Incidence of invasive breast cancer in women treated with testosterone implants: Dayton prospective cohort study, 15-year update

Incidence of invasive breast cancer in women treated with testosterone implants: Dayton prospective cohort study, 15-year update | 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 Incidence of invasive breast cancer in women treated with testosterone implants: Dayton prospective cohort study, 15-year update Rebecca L. Glaser, Constantine Dimitrakakis, Izabelle M Gindri, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4248378/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background: We previously published 10-year results (from March 2008-March 2018) from the Dayton prospective breast cancer prevention study, which showed a 40% reduction in the incidence of invasive breast cancer in women receiving testosterone or testosterone with anastrozole implant therapy compared to the age-matched Surveillance Epidemiology and End Results (SEER) expected incidence rate. We continued to follow the study subjects on therapy through March 2023. Methods: This 10-year prospective cohort study was approved in March 2008, at which time recruitment was initiated. Recruitment was closed in March 2013. Pre- and postmenopausal women who received at least two pellet insertions were eligible for analysis (n=1267). Breast cancer incidence rates are reported as an unadjusted, unweighted value of newly diagnosed cases divided by the sum of the person-time of observation for the at-risk population. The incidence rates on testosterone therapy were compared to age-specific SEER incidence rates and expected local Montgomery County incidence rates (the location of most study patients). Results: As of March 1, 2023, a total of 16 (versus 30 expected) eligible patients were diagnosed with invasive breast cancer within 240 days of their last testosterone pellet insert equating to an incidence rate of 189/100000 p-y, which is significantly less than the national SEER expected incidence rate of 355/100000, i.e., a 47% reduction. Interestingly, local incidence rates in Montgomery County are higher than US national averages. Conclusion: The 15-year follow-up data revealed a reduced incidence of invasive breast cancer with long-term testosterone or testosterone combined with anastrozole implant therapy. Because of the increased incidence of invasive breast cancer in our area, the amount of reduction (benefit) from testosterone therapy may be underestimated using national data/statistics for comparison. Androgens Testosterone Breast Cancer Incidence Prevention Dayton Ohio Background Extensive preclinical [ 1 , 2 ] and clinical [ 2 ] evidence supports the beneficial effect of testosterone in breast tissue and breast cancers. Data on the protective role of hormone balance in breast cancer prevention continues to evolve [ 3 , 4 ]. Since 1937, subcutaneous testosterone (T) implants have been used to treat a wide range of hormonal imbalances, including breast cancer. We have previously reported the results of our prospective, institutional review board-approved, 10-year cohort study on the reduced incidence of invasive breast cancer in women treated with T or testosterone combined with anastrozole (T + A) implant therapy. Details of the ‘Dayton study,’ including the STROBE checklist, study design, approval, methods, results, and statistical analysis have been previously published and can be found here [ 3 , 4 ]. Although the study was designed as a 10-year prospective study, patients were followed through year 15, which ended March 1, 2023. All patients were seen at a single practice location and treated by a breast cancer surgeon (RG) with access to all records and data throughout the entire 15-year period. We again compared our results to national age-specific Surveillance Epidemiology and End Results (SEER) age-matched incidence rates [ 5 ]. In addition, we discuss local (Montgomery County) overall and age-adjusted breast cancer incidence rates [ 6 , 7 , 8 ] and how they compare to Ohio and National rates. Methods As previously reported​​ [ 3 , 4 ], pre- and postmenopausal women who received at least two T pellet implants between March 2008 and March 2013 were included in the analysis (n = 1267). Patients were monitored at each visit and followed prospectively for the incidence of invasive breast cancer. The baseline patient demographics were previously published (Table 1 ) [ 3 ]. Table 1 Patient demographics at first T pellet insertion [ 3 ] N = 1267 Postmenopausal 76.8% Pre/perimenopausal 23.2% Age, mean (SD) 52.1 ± 8.6 y Family history BCA (1st, 2nd ) 29% Age menarche, mean (SD) 12.8 ± 1.6 y Age first birth, mean (SD) 24.8 ± 5.2 y Nulliparous 14.9% Weight kg, mean (SD) 71.03 ± 15.5 kg BMI, mean (SD) 26.3 ± 5.5 kg/m 2 Statistical methods The incidence rates of invasive breast cancer for the Dayton study are reported as an unadjusted, unweighted value of newly