对于激素受体阳性乳腺癌男性患者，标准内分泌治疗后雌二醇水平变化程度尚不明确，这些变化相关性功能和生活质量尚未得到充分评估。
2021年2月4日，美国医学会旗下《美国医学会杂志》肿瘤学分册在线发表德国乳腺癌研究协作组的MALE研究报告，对男性乳腺癌患者内分泌治疗后的雌二醇水平变化进行了定量分析。
MALE (NCT01638247): A Prospective, Randomised, Multi-centre Phase II Study Evaluating the Adjuvant, Neoadjuvant or Palliative Treatmant With Tamoxifen +/- GnRH Analogue Versus Aromatase Inhibitor + GnRH Analogue in Male Breast Cancer Patients
该多中心随机对照二期临床研究于2012年10月～2017年5月从德国24家乳腺中心入组激素受体阳性乳腺癌男性患者56例，年龄37～83岁，中位61.5岁，按1∶1∶1的比例随机分为三组：他莫昔芬单药、他莫昔芬＋戈舍瑞林或亮丙瑞林、依西美坦＋戈舍瑞林或亮丙瑞林，治疗6个月。主要终点为治疗3个月后雌二醇水平变化。次要终点包括治疗6个月后雌二醇水平变化、其他激素指标、不良反应、性功能、治疗3个月和6个月后生活质量变化。最后1例患者于2017年12月完成6个月治疗。分析数据截至2018年8月24日，并于2018年12月19日完成分析。
结果，其中52例开始治疗，其中3例过早停止治疗，每组各1例。50例患者可评估主要终点。
治疗3个月后，三组患者的雌二醇中位水平显著不同（P<0.001）
他莫昔芬单药组：升高67%（+17.0ng/L）
他莫昔芬瑞林组：降低85%（-23.0ng/L）
依西美坦瑞林组：降低72%（-18.5ng/L）
治疗6个月后，三组患者的雌二醇中位水平显著不同（P<0.001）
他莫昔芬单药组：升高41%（+12ng/L）
他莫昔芬瑞林组：降低61%（-19.5ng/L）
依西美坦瑞林组：降低64%（-17.0ng/L）
他莫昔芬或依西美坦＋戈舍瑞林或亮丙瑞林，与他莫昔芬单药相比，性功能和生活质量显著降低。
因此，该二期随机对照临床研究结果表明，他莫昔芬或芳香酶抑制剂＋促性腺激素释放激素激动剂类似物，与他莫昔芬单药相比，雌二醇水平持续降低，性功能和生活质量也显著降低。
相关链接
JAMA Oncol. 2021 Feb 4. Online ahead of print.
Efficacy of Endocrine Therapy for the Treatment of Breast Cancer in Men: Results from the MALE Phase 2 Randomized Clinical Trial.
Reinisch M, Seiler S, Hauzenberger T, Kamischke A, Schmatloch S, Strittmatter HJ, Zahm DM, Thode C, Furlanetto J, Strik D, Mobus V, Reimer T, Sinn BV, Stickeler E, Marmé F, Janni W, Schmidt M, Rudlowski C, Untch M, Nekljudova V, Loibl S.
Kliniken Essen-Mitte, Essen, Germany; German Breast Group, GBG Forschungs GmbH Neu-Isenburg, Germany; Klinikum St. Marien, Amberg, Germany; MVZ Kinderwunschzentrum Münster, Germany; Elisabeth Krankenhaus Kassel, Germany; Rems-Murr-Klinik-Winnenden, Germany; SRH Wald-Klinikum, Gera, Germany; Amedes MVZ Wagnerstibbe für Laboratoriumsmedizin, medizinische Mikrobiologie und Immunologie, Gottingen, Germany; Endokrinologikum Berlin, Germany; Goethe University of Frankfurt, Germany; Universitatsfrauenklinik Rostock, Germany; Charité - Universitatsmedizin Berlin, Germany; Universitatsfrauenklinik Aachen, Germany; Universitatsfrauenklinik Mannheim, Germany; Universitatsfrauenklinik Ulm, Germany; Universitatsklinikum Mainz, Germany; Evangelisches Krankenhaus Bergisch Gladbach, Germany; Helios-Kliniken Berlin-Buch, Berlin, Germany; Centre for Haematology and Oncology Bethanien, Frankfurt/Main, Germany.
