2f:I[703058,["/_next/static/immutable/chunks/3bhq_5eh1d760.js","/_next/static/immutable/chunks/1855-ogyi8eh4.js","/_next/static/immutable/chunks/2pfsjpn6k6zlg.js","/_next/static/immutable/chunks/26c7v3_3uwnwu.js","/_next/static/immutable/chunks/25a3ozcrvi1ff.js","/_next/static/immutable/chunks/2r4wx50nvjh_4.js","/_next/static/immutable/chunks/23fsw06hsi5b1.js","/_next/static/immutable/chunks/06_yt270h41rg.js","/_next/static/immutable/chunks/3ezsiz-7shkna.js","/_next/static/immutable/chunks/20x2y96ldu5wx.js","/_next/static/immutable/chunks/2lxntcm3pd1_h.js","/_next/static/immutable/chunks/00dgco8irq3jw.js","/_next/static/immutable/chunks/00nwe-kq0rboc.js","/_next/static/immutable/chunks/2051ffx3xzio9.js"],"PaperListPageClient"] 30:T67f,(Z)-endoxifen is the tamoxifen metabolite that possesses the highest affinity to the estrogen receptor and is evolving as an alternative to tamoxifen. Mammographic breast density (MBD) change has been shown to be a proxy for tamoxifen therapy response. The objective was to measure the effect of 2 different doses of (Z)-endoxifen on MBD, safety, and side effects in healthy women. Healthy premenopausal women included in the national Swedish screening program in Stockholm were invited to KARISMA Endoxifen, a proof of principle, dose determining, double-blinded, randomized, placebo-controlled trial. Women were randomly assigned to placebo or 1 or 2 mg of (Z)-endoxifen daily for 6 months. In all, 240 women were randomly assigned. There was a significant relative change in MBD in both (Z)-endoxifen arms compared to placebo: -19.3% (95% confidence interval [CI] = -6.15% to -32.4%) in the 1 mg arm and -26.5% (95% CI = -14.1% to -38.9%) in the 2 mg arm. The number of participants discontinuing because of adverse events related to the investigational medicinal product was 4 (placebo), 5 (1 mg), and 11 (2 mg), respectively. Participants on 2 mg of (Z)-endoxifen reported significantly higher scores of vasomotor symptoms, compared with placebo. No clinically significant changes in hematological safety tests or vital signs were noted. Both 1 and 2 mg of (Z)-endoxifen significantly reduced MBD to a degree comparable to the established 20 mg dose of tamoxifen. The 1 mg dosage of (Z)-endoxifen indicated superior tolerability. Future studies are necessary to confirm impact on breast cancer incidence. ClinicalTrials.gov ID: NCT05068388.31:T9a7,Abstract Background (Z)-endoxifen is the tamoxifen metabolite that possesses the highest affinity to the estrogen receptor and is evolving as an alternative to tamoxifen. Mammographic breast density (MBD) change has been shown to be a proxy for tamoxifen therapy response. The objective was to measure the effect of 2 different doses of (Z)-endoxifen on MBD, safety, and side effects in healthy women. Methods Healthy premenopausal women included in the national Swedish screening program in Stockholm were invited to KARISMA Endoxifen, a proof of principle, dose determining, double-blinded, randomized, placebo-controlled trial. Women were randomly assigned to placebo or 1 or 2 mg of (Z)-endoxifen daily for 6 months. Results In all, 240 women were randomly assigned. There was a significant relative change in MBD in both (Z)-endoxifen arms compared to placebo: −19.3% (95% confidence interval [CI] = −6.15% to −32.4%) in the 1 mg arm and −26.5% (95% CI = −14.1% to −38.9%) in the 2 mg arm. The number of participants discontinuing because of adverse events related to the investigational medicinal product was 4 (placebo), 5 (1 mg), and 11 (2 mg), respectively. Participants on 2 mg of (Z)-endoxifen reported significantly higher scores of vasomotor symptoms, compared with placebo. No clinically significant changes in hematological safety tests or vital signs were noted. Conclusion Both 1 and 2 mg of (Z)-endoxifen significantly reduced MBD to a degree comparable to the established 20 mg dose of tamoxifen. The 1 mg dosage of (Z)-endoxifen indicated superior tolerability. Future studies are necessary to confirm impact on breast cancer incidence. Trial Registration ClinicalTrials.gov ID: NCT05068388. 25:[[["$","script","0",{"type":"application/ld+json","dangerouslySetInnerHTML":{"__html":"{\"@context\":\"https://schema.org\",\"@type\":\"CollectionPage\",\"name\":\"Breast Cancer Risk Reduction: condition Research & Clinical Takeaways\",\"description\":\"Explore peer-reviewed papers on Breast Cancer Risk Reduction (condition). Clinician-written summaries and actionable practice insights. 