Ovarian Cancer Detection with Blood- and Imaging-Based Biomarkers

卵巢癌的一个中心问题是诊断晚，这导致5年生存率直线下降 低于50%。卵巢癌的症状是模糊的和非特异性的，目前的筛查一般不 有效由于卵巢癌是如此致命，降低风险的输卵管卵巢切除术（RRSO）往往是 建议高危妇女使用;然而，RRSO会对生育和健康产生影响。现在 认为卵巢高级别浆液性癌（HGSC）可能开始于输卵管（FT）， 输卵管上皮内癌（STIC），癌前病变是可检测的转移到 卵巢和腹膜腔发生。我们的初步数据表明，血清中有显着的变化， HGSC病例中的蛋白质生物标志物在诊断前12-84个月。此外，我们还表明， 发生在正常和癌性卵巢和FT的多光谱荧光图像标记中，我们可以 建立一个薄的输卵管镜适合穿越子宫和FT成像和细胞收集。 我们将解决STIC和早期（I/II期）卵巢癌的微创检测未满足的临床需求。 癌目前，没有方法能够检测提前时间超过12个月的卵巢HGSC。 总的来说，我们的工作将满足在尽可能早的阶段检测侵袭性癌症的需要。我们最初 目标人群是希望延迟或避免RRSO的卵巢癌高危女性。我们将联合收割机 使用微创输卵管镜进行光学成像和FT细胞的蛋白质标记物血液筛查 收藏.我们的手术将在一项对接受双侧输卵管切除术的高危妇女的研究中进行测试- 卵巢切除术和子宫切除术，这将使我们能够获得并比较测试结果与金标准 组织学具体目标是： 1)开发和验证检测STIC和早期上皮性卵巢癌的生物标志物。完善 在我们现有的基于截断的算法与新发现的标记，以及开发一个基于速度 生物标记算法在诊断前12-84个月检测疾病的算法将在 一组独立的盲态临床血液样本。 2)开发内窥镜成像和病理学标记。我们将改进我们的原型falloposcope 系统具有更高的分辨率多光谱成像和改进的细胞收集能力。我们将开发 来自FT图像和收集的细胞的成像和核型标记，并进行初步体内研究。 3)制定一个可行的临床策略，早期发现上皮性卵巢癌。一项研究将 在计划RRSO的高风险女性中进行。那些在我们的血液测试中呈阳性的人 在特定目标1中开发的将使他们的组织经历输卵管镜检查。成像和病理组学数据将 用于开发分类器，该分类器将与正常FT、STIC或 隐匿性HGSC

A central problem in ovarian cancer is late diagnosis, which causes the 5-year survival rate to plummet below 50%. Ovarian cancer symptoms are vague and nonspecific, and current screening is generally not effective. Because ovarian cancer is so deadly, risk-reducing salpingo-oophorectomy (RRSO) is often recommended for women at high risk; however, RRSO has fertility and health consequences. It is now believed that ovarian high-grade serous carcinoma (HGSC) may begin in the fallopian tubes (FTs) as serous tubal intraepithelial carcinoma (STIC), and that precancerous changes are detectable before metastasis to the ovary and peritoneal cavity occurs. Our preliminary data indicate that there are significant changes in serum protein biomarkers in HGSC cases 12-84 months prior to diagnosis. Further, we have also shown that changes occur in multispectral fluorescence image markers of normal and cancerous ovaries and FTs, and that we can build a thin falloposcope suitable for traversing the uterus and FT for imaging and cell collection. We will address the unmet clinical need for a minimally invasive test for STIC and early (stage I/II) ovarian cancer. Currently, no methods enable the detection of ovarian HGSC with a lead time of more than 12 months. Overall, our work will meet the need to detect aggressive cancers at the earliest possible stage. Our initial target population is women at high risk for ovarian cancer who wish to delay or avoid RRSO. We will combine blood screening for protein markers with a minimally invasive falloposcopy for optical imaging and FT cell collection. Our procedure will be tested in a study of women at high risk undergoing bilateral salpingo- oophorectomy with hysterectomy, which will enable us to obtain and compare test results to gold standard histology. The specific aims are to: 1) Develop and validate biomarkers that detect STIC and early epithelial ovarian cancer. We will improve upon our existing cut-off based algorithm with newly-discovered markers as well develop a velocity-based biomarker algorithm. The algorithm that detects disease 12-84 months prior to diagnosis will be confirmed in an independent, blinded set of clinical blood samples. 2) Develop endoscopic imaging and pathomics markers. We will improve our prototype falloposcope system with higher resolution multispectral imaging and improved cell collection ability. We will develop imaging and karyometric markers from the FT images and the cells collected, and perform a pilot in vivo study. 3) Develop an actionable clinical strategy for early detection of epithelial ovarian cancer. A study will be performed in women at high risk who are planning a RRSO. Those who test positive from our blood test developed in Specific Aim 1 will have their tissue undergo a falloposcopy. Imaging and pathomics data will be used to develop a classifier, which will be compared to gold standard histology findings of normal FT, STIC, or occult HGSC.