This randomized, multicenter clinical trial assesses changes in estradiol levels in male patients with hormone receptor-positive breast cancer after treatment with aromatase inhibitor plus gonadotropin-releasing hormone analogue, with gonadotropin-releasing hormone analogue plus tamoxifen, or with tamoxifen alone.
QUESTION: How do estradiol levels in male patients with hormone receptor-positive breast cancer change after 3 months of therapy with aromatase inhibitor (AI) plus gonadotropin-releasing hormone analogue (GnRHa) compared with GnRHa plus tamoxifen or tamoxifen alone?
FINDINGS: A total of 52 patients were evaluable in this multicenter, phase 2 randomized clinical trial. There was a profound decrease of estradiol levels in patients receiving tamoxifen plus GnRHa (-85%) vs AI plus GnRHa (-72%), and an increase of estradiol in patients receiving tamoxifen alone (+67%).
MEANING: The combination of AI or tamoxifen with GnRHa significantly decreases the estradiol levels in male patients in contrast to tamoxifen alone after 3 months of therapy.
IMPORTANCE: The extent of changes in estradiol levels in male patients with hormone receptor-positive breast cancer receiving standard endocrine therapies is unknown. The sexual function and quality of life related to those changes have not been adequately evaluated.
OBJECTIVE: To assess the changes in estradiol levels in male patients with breast cancer after 3 months of therapy.
DESIGN, SETTING, AND PARTICIPANTS: This multicenter, phase 2 randomized clinical trial assessed 56 male patients with hormone receptor-positive breast cancer. Patients were recruited from 24 breast units across Germany between October 2012 and May 2017. The last patient completed 6 months of treatment in December 2017. The analysis data set was locked on August 24, 2018, and analysis was completed on December 19, 2018.
INTERVENTIONS: Patients were randomized to 1 of 3 arms: tamoxifen alone or tamoxifen plus gonadotropin-releasing hormone analogue (GnRHa) or aromatase inhibitor (AI) plus GnRHa for 6 months.
MAIN OUTCOMES AND MEASURES: The primary end point was the change in estradiol levels from baseline to 3 months. Secondary end points were changes of estradiol levels after 6 months, changes of additional hormonal parameters, adverse effects, sexual function, and quality of life after 3 and 6 months.
RESULTS: In this phase 2 randomized clinical trial, a total of 52 of 56 male patients with a median (range) age of 61.5 (37-83) years started treatment. A total of 3 patients discontinued study treatment prematurely, 1 in each arm. A total of 50 patients were evaluable for the primary end point. After 3 months the patients' median estradiol levels increased by 67% (a change of +17.0 ng/L) with tamoxifen, decreased by 85% (-23.0 ng/L) with tamoxifen plus GnRHa, and decreased by 72% (-18.5 ng/L) with AI plus GnRHa (P < .001). After 6 months, median estradiol levels increased by 41% (a change of +12 ng/L) with tamoxifen, decreased by 61% (-19.5 ng/L) with tamoxifen plus GnRHa, and decreased by 64% (-17.0 ng/L) with AI plus GnRHa (P < .001). Sexual function and quality of life decreased when GnRHa was added but were unchanged with tamoxifen alone.
CONCLUSIONS AND RELEVANCE: This phase 2 randomized clinical trial found that AI or tamoxifen plus GnRHa vs tamoxifen alone led to a sustained decrease of estradiol levels. The decreased hormonal parameters were associated with impaired sexual function and quality of life.
TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01638247
PMID: 33538790
DOI: 10.1001/jamaoncol.2020.7442
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