Tamoxifen Dose De-Escalation: An Effective Strategy for Reducing Adverse Effects?

Tamoxifen, a cornerstone in the adjuvant treatment of estrogen receptor-positive breast cancer, significantly reduces breast cancer recurrence and breast cancer mortality; however, its standard adjuvant dose of 20 mg daily presents challenges due to a broad spectrum of adverse effects, contributing to high discontinuation rates. Dose reductions of tamoxifen might be an option to reduce treatment-related toxicity, but large randomized controlled trials investigating the tolerability and, more importantly, efficacy of low-dose tamoxifen in the adjuvant setting are lacking. We conducted an extensive literature search to explore evidence on the tolerability and clinical efficacy of reduced doses of tamoxifen. In this review, we discuss two important topics regarding low-dose tamoxifen: (1) the incidence of adverse effects and quality of life among women using low-dose tamoxifen; and (2) the clinical efficacy of low-dose tamoxifen examined in the preventive setting and evaluated through the measurement of several efficacy derivatives. Moreover, practical tools for tamoxifen dose reductions in the adjuvant setting are provided and further research to establish optimal dosing strategies for individual patients are discussed.

[Effects of extended aromatase inhibitors in women with hormone-dependent breast cancer who have already received five years of adjuvant hormone therapy: A systematic review and meta-analysis]. / Analyse des effets des inhibiteurs de l'aromatase en traitement prolongé chez les femmes ménopausées atteintes d'un cancer du sein non métastatique hormonodépendant ayant déjà reçu cinq ans d'hormonothérapie adjuvante : revue systématique et méta-analyse.

INTRODUCTION: Evaluating the benefits and risks of prolonged hormonal treatment with aromatase inhibitors (AIs) for treating hormone-dependent breast cancer. METHODS: A systematic review and meta-analysis was conducted. Studies reporting on randomized clinical trials concerning prolongating hormonal therapy with AIs as compared to a placebo or no prolongation, after an initial five years of hormonal therapy, were eligible. RESULTS: Seven clinical trials were included. Prolonged AI therapy was associated with a statistically significant improvement in disease-free survival (RR=0.70, 95% CI 0.60 to 0.80). A statistically significant increase was observed for osteoporosis (RR=1.17, 95% CI 1.03 to 1.33), hot flushes/flashes (RR=1.27, 95% CI 1.08 to 1.49), myalgia (RR=1.23, 95% CI 1.09 to 1.39), fractures (RR=1.26, 95% CI 1.09 to 1.45) and arthralgia (RR=1.17, 95% CI 1.10 to 1.25). However, no statistically significant association was observed between prolonged AI therapy and overall survival, cardiovascular events, and bone pain. DISCUSSION: Prolonged AI therapy has significant benefits in terms of disease-free survival in women with hormone-dependent breast cancer. However, adverse effects and a lack of evidence for a benefit on overall survival must be considered in the decision-making process regarding adjuvant hormone therapy extension.

Hemostatic imbalance induced by tamoxifen in estrogen receptor-positive breast cancer patients: An observational study.

BACKGROUND: Estrogen receptor (ER)-positive (ER+) breast cancer accounts for approximately 75% of all breast cancers. Tamoxifen, a selective estrogen receptor modulator, is the standard adjuvant treatment. Although better tolerated than aromatase inhibitors, tamoxifen increases the risk of venous thromboembolism (VTE) 1.4-fold. AIM: To assess the hemostatic imbalance induced by tamoxifen in adjuvant treatment of ER+ breast cancer. METHOD: Twenty-five patients in remission from ER+ breast cancer under tamoxifen were included. One hundred and thirty one age- and BMI-matched healthy controls were included to establish reference ranges of thrombin generation assay (TGA) parameters. TGA was performed in the absence and presence of exogenous activated protein C (APC) to calculate the normalized APC sensitivity ratio (nAPCsr), a marker of APC resistance. RESULTS: All TG parameters except the endogenous thrombin potential (ETP) (-APC) were significantly impacted by tamoxifen (p < 0.001). In absence of APC, regardless of TGA parameters, at least 50% of results were outside the reference ranges except for ETP, which was above the upper reference limit in only two individuals. The most impacted parameter was the Peak Height with 52% (-APC) and 80% (+APC) of results above the upper reference range limit, respectively. The nAPCsr was significantly higher in tamoxifen users (mean ± standard deviation = 3.18 ± 0.91) compared to the control group (2.19 ± 0.92, p < 0.0001). CONCLUSION: This observational study showed that patients in remission from ER+ breast cancer taking tamoxifen had altered thrombin generation, as well as an acquired APC resistance. Moreover, this is the first study using the validated ETP-based APC resistance assay in tamoxifen-treated patients.

