The NRG Oncology research organization and NSABP B-35 randomized clinical trial prospectively collected margin width data on postmenopausal women with hormone receptor (HR)-positive ductal carcinoma in situ (DCIS) who underwent lumpectomy, whole-breast irradiation (WBI), and randomly assigned adjuvant anastrozole or tamoxifen therapy. This permitted analysis of outcomes per margin width. To analyze the effect of margin width on ipsilateral breast tumor recurrence (IBTR). NSABP B-35 was a phase 3, double-blind, randomized clinical trial in which patients were randomized to either 5 years of tamoxifen or anastrozole. Postmenopausal women with HR-positive DCIS and tumor-free margins were eligible. Enrollment was from January 6, 2003, to June 15, 2006, in academic and community hospital members of the NSABP. Study data were analyzed from July 2024 to April 2025. There were no specific interventions based on lumpectomy margin width. Lumpectomy margin width data were prospectively collected within 3 months of randomization. A pathology form classified margins as positive (ink on tumor), close (<1 mm), or negative (≥1 mm). For the negative margin subgroup, closest margin width was stated separately. Thus, an ancillary analysis using 1-mm and 2-mm margin width partitions was performed. A total of 3104 postmenopausal women (mean [SD] age, 61 [7.8] years) were enrolled in NSABP B-35. In an ancillary analysis, 2707 patients were included in the 1-mm margin width partition group, and 2546 patients were included in the 2-mm margin width partition group. IBTR was the most common first event, occurring in 90 of 2707 patients (3.3%): 24 of 502 patients (4.8%) with a margin width less than 1 mm and 66 of 2205 patients (3.0%) with a margin width greater than or equal to 1 mm. Ten-year unadjusted cumulative incidence of IBTR events was 5.6% vs 4.0% for margins less than 1 mm vs margins greater than or equal to 1 mm (P = .04). Using 2 mm as the discriminant threshold for margin width, 39 of 879 patients (4.4%) with margins less than 2 mm and 49 of 1667 patients (2.9%) with margins greater than or equal to 2 mm experienced an IBTR first. Ten-year unadjusted cumulative incidence of IBTR events with margins less than or equal to 2 mm was 5.3% vs 3.8% for those with margins greater than 2 mm (P = .05). In models adjusting for other patient and tumor factors, margin width was not a significant predictor of IBTR risk (2-mm threshold hazard ratio, 1.33; 95% CI, 0.86-2.06). Results of this ancillary analysis of the NSABP B-35 trial show that absolute differences in IBTR rates using margin width groupings of less than 1 mm or greater than or equal to 1 mm and margin width groupings of less than 2 mm or greater than or equal to 2 mm in postmenopausal women with HR-positive DCIS receiving lumpectomy, WBI, and adjuvant endocrine therapy were small. Omission of reexcision lumpectomies based on margin widths of less than 1 mm or less than 2 mm can be reconsidered in appropriate patients. ClinicalTrials.gov Identifier: NCT00053898.

Bee venom pharmacopuncture for symptom relief in rheumatoid arthritis in a tamoxifen-treated breast cancer survivor who declined methotrexate: A case report.

BackgroundDesmoid tumor is a locally aggressive fibroblastic/myofibroblastic neoplasm frequently arising in deep soft tissues. Although it can be well circumscribed, a desmoid tumor generally infiltrates surrounding tissues and tends to recur locally without metastasizing. While commonly arising in the extremities and abdominal wall, primary hepatic involvement is exceedingly uncommon.Case ReportWe report the case of a 20‐year‐old woman presenting with progressive jaundice, pruritus, weight loss, and abdominal pain. Imaging revealed a 3 × 3 cm hepatic hilar mass with bile duct dilation, initially suggestive of cholangiocarcinoma. Histopathological examination following a tru‐cut biopsy demonstrated features consistent with desmoid‐type fibromatosis, confirmed by nuclear β‐catenin positivity. Due to clinical deterioration, the patient underwent a left hemihepatectomy. The postoperative course was uneventful. Adjuvant tamoxifen therapy was administered, and follow‐up imaging showed no recurrence. Despite the hormonal changes of a subsequent pregnancy, no disease progression was observed.ConclusionThis report highlights an extremely rare presentation of desmoid tumor in the hepatic hilum, mimicking malignancy. It underscores the importance of histopathological confirmation, multidisciplinary management, and individualized follow‐up strategies, especially in women of reproductive age.

