Tamoxifen Group Research Articles

Is tamoxifen good enough for the Asian population in ER+ HER2- post-menopausal women with early breast cancer? A nationwide population-based cohort study.

Numerous clinical trials have compared the efficacy of endocrine therapy in post-menopausal breast cancer patients. This study aims to explore whether there is a difference in recurrence rates between this population using tamoxifen and aromatase inhibitors (AIs) by analyzing real-world data. This retrospective cohort study utilized the National Health Insurance (NHI) claims data and the Taiwan Cancer Registry (TCR). We identified 6,050 patients aged over 55 diagnosed with ER-positive, HER2-negative early breast cancer between 2012 and 2016 (4,451 on AIs alone and 1,599 on tamoxifen alone). Recurrence in both groups was assessed until the end of 2020. Hazards were measured based on age of diagnosis, cancer stage, adjuvant chemotherapy, radiation therapy, type of endocrine therapy used, and adherence. Recurrence‑free survival between the AIs and tamoxifen groups was evaluated using the Kaplan-Meier model. The average age was 65.1 years, with a median follow-up time of 5.7 years and a median duration of endocrine therapy of 4.5 years. The recurrence rate was 2.2%. Using tamoxifen as endocrine therapy reduces the risk of recurrence compared to AIs (adjusted HR: 0.32, p < 0.0001). There was no statistical difference between the two drugs in stage 1 breast cancer. However, in stage 2, the risk of breast cancer recurrence decreased to 0.15 times with the use of tamoxifen compared to AIs (p = 0.0002). Stage 2 cancer, histological grade 3, and non-adherence increased recurrence risk in post-menopausal breast cancer patients. Based on real-world data analysis, in ER-positive, HER2-negative post-menopausal women with early breast cancer in Taiwan, the use of tamoxifen compared to AIs is associated with a lower risk of recurrence. Improved adherence to medication can break the cycle of recurrence and improve health outcomes.

Evaluation of the Protective Effects of Vitamins E and D on Oxidative Stress and Inflammation Caused by Tamoxifen in the Renal Tissue of Female Wistar Rats

Background: Tamoxifen is an effective drug for breast cancer treatment and its side effects are the production of reactive oxygen species and kidney damage. As antioxidants, vitamins E and D may help decrease kidney dysfunction. Objectives: In the present study, the protective effects of vitamins E and D on renal toxicity caused by tamoxifen in female Wistar rats were investigated. Materials and Methods: Twenty-five adult female rats weighing 180-200 were randomly divided into five groups with 5 rats. Group C, T, TE, TD, and TED were treated with olive oil, tamoxifen, tamoxifen + vitamin E, tamoxifen +vitamin D, and tamoxifen + both vitamins for four weeks. ELISA Kits measured the oxidant and antioxidant tests and TNF-α in kidney tissue. The spectrophotometric method measured urea, uric acid, and creatinine in serum and urine. Results: Tamoxifen significantly decreased the weight of rats, GPx, CAT, SOD levels and increased TNF-α, urinary creatinine level and, serum uric acid, urea levels (P &lt; 0.05). But, treatment with vitamin D and simultaneous administration of vitamins led to a significant decrease in the level of (TNF-α) compared to the tamoxifen group (p &lt; 0.01). Also, the histopathology results showed that the simultaneous administration of vitamins has significantly resolved the damage caused by the use of tamoxifen. Conclusion: The present study's findings showed that using vitamins E and D prevents kidney damage through antioxidant and anti-inflammatory effects. In addition, using vitamins E and D probably showed stronger synergistic effects against kidney damage.

P-317 Risk of endometrial polyps and hyperplasia after tamoxifen treatment in women with breast cancer: a population-based study in Taiwan

Abstract Study question This study aimed to examine the association between tamoxifen treatment and incident risks of uterine disease among breast cancer patients in Taiwan. Summary answer We found tamoxifen treatment group may have greater risk of endometrial polyps and hyperplasia than unexposured group after adjusting for age and body mass index. What is known already In the worldwide Adjuvant Tamoxifen: Longer Against Shorter (ATLAS) breast cancer treatment trail reported that the women continue tamoxifen up to 10 years, compared with 5 years may reduce breast cancer recurrence and mortality rate. However, tamoxifen use has been reported to be associated with the cumulative risk of subsequently endometrial cancer during 5–14 years was 3.1%. Specifically, several Western studies have showed that the high incidence of endometrial cancer in breast cancer survivors with tamoxifen treatment. Study design, size, duration We conducted a retrospective cohort study using population-based data from Taiwan Cancer Registry and the National Health Insurance Research Database (NHIRD), and the National Population Registry Data set from 2011 to 2020. Participants/materials, setting, methods A total 138,934 newly diagnosed breast cancer female patients with age greater than 18 years old were included. We further used a 1-to-1 propensity score matching to generate comparable exposure and un-exposure groups. Cox proportional hazard regression models were used to examine the research question. All statistical analysis was performed using SAS version 9.4, and p-values &amp;lt; 0.05 were considered statistically significant Main results and the role of chance Incidence rate ratio (IRR) to compare incidence rate of uterine disease between tamoxifen treatment groups and unexposed group, adjusting for age and BMI. Our results showed that IRR were 1.36, 0.33, 3.73, 0.63, endometrial polyps, endometrial carcinoma, endometrial hyperplasia and uterine carcinosarcoma, respectively. This study found possible correlations between tamoxifen exposure with endometrial polyps and hyperplasia among breast cancer. During the 10-year study period, tamoxifen group did not significantly increase the risk of endometrial cancer in breast cancer survivors at aged 40 and over. Limitations, reasons for caution Our cohort study with 10-year period is its short study period, Tamoxifen group did not significantly increase the risk of endometrial cancer. Wider implications of the findings This cohort study found higher endometrial polyps and hyperplasia incidence rates among women with breast cancer who received tamoxifen women than those not treated with tamoxifen. Results of this study suggest that clinicians should consider the risk of uterine disease among tamoxifen use and counsel patients accordingly. Trial registration number KMUHIRB-G(II)20200217