Tamoxifen in breast cancer and risk of Parkinson's disease: A meta-analysis.

BACKGROUND: Tamoxifen is widely used for hormone-sensitive breast cancer, achieved by modulating the estrogen receptor activity in a tissue-specific manner. There is evidence to support the protective effects of estrogen against Parkinson's disease (PD), a common neurodegenerative condition. Some epidemiologic studies suggest the use of tamoxifen may modulate the PD risk. We conducted a meta-analysis to examine the association between tamoxifen and risk of PD. METHODS: A search of PubMed using search terms synonymous with "tamoxifen" and "Parkinson's disease" was conducted. Outcomes of interest were the odds ratio (OR) of PD comparing tamoxifen-exposed to -unexposed women, as well as the incidence rate of PD in tamoxifen-exposed women. RESULTS: A total of 37,932 subjects with breast cancer, comprising 17,233 tamoxifen-exposed subjects and 20,699 tamoxifen-unexposed subjects, satisfied the inclusion criteria. The exposure to tamoxifen ranged from 30-96 months. Using the common-effect model, the pooled OR of PD was 2.4, with (95% CI 1.91-3.01, P < 0.0001), with high heterogeneity (I2 = 81.5%, Cochran's Q test P = 0.001). Pooling 28,640 tamoxifen-exposed patients under the common-effect model found an incidence rate of 5.86 events per 10,000 person-years (95% CI 4.82-7.12) with minimal heterogeneity (I2 = 26%, Cochran's Q test P = 0.258). CONCLUSIONS: Our meta-analysis suggests that tamoxifen use may be associated with an increased PD risk in women. However, due to heterogeneity and potential limitations of some of the studies, further clinical and functional validation will be needed. Longitudinal studies supported by imaging and biomarkers evaluation will be useful to identify the mechanisms linking tamoxifen and PD risk.

Using 3% retinol peeling and cosmeceuticals for the aesthetic wellness of the oncological patient after precautionary endocrine treatment: A case series.

BACKGROUND: Roughness, sagging, and skin rash are common in patients with breast cancer treated with LH-RH analog plus tamoxifen or aromatase inhibitors as adjuvant postsurgical endocrine therapy. The use of topical retinol (vitamin A) has shown to be an efficacious cosmetic treatment. AIMS: Peeling with an advanced retinol peel formulation based on 3% retinol, 4% triethyl citrate, 0.1% aminophil, bisabolol, and 1% vitamin E acetate, in a vehicle in an alcoholic solution has been successfully used to ameliorate skin appearance on subjects with photodamage and in the aged population. We aimed to verify its use during adjuvant chemotherapy. PATIENTS: Four subjects experiencing skin issues during postsurgical adjuvant therapy for their breast cancer received retinol peel at least 6 weeks after stopping their postsurgery therapy as a low invasive aesthetic medical treatment to be used both at the dermatology desk and at home. RESULTS: Retinol peel was effective, safe, and well-tolerated, improving skin brightness and firmness in all the patients, since 4 weeks after the beginning of the treatment. Patients declared to be satisfied with the treatment and their skin appearance letting them feel better for cancer recovery, too. CONCLUSION: These preliminary observations suggest that the use of an advanced retinol peel formulation might improve skin appearance in women experiencing skin damages caused by adjuvant therapy after breast cancer surgery.

Anastrozole as a therapeutic option for gynecomastia in a person receiving antiretroviral therapy: Case report.

A middle-aged Caucasian man living with HIV, clinically stable (viral load <20 copies/mL) on injectable antiretroviral cabotegravir plus rilpivirine every 2 months presented with a 6-month history of bilateral enlargement of the breasts associated with pain. His hormonal profile was normal, and no other underlying cause was identified. He was diagnosed with idiopathic gynecomastia. Tamoxifen is an anti-oestrogen recommended for gynecomastia and has been described in people living with HIV but can potentially induce the activity of cytochrome P450 3A4 (CYP3A4), reducing rilpivirine concentrations, which consequently may cause virological failure and resistance. This is the same for other antiretroviral agents majorly induced by CYP3A4. To date, there have been no reported cases of using anastrozole as a treatment for gynecomastia in people living with HIV or of its co-administration with antiretroviral. We describe the use of an aromatase inhibitor instead of tamoxifen in a person living with HIV, diagnosed with gynecomastia.

Diabetes mellitus in breast cancer survivors: metabolic effects of endocrine therapy.

