A Circulating Biomarker for use in Monitoring Metastatic Breast Cancer

转移性乳腺癌患者的成本效益和微创监测 在疾病的临床治疗中，进展或对治疗的反应是一个未得到满足的需求。成象 目前，技术是此类监测的黄金标准。然而，有争议的是关于 所需的成像类型和频率。成像昂贵、耗时，检测疾病变化的速度很慢 并引发了人们对反复辐射暴露的担忧，而且保险并不总是涵盖这些费用。 在标准中使用了互补的成像方法，如循环肿瘤细胞和生物标记物 护理(SOC)，尽管它们的应用仍然有限。一种简单、经济实惠的血液测试来测量这种水平 作为疾病侵袭性驱动因素的生物标记物应该为实时 监测治疗反应，减少对MBC人群中成像的依赖。私家侦探已经确认 一个88 kDa的糖蛋白GP88(原颗粒蛋白)，阐明了其作为自分泌生长和存活的生物学活性 因素。GP88由癌细胞分泌，在乳腺癌患者体内可在较高水平的生物液中检测到 患者与健康个体相比。基于这些特征，一种创新的诊断测试(酶 建立了检测循环中GP88的免疫分析-EIA法。我们的SBIR第一阶段回顾研究 证实了EIA检测的血清GP88水平与客观的 疾病测量，即101例MBC患者的RECIST 1.1。我们确定血清GP88水平为56 ng/毫升 是一个分层点，低于这个点，患者的总存活率有所提高，而服用GP88&>56 ng/ml的患者 结果很糟糕。我们表明，血清GP88水平与治疗反应在统计上相关 与SOC生物标记物CA15-3不同，CA15-3仅与疾病的进展有关 疾病。基于这些有希望的数据，我们建议进行SBIR第二阶段前瞻性纵向研究 通过每月测量血清GP88水平，在两个临床地点招募120名MBC患者，为期15个月 每3个月进行一次影像检查。目标是验证阶段1的结果，并建立 GP88检测在监测MBC患者疾病进展/应答中的预测性应用 对此类患者进行成像和辅助临床治疗。具体地说，我们将(1)验证血清GP88 水平与成像结果定义的疾病反应/进展相关；(2)检查 连续的高(56 ng/毫升)和低(56 ng/毫升)血中GP88水平对未来反应/进展和时间的影响 按照成像结果定义的进展；(3)验证持续低(&lt；56 ng/mL)GP88的患者 与持续高(&gt；56 ng/mL)GP88血液的患者相比，患者的存活率有所提高 级别。第二阶段的结果将是建立临床数据，以支持GP88 EIA的商业化 作为MBC患者临床管理的一个组成部分，将有助于改善对MBC患者的护理 降低了成本。

Cost-effective and minimally invasive monitoring of metastatic breast cancer (MBC) patients for disease progression or response to therapy is an unmet need in the clinical management of the disease. Imaging technologies are currently the gold standard of such monitoring. However, there is controversy regarding the type & frequency of imaging required. Imaging is expensive, time consuming, slow to detect disease changes and raises concern about repeated radiation exposure and costs are not always covered by insurance. Complementary approaches to imaging such as circulating tumor cells and biomarkers are used in the Standard of Care (SOC), although their application remains limited. A simple, cost-effective blood test to measure the level of biomarkers which are drivers of the disease aggressiveness should provide novel solutions for real-time monitoring of therapy response and reduce dependency on imaging in the MBC population. The PI has identified an 88kDa glycoprotein GP88 (progranulin), elucidated its biological activity as an autocrine growth & survival factor. GP88 is secreted from cancer cells and measurable in biological fluids at higher levels in breast cancer patients, compared to healthy individuals. Based on these characteristics, an innovative diagnostic test (Enzyme Immunoassay – EIA) to measure GP88 in circulation was established. Our SBIR Phase 1 retrospective study demonstrated a statistical association between serum GP88 levels measured by the EIA test and objective measures of disease, i.e. RECIST 1.1 in 101 MBC patients. We established that a serum GP88 level of 56ng/mL was a stratification point below which patients have improved overall survival while patients with GP88>56 ng/ml have a poor outcome. We showed that serum GP88 levels were statistically correlated to response to therapy in addition to progression of disease unlike the SOC biomarker CA15-3 which is only associated to progression of disease. Based on these promising data, we are proposing an SBIR Phase 2 prospective longitudinal study over a 15-month period enrolling 120 MBC patients at two clinical sites by measuring serum GP88 level every month with imaging performed every 3 months. The objectives are to validate the findings of phase 1 and establish the predictive use of the GP88 test in monitoring MBC patients for disease progression/ response as an adjunct to imaging and aid in the clinical management of such patients. Specifically, we will (1) Validate that serum GP88 levels are correlated to disease response/ progression as defined by imaging results; (2) Examine the impact of successive high (>56ng/mL) and low (<56ng/mL) GP88 blood levels on future response/ progression and time to progression as defined by imaging results; (3) Validate that patients with consistent low (<56ng/mL) GP88 blood levels, have improved survival compared with patients with consistently high (>56ng/mL) GP88 blood levels. The outcomes of this phase 2 will be to establish clinical data to support commercialization of GP88 EIA as an integral part of clinical management of MBC patients that will contribute to improved care of MBC patients at reduced cost.