Functional Genetic Tests for Breast Cancer Diagnosis

描述(申请人提供)：乳腺癌是美国女性中最常见的癌症形式，发病率为12%，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包括手术切除肿瘤，然后进行放射或化疗，试图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，这些患者接受他莫昔芬或相关药物雷洛昔芬的治疗。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、雌激素依赖的乳腺癌细胞的生长，已被明确证明是预防或延缓癌症缓解的有效术后佐剂。 由于他莫昔芬的有效性和低毒性，目前基本上所有的乳腺癌都要接受ER状态的检测。目前的标准诊断测试是免疫组织化学(IHC)检测，在美国，每年大约有20万例IHC检测乳腺肿瘤活检。不同检测实验室之间的检测条件和试剂有相当大的差异，报告ER阳性状态时使用的染色截止值也不同。更重要的是，这些检测只是测量蛋白质的存在。在乳腺肿瘤中观察到ER的大量突变和剪接变体，其中许多变化影响蛋白质功能。功能丧失、体质活跃(不依赖雌二醇)、激素反应性增强和辅因子亲和力改变都已观察到。 在第一阶段的研究中，将开发出比目前的IHC分析更定量和更有信息量的ER状态的功能遗传学测试。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，可以确定单个ER变异体对辅因子的反应。这些新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(荷尔蒙)疗法。通过将乳腺癌的ER功能状态与可用的治疗化合物进行匹配，这些改进的诊断方法应该会增加目前可用的治疗方法和未来开发的治疗方法的有效性。

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.