Tamoxifen may contribute to preserve cardiac function in Duchenne muscular dystrophy

Duchenne muscular dystrophy is life-limiting. Cardiomyopathy, which mostly ensues in the second decade of life, is the main cause of death. Treatment options are still limited. The TAMDMD (NCT03354039) trial assessed motor function, muscle strength and structure, laboratory biomarkers, and safety in 79 ambulant boys with genetically confirmed Duchenne muscular dystrophy, 6.5–12 years of age, receiving either daily tamoxifen 20 mg or placebo for 48 weeks. In this post-hoc analysis, available echocardiographic data of ambulant patients recruited at one study centre were retrieved and compared before and after treatment. Data from 14 patients, median 11 (interquartile range, IQR, 11–12) years of age was available. Baseline demographic characteristics were similar in participants assigned to placebo (n = 7) or tamoxifen (n = 7). Left ventricular end-diastolic diameter in the placebo group (median and IQR) was 39 (38–41) mm at baseline and 43 (38–44) mm at study end, while it was 44 (41–46) mm at baseline and 41 (37–46) mm after treatment in the tamoxifen group. Left ventricular fractional shortening in the placebo group was 35% (32–38%) before and 33% (32–36%) after treatment, while in the tamoxifen group it was 34% (33–34%) at baseline and 35% (33–35%) at study end. No safety signals were detected.Conclusion: This hypothesis-generating post-hoc analysis suggests that tamoxifen over 48 weeks is well tolerated and may help preserving cardiac structure and function in Duchenne muscular dystrophy. Further studies are justified.ClinicalTrials.gov Identifier: EudraCT 2017–004554–42, NCT03354039What is known:• Duchenne muscular dystrophy (DMD) is life-limiting. Cardiomyopathy ensues in the second decade of life and is the main cause of death. Treatment options are still limited.• Tamoxifen reduced cardiac fibrosis in mice and improved cardiomyocyte function in human-induced pluripotent stem cell-derived cardiomyocytes.What is new:• In this post-hoc analysis of the TAMDMD trial among 14 boys, median 11 years of age, treated with either tamoxifen or placebo for 48 weeks, treatment was well-tolerated.• A visual trend of improved left-ventricular dimensions and better systolic function preservation generates the hypothesis of a potential beneficial effect of tamoxifen in DMD cardiomyopathy.

Treatment modalities for advanced solid pseudopapillary tumor of the pancreas.

e16327 Background: Solid pseudopapillary tumor (SPT) of the pancreas is a rare low-grade malignant tumor. However, a minority of SPT patients present aggressive behavior and develop recurrent or metastatic diseases. The treatment strategies of advanced SPTs remain unclear. Our study aimed to explore the treatment modalities of aggressive SPTs and the role of endocrine therapy. Methods: The data on clinicopathologic characteristics and treatment of advanced SPT patients from Sun Yat-Sen University Cancer Center and Shen Zhen People's Hospital were collected. The treatment modalities were explored by co-analyzing our local cohort and published literatures. Single sample gene set enrichment analysis (ssGSEA) was used to explore the functional enrichment pathway (GSE43795). Fresh surgical specimens from 10 SPT patients were collected for endocrine drugs sensitive test in vitro by performing tumor histoculture end-point staining computer image analysis (TECIA). Results: A total of 77 advanced SPT patients including 14 cases in our local cohort and 63 cases from published literatures were enrolled. 60 patients received local treatment including cytoreductive surgery, interventional therapy or radiation therapy. 55 patients who had undergone cytoreductive surgery have better outcome compared with others (P = 0.046, HR = 4.12). 31 patients received systemic chemotherapy and 6 patients received targeted therapy. There were 2 patients achieved partial response after chemotherapy. In our local cohort, 5 patients received endocrine therapy with tamoxifen plus megestrol. One patient achieved partial response with duration of response (DOR) of 89 months. 4 patients showed stable disease. ssGSEA for GSE43795 showed that Wnt signaling pathway and its inhibitory pathway-progesterone receptor signaling pathway were simultaneously enriched in SPTs. The results of endocrine drug sensitive test in vitro by TECIA showed response rate of 50% (5/10) in megestrol group, 40% (4/10) in tamoxifen group, and 30% (3/10) in testosterone propionate group. Conclusions: Advanced SPTs did not appear chemosensitive. Cytoreductive surgery may improve survival. Simultaneously enriching Wnt and progesterone receptor signaling pathway may partially explain the low aggressive ability of SPT and their unbalance may lead to the aggressive behavior of SPT. Endocrine therapy with tamoxifen plus megestrol, by enhancing the progesterone signaling pathway, seems to be a promising regimen for advanced SPTs, which is worth to be noted and further studied.

ETHAN: A phase II study comparing different endocrine therapies for male breast cancer.

