− BC between June 2022 and January 2025, with a follow-up completed in October 2025. A total of 132 patients who met the criteria were included. Results: The median progression-free survival (PFS) in the entire group was 30 months, while the 12-, 24-, and 36-month PFS were 82.15%, 72.24%, and 28.75%, respectively. The overall response rate (ORR) was 41.7%, while the clinical benefit rate (CBR) was 89.3%. There was no statistically significant difference in PFS with respect to tumor grade (p = 0.54), Ki 67 level (<20% vs. >20%, p = 0.83), or the type of adjuvant endocrine therapy used (tamoxifen vs. AI) It is important to emphasize that female patients who had not previously received chemotherapy had a better response to ribociclib compared to those who had (33 m vs. 28 m, p = 0.05). Although a numerical difference in PFS was found in patients with bone-only metastases compared to those with metastases in other organs, the difference was not statistically significant (PFS 33 m vs. 30 m, p = 0.27;), and efficacy was consistent across menopausal status groups. The most common adverse effect was neutropenia, occurring in 89.4% of patients, 47.7% of whom presented with grade 3 or 4. As for hepatotoxicity, transaminase increase occurred in 25 patients (18.8%), 5 of whom (3.8%) were grade 3–4, and QTc interval prolongation occurred in 5.3% of patients. Conclusions: The results in terms of PFS and AEs are consistent with those of pivotal studies and real clinical practice data, but a direct comparison is not possible due to differences in patient populations. Ribociclib once again demonstrated efficacy in all patient subgroups and remains the gold standard, alongside ET, for first-line HR+/HER2-negative mBC. Full article

Background/Objectives: Breast cancer remains the most prevalent malignancy among women worldwide, with letrozole (LZ) serving as a critical aromatase inhibitor for hormone receptor–positive cases. However, long-term oral administration of LZ is often associated with systemic adverse effects and poor patient compliance. To overcome these limitations, new non-aqueous nanoemulgels (NEMGs) were developed for transdermal delivery of LZ. Methods: The NEMGs were formulated using glyceryl monooleate (GMO), Sepineo P600^®, Transcutol, propylene glycol, and penetration enhancers propylene glycol laurate (PGL), propylene glycol monocaprylate (PGMC), and Captex^®. Physicochemical characterization, solubility, stability, and in vitro permeation studies were conducted using Strat-M^® membranes, while in vivo pharmacokinetics were evaluated in rat models. Results: The optimized GMO/PGMC-based NEMG demonstrated significantly enhanced drug flux, higher permeability coefficients, and shorter lag times compared with other NEMGs and suspension emulgels. In vivo, transdermal application of the GMO/PGMC-based NEMG over an area of 2.55 cm² produced dual plasma absorption peaks, with 57% of the LZ dose absorbed relative to oral administration over 12 days. Shelf-life and accelerated stability assessments confirmed excellent physicochemical stability with negligible crystallization. Conclusions: The developed LZ NEMG formulations offer a stable, effective, and patient-friendly transdermal drug delivery platform for breast cancer therapy. This system demonstrates potential to improve patient compliance and reduce systemic toxicity compared to conventional oral administration. Full article

Endocrine-disrupting chemicals (EDCs) are widespread contaminants that interfere with hormonal signaling and compromise reproductive success in aquatic organisms. Vitellogenin (VTG) is one of the most widely established biomarkers of estrogenic exposure, especially in males and juveniles. However, evidence from multi-omics studies indicates that VTG induction occurs within broader transcriptional and regulatory networks, involving genes such as cyp19a1 (aromatase), cyp1a (cytochrome P4501A), and other stress-responsive genes, underscoring the complexity of endocrine disruption. This review focuses on nuclear receptor isoforms, including estrogen receptor alpha (ERα), estrogen receptor beta (ERβ), and androgen receptor (AR) variants. We examine the diversification of vtg gene repertoires across teleost genomes and epigenetic mechanisms, such as DNA methylation and microRNAs, that modulate sex-dependent sensitivity. In addition, we discuss integrative approaches that combine VTG with transcriptomic, epigenetic, and histological endpoints. Within the Adverse Outcome Pathway (AOP) and weight-of-evidence (WoE) frameworks, these strategies provide mechanistic links between receptor activation and reproductive impairment. Finally, we outline future directions, focusing on the development of sex-specific biomarker panels, the integration of omics-based data with machine learning, and advances in ecogenomics. Embedding molecular responses into ecological and regulatory contexts will help bridge mechanistic insights with environmental relevance and support sustainability goals such as SDG 14 (Life Below Water). Full article

