A Phase I Study of DHEA with Letrozole in ER- Breast Cancer

描述（由申请人提供）：长期目标是为ER和PR阴性乳腺癌患者发现和开发有效、无毒、靶向的激素疗法。大约33%的乳腺癌是ER和PR阴性，这种类型的癌症患者目前没有激素治疗的选择。他们唯一的选择是化疗。本研究项目重点关注表达雄激素受体的ER/ PR阴性乳腺癌患者。雄激素受体存在于大约一半的ER/PR阴性乳腺癌中。这项研究提出了一种新的治疗方法，使用直接抑制肿瘤生长的药物，并准备在临床环境中进行测试。这项I期临床试验将结合雄激素脱氢表雄酮（可作为膳食补充剂）和现有的抗癌药物来曲唑，提供一种针对新型癌细胞靶点的非常规药理和生物干预。对该治疗或随后II期试验的反应将作为开展全国SWOG试验的依据。研究的具体目的是：1。探讨雄激素脱氢表雄酮（DHEA）联合来曲唑的最大耐受剂量和剂量限制毒性。2. 目的：测定脱氢表雄酮与来曲唑联合用药的药动学。3. 将酶免疫法测定的DHEA和DHEAS水平与液相色谱/质谱法测定的水平相关联4。确定当DHEA作为雄激素使用时是否会出现男性化的副作用，如果是的话，在多大的剂量下以及在多大的血清DHEA和DHEAS，睾酮和双氢睾酮水平下发生。5. 确定ER-/PR-/AR+乳腺癌患者是否从DHEA治疗中获得客观反应和/或临床获益。大约33%的乳腺癌同时缺乏ER和PR。由于对传统的激素治疗没有反应，因此被认为对激素不敏感。复发和转移性ER -/ PR -肿瘤患者只能选择接受化疗，因此这组患者迫切需要毒性较小的治疗方案。大约50%的ER-/PR-肿瘤表达雄激素受体（AR），因此可能对基于雄激素的激素治疗有反应。如果成功，本研究将为这类乳腺癌提供第一个有效的激素治疗选择，这将是ER-/PR-乳腺癌治疗的重大进展。

DESCRIPTION (provided by applicant): The long-term objectives are to discover and develop effective, non-toxic, targeted hormone therapies for patients with ER and PR negative breast cancer. Approximately 33% of breast cancers are ER and PR negative and patients with this type of cancer currently have no hormone therapy options. Their only option is chemotherapy. This research project focuses on patients with ER/ PR negative breast cancers that express the androgen receptor. The androgen receptor is present in about half of ER/PR negative breast cancers. This research proposal presents a novel therapeutic approach that uses agents which directly inhibit tumor growth and are ready to be tested in the clinical setting. This Phase I clinical trial will combine the androgen dehydroepiandrosterone, which is available as a dietary supplement, with the established anti-cancer drug letrozole to provide an unconventional pharmacological and biological intervention aimed at a novel cancer cell target. Responses to this treatment or in a subsequent phase II trial will be used as the rationale for conducting a national SWOG trial. The specific aims of the study will be: 1. To determine the maximum tolerable dose and dose limiting toxicity of the androgen dehydroepiandrosterone (DHEA) combined with letrozole. 2. To determine the pharmacokinetics of DHEA combined with letrozole. 3. To correlate DHEA and DHEAS levels clinically measured by enzyme immunoassays with levels measured by liquid chromatography/mass spectrometry 4. To determine whether virilizing side effects occur when DHEA is used as an androgen and, if so, at what dose and at what serum DHEA and DHEAS, testosterone and dihydrotestosterone levels they occur. 5. To determine if patients with ER-/PR-/AR+ breast cancer experience objective responses and/or clinical benefit from treatment with DHEA . Approximately 33% of breast cancers lack both ER and PR. They are considered hormone insensitive, as they do not respond to conventional hormone therapies. Patients with recurrent and metastatic ER -/ PR - tumors have only the option of receive chemotherapy and therefore less toxic treatment options for this group of patients are desperately needed. About 50% of ER-/PR- tumors express the androgen receptor (AR) and therefore may respond to and androgen based hormone therapy. If successful, this study will provide the first effective hormone treatment option for this type of breast cancer, which will be a major advancement in the treatment of ER-/PR- breast cancer.