TPS632 Background: Male breast cancer is a rare disease, and most cases are hormone receptor-positive (HR+). Due to a lack of clinical trials, male breast cancer has historically been treated based on data extrapolated from women. However, there are substantial knowledge gaps in the comparative efficacy, safety, and patient-reported outcomes of endocrine therapies for male breast cancer. While tamoxifen is the current standard of care, additional data are warranted for aromatase inhibitors (AI), gonadal suppression, and cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Methods: This is an open-label, multicenter, randomized, phase II trial designed to evaluate different endocrine therapies in men with HR+ and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. A total of 60 men will be enrolled across nine (9) sites within the Translational Breast Cancer Research Consortium (TBCRC). Key eligibility criteria include male sex and stage I, II, or III HR+/HER2- breast cancer before surgical resection of the primary tumor and axillary nodes. Key exclusion criteria include prior anti-cancer therapy for the current breast cancer or any other malignancy within the past 12 months, and inflammatory breast cancer. The trial has two phases. The first phase is a window of opportunity component in which newly diagnosed men are randomized 1:1:1 to either tamoxifen (Arm A), anastrozole (Arm B), or anastrozole plus degarelix (Arm C) given for three weeks. The primary endpoint for the window phase is Ki-67 reduction from the baseline diagnostic biopsy to the research biopsy at the end of the window phase. The second phase consists of neoadjuvant treatment, in which the tamoxifen group is randomized 1:1 to tamoxifen (Arm D) versus tamoxifen plus abemaciclib (Arm E), and the anastrozole alone (Arm B) and anastrozole plus degarelix (Arm C) groups are merged and then randomized 1:1 to anastrozole plus degarelix (Arm F) versus anastrozole plus degarelix plus abemaciclib (Arm G). The duration of the neoadjuvant phase is four (4) months, and the primary endpoint of this phase is residual cancer burden (RCB) index at time of surgery. The trial is powered for the RCB endpoint in a 2 x 2 factorial design to detect a 0.6 unit decrease in RCB index with 80% power and alpha=10%. For the Ki-67 endpoint, we assume an approximately 50% reduction in Arms A and B; Arm C will be of interest if it leads to ≥80% reduction in Ki-67. Secondary endpoints include: estradiol and testosterone levels at baseline, end of window, and during neoadjuvant phase; preoperative endocrine prognostic index (PEPI) score at surgery; adverse events; and patient-reported outcomes (including quality of life). Tumor tissue will be collected for correlative analyses. The study opened to enrollment at Dana-Farber in October 2023, and additional sites will open in 2024. Clinical trial information: NCT05501704 .

Abstract PO1-02-04: The efficacy of endocrine therapy during the waiting period for surgery for hormone receptor-positive breast cancer

Abstract Background: Although neoadjuvant endocrine therapy has been used to improve breast conservation rate, its prognostic relevance is unknown. The search for a valid prognostic factor equivalent to pCR in neoadjuvant chemotherapy is a current challenge in neoadjuvant endocrine therapy. In this study, we investigated the efficacy of short term neoadjuvant endocrine therapy utilizing the waiting period for surgery and the prognostic factor including Preoperative Endocrine Prognostic Index (PEPI) score. Methods: A total of 480 patients with StageⅠ-Ⅲ hormone receptor-positive, HER2-negative breast cancer was treated with endocrine therapy during the waiting period for surgery between October 2012 and December 2021. Premenopausal and postmenopausal patients received tamoxifen (TAM) and non-steroidal aromatase inhibitor (AI), respectively. The primary endpoint was change in tumor size by ultrasound and Ki67 expression before and after short term endocrine therapy. The secondary endpoint was prognosis of patients divided by PEPI score which was calculated using tumor size, lymph node metastasis, Ki67 expression, and ER Allred score. This study was approved by the institutional review board of Teikyo University. Results: Median age and tumor size of the entire 480 patients was 55 years (range, 31 - 89), 1.65 cm (range, 0.4 – 7.5), respectively. The median duration of endocrine therapy was 39 days (range, 1-90). 19 (0.3 %) pts were clinically node-positive. Of the entire 480 patients, 211 and 269 patients had TAM and AI, respectively. After short term endocrine therapy, the tumor size was significantly reduced from 1.83cm to 1.62cm in AI group (p=0.02), although TAM did not decrease the tumor size (p=0.89). The Ki67 expression was significantly decreased from 16.4% to 11.3% in TAM group (p=0.002), and from 15.9% to 6.98% in AI group (p &amp;lt; 0.001). There were significant differences in the distribution of PEPI scores between TAM and AI group (p &amp;lt; 0.05) (Table). At the median follow-up of 1012 days, patients with PEPI score ≥ 4 showed worse disease-free survival compared with patients with PEPI score &amp;lt; 4 in TAM group (Figure1). Overall survival is not available because there were no deaths in TAM group. At the median observation period of 833 days, patients with PEPI score ≥ 4 showed worse disease-free survival compared with patients with PEPI score &amp;lt; 4 in AI group (Figure2). In terms of mortality, patients with PEPI score ≥ 4 had worse overall survival than patients with PEPI score 0 and 1-3 (p=0.07). Conclusions: These results suggested that neoadjuvant endocrine therapy during the waiting period for surgery might be effective in reducing Ki67 expression level and PEPI score might be useful in predicting the prognosis of hormone receptor positive breast cancer patients. Table. Distribution of PEPI score Figure 1. Disease-free survival in patients treated with tamoxifen Figure 2. Disease-free survival in patients treated with non-steroidal aromatase inhibitor Citation Format: Yuka Maeda, Saki Naruse, Yuka Isono, Ayana Sato, Akiko Matsumoto, Tatsuhiko Ikeda, Hiromitsu Jinno. The efficacy of endocrine therapy during the waiting period for surgery for hormone receptor-positive breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-02-04.