Background: Adjuvant endocrine therapy (AET) enhances survival outcomes in hormone receptor–positive (HR+) breast cancer. However, this treatment is associated with toxicities that may adversely affect the quality of life (QoL) and impact patient–physician communication. A thorough understanding of symptom-reporting behaviors is essential for optimizing survivorship care. Methods: This cross-sectional study surveyed 191 female patients with HR+ breast cancer undergoing adjuvant AET (tamoxifen or aromatase inhibitors ± ovarian function suppression [OFS]) at Antalya Training and Research Hospital between July and August 2025. QoL, symptom burden, and adverse event (AE) reporting behaviors were assessed using validated instruments (European Organization for Research and Treatment of Cancer Quality of Life Questionnaire C30 [EORTC QLQ-C30], adapted Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events [PRO-CTCAE]). Categorical variables were compared using chi-square tests, and multivariate analyses were performed using logistic regression. Results: The median age was 54 years (interquartile range [IQR]: 46–61 years). The following independent variables were identified as predictors of a higher symptom burden: prior chemotherapy (odds ratio [OR]: 3.75; 95% confidence interval [CI]: 1.46–9.69; p = 0.006), OFS use (OR: 3.29; 95% CI: 1.51–7.15; p = 0.003), AE reporting to physicians (OR: 3.52; 95% CI: 1.80–6.88; p < 0.001), and complementary and alternative medicine (CAM) use (OR: 7.27; 95% CI: 1.57–33.63; p = 0.011). Independent predictors of poor QoL included receiving psychological support (OR: 0.36; 95% CI: 0.19–0.67; p = 0.002) and AE reporting (OR: 0.28; 95% CI: 0.13–0.64; p = 0.001). Conclusions: Symptom burden and QoL in patients with HR+ breast cancer receiving AET are influenced by clinical history, including chemotherapy and OFS; behavioral factors, such as reporting behaviors; and supportive care, including CAM and psychological support. The routine integration of patient-reported outcomes and proactive symptom monitoring is crucial for delivering personalized and effective survivorship care. Full article

Background: Ectopic pregnancy (EP) is a serious condition often treated with methotrexate. Letrozole, a safer aromatase inhibitor, may offer an effective alternative. This study presents a meta-analysis comparing the efficacy and safety of single-agent letrozole versus methotrexate for EP management. Methods: A systematic review and meta-analysis were conducted following PRISMA guidelines. Six sources of information underwent screening until 12 June 2025. Risk of bias and evidence certainty of evidence were assessed. Primary outcome was treatment success rate. Results were presented as mean difference (MD) or risk ratio (RR) along with a 95% confidence interval (CI) using a random-effects model. Results: Six studies (three randomized controlled trials and three nonrandomized prospective cohort studies) comprising seven arms and 260 patients (letrozole = 130, methotrexate = 130) were included. Almost all studies (n = 5) had overall moderate or high risk. Treatment success rates were comparable between groups (n = 7 arms; RR = 1.05; 95% CI: [0.94, 1.17]; p = 0.40). Letrozole was associated with significantly lower β-hCG levels on day 4 (n = 5 arms; MD = −95 mIU/mL; 95% CI: [−189.7, −0.91]; p = 0.048), day 7 (n = 5 arms; MD = −86.24 mIU/mL; 95% CI: [−143.1, −29.36]; p < 0.001), and day 14 (n = 3 arms; MD = −9.15 mIU/mL; 95% CI: [−17.24, −1.06]; p = 0.03); however, the differences were not clinically meaningful. Letrozole showed a better safety profile with higher platelet counts and lower liver enzymes. AMH levels were similar between groups. Most analyses were consistent, though secondary outcomes were less stable. Overall evidence certainty was rated ‘very low’ due to seriousness of risk of bias and imprecision. Conclusions: While letrozole shows comparable efficacy to methotrexate and a potentially better safety profile in the management of EP, the certainty of evidence is ‘very low’ due to risk of bias and imprecision. Therefore, these findings should be interpreted with caution, and further high-quality studies are urgently needed to confirm the results. Full article