RE: Tamoxifen therapy benefit in luminal a and B breast cancer with 20-year follow-up.

RE: Tamoxifen therapy benefit in luminal a and B breast cancer with 20-year follow-up.

Tamoxifen (TMX) resistance presents a significant challenge in the treatment of ER+ breast cancer. In this study, four novel tamoxifen-based dimers were synthesized and evaluated for their antitumor activities. Among these, (Z,Z)-1 exhibited potent antiproliferative effects in ER+ cells, demonstrating selective toxicity toward cancer cells over normal cells. (Z,Z)-1 significantly outperformed tamoxifen with IC50 values of 9.18 μM (24 h) and 6.86 μM (48 h) against MCF-7 cells. Additionally, it showed greater selectivity toward ER+ breast cancer cells compared with both triple-negative cancer cells and non-cancerous cells. Mechanistic studies indicated that (Z,Z)-1 induces apoptosis in MCF-7 cells through a cell-cycle-independent mechanism, unlike TMX, which arrests cells at the G0/G1 phase. These findings suggest that (Z,Z)-1 may be a promising candidate for further development as an alternative to tamoxifen therapy in ER+ breast cancer treatment. The docking studies revealed that (Z,Z)-1 exhibits the strong binding affinity to ERα, highlighting its potential as a promising therapeutic candidate for ER+ breast cancer treatment.

(Z)-endoxifen is the tamoxifen metabolite that possesses the highest affinity to the estrogen receptor and is evolving as an alternative to tamoxifen. Mammographic breast density (MBD) change has been shown to be a proxy for tamoxifen therapy response. The objective was to measure the effect of 2 different doses of (Z)-endoxifen on MBD, safety, and side effects in healthy women. Healthy premenopausal women included in the national Swedish screening program in Stockholm were invited to KARISMA Endoxifen, a proof of principle, dose determining, double-blinded, randomized, placebo-controlled trial. Women were randomly assigned to placebo or 1 or 2 mg of (Z)-endoxifen daily for 6 months. In all, 240 women were randomly assigned. There was a significant relative change in MBD in both (Z)-endoxifen arms compared to placebo: -19.3% (95% confidence interval [CI] = -6.15% to -32.4%) in the 1 mg arm and -26.5% (95% CI = -14.1% to -38.9%) in the 2 mg arm. The number of participants discontinuing because of adverse events related to the investigational medicinal product was 4 (placebo), 5 (1 mg), and 11 (2 mg), respectively. Participants on 2 mg of (Z)-endoxifen reported significantly higher scores of vasomotor symptoms, compared with placebo. No clinically significant changes in hematological safety tests or vital signs were noted. Both 1 and 2 mg of (Z)-endoxifen significantly reduced MBD to a degree comparable to the established 20 mg dose of tamoxifen. The 1 mg dosage of (Z)-endoxifen indicated superior tolerability. Future studies are necessary to confirm impact on breast cancer incidence. ClinicalTrials.gov ID: NCT05068388.

Background and Objectives: Tamoxifen, a cornerstone selective estrogen receptor modulator in breast cancer therapy, is increasingly recognized to be associated with retinal toxicity characterized by mitochondrial dysfunction, oxidative stress, lipid peroxidation, and oxidative DNA injury. By targeting mitochondrial bioenergetic dysfunction and redox disequilibrium, adenosine triphosphate (ATP) emerges as a biologically plausible candidate for retinal cytoprotection. This study aimed to evaluate the protective effect of ATP against tamoxifen-induced retinal toxicity in a rat model. Materials and Methods: Twenty-four male albino Wistar rats were randomly assigned to four groups: healthy control (HG), ATP-alone (ATPG, 4 mg/kg, intraperitoneally), tamoxifen-alone (TAMG, 5 mg/kg, orally), and tamoxifen plus ATP-treated (ATAG; ATP, 4 mg/kg, intraperitoneally; tamoxifen, 5 mg/kg, orally). Treatments were administered once daily for 30 days. Oxidative stress markers (malondialdehyde, total glutathione), antioxidant enzyme activities (superoxide dismutase, catalase), and oxidative DNA damage (8-hydroxy-2'-deoxyguanosine) were assessed in ocular tissues. Retinal histopathological evaluation included hematoxylin-eosin staining with semiquantitative assessment of edema, vascular congestion, polymorphonuclear leukocyte infiltration, and cytoplasmic vacuolization, together with quantitative measurements of retinal layer thicknesses and ganglion cell layer (GCL) cell counts. Results: Tamoxifen administration induced marked oxidative stress, antioxidant depletion, and increased oxidative DNA damage in ocular tissues, accompanied by significant thickening of retinal layers, reduced GCL cell counts, and pronounced disruption of retinal architecture. By comparison, ATP co-administration significantly suppressed lipid peroxidation and restored antioxidant defenses, thereby reducing oxidative DNA damage and preserving retinal structural integrity, as reflected by partial normalization of retinal layer thicknesses, preservation of GCL cell counts, and the presence of only mild residual edema. Conclusions: These findings indicate that ATP attenuates tamoxifen-induced retinal toxicity by supporting mitochondrial energy balance and redox homeostasis. Accordingly, ATP administration may represent a promising protective approach for reducing retinal injury associated with long-term tamoxifen therapy.

