Enhancing prognostic power of tumor grade by revisiting Ki67-mitosis relationship

通过重新审视 Ki67-有丝分裂关系增强肿瘤分级的预后能力

• 批准号: 8895609
• 负责人: Ritu Aneja
• 金额: $ 7.4万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8895609
• 关键词: Address; Antibodies; Apple; Behavior; Breast Cancer Patient; Carcinoma; Categories; Cell Cycle; Cells; Clinical; Clinical Trials; Consensus; Cues; Data Set; Decision Making; Diagnostic; Disease; Distant; Drug Targeting; Elements; Estrogen Receptor Status; Failure; Formalin; Frequencies; Generations; Glean; Histology; Hormone Receptor; Hot Spot; Image; Immune; Immunofluorescence Immunologic; In Vitro; Individual; Label; Malignant Neoplasms; Mammary Neoplasms; Measurement; Medical Records; Metastatic to; Methods; Microscopic; Mitosis; Mitotic; Mitotic Cell Cycle; Neoplasm Metastasis; Oranges; Outcome; Paraffin Embedding; Pathologist; Pathology; Patients; Pharmaceutical Preparations; Prognostic Marker; Proliferating; Reporting; Reproducibility; Research Personnel; Risk; S-Phase Fraction; Sampling; Site; Staining method; Stains; Statistical Methods; Stratification; System; Testing; Therapeutic; Tissues; Validation; base; cancer cell; clinical application; clinical practice; cohort; high risk; improved; indexing; innovation; malignant breast neoplasm; malignant phenotype; molecular marker; neoplastic cell; novel; outcome forecast; personalized medicine; prevent; prognostic; public health relevance; tool; trend; tumor

 DESCRIPTION (provided by applicant): Prognostic and predictive molecular markers for breast cancer commonly used in clinical practice include Ki67, ER, PR, Her2, and mitotic index (MI). Of these markers, Ki67 proliferation index (KI), is a universal independent prognostic marker, and MI is an integral element of the current tumor grading system. Unfortunately, these markers have not achieved sufficient reproducibility and reliability to accurately predict disease prognosis and aggressiveness. The limited risk-predictive power of currently-available clinical prognosticators (KI and MI) is the critical barrier preventing accurate patient stratification for optimal therapeutic decision-making. In diagnostic pathology, KI and MI are essentially derived from non-overlapping microscopic fields and are on disparate scales, owing to which they are incomparable and valuable information is lost. Our objective is to bring a tumor's KI and MI on the same measurement scale so as to more accurately harness their true prognostic potential and augment the risk-predictive power of tumor grade. Our central hypothesis predicts that the mitotic frequency within a low-grade tumor drives its ability to acquire highly aggressive and malignant phenotypes. We propose a novel method to rationally integrate KI and MI by defining a combined "Mitotic Frequency Risk Index" (MFRI) which may serve as a better clinical prognosticator and predictor of metastatic risk associated with a low-grade tumor, than MI. Innovation lies in extracting both KI and MI from the same field by co-staining them immune-fluorescently using anti-Ki67 and anti-phosphohistoneH3 antibody (that stains mitotic cells) to glean an extra layer of relevant information that may enhance the prognostic power of grade. The significance and impact of our approach lies in the broad clinical applicability of MFRI, which would replace MI in the tumor grading system and predict metastatic risk reproducibly and reliably in a variety of tumor types. Our novel paradigm that mitotic frequency among cycling cells (MFRI) is a better prognosticator than MI in low-grade tumors is a groundbreaking concept and holds translational promise in early prediction of tumor behavior. AIM 1 will involve a retrospective review of 5000 medical records of breast cancer patients to (i) evaluate the variable correlation between KI and MI across different grades of breast tumors, and (ii) establish that replacement of MI by the mean MI/mean KI ratio improves prognostic accuracy of tumor grade. AIM 2 will determine the Mitotic Frequency Risk Index (MFRI) for a large cohort of Grade 1 (n=200) and Grade 2 (n=200) breast cancer samples and examine its correlation with clinical outcomes. The successful completion of this project may shift current clinical practice paradigms related to risk prognostication by aiding stratification of patients with Grade 1 and 2 tumors into low- and high-risk categories for personalized medicine. It is likely that MFRI, the novel risk index, may also offer insightful cues into why some low-grade, non-invasive breast cancers transform into aggressive tumors that have the ability to metastasize to distant sites.

 描述（申请人提供）：临床实践中常用的乳腺癌预后和预测分子标志物包括Ki67、ER、PR、Her2，其中Ki67增殖指数（KI）是通用的。不幸的是，这些标记物尚未实现足够的可重复性和可靠性来准确预测疾病的预后和侵袭性，但风险预测能力有限。目前可用的临床预测器（KI 和 MI）的数量是阻碍准确患者分层以做出最佳治疗决策的关键障碍。在本质上的诊断病理学中，KI 和 MI 源自不重叠的微观视野，并且具有不同的尺度。我们的目标是将肿瘤的 KI 和 MI 置于同一测量范围内，以便更准确地利用它们的真实预后潜力并增强肿瘤分级的风险预测能力。中心假设预测，低级别肿瘤内的有丝分裂频率驱动其获得高度侵袭性和恶性表型的能力，我们提出了一种通过定义组合的“有丝分裂频率风险指数”（MFRI）来合理整合 KI 和 MI 的新方法。与 MI 相比，它可以作为与低度肿瘤相关的转移风险更好的临床预后指标和预测指标。创新在于通过使用免疫荧光共染色从同一区域提取 KI 和 MI。抗 Ki67 和抗磷酸组蛋白 H3 抗体（对有丝分裂细胞进行染色）收集额外一层相关信息，可能会增强分级的预后能力。我们方法的意义和影响在于 MFRI 的广泛临床适用性，它将取代 MFRI。 MI 在肿瘤分级系统中的应用，并可重复且可靠地预测各种肿瘤类型的转移风险。我们的新范例是，循环细胞有丝分裂频率 (MFRI) 是比 MI 更好的预测指标。 AIM 1 将回顾性审查 5000 份乳腺癌患者的医疗记录，以 (i) 评估不同级别的 KI 和 MI 之间的可变相关性。 (ii) 确定用平均 MI/平均 KI 比率替代 MI 可提高肿瘤分级的预后准确性 AIM 2 将确定大型 1 级队列的有丝分裂频率风险指数 (MFRI)。 (n=200) 和 2 级 (n=200) 乳腺癌样本，并检查其与临床结果的相关性。该项目的成功完成可能会通过帮助对 1 级和 2 级患者进行分层，从而改变当前与风险预后相关的临床实践范式。将肿瘤分为低风险和高风险类别以进行个性化医疗 MFRI（新的风险指数）也可能为为什么一些低级别、非侵袭性乳腺癌转变为具有侵袭性肿瘤的能力提供深刻的线索。转移到远处的部位。