Abstract PO3-01-08: Interaction of Prior Chemotherapy and Addition of Ovarian Function Suppression on Menopausal Symptoms in Tamoxifen-Treated Breast Cancer Patient: A prospective, Observational study

Abstract Background: Adjuvant endocrine therapy (AET) is commonly used for hormone receptor-positive breast cancer patients. Combining ovarian function suppression (OFS) with tamoxifen improves survival outcomes, but is associated with menopausal symptom-related issues and treatment discontinuation. This study aimed to compare menopausal symptoms between tamoxifen alone and tamoxifen plus OFS over 12 months and identify related factors. Methods: This prospective study included 209 premenopausal breast cancer patients on tamoxifen. Menopausal symptoms were assessed using the Menopausal Rating Scale (MRS) at baseline, 3, 6, and 12 months. Statistical analysis involved linear regression and generalized estimating equations. Results: Of the participants, 27.8% received tamoxifen plus OFS and were younger and more likely to be unmarried. The tamoxifen plus OFS group had lower baseline MRS scores, but higher scores at 6 and 12 months compared to tamoxifen alone. MRS scores increased significantly in both groups, plateauing at 6 months with tamoxifen alone and at 12 months with tamoxifen plus OFS. Factors associated with higher MRS scores at 6 months were baseline MRS scores and addition of OFS. Impact of OFS on MRS scores varied with prior chemotherapy status, being significant in patients without prior chemotherapy. Conclusion: Adding OFS to tamoxifen in premenopausal breast cancer patients was associated with a higher burden of menopausal symptoms compared to tamoxifen alone, particularly in patients who have not undergone prior chemotherapy. Therefore, careful consideration and decision-making regarding this issue are crucial in terms of both treatment outcomes and quality of life. Table 1. Baseline characteristics, Overall and According to adjuvant endocrine therapy, tamoxifen alone versus tamoxifen plus ovarian function suppression (OFS) Table 2. Multivariable linear regression about MRS scores from the baseline to 6 months, and with interaction between addition of OFS and prior chemotherapy effect Table 3. Interaction effect of additional OFS depending on prior chemotherapy; (a) without prior chemotherapy, (b) with prior chemotherapy Citation Format: Youngwon Lee, Jong Won Lee, Sae Byul Lee, Byung Ho Son, Hee Jeong Kim, Beom Seok Ko, Jisun Kim, Il-Yong Chung, Tae-Kyung Yoo. Interaction of Prior Chemotherapy and Addition of Ovarian Function Suppression on Menopausal Symptoms in Tamoxifen-Treated Breast Cancer Patient: A prospective, Observational study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-01-08.

Anxiolytic Effect of Anethum Graveolens Seed Extract Combined With the Antagonist of Estrogen Receptor in Female Rats With Anxiety

Background: Anxiety as an important psychological disorder that has affected many people and has made them to spend a lot of money for its treatment. Objectives: This study aims to assess the anxiolytic effect of the hydro-alcoholic extract of Anethum Graveolens L. seed (AGS) combined with the antagonist of estrogen receptor in female rats with anxiety. Materials &amp; Methods: In this study, 66 female Wistar rats were divided into eight groups as follow as: Negative control (10 ml/kg saline), positive control (0.6 mg/kg diazepam), five groups of AGS extract (0.1, 1, 10, 100 and 1000 mg/kg) and tamoxifen+AGS extract (10 mg/kg). Anxiety indicators were measured by the elevated plus maze (EPM) test. Results: The percentage of time spent open arms (%OAT) and percentage open arms entry (%OAE) significantly increased after using 10 mg/Kg dose of AGS extract compared to control group. Tamoxifen could significantly reduce this increase caused by AGS extract on anxiety indices. Conclusion: Considering the anxiolytic effect of the hydro-alcoholic extract of AGS and the reduction of this effect by the antagonist of estrogen receptor (tamoxifen), it can be concluded that the extract’s anxiolytic effect may be due to interaction with estrogen receptor.

Using hormonotherapy in breast cancer and its relationship with metabolic syndrome

Aims: This study aims to investigate whether the use of hormonotherapy pharmaceuticals causes metabolic syndrome-like symptoms in patients diagnosed with breast cancer and to compare the long-term effects of the drugs. Methods: This retrospective file analysis was conducted on breast cancer patients who presented to the Radiation Oncology clinic between January 2019 and April 2022. Files of 75 patients diagnosed with breast cancer, postmenopausal, and without any previous chronic diseases such as diabetes or hypertension were included in the study. Patients who were started on medications with different active ingredients (tamoxifen citrate, letrozole or anastrazole) in the adjuvant period were examined in 3 groups. Waist circumference thickness, body weight, blood pressure, and blood biochemical tests (blood glucose, lipid levels) were measured before and 6 months after the start of the drugs, and the values were compared retrospectively. Results: Of the 75 patients included in the study, the average age of patients using tamoxifen was 59.6; The average age of patients using letrozole was 59.12 years and the average age of patients using anastrozole was 63.56 years. There was an increase in fasting blood sugar (p:0.014) and waist circumference (p:0.009) in the tamoxifen group. There was an increase in fasting blood sugar, weight, waist circumference, blood pressure and lipid levels in the letrozole and anastrazole arms (p&amp;lt;0.0001 for all). Furthermore, comorbidities such as diabetes mellitus and hypertension that developed after using drugs were ascertained. Conclusion: We think that there is a significant association between hormonotherapy medicines used in breast cancer and metabolic syndrome. While we found increases in blood lipids, FBG, body weight, and waist circumference in most of the patients, we observed that these increases were significantly higher in the groups using aromatase inhibitors. These patients should be examined in detail before starting hormone therapy. Diet, active lifestyle, and sports should be recommended.

