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Functional Genetic Tests for Breast Cancer Diagnosis

乳腺癌诊断的功能基因检测

基本信息

批准号：
6641026
负责人：
GRANT A. BITTER
金额：
$ 10万
依托单位：
BITTECH, INC.
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-05-01 至 2005-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6641026
关键词：
breast neoplasm /cancer diagnosis diagnosis design /evaluation estrogen receptors functional /structural genomics genetic strain hormone sensitivity /resistance hormone therapy receptor expression reporter genes

项目摘要

DESCRIPTION (provided by applicant): Breast cancer is the most common form of cancer in women in the U.S., occurring in 12% of the female population, and is the leading cause of cancer deaths in women under age 55. Current breast cancer therapy typically involves surgical removal of the tumor, followed by radiation or chemotherapy in an attempt to eliminate any tumor cells remaining after surgery. Approximately 50-70% of breast cancers are classified as estrogen receptor alpha (ER) positive, and these patients are treated with tamoxifen, or the related drug raloxifene. Tamoxifen is a selective estrogen receptor modulator (SERM) that inhibits the growth of estrogen receptor-positive, estradiol-dependent breast cancer cells and has been clearly demonstrated to be an effective post-surgery adjuvant to prevent or delay cancer remission. Because of the effectiveness and low toxicity of tamoxifen, essentially all breast cancers are currently tested for ER status. The current standard diagnostic tests are immunohistochemical (IHC) assays, and approximately 200,000 IHC tests are performed annually in the US on breast tumor biopsies. There is considerable variability of assay conditions and reagents between testing labs, as well as different staining cutoffs used in reporting ER positive status. More importantly, these assays merely measure the presence of the protein. A large number of mutations and splice variants of the ER have been observed in breast tumors, and many of these alterations affect protein function. Loss of function, constitutively active (estradiol independent), increased hormone responsiveness and altered cofactor affinity has all been observed. During Phase I research, functional genetic tests of ER status will be developed that are more quantitative and informative than current IHC assays. With these tests, the responsiveness of the tumor specific ER to estradiol, or other hormones, can be measured and, furthermore, the response of individual ER variants to cofactors can be determined. The increased information generated with these new tests will facilitate prescribing the most appropriate (hormonal) therapy for the particular breast cancer. These improved diagnostics should increase the effectiveness of both currently available therapeutics and those developed in the future by matching ER functional status of the breast cancer to available therapeutic compounds.

描述（由申请人提供）：乳腺癌是美国女性最常见的癌症形式，发生在12%的女性人口中，是55岁以下女性癌症死亡的主要原因。目前的乳腺癌治疗通常涉及手术切除肿瘤，然后进行放射或化疗，以消除手术后残留的任何肿瘤细胞。大约50-70%的乳腺癌被归类为雌激素受体α（ER）阳性，这些患者用他莫昔芬或相关药物雷洛昔芬治疗。他莫昔芬是一种选择性雌激素受体调节剂（SERM），可抑制雌激素受体阳性、雌二醇依赖性乳腺癌细胞的生长，并已被明确证明是一种有效的术后辅助剂，可预防或延迟癌症缓解。由于他莫昔芬的有效性和低毒性，目前基本上所有乳腺癌都进行了ER状态检测。目前的标准诊断测试是免疫组织化学（IHC）测定，在美国每年对乳腺肿瘤活检进行约200，000次IHC测试。检测实验室之间的检测条件和试剂存在相当大的差异，报告ER阳性状态时使用的染色临界值也不同。更重要的是，这些检测仅仅测量蛋白质的存在。在乳腺肿瘤中已经观察到ER的大量突变和剪接变体，其中许多改变影响蛋白质功能。已观察到功能丧失、组成性活性（雌二醇非依赖性）、激素反应性增加和辅因子亲和力改变。在I期研究期间，ER状态的功能性基因检测将被开发，其比当前的IHC检测更具定量性和信息性。通过这些测试，可以测量肿瘤特异性ER对雌二醇或其他激素的反应性，此外，可以确定个体ER变体对辅因子的反应。这些新的测试产生的更多信息将有助于为特定的乳腺癌开出最合适的（激素）治疗处方。这些改进的诊断应该增加目前可用的治疗剂和将来通过将乳腺癌的ER功能状态与可用的治疗化合物相匹配而开发的那些治疗剂的有效性。