diagnosed cases divided by the sum of ‘person-time of observation’ (in years) of the ‘at risk’ population. Person-days of observation were calculated from the date of first T pellet insertion for each participant up to the date of cancer registration, the date of death, 240 days after the last pellet insert a ., or the set date of March 1, 2023, whichever came first. Person-years (p-y) were calculated by dividing person-days by 365.25. The incidence of breast cancer was calculated per 100 000 p-y so that our results could be compared to SEER incidence rates and age-adjusted Montgomery County incidence rates. The observed breast cancer incidence rates for Dayton study patients were compared to the expected (adjusted) SEER breast cancer incidence rates calculated from the age composition of Dayton study patients and the published SEER age-grouped breast cancer incidence rates [ 4 ]. Details can be found in Supplement 1 . Results As of March 1, 2018, 425 patients remained active and continued to receive T or T + A therapy. The mean age was 60.7 ± 8.3 years. As of 1 March 2023, there were 299 patients on therapy with a mean age of 65.4 ± 7.8 years. As of March 2023, a total of 15 patients who were adherent to therapy had been diagnosed with invasive breast cancer since March 2008 out of 1267 patients. One patient discontinued therapy for 259 days, received a single pellet implant and was diagnosed with breast cancer within less than 6 weeks, i.e., nonadherence to therapy a . Interestingly, she had received testosterone implants consistently prior to this (14 years) and it was only after an extended absence that her stage 1, low grade, estrogen receptor (ER)-positive cancer was diagnosed. Patient 16 was included in the analysis. One patient was diagnosed with breast cancer within the first 240 days following her initial T pellet insertion and, per protocol, was excluded from analysis. Another patient, who was off therapy for more than 240 days (352 days) prior to diagnosis, was excluded from the analysis per protocol. Both patients also had stage 1, ER-positive breast cancer. The total person-time for eligible patients was 8464 years, which translates to a breast cancer incidence (BCI) of 189/100000 p-y (N = 16). The age-adjusted SEER expected BCI rate was 355/100000 p-y, and the number of expected cases was 30. These results represent a BCI reduction of 47% compared to the national SEER data. If all 18 diagnosed patients were included, the BCI rate would be 213/1000000 p-y, which is still a 40% reduction in the incidence of invasive breast cancer. The results are summarized in Table 2 . The difference in the confidence intervals between the Dayton BCI and the expected age-adjusted SEER BCI was statistically significant. Table 2 Observed Dayton and expected SEER invasive breast cancer incidence (BCI) (95% confidence interval) (P values of Dayton BCI compared to expected SEER BCI) BCI P value Dayton (15 adherent a patients) 177.2 (99.2, 292.2) P = 0.004 Dayton (16 eligible patients) 189.0 (108.0, 307.0) P = 0.008 Dayton (18 total patients) 212.6 (126.0, 336.1) P = 0.028 SEER expected (30 patients) 355.1 (239.1, 505.9) Patient data and tumor characteristics The breast cancer patient data and tumor characteristics are described in Supplement 2 . The mean age at first pellet insertion was 53.4 ± 6.9 (39.7–67.6) years. The mean age at diagnosis was 61.2 ± 8.4 (43.4–70.9) years. The mean baseline BMI of the patients diagnosed with invasive breast cancer was 29.0 ± 6.0 (19.2–39.3), which was greater than the mean cohort baseline BMI of 26.3 ± 5.5 (16.5–53.2) (P = 0.057). A total of 14/16 (87.5%) of the tumors were ER positive and 13/16 (81%) were progesterone receptor (PR) positive. Interestingly, only 1/16 (6.25%) tumors were human epidermal growth factor 2 (HER2)-positive, which is lower than the expected rate of 22% [ 9 ]. Ten of 16 patients were stage 1 at the time of diagnosis. Eight of 11 patients diagnosed in the last ten years have continued T or T + A implant therapy following diagnosis. Discussion Our 15-year results support the beneficial effect of T or T + A delivered by subcutaneous implants on the long-term incidence of invasive breast cancer. We demonstrated a greater than 40% reduction in the incidence of invasive breast cancer compared to the national SEER expected incidence rates. Testosterone implants have been shown to actively inhibit the growth of invasive breast cancer tumors [ 2 ]. When nonadherent patients stop therapy for more than 8 months, tumors may develop or progress. Even with the inclusion of ineligible patients, there was still a significant reduction in BCI compared to the national data. Additionally, most tumors from patients diagnosed while receiving T therapy exhibit favorable histologic and immunohistochemical characteristics, i.e., being ER positive, PR positive, and Her-2 negative. Notably, HER2-positive tumors are more aggressive