芳香化酶通过将雄激素催化为雌激素，可促进雌激素受体阳性乳腺癌的发生和发展。依西美坦是目前最常用的甾体类芳香化酶抑制剂，与他莫昔芬或安慰剂相比，可显著降低高风险绝经后女性的乳腺癌发生率和复发率，但是用于乳腺癌预防或术后辅助治疗需要长期坚持每天口服25毫克，大多数女性由于不良反应而难以坚持，故有必要探索预防乳腺癌发生或复发的最小有效剂量。 2023年3月23日，《美国医学会杂志》肿瘤学分册在线发表意大利米兰大学欧洲肿瘤研究院、热那亚大学加列拉医院和斯卡西医院、美国国家癌症研究所、德克萨斯大学MD安德森癌症中心、哥伦比亚大学欧文医学中心、南佛罗里达大学莫菲特癌症中心、挪威卑尔根大学霍克兰医院、英国伦敦大学玛丽王后学院的研究报告，对绝经后女性雌激素受体阳性乳腺癌术前每周3次、每周1次、每天1次口服依西美坦25毫克的有效性和安全性进行了比较。NCI-2015-01821 / MDA2014-04-01 (ClinicalTrials.gov: NCT02598557; EudraCT: 2015-005063-16): Alternative Dosing of Exemestane Before Surgery in Treating Postmenopausal Patients With Stage 0-II Estrogen Positive Breast Cancer (Alternative Dosing of Exemestane in Postmenopausal Women With Stage 0-II ER-Positive Breast Cancer: A Randomized Presurgical Trial) 该国际多中心术前双盲随机对照二期临床试验于2017年2月1日～2019年8月31日从美国和意大利入组绝经后女性0～II期雌激素受体阳性乳腺癌术前患者180例，按1∶1∶1随机分为3组，连续4～6周口服依西美坦25毫克： 主要终点为血清雌二醇浓度变化：首次和末次就诊时采集血液样本，由美国国家癌症研究所集中通过固相萃取液相色谱串联质谱法测定，预设雌二醇非劣效百分比变化界值为-6%。 次要终点包括Ki-67、孕激素受体、性激素结合球蛋白、高密度脂蛋白胆固醇、毒性反应：2020年4月～2021年12月各中心实验室根据诊断活检标本和手术标本，通过免疫组织化学法对组织生物学标志物进行测定；根据美国国家癌症研究所不良事件通用术语标准对毒性反应进行分级。 结果，171例患者完成治疗并提供血液样本，血清雌二醇最小平方平均百分比变化为：- 每周3次（56例）-85%（与每天1次相差-3.6%，97.5%置信下限：-17.8，非劣效P=0.37）
- 每周1次（60例）-60%（与每天1次相差-28.8%，97.5%置信下限：-48.7，非劣效P=0.98）
其中153例患者完成治疗剂量≥80%并提供血液样本，血清雌二醇最小平方平均百分比变化为：- 每周3次（52例）-85%（与每天1次相差+2.0%，97.5%置信下限：-5.6%，非劣效P=0.02）
- 每周1次（54例）-60%（与每天1次相差-21.5%，97.5%置信下限：-31.4，非劣效>0.99）
- 每周3次：-5.0%（与每天1次相比P=0.31）
- 每周1次：-4.0%（与每天1次相比P=0.06）
- 每周3次：-9.0%（与每天1次相比P=0.44）
- 每周1次：-7.0%（与每天1次相比P=0.06）
每周3次与每天1次相比，性激素结合球蛋白、高密度脂蛋白胆固醇水平变化较小。 因此，该研究结果表明，对于绝经后女性0～II期雌激素受体阳性乳腺癌术前完成治疗剂量≥80%的患者，口服依西美坦25毫克每周3次与每天1次相比，血清雌二醇水平降低幅度并不逊色，故有必要进一步开展预防和辅助治疗研究，对不能耐受每天口服依西美坦的女性验证该新方案。 对此，美国堪萨斯大学医学中心发表特邀评论：内分泌治疗降频和非劣效研究设计的挑战。JAMA Oncol. 2023 Mar 23. IF: 33.006Efficacy of Alternative Dose Regimens of Exemestane in Postmenopausal Women With Stage 0 to II Estrogen Receptor-Positive Breast Cancer: A Randomized Clinical Trial.Serrano D, Gandini S, Thomas P, Crew KD, Kumar NB, Vornik LA, Lee JJ, Veronesi P, Viale G, Guerrieri-Gonzaga A, Lazzeroni M, Johansson H, D'Amico M, Guasone F, Spinaci S, Bertelsen BE, Mellgren G, Bedrosian I, Weber D, Castile T, Dimond E, Heckman-Stoddard BM, Szabo E, Brown PH, DeCensi A, Bonanni B.European Institute of Oncology IRCCS, Milan, Italy; Ospedali Galliera, Genoa, Italy; Ospedale Villa Scassi ASL3, Genoa, Italy; The University of Texas MD Anderson Cancer Center, Houston; Columbia University Irving Medical Center, New York, New York; Moffitt Cancer Center, University of South Florida, Tampa; National Cancer Institute, Bethesda, Maryland; Haukeland University Hospital, Bergen, Norway; University of Bergen, Bergen, Norway; Wolfson Institute of Population Health, Queen Mary University of London, London, England, United Kingdom.QUESTION: What is the noninferiority percentage change of serum estradiol with 2 exemestane alternative schedules (25 mg 3 times weekly or once weekly) compared with the standard dose of 25 mg once daily?FINDINGS: In this randomized clinical trial of 180 postmenopausal women with estrogen receptor-positive breast cancer, exemestane, 25 mg, given 3 times weekly was noninferior to a once-daily schedule in reducing circulating estradiol in compliant participants, whereas the once-weekly schedule was less effective. Adverse events were similar in all arms.MEANING: Exemestane, 25 mg, given 3 times weekly in adherent patients was noninferior to the standard daily dose; this reduced schedule should be further studied in prevention studies and in women who do not tolerate the daily dose in the adjuvant