Background: Tamoxifen is widely used in the treatment of hormone receptor-positive breast cancer and has been shown to successfully reduce recurrence and mortality rates. Nonetheless, variability in patient response to tamoxifen treatment is observed with up to 40% of patients experiencing recurrence. Genetic polymorphisms in pharmacogenes encoding enzymes involved in tamoxifen metabolism have been linked to some of this observed interindividual variability. The pharmacogenetics of tamoxifen in populations of African descent remain understudied, creating difficulties in pinpointing the primary factors behind the observed variable response. To address this gap, this study aimed to investigate the role of genetic variation in tamoxifen treatment outcomes in a South African cohort. Methods: Participants included 166 Mixed and African Ancestry breast cancer patients who had received tamoxifen treatment. Genetic characterization was performed for 53 single nucleotide polymorphisms (SNPs) and two copy number variations across eight drug-metabolizing enzymes, including cytochrome P450s (CYP2D6, CYP3A4, CYP3A5, CYP2B6), UDP-glucuronosyltransferases (UGT1A4), and sulfotransferases (SULT1A1, SULT1E1, SULT2A1). The association between genotypes and disease-free survival (DFS) was evaluated using Cox proportional hazards regression models. Results: The CYP2B6*1/*6 or *4/*9 genotype showed a nominal association with improved DFS (p = 0.049), with a similar trend observed for UGT1A4 rs11888492. In contrast, SULT1E1 rs3775779 heterozygosity showed a nominal association with reduced DFS (p = 0.044). SULT1A1 SNPs (rs4149393, rs4149394, rs1042157) demonstrated trends toward reduced DFS. Conclusions: These exploratory findings highlight the need for more inclusive pharmacogenomic research and point to potential biomarkers for optimizing tamoxifen therapy in African populations.

We aimed to evaluate the long‐term tamoxifen benefit by progesterone receptor (PR) levels in postmenopausal lymph node‐negative breast cancer patients with estrogen receptor (ER)‐positive/human epidermal growth factor receptor 2‐negative (HER2) tumors in the STO‐3 randomized trial. This is a secondary analysis of the STO‐3 trial including 559 postmenopausal breast cancer patients by PR levels. Patients were randomly assigned to at least 2 years of adjuvant tamoxifen therapy (40 mg once daily) versus no endocrine therapy in the Stockholm (STO)‐3 trial. Twenty‐five‐year distant recurrence‐free interval (DRFI) was assessed by Kaplan–Meier, multivariable Cox proportional hazard regression, and multivariable time‐varying analyses. Univariable Kaplan–Meier analysis showed a significant long‐term tamoxifen benefit for PR‐positive disease using a threshold of 10% or greater (DRFI, tamoxifen treated 85% vs. control 68%; p < .0001). Similarly, patients with high PR gene expressing tumors had a significant long‐term tamoxifen therapy benefit (DRFI, tamoxifen treated 84% vs. control 66%; log‐rank p < .001). In contrast, we report no significant therapy benefit for patients with PR‐negative disease (DRFI, tamoxifen treated 79% vs. control 70%; log‐rank p = .14) or low PR gene expression (DRFI, tamoxifen treated 82% vs. control 74%; log‐rank p = .17). Multivariable Cox proportional hazard regression modelling confirmed the univariable findings for PR‐positive disease (HR = 0.37; 95% CI [0.23–0.61]). Time‐varying analysis revealed a treatment benefit for PR‐positive disease up to 25 years (HR = 0.35; 95% CI [0.16–0.79]), but not for patients with PR‐negative tumors. PR‐positivity as determined by immunohistochemistry predicted long‐term benefit from adjuvant tamoxifen in lymph node‐negative postmenopausal breast cancer patients with ER+/HER2− tumors.