and are associated with a worse prognosis [ 9 ]. Comparing our data to national data may underestimate the beneficial effect of testosterone therapy on breast cancer prevention. Montgomery County (Dayton, Ohio) had the highest overall BCI rates in Ohio in 2016–2020 [ 6 ]. Montgomery County also exhibited a significantly greater BCI rate compared to the national US (SEER + NPCR) and Ohio ‘Age-Adjusted Incidence Rates’ for females aged 50 + and 65 + years (Table 3 ) [ 7 , 8 ]​​. The surrounding counties also have a much higher overall and age-adjusted BCI rates than do the Ohio and US National Rates [ 6 , 7 , 8 ]. The reason for the increased incidence of breast cancer in Dayton and surrounding counties should be further investigated. Table 3 Invasive Breast Cancer (All Stages^), 2016–2020. All Races – by county [ 7 ][ 8 ] Age adjusted incidence rate-cases per 100,000 (95% Confidence Interval) Female, Ages 50+ Age adjusted incidence rate-cases per 100,000 (95% Confidence Interval) Female, Ages 65+ US (SEER + NPCR) (1) 340.5 (339.9, 341.2) 424.1 (423.0, 425.1) Ohio (6) 351.8 (348.4, 355.2) 444.4 (438.8, 450.1) - Montgomery County (6) 394.8 (378.3, 411.8) 500.0 (473.5, 527.7) Conclusion The Dayton 15-year follow-up data continue to support a reduced incidence of invasive breast cancer in patients treated with long-term T or T + A pellet implant therapy, corroborating our 5- and 10-year study results. Testosterone implant therapy was shown to be effective for breast cancer prevention even in areas at increased risk, such as Dayton, Ohio. Our prospective observational study results support preclinical [1] and clinical [2] experimental data demonstrating that testosterone is protective against invasive breast cancer. It is highly unlikely that T or T + A is causative when a patient receiving therapy is diagnosed with breast cancer. It is imperative that physicians understand the relationship between testosterone therapy and breast cancer risk. Abbreviations SEER: Surveillance Epidemiology and End Results; BCI: breast cancer incidence; p-y: person-years; T: testosterone; T+A: testosterone combined with anastrozole; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epidermal growth factor 2 Declarations Ethics approval and consent to participate: Informed written consent was obtained from all participants. This prospective study (Testosterone Implants and Incidence of Breast cancer-TIBcaP 0108) was approved in March of 2008 by the Atrium Medical Center’s Institutional Review Board, One Medical Center Dr., Middletown, Ohio. Consent for publication: All patients signed a consent allowing for publication. Availability of data and materials: Statistical data and analyses are included in Additional file 1. Confidential access to primary data including deidentified spreadsheets will be granted upon reasonable request. Competing interest: RG has a patent issued: Pharmaceutical compositions containing testosterone and an aromatase inhibitor. No financial or other COIs are declared. Funding: None Author contributions: CD and RG designed the study. RG collected the data. RG and DGG participated in analysis of the data. DGG and AP performed the statistical analysis. All authors contributed to writing the manuscript and approved the final manuscript. Acknowledgments: We would like to thank Jen Dichito M.A. and Michael Glaser-Garbrick B.S., M.S. for their diligent patient follow-up, and mathematical and computer science work. We would like to acknowledge Carlos Rodrigo de Mello Roesler and Darlan Dallacosta for their contributions and review of the manuscript. References Hickey, T. E. et al. The androgen receptor is a tumor suppressor in estrogen receptor–positive breast cancer. Nat. Med. 2021;27(2): 310–320. Glaser, R and Dimitrakakis, C. Testosterone Implant Therapy in Women With and Without Breast Cancer: Rationale, Experience, Evidence. Androgens: Clinical Research and Therapeutics. 2021;2(1):94-110. Glaser, R. L. & Dimitrakakis, C. Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: A prospective, observational study. Maturitas. 2013;76: 342–349. Glaser, R. L., York, A. E. & Dimitrakakis, C. Incidence of invasive breast cancer in women treated with testosterone implants: A prospective 10-year cohort study. BMC Cancer. 2019; 19: 1271. National Program of Cancer Registries and Surveillance, Epidemiology, and End Results SEER. United States Department of Health and Human Services, Centers for Disease Control and Prevention. 2022. https://www.cdc.gov/cancer/npcr/index.htm. Department of Health, O. Ohio Annual Cancer Report 2023. https://odh.ohio.gov/wps/portal/gov/odh/know-our-programs/ohio-cancer-incidence-. State Cancer Profiles - Incidence Rate Report for Ohio by County. 2020. https://statecancerprofiles.cancer.gov/incidencerates/index.php?stateFIPS=39&areatype=county&cancer=055&race=00&age=136&stage=999&type=incd&sortVariableName=rate&sortOrder=default&output=0#results. State Cancer Profiles - Incidence Rate Report for Ohio by County. 