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、靶向激素疗法。大约33%的乳腺癌是ER和PR阴性的，患有这种类型的癌症的患者目前没有激素治疗选择。唯一的选择就是化疗。该研究项目的重点是表达雄激素受体的ER/ PR阴性乳腺癌患者。大约一半的ER/PR阴性乳腺癌中存在雄激素受体。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。本次I期临床试验将联合收割机将作为膳食补充剂的雄激素脱氢表雄酮与已确立的抗癌药物来曲唑相结合，提供一种针对新型癌细胞靶点的非常规药理学和生物学干预。对该治疗或后续II期试验的反应将用作进行国家SWOG试验的依据。本研究的具体目的是：1.目的探讨脱氢表雄酮（DHEA）联合来曲唑的最大耐受量及剂量限制性毒性。2.目的：研究脱氢表雄酮（DHEA）与来曲唑合用的药代动力学。3.将酶免疫测定法临床测量的DHEA和DHEAS水平与液相色谱/质谱法测量的水平相关联4.确定DHEA作为雄激素使用时是否会发生男性化副作用，如果是，在什么剂量和血清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治疗中获得客观缓解和/或临床获益。大约33%的乳腺癌同时缺乏ER和PR。它们被认为是激素不敏感的，因为它们对传统的激素治疗没有反应。复发性和转移性ER -/ PR -肿瘤患者只能选择接受化疗，因此迫切需要针对这类患者的毒性较小的治疗选择。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，这项研究将为这种类型的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.