Venlafaxine reduces hot flashes in hormone receptor-positive breast cancer patients receiving tamoxifen: a prospective single‑arm, open‑label trial

Venlafaxine reduces hot flashes in hormone receptor-positive breast cancer patients receiving tamoxifen: a prospective single‑arm, open‑label trial | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Venlafaxine reduces hot flashes in hormone receptor-positive breast cancer patients receiving tamoxifen: a prospective single‑arm, open‑label trial Riko Sato, Rena Kamohara, Tomohei Matsuo, Sawa Aya, Mai Okazaki, and 9 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7522015/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 05 Feb, 2026 Read the published version in Breast Cancer → Version 1 posted 5 You are reading this latest preprint version Abstract Background We conducted a prospective, singlearm, openlabel trial to evaluate venlafaxine efficacy and safety in hormone receptor-positive breast cancer patients on tamoxifen experiencing moderatetosevere hot flashes. Methods Twenty patients received venlafaxine at 37.5 mg/day for 4 weeks, with optional escalation to 75 mg/day. Weekly hot flash scores, adverse events, and serum concentrations of tamoxifen, its metabolites, and venlafaxine (as well as CYP2D6 genotype associations) were assessed. Of the 20 patients, 17 were included in the primary efficacy analysis, 20 in the safety population for adverse events, and 18 in the pharmacokinetic analysis. Results At Week 4, hot flash scores declined by 49.8% from baseline (P < 0.001). Venlafaxine did not affect serum concentrations of tamoxifen or its metabolites. CYP2D6 intermediate metabolizers had higher venlafaxine concentrations than extensive metabolizers (P = 0.007), although symptom improvement occurred regardless of genotype. All adverse events were Grade 1–2. Conclusions These findings demonstrate that venlafaxine safely and effectively alleviates hot flashes in hormone receptor-positive breast cancer patients undergoing tamoxifen-based endocrine therapy. hot flashes tamoxifen venlafaxine CYP2D6 breast cancer Figures Figure 1 Figure 2 Figure 3 Introduction Hot flashes during tamoxifen (TAM)-based adjuvant endocrine therapy after breast cancer surgery are a common adverse event [ 1 ], occurring in up to 86% of premenopausal patients, and are often more severe with concomitant luteinizing hormone-releasing hormone agonists (LHRHa) [ 2 ]. Hot flashes are a known factor for reduced medication adherence in female breast cancer patients receiving adjuvant endocrine therapy [ 1 , 3 ], evidenced by a previous report that demonstrated a 3.9% decrease in adherence rates for women experiencing moderate-to-severe hot flashes while receiving adjuvant endocrine therapy [ 4 ]. Furthermore, patients with severe hot flashes experience significantly lower overall quality of life (QOL), along with higher rates of depression and sleep disturbances, compared to those with no or mild symptoms [ 5 ]. Effective management of hot flashes is therefore essential for improving adherence to endocrine therapy and enhancing patient QOL after breast cancer treatment. Venlafaxine, a serotonin and noradrenalin reuptake inhibitor (SNRI), is a recommended non-hormonal pharmacologic option for the management of hot flashes [ 6 ], with an efficacy demonstrated in several randomized, controlled trials [ 7 , 8 ]. However, previous studies have mainly focused on postmenopausal women while evidence in premenopausal breast cancer patients, especially those receiving concomitant luteinizing LHRHa, remains scarce. Moreover, to our best knowledge, no data have been reported in Asian populations and control of hot flash symptoms may improve medication adherence for better clinical outcomes in Japanese premenopausal women undergoing adjuvant endocrine therapy after breast cancer resection. Both TAM and venlafaxine are metabolized in part by the hepatic CYP2D6 enzyme pathway [ 9 ] and, among the identified CYP2D6 variant alleles, the CYP2D6*10 allele (a reduced-function variant common in East Asians) is strongly associated with decreased venlafaxine metabolism [ 10 ]. Although previous studies have suggested that venlafaxine does not directly inhibit TAM metabolism [ 11 ], no study, to our best knowledge, has comprehensively evaluated the interaction between venlafaxine and TAM in the context of CYP2D6 polymorphisms present in East Asians. This study was an interventional clinical trial in which venlafaxine was administered to women experiencing moderate-to-severe hot flashes during TAM-based adjuvant endocrine therapy for breast cancer. The primary objective was to evaluate the efficacy and safety of venlafaxine in managing hot flash symptoms associated with postoperative endocrine therapy, including TAM. We also measured serum concentrations of venlafaxine, TAM, and its active metabolites (N-desmethyltamoxifen [NDT], 4-hydroxytamoxifen [4-OHT], and endoxifen [EDF]), according to CYP2D6 genotype, to assess potential pharmacokinetic interactions. Methods Study design and setting This was a single-center, prospective, single-arm, open-label pilot study conducted at Tsukuba University Hospital to evaluate the feasibility and efficacy of venlafaxine for tamoxifen-including hormone therapy-induced hot flashes in breast cancer survivors. The study was conducted as a Specified Clinical Trial under the Japanese Clinical Trials Act, and was approved by the Certified Review Board of the University of Tsukuba Hospital (approval number: CRB21-015). It was registered in the Japan Registry of Clinical Trials (jRCTs031220435). Inclusion criteria Eligible participants were women with hormone receptor-positive primary breast cancer, classified from Stage I to Stage IIIC, who were receiving adjuvant TAM therapy after surgery. The use of a luteinizing LHRHa in combination with TAM was permitted but not specified as an inclusion criterion. Participants were required to be between 18 and 60 years of age, report at least 14 troublesome hot flashes per week, and have an Eastern Cooperative Oncology Group performance status of 0 to 1. As this was an exploratory study, no formal sample size calculation was performed. Exclusion criteria The following exclusion criteria were applied: A clinical diagnosis of major depressive disorder or depression Ongoing treatment for thyroid disease An estimated glomerular filtration rate of less than 15 ml/min or current dialysis treatment Severe hepatic impairment, defined as a serum bilirubin level of 2 mg/dl or higher, or aspartate aminotransferase or alanine aminotransferase levels exceeding 100 U/L Use of any of the following medications: selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors other than the investigational drug, strong or moderate inhibitors of CYP2D6, inhibitors or inducers of CYP3A, gabapentinoids, or monoamine oxidase inhibitors A known allergy or hypersensitivity to venlafaxine Intervention Baseline Before starting the assigned medication, each participant was asked to complete a daily hot flash diary for one baseline week. Weeks 1–4 Participants received oral venlafaxine at a dose of 37.5 mg once daily for four weeks. Venlafaxine was administered as Effexor SR capsules (37.5 mg or 75 mg, Viatris Inc., Tokyo, Japan). If symptom control was insufficient and the participant requested it, the dose could be increased to 75 mg once daily at Week 2. Throughout the treatment period, participants continued to complete daily hot flash diaries. Clinical evaluations were conducted by study physicians at Week 2 (±3 days) and at the end of Week 4 (±3 days) to assess adverse events. Three months after the end of Week 4 Continuation of venlafaxine use was assessed through clinical interviews conducted at scheduled follow-up visits. Outcomes Hot flash scores were calculated from a daily diary, the validity of which has been established in previous studies, by assigning a numerical value (1 to 4) to each severity level: mild, moderate, severe, or very severe [12]. These values were multiplied by the number of hot flashes reported for each severity level over a 24-hour period and the results were summed to yield the daily hot flash score. Weekly scores were then obtained by summing the daily scores over seven consecutive days. For safety assessments, blood samples were collected at baseline, on Day 1 of Week 2 (±3 days), and at the end of Week 4 (±3 days). Serum concentrations of TAM and its active metabolites (NDT, 4-OHT, EDF) were measured by a validated high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method [13, 14] at baseline, Week 2 Day 1 (±3 days), and Week 4 end (±3 days). Serum concentrations of venlafaxine were measured by the same validated LC-MS/MS method [15] on Day 1 of Week 2 and at the end of Week 4 (both ±3 days). At baseline, CYP2D6 genotyping was performed for common alleles in the Japanese population ( *2 , *5 , *10 , *14 , *21 , *36 , and gene duplication) and participants were classified as IMs or EMs based on their genotypes, according to the classification criteria described by Doki et al. [16]. Adverse events were assessed on Day 1 of Week 2 (±3 days) and at the end of Week 4 (±3 days) using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. Reagents The following analytical standards and internal standards were used in the serum concentration analysis: D,L-venlafaxine hydrochloride (50 mg, Toronto Research Chemicals, Cat# V120000), (±)-venlafaxine-d₆ HCl (1 