2020 https://statecancerprofiles.cancer.gov/incidencerates/index.php?stateFIPS=39&areatype=county&cancer=055&race=00&age=157&stage=999&type=incd&sortVariableName=rate&sortOrder=default&output=0#results. Ross JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti–HER-2 Therapy and Personalized Medicine. The Oncologist. 2009;14:320-368. https://doi.org/10.1634/theoncologist.2008-0230 Footnote a. Subcutaneous implants are long acting (sustained release) The incidence of breast cancer was reported for a predetermined time frame of 240-days post implantation or 2.5 times the average length of clinical efficacy of 96 days (approximately 3 months), i.e., ‘eligible for analysis’. Patients who were adherent to therapy were those who received testosterone pellet implants within the 240-day time frame. Nonadherence indicates >240 days of absence between implant therapies. Additional Declarations Competing interest reported. RG has a patent issued: Pharmaceutical compositions containing testosterone and an aromatase inhibitor. No financial or other COIs are declared. IG and AP are employed by bio meds Pharmaceutica LTDA, Florianópolis, SC, BR which produces pellet implants in Brazil. CD, DGG, and LPSP have no COI Supplementary Files S1V410msSupplement1.docx S2V410Supplement2BCpatients.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4248378","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":290337148,"identity":"ee35033c-93fd-4e99-92db-2a8765c75c7f","order_by":0,"name":"Rebecca L. 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RG has a patent issued: Pharmaceutical compositions containing testosterone and an aromatase inhibitor. No financial or other COIs are declared. \nIG and AP are employed by bio meds Pharmaceutica LTDA, Florianópolis, SC, BR which produces pellet implants in Brazil. \nCD, DGG, and LPSP have no COI","formattedTitle":"Incidence of invasive breast cancer in women treated with testosterone implants: Dayton prospective cohort study, 15-year update","fulltext":[{"header":"Background","content":"\u003cp\u003eExtensive preclinical [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] and clinical [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] evidence supports the beneficial effect of testosterone in breast tissue and breast cancers. Data on the protective role of hormone balance in breast cancer prevention continues to evolve [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSince 1937, subcutaneous testosterone (T) implants have been used to treat a wide range of hormonal imbalances, including breast cancer. We have previously reported the results of our prospective, institutional review board-approved, 10-year cohort study on the reduced incidence of invasive breast cancer in women treated with T or testosterone combined with anastrozole (T\u0026thinsp;+\u0026thinsp;A) implant therapy. Details of the \u0026lsquo;Dayton study,\u0026rsquo; including the STROBE checklist, study design, approval, methods, results, and statistical analysis have been previously published and can be found here [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Although the study was designed as a 10-year prospective study, patients were followed through year 15, which ended March 1, 2023. All patients were seen at a single practice location and treated by a breast cancer surgeon (RG) with access to all records and data throughout the entire 15-year period.\u003c/p\u003e \u003cp\u003eWe again compared our results to national age-specific Surveillance Epidemiology and End Results (SEER) age-matched incidence rates [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In addition, we discuss local (Montgomery County) overall and age-adjusted breast cancer incidence rates [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e] and how they compare to Ohio and National rates.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eAs previously reported​​ [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e], pre- and postmenopausal women who received at least two T pellet implants between March 2008 and March 2013 were included in the analysis (n\u0026thinsp;=\u0026thinsp;1267). Patients were monitored at each visit and followed prospectively for the incidence of invasive breast cancer. The baseline patient demographics were previously published (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e].