The role of latrophilin-2 in maintaining cardiac cell-to-cell junctions and its implications for dilated cardiomyopathy and sudden death

Abstract Background Identifying genes that are important for maintaining heart function and characterizing their roles and pathways are essential for developing therapeutic approaches. Latrophilin-2 (LPHN2), a relatively unknown GPCR, critically contributes to differentiation from pluripotent stem cells (PSC) to the cardiac lineage, but it is not known whether LPHN2 is active in the adult heart. Purpose In this study, we explored the functions of LPHN2 in adult hearts. Methods and Results To determine whether there is an association between variation in LPHN2 and cardiac phenotypes in humans, we used gnomAD and UK Biobank data. The data suggested that LPHN2 variants could be fatal. Accordingly, we developed a mouse model for further analysis of Lphn2. Deletion of Lphn2 causes embryonic lethality, so we generated a cardiac-specific, tamoxifen-inducible Lphn2 conditional knockout mouse (Lphn2icKO mouse) by cross-breeding Lphn2flox/flox mice with the TMX-inducible Cre recombinase (MerCreMer) under control of the α-Myh6 (α-myosin heavy chain) promoter mice. After administering tamoxifen, we found that the left ventricle became dilated and the systolic function was decreased, and gaps were created between cardiomyocytes. We also observed ventricular tachycardia and atrioventricular block associated with the dilated cardiomyopathy and subsequent sudden cardiac death. Cell-to-cell junctions (adherence, gap, and desmosomes,) were found to be dysregulated in the Lphn2icKO adult mouse heart and the heart at embryonic day 13.5 of Lphn2−/− (homozygous Lphn2 deficiency). To investigate Lphn2 function in a disease model, we generated a myocardial infarction (MI) in Lphn2icKO mice. MI with tamoxifen group showed wide QRS tachycardia and various types of block, and a survival reduction of 40% compared with that of the MI group. Regarding underlying mechanisms, we found that PGC-1α, a factor downstream of p38-MAPK that contributes to arrhythmia and maturation of PSC-derived cardiomyocytes, was downregulated (Figure). Conclusions LPHN2 is a key molecule that maintain adult heart integrity via its effects on cell-to-cell junctions, and the deficiency of Lphn2 exacerbates heart failure. Our findings provide evidence in support of LPHN2 being a pivotal regulator of heart function through the p38-MAPK-PGC-1α pathway.Schematic illustration

Presurgical Oral Tamoxifen vs Transdermal 4-Hydroxytamoxifen in Women With Ductal Carcinoma In Situ

Oral tamoxifen citrate benefits women with ductal carcinoma in situ (DCIS), but concern about toxic effects has limited acceptance. Previous pilot studies have suggested transdermal 4-hydroxytamoxifen gel has equivalent antiproliferative efficacy to oral tamoxifen, with low systemic exposure. To demonstrate that 4-hydroxytamoxifen gel applied to the breast skin is noninferior to oral tamoxifen in its antiproliferative effect in DCIS lesions. This randomized, double-blind, phase 2 preoperative window trial was performed at multicenter breast surgery referral practices from May 31, 2017, to January 27, 2021. Among 408 women with estrogen receptor-positive DCIS who were approached, 120 consented and 100 initiated study treatment. The most common reasons for nonparticipation were surgical delay, disinterest in research, and concerns about toxic effects. Data were analyzed from January 26, 2021, to October 5, 2022. Random assignment to oral tamoxifen citrate, 20 mg/d, and gel placebo or 4-hydroxytamoxifen gel, 2 mg/d per breast, and oral placebo, for 4 to 10 weeks, followed by DCIS resection. The primary end point was absolute change in DCIS Ki-67 labeling index (Ki67-LI). Secondary end points included 12-gene DCIS Score, breast tissue tamoxifen metabolite concentrations, tamoxifen-responsive plasma protein levels, and patient-reported symptoms. Noninferiority of Ki67-LI reduction by 4-hydroxytamoxifen gel was tested using analysis of covariance; within- and between-arm comparisons were performed with paired t tests for mean values or the Wilcoxon rank sum test for medians. Of 90 participants completing treatment (mean [SD] age, 55 [11] years; 8 [8.9%] Asian, 16 [17.8%] Black, 8 [8.9%] Latina, and 53 [58.9%] White), 15 lacked residual DCIS in the surgical sample, leaving 75 evaluable for the primary end point analysis (40 in the oral tamoxifen group and 35 in the 4-hydroxytamoxifen gel group). Posttreatment Ki67-LI was 3.3% higher (80% CI, 2.1%-4.6%) in the 4-hydroxytamoxifen gel group compared with the oral tamoxifen group, exceeding the noninferiority margin (2.6%). The DCIS Score decreased more with oral tamoxifen treatment (-16 [95% CI, -22 to -9.4]) than with 4-hydroxytamoxifen gel (-1.8 [95% CI, -5.8 to 2.3]). The median 4-hydroxytamoxifen concentrations deep in the breast were nonsignificantly higher in the oral tamoxifen group (5.7 [IQR, 4.0-7.9] vs 3.8 [IQR, 1.3-7.9] ng/g), whereas endoxifen was abundant in the oral tamoxifen group and minimal in the 4-hydroxytamoxifen gel group (median, 13.0 [IQR, 8.9-20.6] vs 0.3 [IQR, 0-0.3] ng/g; P < .001). Oral tamoxifen caused expected adverse changes in plasma protein levels and vasomotor symptoms, with minimal changes in the transdermal group. In this randomized clinical trial, antiproliferative noninferiority of 4-hydroxytamoxifen gel to oral tamoxifen was not confirmed, potentially owing to endoxifen exposure differences. New transdermal approaches must deliver higher drug quantities and/or include the most potent metabolites. ClinicalTrials.gov Identifier: NCT02993159.