ホルモン受容体陽性乳癌の治療として内分泌療法が推奨されているが，そのキードラッグであるタモキシフェンは，脂肪肝を伴う薬物性肝障害の原因薬物として知られている．本研究では，当院で2008年から2023年までに術後再発防止目的でタモキシフェンを含むホルモン療法を4.7（3.4-5.0）年施行された患者186例を対象に，肝機能検査や画像所見を用いて後方視的に検討した．解析の結果，治療前後でALT（P=0.002），γ-GTP（P＜0.001），FIB-4 index（P＜0.001）は有意に上昇したが，ALBI scoreは有意な変化を認めなかった（P=0.054）．また，観察終了時にALT高値である症例のうち67%に脂肪肝を認めた．タモキシフェン内服中の肝機能障害には脂肪肝の関与が示唆され，定期的な肝機能検査や肝臓専門医との連携が重要である．

Patients with ER-positive breast cancer have a substantial late risk of distant recurrence, but the long-term subtype-specific tamoxifen benefit remains poorly understood. Secondary analysis of the Stockholm Tamoxifen (STO) randomized trials (1976-1997, n = 3930) with 20-year follow-up. FFPE blocks were available for 2250 patients. 952 patients with ER-positive/HER2-negative tumors classified as luminal A (n = 688) and luminal B (n = 264) using Agilent microarrays were analyzed. Patients were randomized to at least 2 years of tamoxifen therapy or no endocrine therapy. Distant recurrence-free interval (DRFI) was assessed by Kaplan-Meier analysis and multivariable Cox proportional-hazards regression. Patients with luminal A tumors had low early risk and modest early benefit from tamoxifen therapy (5-year DRFI treated vs control: 93% vs 89%, absolute difference 4%) that increased over the 20-year follow-up (20-year DRFI: 76% vs 66%, absolute difference 10%), highlighting long-term benefit. In contrast, patients with luminal B tumors had larger early risk and treatment benefit (5-year DRFI: 72% vs 57%, absolute difference 15%), which remained stable over time (20-year DRFI: 55% vs 37%, 18% absolute difference).Multivariable analyses showed that luminal patients benefited from tamoxifen therapy (luminal A adjusted hazard ratio [aHR]=0.57, 95% CI 0.42-0.78 and luminal B aHR = 0.68, 95% CI 0.46-0.99). Patients with favorable tumor characteristics benefited regardless of luminal subtype. Tamoxifen reduces the long-term risk of distant recurrence in both luminal A and B tumors, although timing of benefit varies by subtype. Even after treatment, patients with luminal tumors have a substantial late risk, highlighting the need for long-term follow-up.