\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 demographics at first T pellet insertion [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]\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\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eN\u0026thinsp;=\u0026thinsp;1267\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePostmenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e76.8%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePre/perimenopausal\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e23.2%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52.1\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;8.6 y\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eFamily history BCA (1st, 2nd )\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e29%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge menarche, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12.8\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;1.6 y\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge first birth, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e24.8\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;5.2 y\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNulliparous\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e14.9%\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eWeight kg, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e71.03\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;15.5 kg\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBMI, mean (SD)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e26.3\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;5.5 kg/m\u003csup\u003e2\u003c/sup\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical methods\u003c/h2\u003e \u003cp\u003eThe incidence rates of invasive breast cancer for the Dayton study are reported as an unadjusted, unweighted value of newly diagnosed cases divided by the sum of \u0026lsquo;person-time of observation\u0026rsquo; (in years) of the \u0026lsquo;at risk\u0026rsquo; population. Person-days of observation were calculated from the date of first T pellet insertion for each participant up to the date of cancer registration, the date of death, 240 days after the last pellet insert \u003csup\u003ea\u003c/sup\u003e., or the set date of March 1, 2023, whichever came first. Person-years (p-y) were calculated by dividing person-days by 365.25. The incidence of breast cancer was calculated per 100 000 p-y so that our results could be compared to SEER incidence rates and age-adjusted Montgomery County incidence rates. The observed breast cancer incidence rates for Dayton study patients were compared to the expected (adjusted) SEER breast cancer incidence rates calculated from the age composition of Dayton study patients and the published SEER age-grouped breast cancer incidence rates [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Details can be found in \u003cb\u003eSupplement 1\u003c/b\u003e.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eAs of March 1, 2018, 425 patients remained active and continued to receive T or T\u0026thinsp;+\u0026thinsp;A therapy. The mean age was 60.7\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;8.3 years. As of 1 March 2023, there were 299 patients on therapy with a mean age of 65.4\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;7.8 years.\u003c/p\u003e \u003cp\u003eAs of March 2023, a total of 15 patients who were adherent to therapy had been diagnosed with invasive breast cancer since March 2008 out of 1267 patients. One patient discontinued therapy for 259 days, received a single pellet implant and was diagnosed with breast cancer within less than 6 weeks, i.e., nonadherence to therapy\u003csup\u003ea\u003c/sup\u003e. Interestingly, she had received testosterone implants consistently prior to this (14 years) and it was only after an extended absence that her stage 1, low grade, estrogen receptor (ER)-positive cancer was diagnosed. Patient 16 was included in the analysis.\u003c/p\u003e \u003cp\u003eOne patient was diagnosed with breast cancer within the first 240 days following her initial T pellet insertion and, per protocol, was excluded from analysis. Another patient, who was off therapy for more than 240 days (352 days) prior to diagnosis, was excluded from the analysis per protocol. Both patients also had stage 1, ER-positive breast cancer.\u003c/p\u003e \u003cp\u003eThe total person-time for eligible patients was 8464 years, which translates to a breast cancer incidence (BCI) of 189/100000 p-y (N\u0026thinsp;=\u0026thinsp;16). The age-adjusted SEER expected BCI rate was 355/100000 p-y, and the number of expected cases was 30.\u003c/p\u003e \u003cp\u003eThese results represent a BCI reduction of 47% compared to the national SEER data. If all 18 diagnosed patients were included, the BCI rate would be 213/1000000 p-y, which is still a 40% reduction in the incidence of invasive breast cancer. The results are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The difference in the confidence intervals between the Dayton BCI and the expected age-adjusted SEER BCI was statistically significant.\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\u003eObserved Dayton and expected SEER invasive breast cancer incidence (BCI) (95% confidence interval) (P values of Dayton BCI compared to expected SEER BCI)\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eBCI\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDayton (15 adherent \u003csup\u003ea\u003c/sup\u003e patients)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e177.2\u0026nbsp;(99.2, 292.