mg, N,N-dimethyl-d₆; Toronto Research Chemicals, Cat# V120001), tamoxifen (500 mg, Toronto Research Chemicals, Cat# T006000), endoxifen hydrochloride (10 mg, Axon Medchem, Cat# Axon2707), (E,Z)-4-hydroxytamoxifen (5 mg, LKT Laboratories, Cat# H9716), N-desmethyl tamoxifen hydrochloride (5 mg, Toronto Research Chemicals, Cat# D293900), and clomiphene citrate (1 g, Cayman Chemical, Cat# 16087). Analysis The primary endpoint was the percentage change in hot flash score at Week 4 compared to baseline, calculated as the total hot flash score for the Week 4 period divided by the total score at baseline (Week 4 weekly total / baseline weekly total). To complement the primary analysis, weekly trends in raw hot flash scores were also assessed to visualize the time-course of symptom improvement. The secondary endpoints included (1) the effect of venlafaxine on TAM metabolism, (2) the association between venlafaxine serum concentrations and CYP2D6 polymorphisms, (3) the association between venlafaxine serum concentrations and hot flash scores, and (4) the incidence of adverse events observed in this study. To evaluate the effect of venlafaxine on TAM metabolism, serum concentrations of TAM and its active metabolites (N-desmethyltamoxifen [NDT], 4-hydroxytamoxifen [4-OHT], and endoxifen [EDF]) were compared between baseline and Week 4. To assess whether differences in venlafaxine serum concentrations were associated with differences in hot flash scores, a univariable linear regression analysis was performed using venlafaxine concentration at Week 4 as the independent variable and the hot flash score at the same time point as the dependent variable. Similarly, to evaluate the influence of CYP2D6 polymorphisms on venlafaxine serum concentrations, a separate univariable linear regression analysis was conducted using CYP2D6 genotype as the independent variable and venlafaxine serum concentration as the dependent variable. The incidence of adverse events was also recorded. All statistical analyses were performed using R software (version 4.5.0). The primary analysis was conducted on participants who met the eligibility criteria and completed the study without dropout (n = 17). Safety assessments were performed using data from all enrolled participants (n = 20), while pharmacokinetic analyses were conducted on participants with available blood samples (n = 18). The Wilcoxon signed-rank test was used for paired comparisons (e.g., hot flash scores between baseline and Week 4), as the data were not normally distributed and demonstrated right-skewed distributions. For association analyses, univariable linear regression was used with venlafaxine serum concentration or CYP2D6 genotype as the independent variable. All tests were two-tailed, and the significance level was set at 0.05. No adjustment for multiplicity was applied to either the primary analysis (single primary endpoint) or the secondary endpoints (exploratory). Descriptive statistics are presented as mean ± standard deviation (SD) or median and interquartile range (IQR), as appropriate. Figures display full data distributions using box-and-whisker plots with individual data points overlaid. Results A total of 20 participants were enrolled between November 2022 and June 2024. Of these, two participants discontinued the study early during Week 1 due to Grade 1, study-related adverse events (e.g., dizziness) and were excluded from the primary analysis and pharmacokinetic evaluations. Additionally, one participant was later found ineligible based on pathological findings after treatment completion; although this participant was excluded from the primary analysis, safety data regarding adverse events were included (Fig. 1 ). The study population of 20 participants was subdivided as follows: Primary analysis population (n = 17), safety population for adverse events (n = 20), and safety population for pharmacokinetic analysis (n = 18). Detailed patient characteristics are presented in Table 1 , while baseline characteristics are shown in Supplementary Table S1 for all participants (n = 20) and in Supplementary Table S2 for the safety population for pharmacokinetic analysis (n = 18). Table 1 Patient characteristics for the primary analysis population Variable Value (n = 17) Age (years), mean ± SD 45.5 ± 6.59 ECOG Performance Status, n (%) 0 17 (100%) 1 0 (0%) 2 0 (0%) Menopausal Status, n (%) Premenopausal 17 (100%) Postmenopausal 0 (0%) Subtype, n (%) HR+ / HER2- (Luminal) 17 (100%) HR+ / HER2+ (Luminal HER2) 0 (0%) Stage, n (%) I 7 (41%) II 8 (47%) III 2 (12%) History of Chemotherapy, n (%) Yes 5 (29%) No 12 (71%) Postoperative Hormonal Therapy Regimen, n (%) Tamoxifen 4 (24%) LHRH agonist + Tamoxifen 11 (65%) LHRH agonist + Tamoxifen + Abemaciclib 2 (11%) Medication Adherence Rate (%) 96.4 Values are presented as mean ± SD for continuous variables and n (%) for categorical variables. The medication adherence rate is calculated as: (number of days the medication was taken ÷ number of days prescribed) × 100. Among the 17 patients who met the eligibility criteria and continued venlafaxine at the start of Week 2, five patients (29.4%) underwent dose escalation to 75 mg once daily from Week 2 onwards. All 17 patients completed the 4-week treatment period and 15 (88%) expressed a desire to continue venlafaxine at both study end and 3 months post-study. Primary analysis The weekly hot flash score, determined by a previously reported patient diary analysis protocol [ 12 ], decreased by 49.8% on average at Week 4 compared with baseline (baseline: mean 109.8, SD 74.4, median 79, interquartile range [IQR] 49 to 125; Week 4: mean 55.1, SD 56.9, median 33, IQR 11 to 75; P < 0.001). The temporal changes in hot flash scores are shown in Fig. 2 . A reduction in scores was observed from the early phase of venlafaxine administration and was evident at every weekly timepoint (Week 1: mean 69.3, SD 52.7, median 54, IQR 25 to 101; P < 0.001; Week 2: mean 56.1, SD 52.9, median 44, IQR 13 to 81; P < 0.001; Week 3: mean 55.4, SD 53.9, median 37, IQR 9 to 80; P < 0.001). Evaluation of drug metabolism and safety Effect of venlafaxine on TAM metabolism Compared with baseline,no significant difference was observed in serum TAM concentrations at Week 4 (baseline: mean 181.9 ng/mL, SD 57.7, median 161.0, IQR 146.0 to 212.75; Week 4: mean 164.4 ng/mL, SD 57.3, median 149.5, IQR 128.5 to 201.25; P = 0.055). Similarly, no significant reduction was observed in the serum concentrations of the active metabolites of TAM, including NDT (baseline: mean 238.1 ng/mL, SD 71.2, median 239.5, IQR 191.3 to 276.0; Week 4: mean 232.2 ng/mL, SD 78.4, median 223.5, IQR 187.0 to 285.5; P = 0.486), 4-OHT (baseline: mean 2.94 ng/mL, SD 1.34, median 2.47, IQR 2.09 to 3.17; Week 4: mean 2.84 ng/mL, SD 1.45, median 2.44, IQR 1.75 to 3.30; P = 0.442), or EDF (baseline: mean 10.25 ng/mL, SD 4.90, median 8.83, IQR 7.50 to 11.75; Week 4: mean 9.09 ng/mL, SD 5.16, median 6.48, IQR 5.76 to 12.90; P = 0.119) (Fig. 3 ). Association between serum venlafaxine levels and CYP2D6 polymorphisms Participants with the intermediate metabolizer (IM) phenotype of CYP2D6 (n = 3) had significantly higher serum concentrations of venlafaxine at the end of treatment compared with carriers of the extensive metabolizer (EM) phenotype (n = 17) (regression coefficient = 42.22, 95% CI 15.19 to 69.26; P = 0.007). Association between serum venlafaxine levels and hot flash score Serum concentrations of venlafaxine at Week 4 were not significantly associated with hot flash scores at the same time point (regression coefficient = 0.465, 95% CI − 0.524 to 1.453; P = 0.371). Incidence of adverse events All adverse events were graded as Grade 1 or 2, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The most frequently reported events were headache (7 patients, 35.0%), insomnia (5 patients, 25.0%), dry mouth (4 patients, 20.0%), and dizziness (4 patients, 20.0%). No Grade ≥ 3 events were observed. A detailed summary is presented in Table 2 . Table 2 Summary of adverse events Adverse Event All Grade (n, %) Grade 1 (n, %) Grade 2 (n, %) Grade ≥ 3 (n, %) Headache 7/20 (35.0%) 7/20 (35.0%) 0/20 (0%) 0/20 (0%) Insomnia 5/20 (25.0%) 4/20 (20.0%) 1/20 (5.0%) 0/20 (0%) Dry mouth 4/20 (20.0%) 4/20 (20.0%) 0/20 (0%) 0/20 (0%) Dizziness 4/20 (20.0%) 4/20 (20.0%) 0/20 (0%) 0/20 (0%) Fatigue 2/20 (10.0%) 2/20 (10.0%) 0/20 (0%) 0/20 (0%) Palpitations 2/20 (10.0%) 2/20 (10.0%) 0/20 (0%) 0/20 (0%) Constipation 2/20 (10.0%) 2/20 (10.0%) 0/20 (0%) 0/20 (0%) Nausea 1/20 (5.0%) 1/20 (5.0%) 0/20 (0%) 0/20 (0%) Diarrhea 1/20 (5.0%) 1/20 (5.0%) 0/20 (0%) 0/20 (0%) Oral Dysesthesia 1/20 (5.0%) 1/20 (5.0%) 0/20 (0%) 0/20 (0%) Somnolence 1/20 (5.0%) 1/20 (5.0%) 0/20 (0%) 0/20 (0%) Abdominal Bloating 1/20 (5.0%) 1/20 (5.0%) 0/20 (0%) 0/20 (0%) Adverse events are graded using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and presented as n (%) by severity (Grade 1, Grade 2, and Grade ≥ 3). Discussion Here, we report the efficacy and safety of venlafaxine for ablation of hot flashes induced by hormonal therapy in patients with breast cancer receiving TAM. We observed a marked reduction in hot flash scores following venlafaxine administration but no substantial changes were noted in the serum concentrations of TAM or its active metabolites after treatment. All adverse events were mild in nature and led to very few participants discontinuing the study medication. Multiple clinical trials and meta-analyses have