Breast cancer is the most common invasive malignancy in the world, with millions of survivors living today. Type 2 diabetes mellitus (T2DM) is also a globally prevalent disease that is a widely studied risk factor for breast cancer. Most breast tumours express the oestrogen receptor and are treated with systemic therapies designed to disrupt oestrogen-dependent signalling. Since the advent of targeted endocrine therapy six decades ago, the mortality from breast cancer has steadily declined; however, during the past decade, an elevated risk of T2DM after breast cancer treatment has been reported, particularly for those who received endocrine therapy. In this Review, we highlight key events in the history of endocrine therapies, beginning with the development of tamoxifen. We also summarize the sequence of reported adverse metabolic effects, which include dyslipidaemia, hepatic steatosis and impaired glucose tolerance. We discuss the limitations of determining a causal role for breast cancer treatments in T2DM development from epidemiological data and describe informative preclinical studies that suggest complex mechanisms through which endocrine therapy might drive T2DM risk and progression. We also reinforce the life-saving benefits of endocrine therapy and highlight the need for better predictive biomarkers of T2DM risk and preventive strategies for the growing population of breast cancer survivors.

Tamoxifen retinopathy: A comprehensive review.

Tamoxifen is a selective estrogen receptor modulator used mainly for the treatment of breast cancer. Based on the case reports and studies performed to date on the retinal toxicity of tamoxifen, retinopathy appears to occur in as many as 12% of patients taking 20 mg tamoxifen a day for over 2 years. Of this 12%, as many as half develop symptomatic changes in visual acuity. Retinal changes consist primarily of crystalline deposits, cystoid macular edema, hyperreflective deposits in the inner retinal layers, and telangiectasia. Tamoxifen retinopathy is currently managed by discontinuing tamoxifen therapy as the cancer prognosis permits; however, discontinuing therapy demonstrates little to no improvement in visual acuity once visual changes have taken place. Intravitreal injections of steroids or antivascular endothelial growth factor therapy have been performed, but require further studying before conclusions can be made. Until then, optical coherence tomography screening for retinal changes should be performed every 6 months for patients who have been on tamoxifen therapy for 2 years or more. This way, patients can become aware of retinal changes, and their physicians can consider adjusting tamoxifen therapy before they risk developing changes in visual acuity.

The lived experience of patients with breast cancer on adjuvant endocrine therapy: side effects and coping strategies during the first year of medication initiation.

PURPOSE: Adjuvant endocrine therapy (AET) is pivotal for hormone receptor-positive breast cancer patients, significantly enhancing survival rates. Yet, adherence to AET remains challenging due to side effects. This study delves into the lived experience of breast cancer survivors concerning AET-induced side effects and examines differences in symptom profiles between Tamoxifen and aromatase inhibitors (AIs). METHODS: We interviewed 35 breast cancer survivors on AET, conducting qualitative iterative analysis using grounded theory. A codebook was developed to aid data coding and interpretation. NVIVO software facilitated comprehensive transcript analysis. RESULTS: Survivors reported a spectrum of side effects like hot flashes, sexual issues, joint pain, stiffness, mood swings, and fertility concerns. Symptom profiles differed based on AET type. Tamoxifen users experienced more frequent sexual side effects and mood swings, while AIs were linked to joint pain, stiffness, and bone health worries. Those on AET for over 6 months expressed heightened concerns about side effects. CONCLUSION: Tailored patient education, aligned with AET type, empowers survivors to manage side effects using self-regulatory strategies. Acknowledging distinct symptom profiles enables informed decisions, improving adherence and quality of life. IMPLICATIONS: This study underscores tailored survivorship support, equipping patients with tools to manage side effects, enhancing adherence, and long-term outcomes. The findings inform the integration of comprehensive survivorship programs, emphasizing individualized strategies for managing side effects and promoting better adherence and improved quality of life.

Foveal cone loss in tamoxifen maculopathy: a case report.

BACKGROUND: Tamoxifen is used in low dose concentrations (20-40 mg per day) as a therapy for breast cancer but is known to have ocular side effects. In this case report, the foveal cone integrity in a tamoxifen-treated patient who complained of a small central scotoma in the left eye while reading was examined using high resolution adaptive optics imaging. CASE PRESENTATION: Both eyes of a 54-year-old Caucasian, non-hispanic female who had been treated with tamoxifen for 1.5 years were examined using various imaging modalities including fundus photography, fundus autofluorescence, fluorescein angiography, spectral-domain optical coherence tomography, and adaptive optics scanning laser ophthalmoscopy. Clinical spectral-domain optical coherence tomography showed a very small disruption to the photoreceptor layer at the fovea in the left eye only. However, adaptive optics scanning laser ophthalmoscopy imaging revealed foveal cone loss in both eyes, but to a lesser extent in the right eye. Inner retinal changes were not observed in either eye. CONCLUSION: The area of cone loss was similar in size to a single newsprint letter when projected onto the retina, matching the patient's description of a scotoma in the left eye. Given the isolated loss of foveal cone photoreceptors with the absence of previously reported inner retinal and vascular changes, our results may indicate the earliest retinal changes associated with tamoxifen retinopathy.