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There was a significant relative change in MBD in both (Z)-endoxifen arms compared to placebo: -19.3% (95% confidence interval [CI] = -6.15% to -32.4%) in the 1 mg arm and -26.5% (95% CI = -14.1% to -38.9%) in the 2 mg arm. The number of participants discontinuing because of adverse events related to the investigational medicinal product was 4 (placebo), 5 (1 mg), and 11 (2 mg), respectively. Participants on 2 mg of (Z)-endoxifen reported significantly higher scores of vasomotor symptoms, compared with placebo. No clinically significant changes in hematological safety tests or vital signs were noted.","abstract":"$30","keywords":[],"pubmed_id":"42070780","conclusions":"Both 1 and 2 mg of (Z)-endoxifen significantly reduced MBD to a degree comparable to the established 20 mg dose of tamoxifen. The 1 mg dosage of (Z)-endoxifen indicated superior tolerability. Future studies are necessary to confirm impact on breast cancer incidence.","publication_date":"2026-05-04T00:00:00"},"crossref":{"DOI":"10.1093/jnci/djag087","URL":"https://doi.org/10.1093/jnci/djag087","ISSN":["0027-8874","1460-2105"],"link":[{"URL":"https://academic.oup.com/jnci/advance-article-pdf/doi/10.1093/jnci/djag087/68192919/djag087.pdf","content-type":"application/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https://academic.oup.com/jnci/advance-article-pdf/doi/10.1093/jnci/djag087/68192919/djag087.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"page":null,"type":"journal-article","issue":null,"score":1,"title":["Endoxifen for mammographic density reduction—results from the KARISMA endoxifen trial"],"author":[{"given":"Per","family":"Hall","sequence":"first","affiliation":[{"name":"Department of Medical Epidemiology and Biostatistics, Karolinska Institutet , 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incidence data are reported, so clinical impact_flag of 'practice_changing' reflects density reduction efficacy only — not confirmed cancer prevention benefit.","value_numeric":null},{"paper_doi":"10.1093/jnci/djag087","tag_type":"warning","value":"No direct head-to-head comparison with tamoxifen 20 mg was included in this trial; comparability to tamoxifen is inferred from historical benchmarks.","value_numeric":null},{"paper_doi":"10.1093/jnci/djag087","tag_type":"warning","value":"Trial was conducted in a single country (Sweden) among women in a national screening program, which may limit generalizability to other populations.","value_numeric":null}],"summaries":{"what_studied":"Double-blind RCT in 240 healthy premenopausal women comparing daily (Z)-endoxifen (1 mg or 2 mg) vs. placebo over 6 months, measuring mammographic breast density (MBD) change, safety, and tolerability.","key_result":"Both doses significantly reduced MBD vs. placebo: −19.3% (95% CI −6.15% to −32.4%) with 1 mg 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Discontinuations due to adverse events: 4 (placebo), 5 (1 mg), 11 (2 mg); 2 mg arm had significantly more vasomotor symptoms.","limitations":"MBD is a surrogate endpoint; direct impact on breast cancer incidence is unconfirmed. Trial enrolled only healthy premenopausal women from a single national screening program, limiting generalizability. No active tamoxifen comparator arm was included.","practice_takeaway":"Low-dose (Z)-endoxifen (1 mg/day) reduces mammographic density comparably to standard tamoxifen 20 mg with better tolerability — making it a promising chemoprevention candidate. Clinicians should await breast cancer incidence data before adopting it in practice."}}],"initialOffset":1,"fetchConfig":{"kind":"tags","tags":[{"tag_type":"condition","value":"Breast Cancer Risk Reduction"}]},"breadcrumbItems":[{"name":"Home","href":"/"},{"name":"Research Hub","href":"/hub"},{"name":"Conditions","href":"/hub/tag/condition"},{"name":"Breast Cancer Risk Reduction"}],"hrefConfig":{"basePath":"/hub/papers","webViewQueryParams":{"hub_ctx":"tag","hub_tag_type":"condition","hub_tag_value":"Breast Cancer Risk Reduction"}}}]]

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