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.004\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDayton (16 eligible patients)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e189.0 (108.0, 307.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.008\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDayton (18 total patients)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e212.6 (126.0, 336.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP\u0026thinsp;=\u0026thinsp;0.028\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSEER expected (30 patients)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e355.1 (239.1, 505.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003ePatient data and tumor characteristics\u003c/h2\u003e \u003cp\u003eThe breast cancer patient data and tumor characteristics are described in \u003cb\u003eSupplement 2\u003c/b\u003e. The mean age at first pellet insertion was 53.4\u0026thinsp;\u0026plusmn;\u0026thinsp;6.9 (39.7\u0026ndash;67.6) years. The mean age at diagnosis was 61.2\u0026thinsp;\u0026plusmn;\u0026thinsp;8.4 (43.4\u0026ndash;70.9) years. The mean baseline BMI of the patients diagnosed with invasive breast cancer was 29.0\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;6.0 (19.2\u0026ndash;39.3), which was greater than the mean cohort baseline BMI of 26.3\u0026thinsp;\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e\u0026plusmn;\u003c/span\u003e\u0026thinsp;5.5 (16.5\u0026ndash;53.2) (P\u0026thinsp;=\u0026thinsp;0.057).\u003c/p\u003e \u003cp\u003eA total of 14/16 (87.5%) of the tumors were ER positive and 13/16 (81%) were progesterone receptor (PR) positive. Interestingly, only 1/16 (6.25%) tumors were human epidermal growth factor 2 (HER2)-positive, which is lower than the expected rate of 22% [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Ten of 16 patients were stage 1 at the time of diagnosis. Eight of 11 patients diagnosed in the last ten years have continued T or T\u0026thinsp;+\u0026thinsp;A implant therapy following diagnosis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eOur 15-year results support the beneficial effect of T or T\u0026thinsp;+\u0026thinsp;A delivered by subcutaneous implants on the long-term incidence of invasive breast cancer. We demonstrated a greater than 40% reduction in the incidence of invasive breast cancer compared to the national SEER expected incidence rates. Testosterone implants have been shown to actively inhibit the growth of invasive breast cancer tumors [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. When nonadherent patients stop therapy for more than 8 months, tumors may develop or progress. Even with the inclusion of ineligible patients, there was still a significant reduction in BCI compared to the national data. Additionally, most tumors from patients diagnosed while receiving T therapy exhibit favorable histologic and immunohistochemical characteristics, i.e., being ER positive, PR positive, and Her-2 negative. Notably, HER2-positive tumors are more aggressive and are associated with a worse prognosis [\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eComparing our data to national data may underestimate the beneficial effect of testosterone therapy on breast cancer prevention. Montgomery County (Dayton, Ohio) had the highest overall BCI rates in Ohio in 2016\u0026ndash;2020 [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Montgomery County also exhibited a significantly greater BCI rate compared to the national US (SEER\u0026thinsp;+\u0026thinsp;NPCR) and Ohio \u0026lsquo;Age-Adjusted Incidence Rates\u0026rsquo; for females aged 50\u0026thinsp;+\u0026thinsp;and 65\u0026thinsp;+\u0026thinsp;years (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e) [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]​​. The surrounding counties also have a much higher overall and age-adjusted BCI rates than do the Ohio and US National Rates [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. The reason for the increased incidence of breast cancer in Dayton and surrounding counties should be further investigated.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eInvasive Breast Cancer (All Stages^), 2016\u0026ndash;2020. All Races \u0026ndash; by county [\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e][\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"3\"\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 \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eAge adjusted incidence rate-cases per 100,000\u003c/p\u003e \u003cp\u003e(95% Confidence Interval)\u003c/p\u003e \u003cp\u003eFemale, Ages 50+\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eAge adjusted incidence rate-cases per 100,000\u003c/p\u003e \u003cp\u003e(95% Confidence Interval)\u003c/p\u003e \u003cp\u003eFemale, Ages 65+\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eUS (SEER\u0026thinsp;+\u0026thinsp;NPCR) (1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e340.5 (339.9, 341.