reported the effectiveness of venlafaxine against hot flash symptoms [ 8 , 17 ], with one report revealing reductions in hot flash scores of approximately 40–60% [ 7 , 18 ]. In general, the degree of symptom reduction we observed in the present study (49.8% reduction by Week 4) was congruent with previous findings. Furthermore, the baseline daily hot flash score in this study (15.7) was comparable to previous literature (18.7) [ 7 ] and post-treatment scores were similar. We were additionally able to demonstrate a significant improvement as early as Week 1, suggesting that venlafaxine may be a rapid-onset option for quick relief. In the present study, co-administration of venlafaxine did not result in significant changes in TAM or metabolite serum concentrations, especially EDF (which is closely associated with TAM therapeutic efficacy). These findings are consistent with previous reviews suggesting that venlafaxine, as a weak inhibitor of CYP2D6, does not have a clinically meaningful impact on TAM metabolism [ 11 , 19 – 21 ]. It has been previously reported that CYP2D6 polymorphisms significantly affect venlafaxine serum concentrations in patients receiving TAM following breast cancer surgery [ 20 ]. These polymorphisms are known to vary considerably across ethnic groups and large-scale database studies in Caucasian populations have demonstrated elevated venlafaxine levels in carriers of reduced-function alleles [ 22 ]. In contrast, data in Asian populations remain limited but small-scale clinical studies in Japanese have shown that variants, such as CYP2D6*10 , are associated with altered venlafaxine serum levels [ 10 , 23 ]. In the present study, a significant association between CYP2D6 phenotype (IMs vs. EMs) and venlafaxine serum concentration was also observed, consistent with previous findings. However, the efficacy of venlafaxine in reducing hot flash symptoms was sustained regardless of CYP2D6 genotype, a novel finding that may be particularly relevant for Asian populations. Although dose escalation to 75 mg was permitted during the study, no apparent association was found between CYP2D6 phenotype and dose increase. Nevertheless, we noted that no clear dose trends were observed in our cohort. One possible explanation is that serum venlafaxine concentrations in IMs may quickly reach a therapeutic threshold, beyond which additional clinical benefit does not increase. Importantly, the dose escalation protocol in our study was not expressly designed to achieve specific serum levels and, in addition, interindividual variability in treatment response may be influenced by factors beyond CYP2D6 polymorphisms, such as receptor sensitivity or downstream signaling differences [ 24 ]. In this study, the most commonly observed adverse events associated with venlafaxine were headache, insomnia, dry mouth, dizziness, and constipation. All events were mild and no serious adverse events were reported, consistent with the known safety profile of venlafaxine [ 25 , 26 ] and with previous studies involving breast cancer patients experiencing hot flashes [ 18 ]. However, some participants who experienced mild adverse events nonetheless discontinued treatment, highlighting the importance of subjective experiences and individual discomfort thresholds that may precipitate the need for alternative therapies [ 27 ]. Recently, fezolinetant (VEOZA™) has been approved in the United States as a non-hormonal treatment that regulates changes in body temperature associated with menopause [ 28 ] and clinical trials of this neurokinin 3 receptor blocker in breast cancer patients are currently underway. In the meantime, our findings support venlafaxine as a clinically effective and well-tolerated treatment option for managing hot flashes in clinical settings. To our knowledge, this is the first study to evaluate the efficacy and safety of venlafaxine for the management of hot flashes in premenopausal women undergoing TAM adjuvant endocrine therapy. Although two large studies previously investigated venlafaxine for endocrine therapy-related hot flashes in breast cancer patients [ 7 , 17 ], one investigated only postmenopausal women while the other partially included TAM patients, but without specifying case numbers or LHRHa use. Notably, 76% of our enrolled participants were also receiving LHRHa, which is clinically relevant given that such patients experience more frequent and severe hot flashes [ 2 , 29 ]. Our findings align with previously published literature on reduction of hot flashes with venlafaxine but extends the clinical utility to even premenopausal women, a demographic with an increasing incidence of breast cancer. This study has several limitations due to its single-arm, exploratory nature (without a predefined sample size) as the relatively small number of participants may have underestimated the incidence of adverse events. Although larger-scale studies are warranted to validate these findings, the results of the present study are generally consistent with previous reports conducted primarily in postmenopausal women and Western populations. Third, the study population consisted exclusively of Asian (Japanese) patients, and the analysis of CYP2D6 polymorphisms was limited to variants commonly found in Asian populations. Therefore, the generalizability of the findings to other ethnic groups may be limited. Nonetheless, the study provides valuable insights into the efficacy and safety of venlafaxine based on genetic backgrounds that have been underreported in prior research. In summary, this study prospectively evaluated the efficacy and safety of venlafaxine for managing hot flashes in hormone receptor-positive, breast cancer patients receiving tamoxifen, most of whom were also undergoing LHRHa therapy. A significant reduction in hot flash scores was observed as early as Week 1, with no notable impact on serum concentrations of tamoxifen or its active metabolites. While venlafaxine serum levels varied by CYP2D6 genotype, symptom relief was consistently achieved across genotypes. Adverse events were mild, but some patients discontinued treatment due to subjective discomfort. These findings suggest that venlafaxine is a potentially effective and well-tolerated option for managing vasomotor symptoms in premenopausal high-risk breast cancer patients, particularly those treated with LHRHa. Declarations Acknowledgments We thank Dr. Takeshi Yamada of the University of Tsukuba for their valuable advice during the preparation of this manuscript. We also thank Dr. Bryan J. Mathis for professional English language editing. Author contributions H.B. conceived the study, and R.S. designed the protocol. R.S., H.B., R.K., T.M., A.S., M.O., S.H., and A.I.-M. were responsible for patient enrollment and clinical management. K.D., Y.M., and M.H. performed the serum drug concentration measurements and pharmacokinetic analyses. R.I. and K.S. conducted the statistical analyses. K.D. also conducted the CYP2D6 genotyping. R.S. drafted the manuscript. All authors reviewed and approved the final version of the manuscript. Funding This study was funded by Grant for Implementation of Advanced Medicine (GIAM) [grant number 先進‑107]. The funder played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript. Competing interests All authors declare no financial or non-financial competing interests. Data availability The datasets generated and/or analyzed during the current study are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request. 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The impact of the CYP2D6 and CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese population. Eur J Clin Pharmacol 2000;56:175–80. doi:10.1007/s002280050737. Radosavljevic M, Svob Strac D, Jancic J, Samardzic J. The role of pharmacogenetics in personalizing the antidepressant and anxiolytic therapy. Genes (Basel) 2023;14:1095. doi:10.3390/genes14051095. Kamp CB, Petersen JJ, Faltermeier P, Juul S, Siddiqui F, Moncrieff J, et al. The risks of adverse events with venlafaxine for adults with major depressive disorder: a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis. Epidemiol Psychiatr Sci 2024;33:e51. doi:10.1017/S2045796024000520. StatPearls A. Venlafaxine; 2024. StatPearls [Internet]. Leon-Ferre RA, Majithia N, Loprinzi CL. Management of hot flashes in women with breast cancer receiving ovarian function suppression. Cancer Treat Rev 2017;52:82–90. doi:10.1016/j.ctrv.2016.11.012. Lederman S, Ottery FD, Cano A, Santoro N, Shapiro M, Stute P, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet 2023;401:1091–102. doi:10.1016/S0140-6736(23)00085-5. Day R. Quality of life and tamoxifen in a breast cancer prevention trial: a summary of findings from the NSABP P-1 study. National Surgical Adjuvant Breast and Bowel Project. Ann N Y Acad Sci 2001;949:143–50. doi:10.1111/j.1749-6632.2001.tb04012.x. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7522015","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":514423035,"identity":"0a39728b-9689-43dc-b90a-61571f94ad36","order_by":0,"name":"Riko 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02:42:46","extension":"html","order_by":16,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":112562,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7522015/v1/dad8c62972a7bf663174b17c.html"},{"id":91936598,"identity":"1e90da0a-ed3d-47d1-9845-adc7c48c4e79","added_by":"auto","created_at":"2025-09-23 02:50:46","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":151989,"visible":true,"origin":"","legend":"\u003cp\u003eCONSORT flow diagram of patient enrollment and analysis. A total of 20 patients were enrolled and received treatment. Two patients discontinued during Week 1 due to Grade 1 adverse events (e.g., dizziness) and were excluded from both the primary endpoint analysis and serum concentration-related safety assessments. One additional patient was later deemed ineligible and excluded from the primary endpoint analysis but included in the safety population. As a result, 17 patients were included in the primary endpoint analysis, 20 in the safety population for adverse events, and 18 in the safety population for pharmacokinetic analysis\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7522015/v1/6ae887f115fbf34dbfff2c0a.jpeg"},{"id":91936600,"identity":"f3d05df6-8510-46a4-bea8-d06ec17bfdef","added_by":"auto","created_at":"2025-09-23 02:50:46","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":118385,"visible":true,"origin":"","legend":"\u003cp\u003eWeekly hot flash scores from baseline to Week 4. Box plots show weekly hot flash scores at baseline and Weeks 1 to 4. Boxes indicate the interquartile range (IQR), horizontal lines indicate the median, whiskers extend to 1.5 × IQR, and dots represent outliers. Hot flash scores significantly decreased from baseline at all time points (\u003cem\u003eP\u003c/em\u003e \u0026lt; 0.001, Wilcoxon signed-rank test)\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7522015/v1/323d41fac5b19f1f1688b58c.jpeg"},{"id":91935161,"identity":"e756b532-a25c-4cd2-bb1e-31868913be8a","added_by":"auto","created_at":"2025-09-23 02:42:46","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":239055,"visible":true,"origin":"","legend":"\u003cp\u003eSerum concentrations of tamoxifen and its metabolites at baseline and Week 4. Box plots show serum concentrations of (A) tamoxifen, (B) N-desmethyltamoxifen (NDT), (C) 4-hydroxytamoxifen (4-OHT), and (D) endoxifen (EDF) at baseline and Week 4. Boxes represent the IQR, lines indicate the median, whiskers extend to 1.5×IQR, and dots indicate outliers. Paired data points are overlaid. No significant changes were observed (Wilcoxon signed-rank test, all \u003cem\u003eP\u003c/em\u003e \u0026gt; 0.05)\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-7522015/v1/855ebbaad4d426c49810bbcd.jpeg"},{"id":102234710,"identity":"da3f0524-a77f-4ac2-8166-0a7d751e7d93","added_by":"auto","created_at":"2026-02-09 16:13:03","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1251279,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7522015/v1/d5302ed2-05b1-4969-8d99-df0639a8b742.pdf"},{"id":91935170,"identity":"bffa3491-e1ff-40db-bc75-aca7b0c4b35d","added_by":"auto","created_at":"2025-09-23 02:42:46","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":19274,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryInformation.docx","url":"https://assets-eu.researchsquare.com/files/rs-7522015/v1/1616ed9d2be26821e6de71d0.docx"}],"financialInterests":"","formattedTitle":"Venlafaxine reduces hot flashes in hormone receptor-positive breast cancer patients receiving tamoxifen: a prospective single‑arm, open‑label trial","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHot flashes during tamoxifen (TAM)-based adjuvant endocrine therapy after breast cancer surgery are a common adverse event [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], occurring in up to 86% of premenopausal patients, and are often more severe with concomitant luteinizing hormone-releasing hormone agonists (LHRHa) [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Hot flashes are a known factor for reduced medication adherence in female breast cancer patients receiving adjuvant endocrine therapy [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e], evidenced by a previous report that demonstrated a 3.9% decrease in adherence rates for women experiencing moderate-to-severe hot flashes while receiving adjuvant endocrine therapy [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Furthermore, patients with severe hot flashes experience significantly lower overall quality of life (QOL), along with higher rates of depression and sleep disturbances, compared to those with no or mild symptoms [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Effective management of hot flashes is therefore essential for improving adherence to endocrine therapy and enhancing patient QOL after breast cancer treatment.\u003c/p\u003e\u003cp\u003eVenlafaxine, a serotonin and noradrenalin reuptake inhibitor (SNRI), is a recommended non-hormonal pharmacologic option for the management of hot flashes [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e], with an efficacy demonstrated in several randomized, controlled trials [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. However, previous studies have mainly focused on postmenopausal women while evidence in premenopausal breast cancer patients, especially those receiving concomitant luteinizing LHRHa, remains scarce. Moreover, to our best knowledge, no data have been reported in Asian populations and control of hot flash symptoms may improve medication adherence for better clinical outcomes in Japanese premenopausal women undergoing adjuvant endocrine therapy after breast cancer resection.\u003c/p\u003e\u003cp\u003eBoth TAM and venlafaxine are metabolized in part by the hepatic CYP2D6 enzyme pathway [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e] and, among the identified CYP2D6 variant alleles, the \u003cem\u003eCYP2D6*10\u003c/em\u003e allele (a reduced-function variant common in East Asians) is strongly associated with decreased venlafaxine metabolism [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Although previous studies have suggested that venlafaxine does not directly inhibit TAM metabolism [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e], no study, to our best knowledge, has comprehensively evaluated the interaction between venlafaxine and TAM in the context of CYP2D6 polymorphisms present in East Asians.\u003c/p\u003e\u003cp\u003eThis study was an interventional clinical trial in which venlafaxine was administered to women experiencing moderate-to-severe hot flashes during TAM-based adjuvant endocrine therapy for breast cancer. The primary objective was to evaluate the efficacy and safety of venlafaxine in managing hot flash symptoms associated with postoperative endocrine therapy, including TAM. We also measured serum concentrations of venlafaxine, TAM, and its active metabolites (N-desmethyltamoxifen [NDT], 4-hydroxytamoxifen [4-OHT], and endoxifen [EDF]), according to CYP2D6 genotype, to assess potential pharmacokinetic interactions.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy design and setting\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a single-center, prospective, single-arm, open-label pilot study conducted at Tsukuba University Hospital to evaluate the feasibility and efficacy of venlafaxine for tamoxifen-including hormone therapy-induced hot flashes in breast cancer survivors. The study was conducted as a Specified Clinical Trial under the Japanese Clinical Trials Act, and was approved by the Certified Review Board of the University of Tsukuba Hospital (approval number: CRB21-015). It was registered in the Japan Registry of Clinical Trials (jRCTs031220435).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInclusion criteria\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eEligible participants were women with hormone receptor-positive primary breast cancer, classified from Stage I to Stage IIIC, who were receiving adjuvant TAM therapy after surgery. The use of a luteinizing LHRHa in combination with TAM was permitted but not specified as an inclusion criterion. Participants were required to be between 18 and 60 years of age, report at least 14 troublesome hot flashes per week, and have an Eastern Cooperative Oncology Group performance status of 0 to 1. As this was an exploratory study, no formal sample size calculation was performed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eExclusion criteria\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe following exclusion criteria were applied:\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eA clinical diagnosis of major depressive disorder or depression\u003c/li\u003e\n \u003cli\u003eOngoing treatment for thyroid disease\u003c/li\u003e\n \u003cli\u003eAn estimated glomerular filtration rate of less than 15 ml/min or current dialysis treatment\u003c/li\u003e\n \u003cli\u003eSevere hepatic impairment, defined as a serum bilirubin level of 2 mg/dl or higher, or aspartate aminotransferase or alanine aminotransferase levels exceeding 100 U/L\u003c/li\u003e\n \u003cli\u003eUse of any of the following medications: selective serotonin reuptake inhibitors, serotonin-norepinephrine reuptake inhibitors other than the investigational drug, strong or moderate inhibitors of CYP2D6, inhibitors or inducers of CYP3A, gabapentinoids, or monoamine oxidase inhibitors\u003c/li\u003e\n \u003cli\u003eA known allergy or hypersensitivity to venlafaxine\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eIntervention\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eBaseline\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eBefore starting the assigned medication, each participant was asked to complete a daily hot flash diary for one baseline week.