Tamoxifen induces eryptosis through calcium accumulation and oxidative stress.

Chemotherapy-related anemia is a major obstacle in anticancer therapy. Tamoxifen (TAM) is an antiestrogen prescribed for breast cancer patients with hemolytic potential and apoptotic properties in nucleated cells. However, the eryptotic activity of TAM has hitherto escaped the efforts of investigators. RBCs from apparently healthy volunteers were treated with 1-50 µM of TAM for 24 h at 37 °C. Hemoglobin leakage and LDH, AST, and AChE activities were photometrically determined while K+, Na+, and Mg2+ were detected by ion-selective electrode. Flow cytometry was used to identify eryptotic cells by annexin-V-FITC, intracellular Ca2+ by Fluo4/AM, sell size and morphology by FSC and SSC signals, respectively, and oxidative stress by H2DCFDA. Whole blood was also exposed to 30 µM of TAM for 24 h at 37 °C to examine the toxicity of TAM to WBCs and platelets. TAM caused Ca2+-independent, dose-responsive hemolysis accompanied by K+, LDH, and AST leakage without improving the mechanical stability of RBCs in hypotonic environments. TAM treatment also increased the proportion of cells positive for annexin-V-FITC, Fluo4, and DCF, along with diminished FSC and SSC signals and AChE activity. Notably, TAM toxicity was aggravated by sucrose but abrogated by vitamin C, PEG 8000, and urea. Moreover, TAM exhibited distinct cytotoxic profiles against leukocytes and platelets. TAM-induced eryptosis is characterized by breakdown of membrane asymmetry, inhibition of AChE activity, Ca2+ accumulation, cell shrinkage, and oxidative stress. Vitamin C, PEG 8000, and urea may hold promise to subvert the undesirable toxic effects of TAM on RBCs.

Presurgical Oral Tamoxifen vs Transdermal 4-Hydroxytamoxifen in Women With Ductal Carcinoma In Situ: A Randomized Clinical Trial.

Importance: 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. Objective: To demonstrate that 4-hydroxytamoxifen gel applied to the breast skin is noninferior to oral tamoxifen in its antiproliferative effect in DCIS lesions. Design, Setting, and Participants: 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. Intervention: 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. Main Outcomes and Measures: 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. Results: 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. Conclusions and Relevance: 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. Trial Registration: ClinicalTrials.gov Identifier: NCT02993159.

Breast cancer and incidence of type 2 diabetes mellitus: a systematic review and meta-analysis.

PURPOSE: Breast cancer and its treatments may increase the risk of type 2 diabetes (T2D). We conducted a systematic review and meta-analysis to investigate the association between breast cancer and the incidence of T2D overall, and according to breast cancer treatments. METHODS: We searched PubMed, Embase and references of relevant papers for studies on breast cancer, breast cancer treatment, and subsequent T2D risk. Using random-effects models, we calculated effect estimates and associated 95% confidence intervals of the association between breast cancer, adjuvant breast cancer treatments (i.e., endocrine therapy (tamoxifen, aromatase inhibitors, and combined) and chemotherapy), and subsequent T2D. We used funnel plots to assess publication bias. RESULTS: Among 15 eligible studies, 10 reported on T2D risk after breast cancer, chemotherapy, or endocrine therapy; five studies investigated more than one association. Compared with patients without breast cancer, those with breast cancer and those who received any endocrine therapy had elevated risk of incident T2D (EE = 1.23, 95% CI = 1.13-1.33 and EE = 1.23, 95% CI = 1.16-1.32, respectively). Among breast cancer patients only, the risk of T2D was higher for those who received tamoxifen compared with those who did not receive tamoxifen (EE = 1.28, 95% CI = 1.18-1.38). Due to few studies, analyses investigating T2D risk after treatment with aromatase inhibitors or chemotherapy were inconclusive. CONCLUSION: Our findings suggest an elevated risk of T2D in breast cancer survivors, particularly after tamoxifen therapy. Further research is needed to determine the impact of aromatase inhibitors, and chemotherapy on the incidence of T2D after breast cancer.

Gynecomastia.