Abstract Background: Systemic therapies for breast cancer (BC) can lead to cancer treatment-induced bone loss (CTIBL), increase fracture risk, impair the quality of life, and potentially worsen prognosis. Although CTIBL prevention has been established in postmenopausal patients with BC, CTIBL in premenopausal women remains unclear owing to the limited number of reports. Chemotherapy often induces ovarian suppression and estrogen deficiency, thereby accelerating bone loss. Furthermore, the effects of tamoxifen on the bone are yet to be established in premenopausal patients with BC. In this study, we prospectively evaluated CTIBL in premenopausal patients with BC by monitoring bone mineral density (BMD), hormones, and bone turnover markers. Methods: We recruited 64 premenopausal females diagnosed with early-stage BC. We compared patients receiving tamoxifen monotherapy (T group, n=19; median age, 45 [range, 37-55] years) with those receiving chemotherapy followed by tamoxifen therapy (C group, n=31; median age, 45 years [range, 31-50] years). BMD at the lumbar spine and femoral neck was measured at baseline, immediately after chemotherapy (C group), and at 6, 12, and 18 months after tamoxifen initiation. Serum levels of estradiol (E2), follicle-stimulating hormone (FSH), bone turnover markers, procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase 5b (TRACP-5b), and undercarboxylated osteocalcin (ucOC) were concurrently assessed to evaluate hormonal and metabolic effects on bone health. Results: 1. BMD Changes: T group: The changes(±SD) in BMD were minimal, with a 2.2±5.1% decrease (p=0.13) at the lumbar spine and a 1.6±4.4% increase(p=0.19) at the femoral neck at 24 months.C group: Lumbar spine BMD decreased by 2.4±3.9% post-chemotherapy (p=0.0057) and by 3.4±3.1% at 24 months (p=0.0060). Femoral neck BMD decreased by 1.3±4.6% post-chemotherapy (p=0.24) and 4.1±4.1% at 24 months (p=0.0047). 2. Hormonal Changes: T group: E2 increased by 328.1±385.6% at 6 months (p=0.003) but returned to baseline by 24 months. FSH levels showed no significant changes.C group: E2 decreased by 76.2±49.6% post-chemotherapy (p&amp;lt;0.001), with no significant differences observed at 24 months. FSH increased by 1061.1±890.7% post-chemotherapy (p&amp;lt;0.001), gradually decreased, and remained 53.6±89.8% above baseline at 24 months (p=0.038). 3. Bone Turnover Markers: T group: P1NP and TRACP-5b levels showed no significant changes over 24 months (all p &amp;gt; 0.05). ucOC decreased by 22.6±36.5% at 6 months (p=0.036), stabilizing thereafter.C group: P1NP increased by 98.9±90.0% post-chemotherapy (p&amp;lt;0.001) and gradually returned to baseline levels by 24 months (-5.4±45.0%, p=0.90). TRACP-5b increased by 89.9±106.6% post-chemotherapy (p&amp;lt;0.001) and gradually returned to baseline levels by 24 months (5.7±44.3%, p=0.38). ucOC decreased by 82.6±11.5% post-chemotherapy (p&amp;lt;0.001) and remained suppressed, with no significant recovery observed at 24 months (-89.1±9.2%, p&amp;lt;0.001). Conclusions: The C group showed significant and sustained reductions in BMD. The observed bone loss could be attributed to chemotherapy-induced ovarian suppression and estrogen deficiency. Increased bone turnover markers were consistent with a high bone resorption state and bone loss. Conversely, BMD was preserved in the T group, consistent with stable hormone levels and bone turnover markers. These findings indicate the need for proactive bone health management, including regular BMD monitoring and consideration of bone-protective treatments, especially in premenopausal patients with BC receiving chemotherapy, to improve long-term quality of life without fracture. Citation Format: A. Nishikawa, K. Narui, Y. Fujiwara, Y. Shibata, S. Adachi, K. Kawashima, M. Oshi, A. Yamada, H. Yoshikata, T. Tsuburai, I. Endo. Effects of cancer treatment on bone mineral density in premenopausal patients with early-stage breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS1-03-18.

Abstract Background: Tamoxifen remains a cornerstone in the treatment of early-stage hormone receptor-positive breast cancer and is also used as prophylaxis in high-risk women. However, its use has been associated with an increased risk of venous thromboembolism (2-8%). In Greece, the prevalence of thrombophilic factors (inherited or acquired) is approximately 15%, and these factors may contribute to thrombosis when additional risk factors are present. Methods: We conducted a three-year retrospective analysis, from April 2022 until March 2025, of medical records from breast cancer patients in our department who were evaluated by a hematologist and underwent thrombophilia screening before tamoxifen initiation. Results: Among fifty-nine patients, eighteen (31%) were found to have clinically significant inherited thrombophilic factors, while another twenty (34%) had high-risk acquired thrombophilic conditions. Twelve patients (20%) had no detectable thrombophilic factors, and nine (15%) had non-clinically significant mutations that did not require therapeutic intervention. Following hematological assessment, treatment plans were modified in thirty-eight out of fifty-nine patients (64%). Specifically, four patients received tamoxifen with the addition of aspirin, twenty-five were treated with tamoxifen combined with prophylactic oral anticoagulation (apixaban or rivaroxaban), and in nine cases, an aromatase inhibitor was prescribed instead of tamoxifen due to high thrombotic risk, in combination with antiplatelet or anticoagulant therapy. Conclusions: Pre-treatment hematological evaluation and thrombophilia screening are considered of significant clinical value in patients considered for tamoxifen therapy. Based on their individualized thrombotic risk profile, a substantial proportion of patients may benefit from antithrombotic prophylaxis or a change in hormonal therapy. We intend to further evaluate these findings with a prospective cohort of these patients. Citation Format: S. Gkoura, I. Binas, E. Aravantinou - Fatorou, T. Bilidas, I. Evmorfiadis, C. Poziopoulos, E. Klouva, K. Koutsoukos, G. Oikonomopoulos, G. Karkaletsos, E. Vasili, G. Tsakalos, A. Vassias, G. Klouvas, M. Stathoulopoulou, V. Venizelos, S. Epameinondas, C. Christodoulou, E. Galani. Thrombophilia Screening Prior to Tamoxifen Therapy in Early-Stage Hormone Receptor-Positive Breast Cancer: A Three-Year Retrospective Study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-09-12.