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e424.1 (423.0, 425.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOhio (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e351.8 (348.4, 355.2)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e444.4 (438.8, 450.1)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e- Montgomery County (6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c2\"\u003e \u003cp\u003e394.8 (378.3, 411.8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e500.0 (473.5, 527.7)\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThe Dayton 15-year follow-up data continue to support a reduced incidence of invasive breast cancer in patients treated with long-term T or T + A pellet implant therapy, corroborating our 5- and 10-year study results. Testosterone implant therapy was shown to be effective for breast cancer prevention even in areas at increased risk, such as Dayton, Ohio.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eOur prospective observational study results support preclinical [1] and clinical\u003csup\u003e\u0026nbsp;\u003c/sup\u003e[2] experimental data demonstrating that testosterone is protective against invasive breast cancer. It is highly unlikely that T or T + A is causative when a patient receiving therapy is diagnosed with breast cancer. It is imperative that physicians understand the relationship between testosterone therapy and breast cancer risk.\u0026nbsp;\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eSEER: Surveillance Epidemiology and End Results; BCI: breast cancer incidence; \u0026nbsp;p-y: person-years; T: testosterone; T+A: testosterone combined with anastrozole; ER: estrogen receptor; PR: progesterone receptor; HER-2: human epidermal growth factor 2\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003eEthics approval and consent to participate: Informed written consent was obtained from all participants. This prospective study (Testosterone Implants and Incidence of Breast cancer-TIBcaP 0108) was approved in March of 2008 by the Atrium Medical Center’s Institutional Review Board, One Medical Center Dr., Middletown, Ohio.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eConsent for publication: All patients signed a consent allowing for publication.\u003c/p\u003e\n\u003cp\u003eAvailability of data and materials: Statistical data and analyses are included in\u0026nbsp;Additional file 1. Confidential access to primary data including deidentified spreadsheets will be granted upon reasonable request.\u003c/p\u003e\n\u003cp\u003eCompeting interest: RG has a patent issued: Pharmaceutical compositions containing testosterone and an aromatase inhibitor. No financial or other COIs are declared.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFunding: None\u003c/p\u003e\n\u003cp\u003eAuthor contributions: CD and RG designed the study. RG collected the data. RG and DGG participated in analysis of the data. DGG and AP performed the statistical analysis. All authors contributed to writing the manuscript and approved the final manuscript.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAcknowledgments: We would like to thank Jen Dichito M.A. and Michael Glaser-Garbrick B.S., M.S. for their diligent patient follow-up, and mathematical and computer science work. We would like to acknowledge Carlos Rodrigo de Mello Roesler and Darlan Dallacosta for their contributions and review of the manuscript.\u0026nbsp;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eHickey, T. E. et al. The androgen receptor is a tumor suppressor in estrogen receptor\u0026ndash;positive breast cancer. Nat. Med. 2021;27(2): 310\u0026ndash;320.\u003c/li\u003e\n\u003cli\u003eGlaser, R and Dimitrakakis, C. Testosterone Implant Therapy in Women With and Without Breast Cancer: Rationale, Experience, Evidence. Androgens: Clinical Research and Therapeutics. 2021;2(1):94-110.\u003c/li\u003e\n\u003cli\u003eGlaser, R. L. \u0026amp; Dimitrakakis, C. Reduced breast cancer incidence in women treated with subcutaneous testosterone, or testosterone with anastrozole: A prospective, observational study. Maturitas. 2013;76: 342\u0026ndash;349.\u003c/li\u003e\n\u003cli\u003eGlaser, R. L., York, A. E. \u0026amp; Dimitrakakis, C. Incidence of invasive breast cancer in women treated with testosterone implants: A prospective 10-year cohort study. BMC Cancer. 2019; 19: 1271.\u003c/li\u003e\n\u003cli\u003eNational Program of Cancer Registries and Surveillance, Epidemiology, and End Results SEER. United States Department of Health and Human Services, Centers for Disease Control and Prevention. 2022. https://www.cdc.gov/cancer/npcr/index.htm.