setting.IMPORTANCE: Successful therapeutic cancer prevention requires definition of the minimal effective dose. Aromatase inhibitors decrease breast cancer incidence in high-risk women, but use in prevention and compliance in adjuvant settings are hampered by adverse events.OBJECTIVE: To compare the noninferiority percentage change of estradiol in postmenopausal women with estrogen receptor-positive breast cancer given exemestane, 25 mg, 3 times weekly or once weekly vs a standard daily dose with a noninferiority margin of -6%.DESIGN, SETTING, AND PARTICIPANTS: This multicenter, presurgical, double-blind phase 2b randomized clinical trial evaluated 2 alternative dosing schedules of exemestane. Postmenopausal women with estrogen receptor-positive breast cancer who were candidates for breast surgery were screened from February 1, 2017, to August 31, 2019. Blood samples were collected at baseline and final visit; tissue biomarker changes were assessed from diagnostic biopsy and surgical specimen. Biomarkers were measured in different laboratories between April 2020 and December 2021.INTERVENTIONS: Exemestane, 25 mg, once daily, 3 times weekly, or once weekly for 4 to 6 weeks before surgery.MAIN OUTCOMES AND MEASURES: Serum estradiol concentrations were measured by solid-phase extraction followed by liquid chromatography-tandem mass spectrometry detection. Toxic effects were evaluated using the National Cancer Institute terminology criteria, and Ki-67 was assessed by immunohistochemistry.RESULTS: A total of 180 women were randomized into 1 of the 3 arms; median (IQR) age was 66 (60-71) years, 63 (60-69) years, and 65 (61-70) years in the once-daily, 3-times-weekly, and once-weekly arms, respectively. In the intention-to-treat population (n = 171), the least square mean percentage change of serum estradiol was -89%, -85%, and -60% for exemestane once daily (n = 55), 3 times weekly (n = 56), and once weekly (n = 60), respectively. The difference in estradiol percentage change between the once-daily and 3-times-weekly arms was -3.6% (P for noninferiority = .37), whereas in compliant participants (n = 153), it was 2.0% (97.5% lower confidence limit, -5.6%; P for noninferiority = .02). Among secondary end points, Ki-67 and progesterone receptor were reduced in all arms, with median absolute percentage changes of -7.5%, -5.0%, and -4.0% for Ki-67 in the once-daily, 3-times-weekly, and once-weekly arms, respectively (once daily vs 3 times weekly, P = .31; once daily vs once weekly, P = .06), and -17.0%, -9.0%, and -7.0% for progesterone receptor, respectively. Sex hormone-binding globulin and high-density lipoprotein cholesterol had a better profile among participants in the 3-times-weekly arm compared with once-daily arm. Adverse events were similar in all arms.CONCLUSIONS AND RELEVANCE: In this randomized clinical trial, exemestane, 25 mg, given 3 times weekly in compliant patients was noninferior to the once-daily dosage in decreasing serum estradiol. This new schedule should be further studied in prevention studies and in women who do not tolerate the daily dose in the adjuvant setting.TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02598557; EudraCT: 2015-005063-16DOI: 10.1001/jamaoncol.2023.0089JAMA Oncol. 2023 Mar 23. IF: 33.012Reduced-Frequency Endocrine Therapy and Challenges of Noninferiority Study Designs.Fabian CJ, Mudaranthakam DP.University of Kansas Medical Center, Kansas City.DOI: 10.1001/jamaoncol.2023.0085
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