Tamoxifen is a prodrug that undergoes cytochrome P450(CYP)-mediated bioactivation to its active metabolite endoxifen, primarily due to CYP2D6. We aimed to investigate the clinical impact of CYP2D6 phenotype on the conversion of tamoxifen to endoxifen as well as the interplay of genetic variation and drug interactions. Samples were analyzed from a cohort of 932 breast cancer patients on tamoxifen therapy. CYP2D6 phenotype, tamoxifen, endoxifen, 4-hydroxytamoxifen, and N-desmethyl tamoxifen plasma concentrations and antidepressant CYP2D6 inhibitor use were analyzed. There was a significant effect of CYP2D6 phenotype and CYP2D6 inhibitor use on endoxifen concentrations (pinteraction < 0.05). CYP2D6 inhibition was predictive of patients who attained plasma endoxifen concentrations below the 16nM and 9nM threshold. CYP2D6 poor metabolizers and CYP2D6 normal or intermediate metabolizers on strong CYP2D6 inhibitors had the largest proportion of patients below an endoxifen threshold of 16 or 9nM. Patients on tamoxifen should avoid strong CYP2D6 inhibitors as their endoxifen concentrations are similar to CYP2D6 poor metabolizers. The utility of endoxifen concentrations and which threshold to consider in clinical practice remains unclear. Ultimately, the clinical impact of mild or moderate CYP2D6 inhibitors on CYP2D6 normal or intermediate metabolizer depends on the endoxifen threshold applied.

Uterine Müllerian adenosarcoma associated with tamoxifen therapy: A case report

Cancer treatment-related ischemic arterial events: Focus on peripheral arterial disease and cerebrovascular events.

Circulating estrogen metabolites of the 2-, 4- or 16-hydroxyestrone (OH) pathways may be differentially associated with breast cancer risk due to varying estrogenic and genotoxic activity. However, little is known about the influence of tamoxifen, an effective endocrine therapy, or its metabolites on estrogen metabolism. Among women referred to tamoxifen therapy, 15 circulating estrogens and estrogen metabolites (EMs) were measured at baseline (pre-tamoxifen) and 12months post-tamoxifen initiation using liquid chromatography-tandem mass spectrometry. Changes in EMs were assessed among women postmenopausal at baseline (n=23) using paired t-tests. Using linear regression, cross-sectional associations between circulating tamoxifen, its three metabolites, and EMs were assessed 12-months post-tamoxifen among pre- (n=33) and postmenopausal women (n=27; includes four women who transitioned to postmenopausal during follow-up). Twelve months post-tamoxifen initiation, mean total EM concentrations decreased by 13.8% among postmenopausal women, primarily driven by decreases in 2-OH (15.3%) and 16-OH (17.2%) metabolites (p<0.05). Among women premenopausal at 12-month follow-up, circulating tamoxifen was positively associated with estrone (β=1.24), estradiol (β=1.39), 2-OH metabolites (2-OHE1: β=0.72, 2-ME1: β=1.15), and all 16-OH metabolites (p<0.05). The tamoxifen metabolite, endoxifen, was positively associated with estrone (β=10.1) and estradiol (β=12.4), and select 2-OH and 16-OH metabolites (p<0.05). Positive associations were also observed between 4-hydroxy-tamoxifen and estrone, 2-OHE1, 2-ME1, 4-ME1, and E3 (p<0.05). Among postmenopausal women, only N-desmethyltamoxifen was significantly associated with 3ME1 (β=0.18, p=0.02). Tamoxifen and its metabolites were associated with changes in circulating EMs. Further research is needed to understand tamoxifen-induced EM changes in breast cancer prevention and management.