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eWeeks 1\u0026ndash;4\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eParticipants received oral venlafaxine at a dose of 37.5 mg once daily for four weeks. Venlafaxine was administered as Effexor SR capsules (37.5 mg or 75 mg, Viatris Inc., Tokyo, Japan). If symptom control was insufficient and the participant requested it, the dose could be increased to 75 mg once daily at Week 2. Throughout the treatment period, participants continued to complete daily hot flash diaries. Clinical evaluations were conducted by study physicians at Week 2 (\u0026plusmn;3 days) and at the end of Week 4 (\u0026plusmn;3 days) to assess adverse events.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eThree months after the end of Week 4\u003c/em\u003e\u003c/p\u003e\n\u003cp\u003eContinuation of venlafaxine use was assessed through clinical interviews conducted at scheduled follow-up visits.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eOutcomes\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eHot flash scores were calculated from a daily diary, the validity of which has been established in previous studies, by assigning a numerical value (1 to 4) to each severity level: mild, moderate, severe, or very severe\u003csup\u003e\u0026nbsp;\u003c/sup\u003e[12]. These values were multiplied by the number of hot flashes reported for each severity level over a 24-hour period and the results were summed to yield the daily hot flash score. Weekly scores were then obtained by summing the daily scores over seven consecutive days.\u003c/p\u003e\n\u003cp\u003eFor safety assessments, blood samples were collected at baseline, on Day 1 of Week 2 (\u0026plusmn;3 days), and at the end of Week 4 (\u0026plusmn;3 days). Serum concentrations of TAM and its active metabolites (NDT, 4-OHT, EDF) were measured by a validated high-performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) method [13, 14] at baseline, Week 2 Day 1 (\u0026plusmn;3 days), and Week 4 end (\u0026plusmn;3 days). Serum concentrations of venlafaxine were measured by the same validated LC-MS/MS method [15] on Day 1 of Week 2 and at the end of Week 4 (both \u0026plusmn;3 days). At baseline, \u003cem\u003eCYP2D6\u003c/em\u003e genotyping was performed for common alleles in the Japanese population (\u003cem\u003e*2\u003c/em\u003e, \u003cem\u003e*5\u003c/em\u003e, \u003cem\u003e*10\u003c/em\u003e, \u003cem\u003e*14\u003c/em\u003e, \u003cem\u003e*21\u003c/em\u003e, \u003cem\u003e*36\u003c/em\u003e, and gene duplication) and participants were classified as IMs or EMs based on their genotypes, according to the classification criteria described by Doki et al.\u003csup\u003e\u0026nbsp;\u003c/sup\u003e[16].\u003c/p\u003e\n\u003cp\u003eAdverse events were assessed on Day 1 of Week 2 (\u0026plusmn;3 days) and at the end of Week 4 (\u0026plusmn;3 days) using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eReagents\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe following analytical standards and internal standards were used in the serum concentration analysis: D,L-venlafaxine hydrochloride (50 mg, Toronto Research Chemicals, Cat# V120000), (\u0026plusmn;)-venlafaxine-d₆ HCl (1 mg, N,N-dimethyl-d₆; Toronto Research Chemicals, Cat# V120001), tamoxifen (500 mg, Toronto Research Chemicals, Cat# T006000), endoxifen hydrochloride (10 mg, Axon Medchem, Cat# Axon2707), (E,Z)-4-hydroxytamoxifen (5 mg, LKT Laboratories, Cat# H9716), N-desmethyl tamoxifen hydrochloride (5 mg, Toronto Research Chemicals, Cat# D293900), and clomiphene citrate (1 g, Cayman Chemical, Cat# 16087).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAnalysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe primary endpoint was the percentage change in hot flash score at Week 4 compared to baseline, calculated as the total hot flash score for the Week 4 period divided by the total score at baseline (Week 4 weekly total / baseline weekly total). To complement the primary analysis, weekly trends in raw hot flash scores were also assessed to visualize the time-course of symptom improvement.\u003c/p\u003e\n\u003cp\u003eThe secondary endpoints included (1) the effect of venlafaxine on TAM metabolism, (2) the association between venlafaxine serum concentrations and CYP2D6 polymorphisms, (3) the association between venlafaxine serum concentrations and hot flash scores, and (4) the incidence of adverse events observed in this study. To evaluate the effect of venlafaxine on TAM metabolism, serum concentrations of TAM and its active metabolites (N-desmethyltamoxifen [NDT], 4-hydroxytamoxifen [4-OHT], and endoxifen [EDF]) were compared between baseline and Week 4. To assess whether differences in venlafaxine serum concentrations were associated with differences in hot flash scores, a univariable linear regression analysis was performed using venlafaxine concentration at Week 4 as the independent variable and the hot flash score at the same time point as the dependent variable. Similarly, to evaluate the influence of CYP2D6 polymorphisms on venlafaxine serum concentrations, a separate univariable linear regression analysis was conducted using CYP2D6 genotype as the independent variable and venlafaxine serum concentration as the dependent variable. The incidence of adverse events was also recorded.\u003c/p\u003e\n\u003cp\u003eAll statistical analyses were performed using R software (version 4.5.0). The primary analysis was conducted on participants who met the eligibility criteria and completed the study without dropout (n = 17). Safety assessments were performed using data from all enrolled participants (n = 20), while pharmacokinetic analyses were conducted on participants with available blood samples (n = 18). The Wilcoxon signed-rank test was used for paired comparisons (e.g., hot flash scores between baseline and Week 4), as the data were not normally distributed and demonstrated right-skewed distributions. For association analyses, univariable linear regression was used with venlafaxine serum concentration or CYP2D6 genotype as the independent variable.\u003c/p\u003e\n\u003cp\u003eAll tests were two-tailed, and the significance level was set at 0.05. No adjustment for multiplicity was applied to either the primary analysis (single primary endpoint) or the secondary endpoints (exploratory). Descriptive statistics are presented as mean \u0026plusmn; standard deviation (SD) or median and interquartile range (IQR), as appropriate. Figures display full data distributions using box-and-whisker plots with individual data points overlaid.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eA total of 20 participants were enrolled between November 2022 and June 2024. Of these, two participants discontinued the study early during Week 1 due to Grade 1, study-related adverse events (e.g., dizziness) and were excluded from the primary analysis and pharmacokinetic evaluations. Additionally, one participant was later found ineligible based on pathological findings after treatment completion; although this participant was excluded from the primary analysis, safety data regarding adverse events were included (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003eThe study population of 20 participants was subdivided as follows: Primary analysis population (n\u0026thinsp;=\u0026thinsp;17), safety population for adverse events (n\u0026thinsp;=\u0026thinsp;20), and safety population for pharmacokinetic analysis (n\u0026thinsp;=\u0026thinsp;18). Detailed patient characteristics are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e, while baseline characteristics are shown in Supplementary Table \u003cspan refid=\"MOESM1\" class=\"InternalRef\"\u003eS1\u003c/span\u003e for all participants (n\u0026thinsp;=\u0026thinsp;20) and in Supplementary Table S2 for the safety population for pharmacokinetic analysis (n\u0026thinsp;=\u0026thinsp;18).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003ePatient characteristics for the primary analysis population\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eValue (n\u0026thinsp;=\u0026thinsp;17)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge (years), mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e45.5\u0026thinsp;\u0026plusmn;\u0026thinsp;6.59\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eECOG Performance Status, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e0\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (100%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003e2\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMenopausal Status, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePremenopausal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (100%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostmenopausal\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSubtype, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHR+ / HER2- (Luminal)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e17 (100%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHR+ / HER2+ (Luminal HER2)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStage, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eI\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7 (41%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e8 (47%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eIII\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (12%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHistory of Chemotherapy, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eYes\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e5 (29%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNo\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e12 (71%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePostoperative Hormonal Therapy Regimen, n (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTamoxifen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4 (24%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLHRH agonist\u0026thinsp;+\u0026thinsp;Tamoxifen\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e11 (65%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLHRH agonist\u0026thinsp;+\u0026thinsp;Tamoxifen\u0026thinsp;+\u0026thinsp;Abemaciclib\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e2 (11%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMedication Adherence Rate (%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e96.