Safety and efficacy of tamoxifen in boys with Duchenne muscular dystrophy (TAMDMD): a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

Drug repurposing could provide novel treatment options for Duchenne muscular dystrophy. Because tamoxifen-an oestrogen receptor regulator-reduced signs of muscular pathology in a Duchenne muscular dystrophy mouse model, we aimed to assess the safety and efficacy of tamoxifen in humans as an adjunct to corticosteroid therapy over a period of 48 weeks. We did a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial at 12 study centres in seven European countries. We enrolled ambulant boys aged 6·5-12·0 years with a genetically confirmed diagnosis of Duchenne muscular dystrophy and who were on stable corticosteroid treatment for more than 6 months. Exclusion criteria included ophthalmological disorders, including cataracts, and haematological disorders. We randomly assigned (1:1) participants using an online randomisation tool to either 20 mg tamoxifen orally per day or matched placebo, stratified by centre and corticosteroid intake. Participants, caregivers, and clinical investigators were masked to treatment assignments. Tamoxifen was taken in addition to standard care with corticosteroids, and participants attended study visits for examinations every 12 weeks. The primary efficacy outcome was the change from baseline to week 48 in scores on the D1 domain of the Motor Function Measure in the intention-to-treat population (defined as all patients who fulfilled the inclusion criteria and began treatment). This study is registered with ClinicalTrials.gov (NCT03354039) and is completed. Between May 24, 2018, and Oct 14, 2020, 95 boys were screened for inclusion, and 82 met inclusion criteria and were initially enrolled into the study. Three boys were excluded after initial screening due to cataract diagnosis or revoked consent directly after screening, but before randomisation. A further boy assigned to the placebo group did not begin treatment. Therefore, 40 individuals assigned tamoxifen and 38 allocated placebo were included in the intention-to-treat population. The primary efficacy outcome did not differ significantly between tamoxifen (-3·05%, 95% CI -7·02 to 0·91) and placebo (-6·15%, -9·19 to -3·11; 2·90% difference, -3·02 to 8·82, p=0·33). Severe adverse events occurred in two participants: one participant who received tamoxifen had a fall, and one who received placebo suffered a panic attack. No deaths or life-threatening serious adverse events occurred. Viral infections were the most common adverse events. Tamoxifen was safe and well tolerated, but no difference between groups was reported for the primary efficacy endpoint. Slower disease progression, defined by loss of motor function over time, was indicated in the tamoxifen group compared with the placebo group, but differences in outcome measures were neither clinically nor statistically significant. Currently, we cannot recommend the use of tamoxifen in daily clinical practice as a treatment option for boys with Duchenne muscular dystrophy due to insufficient clinical evidence. Thomi Hopf Foundation, ERA-Net, Swiss National Science Foundation, Duchenne UK, Joining Jack, Duchenne Parent Project, Duchenne Parent Project Spain, Fondation Suisse de Recherche sur les Maladies Musculaires, Association Monegasque contre les Myopathies.

Effect of tamoxifen in patients with thin endometrium who underwent frozen-thawed embryo transfer cycles: a retrospective study.

Thin endometrium leads to an impaired implantation rate. The aim of the study is to compare the clinical outcomes of tamoxifen (TAM) and hormone replacement therapy (HRT) used in patients with thin endometrium (<7mm) in frozen-thawed embryo transfer (FET)cycles. A total of 176 FET cycles with thin endometrium were retrospectively analyzed in our center from Jan 2020 to May 2022. According to patients' own will, 112 patients were allocated to the HRT group and 64 patients chose the TAM protocol. Clinical outcomes were compared between two groups. The duration of treatment was shorter in the TAM group(12.03±2.34d) than the HRT group (16.07±2.52 d), which was statistically different (p<0.05). The endometrial thickness on the transfer day of the TAM group (7.32±1.28 mm) was significantly thicker than that of the HRT group (6.85±0.89mm, p<0.05). The clinical pregnancy rate of the TAM group (50.0%) was higher than that of the HRT group (36.6%), but there was no significant difference (p >0.05). The early miscarriage rate was significantly lower in the TAM group compared with the HRT group (5.9% Vs 26.8%, adjusted OR 0.10, p<0.05), while the live birth rate was higher in the TAM group (46.9% Vs 26.8%, adjusted OR 2.24, p<0.05) compared with the HRT group. For patients with thin endometrium, TAM effectively improved the endometrial thickness and increased the live birth rate. TAM can be used as an alternative protocol for patients with thin endometrium.

Toremifene, an Alternative Adjuvant Endocrine Therapy, Is Better Than Tamoxifen in Breast Cancer Patients with CYP2D6*10 Mutant Genotypes.

Tamoxifen showed individual differences in efficacy under different CYP2D6*10 genotypes. Our study evaluated the prognosis of tamoxifen or toremifene in hormone receptor (HR)-positive breast cancer patients under different genotypes. CYP2D6*10 genotypes of HR-positive breast cancer patients were determined by Sanger sequencing, and all the patients were divided into tamoxifen group or toremifene group. A total of 268 patients with HR-positive breast cancer were studied. The median follow-up time was 72.0 months (range, 5.0 to 88.0 months). Of these, 88 (32.9%), 114 (42.5%), and 66 (24.6%) patients had C/C, C/T, and T/T genotypes, respectively. Among patients who received tamoxifen (n=176), the 5-year disease-free survival (DFS) rate in patients with C/C and C/T genotype was better than that in patients with T/T genotype, and the difference was statistically significant (p < 0.001 and p=0.030, respectively). In patients receiving toremifene, CYP2D6*10 genotype was not significantly associated with DFS (p=0.325). Regardless of genotypes, the 5-year DFS rate was higher in patients treated with toremifene than in patients with tamoxifen (91.3% vs. 80.0%, p=0.011). Compared with tamoxifen, toremifene remained an independent prognostic marker of DFS in multivariate analysis (hazard ratio, 0.422; p=0.021). For all the 180 patients with CYP2D6*10 C/T and T/T genotypes, the 5-year DFS rate was significantly higher in the toremifene group than in the tamoxifen group (90.8% vs. 70.1%, p=0.003). Toremifene may be an alternative adjuvant endocrine therapy for patients with CYP2D6*10 mutant genotypes.