Female-specific cancers, including breast, ovarian, cervical and uterine malignancies, lack comprehensive early detection approaches, particularly for ovarian and endometrial cancers where effective population-level screening remains limited. This study aimed to develop and validate a computational method for early detection of female-specific cancers using longitudinal healthcare records. We developed a multichannel convolutional neural network (MCNN) to analyse 36-month pre-diagnostic healthcare records from Taiwan's National Health Insurance Research Database. The study included 19 954 female patients (596 cancer cases, 19 358 controls) from 1999 to 2013. Log-likelihood ratio feature selection identified top 10 features across three data modalities (diagnostic codes, medications, medical orders). The six-channel architecture processed temporal patterns through stratified 10-fold cross-validation, with performance compared against nine baseline algorithms. MCNN achieved superior balanced performance with Macro-F₁ score of 0.8443, precision of 0.9135 and recall of 0.7978, outperforming traditional machine learning and deep learning approaches. Feature analysis revealed clinically relevant patterns including tamoxifen therapy, immunohistochemical procedures and cancer-specific diagnostic codes. SHapley Additive exPlanations (SHAP) interpretability analysis demonstrated the model's ability to identify pre-diagnostic phases through temporal healthcare utilisation patterns. Systematic feature selection reduced computational requirements by over 99%, enabling validation on Taiwan's population-scale National Health Insurance Research Database (NHIRD). The multichannel deep learning approach enables unified early detection across four female cancer types using routine administrative data, addressing detection gaps for ovarian and endometrial cancers while providing complementary risk stratification for existing screening programmes. Clinical implementation through electronic health record (EHR) integration offers practical pathways for accessible cancer risk assessment during routine healthcare encounters.

To evaluate changes in gene expression activity during preoperative testing for tumor hormone sensitivity to aromatase inhibitors and tamoxifen in postmenopausal women with ESR+/HER2- breast cancer. The study included 174 breast cancer patients. Pathological examination of FFPE core biopsy specimens, performed before the hormone response test, and surgical specimens were examined, as well as immunohistochemistry (Ki67, ER, PR, HER2/neu) and molecular genetic testing of an expression panel of 45 target genes using quantitative real-time PCR. The use of aromatase inhibitors in the preoperative hormone response test is accompanied by statistically significant changes in the mRNA expression of 37 genes in breast tumors, of which a decrease in the expression level was found for 35 genes (ESR1, PGR, AR, ERBB2, FGFR4, MKI67, MYBL2, CCNB1, AURKA, BIRC5, CCND1, CCNE1, CDKN2A, KIF14, PPP2R2A, PTTG1, TMEM45B, TPX2, ANLN, MMP11, CTSL2, EMSY, PAK1, BCL2, BAG1, PTEN, TYMS, EXO1, UBE2T, NAT1, SCGB2A2, GATA3, FOXA1, ZNF703, CD274/PD-L1), an increase - for two genes (SFRP1, KRT5). While the use of tamoxifen statistically significantly correlates with a decrease in the level of mRNA expression of 35 genes: ESR1, PGR, AR, EGFR, ERBB2, FGFR4, MKI67, MYBL2, CCNB1, AURKA, BIRC5, CCND1, CCNE1, CDKN2A, KIF14, PPP2R2A, PTTG1, TMEM45A, TMEM45B, TPX2, ANLN, MMP11, EMSY, PAK1, BCL2, BAG1, PTEN, TYMS, EXO1, UBE2T, NAT1, GATA3, FOXA1, ZNF703, CD274/PD-L1, and an increase in only one gene - MYC. Comparative mRNA expression analysis confirms that a short preoperative course of aromatase inhibitors induces a more potent and uniform molecular response, characterized by profound suppression of proliferation and complete inhibition of estrogen-dependent signaling. Tamoxifen therapy is also effective but results in less pronounced suppression of key targets and, crucially, may be accompanied by early activation of the MYC oncogene, a potential marker for resistance development.