Enlargement of breasts among boys is termed gynecomastia. This could be due to an alteration in the androgen-estrogen ratio along with the effects of other hormones including growth hormone, insulin like growth factor 1, prolactin, and other factors affecting aromatase enzyme. The common causes of gynecomastia are pubertal gynecomastia, obesity, drugs and hypogonadism. Several other diseases including liver or renal failure, thyrotoxicosis, Klinefelter syndrome, tumors and environmental pollutants can cause gynecomastia. History and clinical examination will help formulate targeted investigations and management. The factors to be evaluated in these include examination of breasts and testes, in addition to other parts of systemic examination. Treatment of underlying disorders can improve gynecomastia, such as use of testosterone in hypogonadism. Some boys may not need any intervention as gynecomastia may resolve on its own. Medical management is useful in simple gynecomastia. Tamoxifen has been tried successfully in adolescents with gynecomastia. Other drugs including clomiphene, danazol, letrozole and anastrozole have not been consistently useful in this age group. In severe chronic gynecomastia, surgery is the treatment of choice.

Evaluation and Comparison of Citalopram and Venlafaxine for Management of Hot Flashes in Women with Breast Cancer.

BACKGROUND: Breast cancer is the most common cancer in women worldwide. Premature menopause and hot flashes are the main complications of breast cancer treatments. About 40 to 50 percent of breast cancer women who undergo chemotherapy are experiencing premature menopause symptoms, including hot flashes. Some endocrine therapies such as tamoxifen and aromatase inhibitors are associated with induction or aggravating hot flashes. Hot flashes are often debilitating and significantly impair daily functions. Therefore many therapeutic options have been studied so far for the management of this adverse effect. However, there are still some clinical challenges in managing hot flashes in patients with breast cancer. OBJECTIVE: We aimed to evaluate and compare the efficacy of venlafaxine and citalopram on hot flashes in breast cancer women receiving tamoxifen. DESIGN: We conducted a double-blind, placebo-controlled trial in forty-one, 35 to 65 years old female patients. The study lasted for four weeks, and the follow-up was for two months. Venlafaxine and citalopram treatments started with doses of 37.5 mg or 10 mg, respectively. Venlafaxine and citalopram dosages were increased in the second week to 75 and 20 mg, respectively. The study was conducted during the year 2017. KEY RESULTS: The results indicated that the total efficacy was significantly different in groups receiving citalopram, venlafaxine, and placebo. Total efficacy in the placebo group, venlafaxine, and citalopram was 14.3, 53.8, and 64.3%, respectively (p=0.02). During the second week, the efficacy in groups receiving citalopram, venlafaxine, and placebo was 57.1, 53.8, and 14.3%, respectively (p=0.04). Generally, both citalopram and venlafaxine were well tolerated. The associated adverse effects were mild to moderate in both groups. CONCLUSIONS: Although citalopram was associated with more adverse effects, including constipation, it was more effective in reducing the frequency of hot flashes when compared to venlafaxine or placebo.

Adding Ovarian Suppression to Tamoxifen for Premenopausal Women With Hormone Receptor-Positive Breast Cancer After Chemotherapy: An 8-Year Follow-Up of the ASTRRA Trial.

PURPOSE: To determine the updated long-term outcomes of the Addition of Ovarian Suppression to Tamoxifen in Young Women With Hormone-Sensitive Breast Cancer Who Remain Premenopausal or Regain Vaginal Bleeding After Chemotherapy (ASTRRA) trial. PATIENTS AND METHODS: This study is a post-trial follow-up of the ASTRRA trial, involving 1,483 premenopausal women younger than 45 years treated with definitive surgery after completing adjuvant or neoadjuvant chemotherapy for estrogen receptor-positive breast cancer. Patients were randomly assigned in a 1:1 ratio to complete 5 years of tamoxifen (TAM) alone (TAM-only) or 5 years of TAM with ovarian function suppression (OFS) for 2 years (TAM + OFS). The primary end point was disease-free survival (DFS), and the secondary end point was overall survival (OS). RESULTS: At 106.4 months of median follow-up, there was a continuous significant reduction in the DFS event rate in the TAM + OFS group. The 8-year DFS rate was 85.4% in the TAM + OFS group and 80.2% in the TAM-only group (hazard ratio [HR], 0.67; 95% CI, 0.51 to 0.87). There were no significant differences in OS between the two groups. The OS rate was 96.5% in the TAM + OFS group and 95.3% in the TAM-only group (HR, 0.78; 95% CI, 0.49 to 1.25). CONCLUSION: Adding OFS for 2 years to adjuvant TAM with a longer follow-up resulted in consistent DFS benefits, suggesting that adding OFS to TAM should be considered for patients who remain in a premenopausal state or resume ovarian function after chemotherapy.