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阴性的乳腺癌患者发现和开发有效的、无毒的、有针对性的激素疗法。大约33%的乳腺癌是ER和PR阴性的，这类癌症的患者目前没有激素治疗选择。他们唯一的选择就是化疗。这项研究的重点是ER/PR阴性的乳腺癌患者，这些患者表达雄激素受体。雄激素受体存在于大约一半ER/PR阴性的乳腺癌中。这项研究提案提出了一种新的治疗方法，它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。这项第一阶段的临床试验将把雄激素脱氢表雄酮作为一种膳食补充剂，与已有的抗癌药物来曲唑结合起来，提供一种针对一种新的癌细胞靶点的非传统药理和生物干预。对这种治疗或在随后的第二阶段试验中的反应将被用作进行全国SWOG试验的理由。本研究的具体目的是：1.确定雄激素脱氢表雄酮(DHEA)联合来曲唑的最大耐受量和剂量限制毒性。2.测定来曲唑与脱氢表雄酮合用后的药代动力学。3.将酶免疫法测定的DHEA和DHEAS的临床水平与液-质联用法测定的DHEA和DHEAS的水平相关联。4.确定DHEA作为雄激素使用时是否会出现男性化副作用，如果有，在什么剂量和在什么水平的血清中出现DHEA和DHEAS，睾酮和双氢睾酮水平。5.确定ER-/PR-/AR+乳腺癌患者接受脱氢表雄酮(DHEA)治疗是否有客观反应和/或临床受益。大约33%的乳腺癌同时缺乏ER和PR。他们被认为对激素不敏感，因为他们对传统的激素疗法没有反应。复发和转移的ER-/PR-肿瘤患者只有接受化疗的选择，因此迫切需要针对这类患者的毒性较低的治疗方案。大约50%的ER/PR肿瘤表达雄激素受体(AR)，因此可能对以雄激素为基础的激素治疗有反应。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步。

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.