\u003c/li\u003e\n\u003cli\u003eDepartment of Health, O. Ohio Annual Cancer Report 2023. https://odh.ohio.gov/wps/portal/gov/odh/know-our-programs/ohio-cancer-incidence-.\u003c/li\u003e\n\u003cli\u003eState Cancer Profiles - Incidence Rate Report for Ohio by County. 2020. https://statecancerprofiles.cancer.gov/incidencerates/index.php?stateFIPS=39\u0026amp;areatype=county\u0026amp;cancer=055\u0026amp;race=00\u0026amp;age=136\u0026amp;stage=999\u0026amp;type=incd\u0026amp;sortVariableName=rate\u0026amp;sortOrder=default\u0026amp;output=0#results.\u003c/li\u003e\n\u003cli\u003eState Cancer Profiles - Incidence Rate Report for Ohio by County. 2020 https://statecancerprofiles.cancer.gov/incidencerates/index.php?stateFIPS=39\u0026amp;areatype=county\u0026amp;cancer=055\u0026amp;race=00\u0026amp;age=157\u0026amp;stage=999\u0026amp;type=incd\u0026amp;sortVariableName=rate\u0026amp;sortOrder=default\u0026amp;output=0#results. \u003c/li\u003e\n\u003cli\u003eRoss JS, Slodkowska EA, Symmans WF, Pusztai L, Ravdin PM, Hortobagyi GN. The HER-2 Receptor and Breast Cancer: Ten Years of Targeted Anti\u0026ndash;HER-2 Therapy and Personalized Medicine. The Oncologist. 2009;14:320-368. https://doi.org/10.1634/theoncologist.2008-0230\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Footnote","content":"\u003cp\u003e\u003csup\u003ea.\u0026nbsp;\u003c/sup\u003eSubcutaneous implants are long acting (sustained release) The incidence of breast cancer was reported for a predetermined time frame of 240-days post implantation or 2.5 times the average length of clinical efficacy of 96 days (approximately 3 months), i.e., \u0026lsquo;eligible for analysis\u0026rsquo;. Patients who were adherent to therapy were those who received testosterone pellet implants within the 240-day time frame. Nonadherence indicates \u0026gt;240 days of absence between implant therapies.\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Androgens, Testosterone, Breast Cancer Incidence, Prevention, Dayton, Ohio","lastPublishedDoi":"10.21203/rs.3.rs-4248378/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4248378/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e We previously published 10-year results (from March 2008-March 2018) from the Dayton prospective breast cancer prevention study, which showed a 40% reduction in the incidence of invasive breast cancer in women receiving testosterone or testosterone with anastrozole implant therapy compared to the age-matched Surveillance Epidemiology and End Results (SEER) expected incidence rate. We continued to follow the study subjects on therapy through March 2023.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eThis 10-year prospective cohort study was approved in March 2008, at which time recruitment was initiated. Recruitment was closed in March 2013. Pre- and postmenopausal women who received at least two pellet insertions were eligible for analysis (n=1267). Breast cancer incidence rates are reported as an unadjusted, unweighted value of newly diagnosed cases divided by the sum of the person-time of observation for the at-risk population. The incidence rates on testosterone therapy were compared to age-specific SEER incidence rates and expected local Montgomery County incidence rates (the location of most study patients).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e As of March 1, 2023, a total of 16 (versus 30 expected) eligible patients were diagnosed with invasive breast cancer within 240 days of their last testosterone pellet insert equating to an incidence rate of 189/100000 p-y, which is significantly less than the national SEER expected incidence rate of 355/100000, i.e., a 47% reduction. Interestingly, local incidence rates in Montgomery County are higher than US national averages.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The 15-year follow-up data revealed a reduced incidence of invasive breast cancer with long-term testosterone or testosterone combined with anastrozole implant therapy. Because of the increased incidence of invasive breast cancer in our area, the amount of reduction (benefit) from testosterone therapy may be underestimated using national data/statistics for comparison.\u003c/p\u003e","manuscriptTitle":"Incidence of invasive breast cancer in women treated with testosterone implants: Dayton prospective cohort study, 15-year update","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-17 09:01:23","doi":"10.21203/rs.3.rs-4248378/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"4807769c-44e0-4363-8cb7-37721a656fe5","owner":[],"postedDate":"April 17th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-02-04T09:28:25+00:00","versionOfRecord":[],"versionCreatedAt":"2024-04-17 09:01:23","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4248378","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4248378","identity":"rs-4248378","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}