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"2\"\u003eValues are presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD for continuous variables and n (%) for categorical variables. The medication adherence rate is calculated as: (number of days the medication was taken\u0026thinsp;\u0026divide;\u0026thinsp;number of days prescribed) \u0026times; 100.\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eAmong the 17 patients who met the eligibility criteria and continued venlafaxine at the start of Week 2, five patients (29.4%) underwent dose escalation to 75 mg once daily from Week 2 onwards. All 17 patients completed the 4-week treatment period and 15 (88%) expressed a desire to continue venlafaxine at both study end and 3 months post-study.\u003c/p\u003e\u003cdiv id=\"Sec14\" class=\"Section2\"\u003e\u003ch2\u003ePrimary analysis\u003c/h2\u003e\u003cp\u003eThe weekly hot flash score, determined by a previously reported patient diary analysis protocol [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], decreased by 49.8% on average at Week 4 compared with baseline (baseline: mean 109.8, SD 74.4, median 79, interquartile range [IQR] 49 to 125; Week 4: mean 55.1, SD 56.9, median 33, IQR 11 to 75; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The temporal changes in hot flash scores are shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. A reduction in scores was observed from the early phase of venlafaxine administration and was evident at every weekly timepoint (Week 1: mean 69.3, SD 52.7, median 54, IQR 25 to 101; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Week 2: mean 56.1, SD 52.9, median 44, IQR 13 to 81; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001; Week 3: mean 55.4, SD 53.9, median 37, IQR 9 to 80; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eEvaluation of drug metabolism and safety\u003c/h2\u003e\u003cdiv id=\"Sec16\" class=\"Section3\"\u003e\u003ch2\u003eEffect of venlafaxine on TAM metabolism\u003c/h2\u003e\u003cp\u003eCompared with baseline,no significant difference was observed in serum TAM concentrations at Week 4 (baseline: mean 181.9 ng/mL, SD 57.7, median 161.0, IQR 146.0 to 212.75; Week 4: mean 164.4 ng/mL, SD 57.3, median 149.5, IQR 128.5 to 201.25; \u003cem\u003eP\u003c/em\u003e\u0026thinsp;=\u0026thinsp;0.055). Similarly, no significant reduction was observed in the serum concentrations of the active metabolites of TAM, including NDT (baseline: mean 238.1 ng/mL, SD 71.2, median 239.5, IQR 191.3 to 276.0; Week 4: mean 232.2 ng/mL, SD 78.4, median 223.5, IQR 187.0 to 285.5; \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.486), 4-OHT (baseline: mean 2.94 ng/mL, SD 1.34, median 2.47, IQR 2.09 to 3.17; Week 4: mean 2.84 ng/mL, SD 1.45, median 2.44, IQR 1.75 to 3.30; \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.442), or EDF (baseline: mean 10.25 ng/mL, SD 4.90, median 8.83, IQR 7.50 to 11.75; Week 4: mean 9.09 ng/mL, SD 5.16, median 6.48, IQR 5.76 to 12.90; \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.119) (Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cem\u003eAssociation between serum venlafaxine levels and\u003c/em\u003e CYP2D6 \u003cem\u003epolymorphisms\u003c/em\u003e\u003c/p\u003e\u003cp\u003eParticipants with the intermediate metabolizer (IM) phenotype of CYP2D6 (n\u0026thinsp;=\u0026thinsp;3) had significantly higher serum concentrations of venlafaxine at the end of treatment compared with carriers of the extensive metabolizer (EM) phenotype (n\u0026thinsp;=\u0026thinsp;17) (regression coefficient\u0026thinsp;=\u0026thinsp;42.22, 95% CI 15.19 to 69.26; \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.007).\u003c/p\u003e\u003c/div\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eAssociation between serum venlafaxine levels and hot flash score\u003c/h2\u003e\u003cp\u003eSerum concentrations of venlafaxine at Week 4 were not significantly associated with hot flash scores at the same time point (regression coefficient\u0026thinsp;=\u0026thinsp;0.465, 95% CI \u0026minus;\u0026thinsp;0.524 to 1.453; \u003cem\u003eP\u0026thinsp;=\u003c/em\u003e\u0026thinsp;0.371).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eIncidence of adverse events\u003c/h2\u003e\u003cp\u003eAll adverse events were graded as Grade 1 or 2, according to the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. The most frequently reported events were headache (7 patients, 35.0%), insomnia (5 patients, 25.0%), dry mouth (4 patients, 20.0%), and dizziness (4 patients, 20.0%). No Grade\u0026thinsp;\u0026ge;\u0026thinsp;3 events were observed. A detailed summary is presented in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eSummary of adverse events\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAdverse Event\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eAll Grade (n, %)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eGrade 1 (n, %)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eGrade 2 (n, %)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003eGrade\u0026thinsp;\u0026ge;\u0026thinsp;3 (n, %)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHeadache\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e7/20 (35.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e7/20 (35.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInsomnia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e5/20 (25.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4/20 (20.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e1/20 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDry mouth\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4/20 (20.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4/20 (20.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDizziness\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e4/20 (20.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4/20 (20.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eFatigue\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2/20 (10.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2/20 (10.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003ePalpitations\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2/20 (10.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2/20 (10.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConstipation\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e2/20 (10.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e2/20 (10.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNausea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1/20 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1/20 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiarrhea\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1/20 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1/20 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eOral Dysesthesia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1/20 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1/20 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSomnolence\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1/20 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1/20 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAbdominal Bloating\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e\u003cp\u003e1/20 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e1/20 (5.0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0/20 (0%)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003ctfoot\u003e\u003ctr\u003e\u003ctd colspan=\"5\"\u003eAdverse events are graded using the Common Terminology Criteria for Adverse Events (CTCAE) v5.0 and presented as n (%) by severity (Grade 1, Grade 2, and Grade\u0026thinsp;\u0026ge;\u0026thinsp;3).\u003c/td\u003e\u003c/tr\u003e\u003c/tfoot\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eHere, we report the efficacy and safety of venlafaxine for ablation of hot flashes induced by hormonal therapy in patients with breast cancer receiving TAM. We observed a marked reduction in hot flash scores following venlafaxine administration but no substantial changes were noted in the serum concentrations of TAM or its active metabolites after treatment. All adverse events were mild in nature and led to very few participants discontinuing the study medication.