Effect and mechanism of Xihuang Pills on rats with precancerous lesions of breast

The purpose of this study was to explore the effect and mechanism of Xihuang Pills on rats with precancerous lesions of the breast. Of 48 healthy female rats, 8 were randomly selected as blank group, and the other 40 were treated with 7,12-dimethylbenzanthracene(DMBA) combined with estrogen and progestin to establish a model of precancerous lesions of the breast. The successfully modeled rats were randomly divided into a model group, a tamoxifen group(1.8 mg·kg~(-1)·d~(-1)), a Xihuang Pills low-dose group(0.3 g·kg~(-1)·d~(-1)), a medium-dose group(0.6 g·kg~(-1)·d~(-1)) and a high-dose group(1.2 g·kg~(-1)·d~(-1)). After 30 days of admi-nistration, the histopathological changes of viscera and breast were observed by haematoxylin and eosin(HE) staining, and the visceral index was calculated. Enzyme linked immunosorbent assay(ELISA) was used to detect the contents of estradiol(E_2) and progesterone(P) in serum. The protein expressions of vascular endothelial growth factor(VEGF) and fibroblast growth factor 2(FGF2) were detected by immunohistochemistry. The protein expressions of VEGF, vascular endothelial growth factor receptor 2(VEGFR2), phosphorylated-vascular endothelial growth factor receptor 2(p-VEGFR2), B-cell lymphoma-2(Bcl-2), and Bcl-2 associated X protein(Bax) were detected by Western blot and the mRNA expressions of VEGF, FGF2, CXC-chemokine receptor 4(CXCR4), cysteine aspartic acid-specific protease(caspase-3), and stromal cell-derived factor 1(SDF-1) were detected by real-time polymerase chain reaction(RT-PCR). HE staining revealed that the model group had some liver and kidney damages and severe hyperplastic mammary tissue, while the Xihuang Pills high-dose group had mild hyperplasia. Compared with the model group, the Xihuang Pills groups had lo-wer ovarian coefficient(P&lt;0.05 or P&lt;0.01) and Xihuang Pills high-dose group had lower uterine coefficient(P&lt;0.01). ELISA results showed that compared with the model group, expressions of E_2 and P in Xihuang Pills high-dose group were significantly decreased(P&lt;0.05 or P&lt;0.01). Immunohistochemistry, Western blot and RT-PCR indicated that compared with the conditions in the model group, the protein and mRNA expressions of VEGF and FGF2 in the Xihuang Pills groups were down-regulated(P&lt;0.05 or P&lt;0.01), and the protein expression of Bcl-2 was lowered(P&lt;0.01); there was a decrease in the protein expressions of VEGFR2 and p-VEGFR2(P&lt;0.01), a down-regulation in the mRNA expressions of CXCR4 and SDF-1(P&lt;0.01), while an increase in the mRNA expression of caspase-3(P&lt;0.01) in both Xihuang Pills medium-dose and high-dose groups; the protein expression of Bax in Xihuang Pills high-dose group was increased(P&lt;0.01). The above results indicated that Xihuang Pills can effectively intervene in precance-rous lesions of the breast, and the mechanism may be related to the regulation of E_2 and P secretion as well as the inhibition of angiogenesis and chemokine receptor expression, thus controlling the occurrence of precancerous lesions of the breast in rats.

Quality of life in Spanish postmenopausal breast cancer patients with localized disease who finish endocrine treatment: a prospective study.

In this article, the quality of life (QOL) of Spanish postmenopausal early-stage breast cancer patients who have finished endocrine therapy (ET), QOL changes after endocrine therapy cessation, and the differences between two endocrine therapy modalities (tamoxifen or aromatase inhibitor [AI]) are studied. More QOL information after endocrine therapy cessation is needed. A prospective cohort study was performed. Participating in the study were 158 postmenopausal patients who had received tamoxifen or AI for 5 years. In some cases, endocrine therapy may have changed during those 5 years.Patients completed the European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR45 questionnaires at baseline, after 6 months, and after 1 year of follow-up. Patients older than 65 years also completed the QLQ-ELD14. Linear mixed-effect models were used to evaluate longitudinal changes in QOL and differences in QOL between endocrine therapy modalities. QOL scores for the whole sample throughout follow-up were high (>80/100 points) in most QOL areas. Moderate limitations (>30 points) occurred in the QLQ-BR45 in sexual functioning and sexual enjoyment, future perspective, and joint symptoms. Moderate limitations also occurred in the QLQ-ELD14 in worries about others, maintaining purpose, joint stiffness, future worries, and family support. In those who had finished endocrine therapy, pain was reduced in all three assessments conducted during the 1-year follow-up period in both groups. Tamoxifen patients showed better QOL in functioning (role functioning, global QOL, financial impact), symptoms (pain), and emotional areas (future perspective and worries about others) than AI patients but worse QOL in skin mucosis symptoms. The results of this study show that postmenopausal early-stage breast cancer patients adapted well to their disease and endocrine therapy treatment. QOL improvements in the 1-year follow-up period appeared in one key area: pain. Differences between endocrine therapy modalities suggested QOL was better in the tamoxifen group than in the AI group.