Low-grade-serous ovarian carcinomas (LGSOC) are rare tumors characterized by a high recurrence rate and limited treatment options. Most LGSOC are estrogen receptor (ER)-positive and demonstrate alterations in the RAS/MAPK pathway. Avutometinib is a dual RAF/MEK clamp, whereas defactinib and VS-4718 are focal adhesion kinase (FAK) inhibitors. Fulvestrant is an ER antagonist/degrader. We assessed the preclinical efficacy of fulvestrant, avutometinib + VS-4718 (FAKi), and the triple combination in a chemotherapy/aromatase inhibitor-resistant LGSOC patient-derived tumor xenograft (PDX) model. Tissue obtained from a LGSOC patient wild-type for KRAS/NRAS/BRAF mutations in progression after chemotherapy/anastrozole was transplanted into female CB17/lcrHsd-Prkdc/SCID mice (PDX-OVA(K)250). The animals were treated with either saline/control, fulvestrant, avutometinib/FAKi, or the triple combination of avutometinib/FAKi/fulvestrant. Avutometinib and FAKi were given five-days on and two-days off through oral gavage. Fulvestrant was administered subcutaneously weekly. Mechanistic studies were performed ex vivo using Western blot assays. Animals treated with the triple combination demonstrated stronger tumor growth inhibition compared to all the other experimental groups including control/saline (p < 0.001), single-agent fulvestrant (p = 0.04 from day eight and onwards), and avutometinib/FAKi (p = 0.02 from day 18). Median survival for mice treated with saline/control was 29 days while mice in all other experimental groups were alive at day 60 (p < 0.0001). Treatment was well tolerated across all experimental treatments. By Western blot, exposure of OVA(K)250 to the triple combination demonstrated a decrease in phosphorylated MEK (p-MEK) and p-ERK levels. The addition of fulvestrant to avutometinib/FAKi is well tolerated in vivo and enhances the antitumor activity of avutometinib/FAKi in a LGSOC-PDX model with acquired resistance to chemotherapy/aromatase inhibitors. These results support the clinical evaluation of avutometinib/defactinib in combination with fulvestrant or an aromatase inhibitor in patients with recurrent LGSOC. Full article

Background and Objectives: The effect of AR expression on prognosis in hormone receptor-positive her2-negative breast cancer is controversial. There are studies showing that AR is a treatment target, a mechanism of resistance to endocrine treatments, and a prognostic indicator in these patients whose standard treatment is a CDK 4/6 inhibitor added to endocrine treatment. We aimed to investigate the effect of AR, the AR/ER ratio, and the AR/PR ratio on CDK4/6 inhibitor treatment response in breast cancer, as well as their effects on PFS, and to validate the hypothesis that AR is a target for research. Materials and Methods: Patients who were diagnosed with metastatic hormone receptor-positive her2-negative breast cancer and received cdk4/6 inhibitor + aromatase inhibitor in first-line therapy were included in this study conducted at Balıkesir Atatürk City Hospital. The tru-cut biopsy samples of the patients were evaluated immunohistochemically for AR, ER, and PR. Kaplan–Meier analysis was used to calculate the estimated median survival in PFS analyses, and the variables were compared with the Log-Rank test. Receiver Operating Characteristic (ROC) analysis was applied to determine the ideal cut-off. Cox regression analysis was used in univariate survival models, and the multivariate model was established with the “Forward: Likelihood Ratio (LR)” method. Hazard ratios (HRs) were also calculated as 95% confidence intervals (95% CIs). A p value below 0.05 was accepted for statistical significance. Results: In total, 41 patients were included in the study, and 73% (n = 30) of the patients were AR-positive. Increased AR (HR 1.014; 95% CI: 1.002–1.026; p = 0.023) was an unfavorable prognostic indicator. In our study, being ≥55 years old, being postmenopausal, not having visceral metastasis, having a non-IDC histology, having a low AR level (<50%), having an AR/ER ratio < 0.74, and having an AR/PR ratio < 1.00 were found to be associated with longer PFS. All factors were evaluated with univariate Cox regression analysis. Increasing AR (HR 1.014; 95% CI: 1.002–1.026; p = 0.023) was an unfavorable prognostic marker. Having an AR/ER ratio ≥ 0.74 (HR: 2.522; 95% CI: 1.004–6.336; p = 0.049) and having AR/PR ≥ 1 (HR: 2.659; 95% CI: 1.029–6.869; p = 0.043) were negative prognostic indicators. Conclusions: Our results were consistent with the literature and demonstrated the value of the androgen receptor as a therapeutic target, a mechanism explaining resistance to endocrine therapy, and an adverse prognostic indicator for creating resistance to endocrine therapy in breast cancer. Full article