\u003c/p\u003e\u003cp\u003eMultiple clinical trials and meta-analyses have reported the effectiveness of venlafaxine against hot flash symptoms [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], with one report revealing reductions in hot flash scores of approximately 40\u0026ndash;60% [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. In general, the degree of symptom reduction we observed in the present study (49.8% reduction by Week 4) was congruent with previous findings. Furthermore, the baseline daily hot flash score in this study (15.7) was comparable to previous literature (18.7) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e] and post-treatment scores were similar. We were additionally able to demonstrate a significant improvement as early as Week 1, suggesting that venlafaxine may be a rapid-onset option for quick relief.\u003c/p\u003e\u003cp\u003eIn the present study, co-administration of venlafaxine did not result in significant changes in TAM or metabolite serum concentrations, especially EDF (which is closely associated with TAM therapeutic efficacy). These findings are consistent with previous reviews suggesting that venlafaxine, as a weak inhibitor of CYP2D6, does not have a clinically meaningful impact on TAM metabolism [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan additionalcitationids=\"CR20\" citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIt has been previously reported that CYP2D6 polymorphisms significantly affect venlafaxine serum concentrations in patients receiving TAM following breast cancer surgery [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e]. These polymorphisms are known to vary considerably across ethnic groups and large-scale database studies in Caucasian populations have demonstrated elevated venlafaxine levels in carriers of reduced-function alleles [\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e]. In contrast, data in Asian populations remain limited but small-scale clinical studies in Japanese have shown that variants, such as \u003cem\u003eCYP2D6*10\u003c/em\u003e, are associated with altered venlafaxine serum levels [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e, \u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. In the present study, a significant association between CYP2D6 phenotype (IMs vs. EMs) and venlafaxine serum concentration was also observed, consistent with previous findings. However, the efficacy of venlafaxine in reducing hot flash symptoms was sustained regardless of CYP2D6 genotype, a novel finding that may be particularly relevant for Asian populations.\u003c/p\u003e\u003cp\u003eAlthough dose escalation to 75 mg was permitted during the study, no apparent association was found between CYP2D6 phenotype and dose increase. Nevertheless, we noted that no clear dose trends were observed in our cohort. One possible explanation is that serum venlafaxine concentrations in IMs may quickly reach a therapeutic threshold, beyond which additional clinical benefit does not increase. Importantly, the dose escalation protocol in our study was not expressly designed to achieve specific serum levels and, in addition, interindividual variability in treatment response may be influenced by factors beyond CYP2D6 polymorphisms, such as receptor sensitivity or downstream signaling differences [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn this study, the most commonly observed adverse events associated with venlafaxine were headache, insomnia, dry mouth, dizziness, and constipation. All events were mild and no serious adverse events were reported, consistent with the known safety profile of venlafaxine [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e] and with previous studies involving breast cancer patients experiencing hot flashes [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e]. However, some participants who experienced mild adverse events nonetheless discontinued treatment, highlighting the importance of subjective experiences and individual discomfort thresholds that may precipitate the need for alternative therapies [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. Recently, fezolinetant (VEOZA\u0026trade;) has been approved in the United States as a non-hormonal treatment that regulates changes in body temperature associated with menopause [\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e] and clinical trials of this neurokinin 3 receptor blocker in breast cancer patients are currently underway. In the meantime, our findings support venlafaxine as a clinically effective and well-tolerated treatment option for managing hot flashes in clinical settings.\u003c/p\u003e\u003cp\u003eTo our knowledge, this is the first study to evaluate the efficacy and safety of venlafaxine for the management of hot flashes in premenopausal women undergoing TAM adjuvant endocrine therapy. Although two large studies previously investigated venlafaxine for endocrine therapy-related hot flashes in breast cancer patients [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], one investigated only postmenopausal women while the other partially included TAM patients, but without specifying case numbers or LHRHa use. Notably, 76% of our enrolled participants were also receiving LHRHa, which is clinically relevant given that such patients experience more frequent and severe hot flashes [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e]. Our findings align with previously published literature on reduction of hot flashes with venlafaxine but extends the clinical utility to even premenopausal women, a demographic with an increasing incidence of breast cancer.\u003c/p\u003e\u003cp\u003eThis study has several limitations due to its single-arm, exploratory nature (without a predefined sample size) as the relatively small number of participants may have underestimated the incidence of adverse events. Although larger-scale studies are warranted to validate these findings, the results of the present study are generally consistent with previous reports conducted primarily in postmenopausal women and Western populations. Third, the study population consisted exclusively of Asian (Japanese) patients, and the analysis of CYP2D6 polymorphisms was limited to variants commonly found in Asian populations. Therefore, the generalizability of the findings to other ethnic groups may be limited. Nonetheless, the study provides valuable insights into the efficacy and safety of venlafaxine based on genetic backgrounds that have been underreported in prior research.\u003c/p\u003e\u003cp\u003eIn summary, this study prospectively evaluated the efficacy and safety of venlafaxine for managing hot flashes in hormone receptor-positive, breast cancer patients receiving tamoxifen, most of whom were also undergoing LHRHa therapy. A significant reduction in hot flash scores was observed as early as Week 1, with no notable impact on serum concentrations of tamoxifen or its active metabolites. While venlafaxine serum levels varied by CYP2D6 genotype, symptom relief was consistently achieved across genotypes. Adverse events were mild, but some patients discontinued treatment due to subjective discomfort. These findings suggest that venlafaxine is a potentially effective and well-tolerated option for managing vasomotor symptoms in premenopausal high-risk breast cancer patients, particularly those treated with LHRHa.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Dr. Takeshi Yamada of the University of Tsukuba for their valuable advice during the preparation of this manuscript. We also thank Dr. Bryan J. Mathis for professional English language editing.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eH.B. conceived the study, and R.S. designed the protocol. R.S., H.B., R.K., T.M., A.S., M.O., S.H., and A.I.-M. were responsible for patient enrollment and clinical management. K.D., Y.M., and M.H. performed the serum drug concentration measurements and pharmacokinetic analyses. R.I. and K.S. conducted the statistical analyses. K.D. also conducted the CYP2D6\u003cem\u003e\u0026nbsp;\u003c/em\u003egenotyping. R.S. drafted the manuscript. All authors reviewed and approved the final version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was funded by Grant for Implementation of Advanced Medicine (GIAM) [grant number\u0026nbsp;先進‑107]. The funder played no role in study design, data collection, analysis and interpretation of data, or the writing of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll authors declare no financial or non-financial competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and/or analyzed during the current study are not publicly available due to patient privacy concerns but are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthical approval\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll procedures performed in this study involving human participants were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eInformed consent\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eInformed consent was obtained from all individual participants included in the study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eCella D, Fallowfield LJ. 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Obstet Gynecol 2005;105:161\u0026ndash;6. doi:10.1097/01.AOG.0000147840.06947.46.\u003c/li\u003e\n \u003cli\u003ePratt VM, Scott SA, Pirmohamed M, Esquivel B, Kattman BL, Co-editor, et al. Medical Genetics Summaries. Bethesda (MD): National Center for Biotechnology Information (US); 2012. Available from: https://www.ncbi.nlm.nih.gov/books/NBK61999/.