Randomized Placebo Controlled Trial of Low-Dose Tamoxifen to Prevent Recurrence in Breast Noninvasive Neoplasia: A 10-Year Follow-Up of TAM-01 Study.

Five-year data of the phase III trial TAM-01 showed that low-dose tamoxifen at 5 mg once daily administered for 3 years in women with intraepithelial neoplasia (IEN) reduced by 52% the recurrence of invasive breast cancer or ductal carcinoma in situ (DCIS), without additional adverse events over placebo. Here, we present the 10-year results. We randomly assigned 500 women with breast IEN (atypical ductal hyperplasia, lobular carcinoma in situ [LCIS], or hormone-sensitive or unknown DCIS) to low-dose tamoxifen or placebo after surgery with or without irradiation. The primary end point was the incidence of invasive breast cancer or DCIS. The TAM-01 population included 500 women (20% atypical ductal hyperplasia, 11% LCIS, and 69% DCIS). The mean (±SD) age at the start of treatment was 54 ± 9 years, and 58% of participants were postmenopausal. After a median follow-up of 9.7 years (IQR, 8.3-10.9 years), 66 breast cancers (15 in situ; 51 invasive) were diagnosed: 25 in the tamoxifen group and 41 in the placebo group (annual rate per 1,000 person-years, 11.3 with tamoxifen v 19.5 with placebo; hazard ratio [HR], 0.58; 95% CI, 0.35 to 0.95; log-rank P = .03). Most recurrences were invasive (77%) and ipsilateral (59%). Regarding contralateral breast cancer incidence, there were six events in the tamoxifen arm and 16 in the placebo arm (HR, 0.36; 95% CI, 0.14 to 0.92; P = .025). The number needed to be treated to prevent one case of breast event with tamoxifen therapy was 22 in 5 years and 14 in 10 years. The benefit was seen across all patient subgroups. There was a significant 50% reduction of recurrence with tamoxifen in the DCIS cohort, which represents 70% of the overall population (HR, 0.50; 95% CI, 0.28 to 0.91; P = .02). No between-group difference in the incidence of serious adverse events was reported during the prolonged follow-up period. Tamoxifen 5 mg once daily for 3 years significantly prevents recurrence from noninvasive breast cancer after 7 years from treatment cessation without long-term adverse events.

A retrospective cohort study of tamoxifen versus surgical treatment for ER-positive gynecomastia

BackgroundGynecomastia is a common condition in clinical practice. The present study aimed to review the clinical data of ER-positive gynecomastia patients treated by tamoxifen (TAM) versus surgery and discussed the clinical effects of the two treatment strategies.MethodWe retrospectively collected the clinical indicators of patients with unilateral or bilateral gynecomastia who received treatment at our hospital between April 2018 and December 2021. Depending on the treatment received, the patients were divided into TAM and surgery groups.ResultA total of 170 patients were recruited, including 91 patients in TAM group and 79 patients in surgery group. The age of the patients differed significantly between the TAM and surgery groups (P < 0.01). The estrogen level was closer in patients with stable and progressive disease, but significantly different in patients of glandular shrinkage in TAM group (P < 0.01). The proportion of patients achieving stable disease was higher among those with clinical grade 1–2. Among patients classified as clinical grade 3, the proportion of patients achieving glandular shrinkage of the breast was higher after TAM treatment (P < 0.05). The age and length of hospital stay were significantly different in patients undergoing open surgery than minimally invasive rotary cutting surgery and mammoscopic-assisted glandular resection (P < 0.01). Patients had significantly different complications including mild postoperative pain, hematoma, nipple necrosis, nipple paresthesias and effusions among the surgery subgroups (all P < 0.05). The estrogen level and the type of surgery were significantly different between the surgical recurrence and non-recurrence subgroups (P < 0.05). The difference in the thickness of glandular tissues upon the color Doppler ultrasound also reached a statistical significance between the two groups (P = 0.050). An elevated estrogen level was a factor leading to TAM failure. Among surgical patients, the thickness of glandular tissues, estrogen level, and type of surgery performed were risk factors for postoperative recurrence (all P < 0.05).ConclusionBoth treatment strategies can effectively treat gynecomastia, but different treatment methods can benefit different patients. TAM treatment is more beneficial than surgery for patients who cannot tolerate surgery, have a low estrogen level, and are clinical grade 1–2. Surgery treatment is better than TAM for patients of clinical grade 3. Different surgery options may lead to different complications. Patients with a greater glandular tissue thickness and a higher estrogen level were shown to have a higher risk of recurrence.

Risk of Secondary Cancer after Adjuvant Tamoxifen Treatment for Ductal Carcinoma In Situ: A Nationwide Cohort Study in South Korea

Endocrine therapy is the mainstay treatment for hormone receptor-positive ductal carcinoma in situ. The aim of this study was to examine the long-term secondary malignancy risk of tamoxifen therapy. The data of patients diagnosed with breast cancer between January 2007 and December 2015 were retrieved from the database of the Health Insurance Review and Assessment Service of South Korea. The International Classification of Diseases, 10th revision, was used to track all-site cancers. Age at the time of surgery, chronic disease status, and type of surgery were considered covariates in the propensity score matching analysis. The median follow-up duration was 89 months. Forty-one patients in the tamoxifen group and nine in the control group developed endometrial cancer. The Cox regression hazard ratio model showed that tamoxifen therapy was the only significant predictor of the development of endometrial cancer (hazard ratio, 2.791; 95% confidence interval, 1.355-5.747; p = 0.0054). No other type of cancer was associated with long-term tamoxifen use. In consonance with the established knowledge, the real-world data in this study demonstrated that tamoxifen therapy is related to an increased incidence of endometrial cancer.