\u003c/li\u003e\n \u003cli\u003eKomahashi-Sasaki H, Yasui-Furukori N, Sasaki T, Shinozaki M, Hayashi Y, Kato K, et al. Effects of CYP2D6 genotypes on venlafaxine metabolism in Japanese psychiatric patients with depression. Ther Drug Monit 2021;43:681\u0026ndash;7. doi:10.1097/FTD.0000000000000854.\u003c/li\u003e\n \u003cli\u003eDesmarais JE, Looper KJ. Interactions between tamoxifen and antidepressants via cytochrome P450 2D6. J Clin Psychiatry 2009;70:1688\u0026ndash;97. doi:10.4088/JCP.08r04856blu\u003c/li\u003e\n \u003cli\u003eGuttuso T, Jr., DiGrazio WJ, Reddy SY. Review of hot flash diaries. Maturitas 2012;71:213\u0026ndash;6. doi:10.1016/j.maturitas.2011.12.003.\u003c/li\u003e\n \u003cli\u003eAntunes MV, Raymundo S, De Oliveira V, Staudt DE, G\u0026ouml;ssling G, Peteffi GP, et al. Ultra-high performance liquid chromatography tandem mass spectrometric method for the determination of tamoxifen, N-desmethyltamoxifen, 4-hydroxytamoxifen and endoxifen in dried blood spots\u0026mdash;development, validation and clinical application during breast cancer adjuvant therapy. Talanta 2015;132:775\u0026ndash;84. doi:10.1016/j.talanta.2014.10.040.\u003c/li\u003e\n \u003cli\u003eJaremko M, Kasai Y, Barginear MF, Raptis G, Desnick RJ, Yu C. Tamoxifen metabolite isomer separation and quantification by liquid chromatography-tandem mass spectrometry. Anal Chem 2010;82:10186\u0026ndash;93. doi:10.1021/ac102337d.\u003c/li\u003e\n \u003cli\u003eGu G, Black M, Cookson C, Fiorella A, Li Y, Gorman SH, et al. Validation of an LC-MS/MS method for simultaneous quantification of venlafaxine and its five metabolites in rat plasma and its application in a pharmacokinetic study. J Chromatogr B Analyt Technol Biomed Life Sci 2018;1087\u0026ndash;1088:29\u0026ndash;35. doi:10.1016/j.jchromb.2018.04.033.\u003c/li\u003e\n \u003cli\u003eDoki K, Shirayama Y, Sekiguchi Y, Aonuma K, Kohda Y, Ieda M, et al. Effect of CYP2D6 genetic polymorphism on peak propafenone concentration: no significant effect of \u003cem\u003eCYP2D6*10\u003c/em\u003e. Pharmacogenomics 2020;21:1279\u0026ndash;88. doi:10.2217/pgs-2020-0105.\u003c/li\u003e\n \u003cli\u003eJoffe H, Guthrie KA, LaCroix AZ, Reed SD, Ensrud KE, Manson JE, et al. Low-dose estradiol and the serotonin-norepinephrine reuptake inhibitor venlafaxine for vasomotor symptoms: a randomized clinical trial. JAMA Intern Med 2014;174:1058\u0026ndash;66. doi:10.1001/jamainternmed.2014.1891.\u003c/li\u003e\n \u003cli\u003eLoprinzi CL, Kugler JW, Sloan JA, Mailliard JA, LaVasseur BI, Barton DL, et al. Venlafaxine in management of hot flashes in survivors of breast cancer: a randomised controlled trial. Lancet 2000;356:2059\u0026ndash;63. doi:10.1016/S0140-6736(00)03403-6.\u003c/li\u003e\n \u003cli\u003eMadlensky L, Natarajan L, Tchu S, Pu M, Mortimer J, Flatt SW, et al. Tamoxifen metabolite concentrations, CYP2D6 genotype, and breast cancer outcomes. Clin Pharmacol Ther 2011;89:718\u0026ndash;25. doi:10.1038/clpt.2011.32.\u003c/li\u003e\n \u003cli\u003eJin Y, Desta Z, Stearns V, Ward B, Ho H, Lee KH, et al. CYP2D6 genotype, antidepressant use, and tamoxifen metabolism during adjuvant breast cancer treatment. J Natl Cancer Inst 2005;97:30\u0026ndash;9. doi:10.1093/jnci/dji005.\u003c/li\u003e\n \u003cli\u003eBradbury M, Hutton B, Beltran-Bless AA, Alzahrani M, Lariviere T, Fernandes R, et al. Time to update evidence-based guideline recommendations about concurrent tamoxifen and antidepressant use? A systematic review. Clin Breast Cancer 2022;22:e362\u0026ndash;73. doi:10.1016/j.clbc.2021.10.003.\u003c/li\u003e\n \u003cli\u003eHaslemo T, Eliasson E, Jukić MM, Ingelman-Sundberg M, Molden E. Significantly lower CYP2D6 metabolism measured as the O/N-desmethylvenlafaxine metabolic ratio in carriers of CYP2D6*41 versus CYP2D6*9 or CYP2D6*10: a study on therapeutic drug monitoring data from 1003 genotyped Scandinavian patients. Br J Clin Pharmacol 2019;85:194\u0026ndash;201. doi:10.1111/bcp.13788.\u003c/li\u003e\n \u003cli\u003eFukuda T, Nishida Y, Zhou Q, Yamamoto I, Kondo S, Azuma J. The impact of the CYP2D6 and CYP2C19 genotypes on venlafaxine pharmacokinetics in a Japanese population. Eur J Clin Pharmacol 2000;56:175\u0026ndash;80. doi:10.1007/s002280050737.\u003c/li\u003e\n \u003cli\u003eRadosavljevic M, Svob Strac D, Jancic J, Samardzic J. The role of pharmacogenetics in personalizing the antidepressant and anxiolytic therapy. Genes (Basel) 2023;14:1095. doi:10.3390/genes14051095.\u003c/li\u003e\n \u003cli\u003eKamp CB, Petersen JJ, Faltermeier P, Juul S, Siddiqui F, Moncrieff J, et al. The risks of adverse events with venlafaxine for adults with major depressive disorder: a systematic review of randomised clinical trials with meta-analysis and Trial Sequential Analysis. Epidemiol Psychiatr Sci 2024;33:e51. doi:10.1017/S2045796024000520.\u003c/li\u003e\n \u003cli\u003eStatPearls A. Venlafaxine; 2024. StatPearls [Internet].\u003c/li\u003e\n \u003cli\u003eLeon-Ferre RA, Majithia N, Loprinzi CL. Management of hot flashes in women with breast cancer receiving ovarian function suppression. Cancer Treat Rev 2017;52:82\u0026ndash;90. doi:10.1016/j.ctrv.2016.11.012.\u003c/li\u003e\n \u003cli\u003eLederman S, Ottery FD, Cano A, Santoro N, Shapiro M, Stute P, et al. Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study. Lancet 2023;401:1091\u0026ndash;102. doi:10.1016/S0140-6736(23)00085-5.\u003c/li\u003e\n \u003cli\u003eDay R. Quality of life and tamoxifen in a breast cancer prevention trial: a summary of findings from the NSABP P-1 study. National Surgical Adjuvant Breast and Bowel Project. Ann N Y Acad Sci 2001;949:143\u0026ndash;50. doi:10.1111/j.1749-6632.2001.tb04012.x.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"breast-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brca","sideBox":"Learn more about [Breast Cancer](http://link.springer.com/journal/12282)","snPcode":"12282","submissionUrl":"https://www.editorialmanager.com/brca/default2.aspx","title":"Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"hot flashes, tamoxifen, venlafaxine, CYP2D6, breast cancer","lastPublishedDoi":"10.21203/rs.3.rs-7522015/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7522015/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eWe conducted a prospective, singlearm, openlabel trial to evaluate venlafaxine efficacy and safety in hormone receptor-positive breast cancer patients on tamoxifen experiencing moderatetosevere hot flashes.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eTwenty patients received venlafaxine at 37.5 mg/day for 4 weeks, with optional escalation to 75 mg/day. Weekly hot flash scores, adverse events, and serum concentrations of tamoxifen, its metabolites, and venlafaxine (as well as CYP2D6 genotype associations) were assessed. Of the 20 patients, 17 were included in the primary efficacy analysis, 20 in the safety population for adverse events, and 18 in the pharmacokinetic analysis.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eAt Week 4, hot flash scores declined by 49.8% from baseline (P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Venlafaxine did not affect serum concentrations of tamoxifen or its metabolites. CYP2D6 intermediate metabolizers had higher venlafaxine concentrations than extensive metabolizers (P\u0026thinsp;=\u0026thinsp;0.007), although symptom improvement occurred regardless of genotype. All adverse events were Grade 1\u0026ndash;2.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eThese findings demonstrate that venlafaxine safely and effectively alleviates hot flashes in hormone receptor-positive breast cancer patients undergoing tamoxifen-based endocrine therapy.\u003c/p\u003e","manuscriptTitle":"Venlafaxine reduces hot flashes in hormone receptor-positive breast cancer patients receiving tamoxifen: a prospective single‑arm, open‑label trial","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-23 02:42:41","doi":"10.21203/rs.3.rs-7522015/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major Revision","date":"2025-11-05T00:42:29+00:00","index":"","fulltext":""},{"type":"reviewerAgreed","content":"","date":"2025-09-13T04:59:53+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-09-13T00:53:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-09-03T09:15:21+00:00","index":"","fulltext":""},{"type":"submitted","content":"Breast Cancer","date":"2025-09-02T22:38:42+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"breast-cancer","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"brca","sideBox":"Learn more about [Breast Cancer](http://link.springer.com/journal/12282)","snPcode":"12282","submissionUrl":"https://www.editorialmanager.com/brca/default2.aspx","title":"Breast Cancer","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"23550947-c42d-414a-9a31-24f123584e9a","owner":[],"postedDate":"September 23rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-02-09T16:07:13+00:00","versionOfRecord":{"articleIdentity":"rs-7522015","link":"https://doi.org/10.1007/s12282-026-01828-5","journal":{"identity":"breast-cancer","isVorOnly":false,"title":"Breast Cancer"},"publishedOn":"2026-02-05 15:59:54","publishedOnDateReadable":"February 5th, 2026"},"versionCreatedAt":"2025-09-23 02:42:41","video":"","vorDoi":"10.1007/s12282-026-01828-5","vorDoiUrl":"https://doi.org/10.1007/s12282-026-01828-5","workflowStages":[]},"version":"v1","identity":"rs-7522015","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7522015","identity":"rs-7522015","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}