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（由适用提供）：临床实践中常用的乳腺癌的预后和预测分子标记包括KI67，ER，PR，HER2和有丝分裂指数（MI）。在这些标记中，KI67增殖指数（KI）是一种通用的独立预后标记，MI是当前肿瘤分级系统的组成部分。不幸的是，这些标记尚未获得足够的可重复性和可靠性来准确预测疾病的进展和攻击性。当前可用的临床概率（KI和MI）的风险预测功率有限，是阻止精确患者分层以实现最佳热决策的关键障碍。在诊断病理学中，Ki和Mi基本上是从非重叠的微观领域得出的，并且处于不同的尺度上，由于它们无与伦比且丢失了有价值的信息。我们的目标是将肿瘤的Ki和Mi以相同的测量量表进行，以便更准确地利用其真正的预后潜力并增强肿瘤级的风险预测能力。我们的中心假设预测，低度肿瘤内有丝分裂频率驱动其获得高度侵略性和恶性表型的能力。我们提出了一种新颖的方法来通过定义一个组合的“有丝分裂频率风险指数”（MFRI）来合理整合Ki和Mi，该方法可以用作比MI相比与低度肿瘤相关的转移性风险的更好的临床前代理和预测指标。创新在于通过使用抗KI67和抗磷酸组织酮和抗磷酸组蛋白H3抗体（染色有丝分裂细胞）将Ki和Mi从同一领域提取Ki和Mi，从而收集一层相关信息，从而增强级别的预后能力。我们方法的重要性和影响在于MFRI的广泛临床适用性，这将取代肿瘤分级系统中的MI，并在多种肿瘤类型中可重复可靠地预测转移性风险。我们的新型范式是，在低级肿瘤中，循环细胞中有丝分裂频率（MFRI）比MI更好，这是一个突破性的概念，在早期预测肿瘤行为时具有转化的希望。 AIM 1将涉及对5000名乳腺癌患者的5000例病历的回顾性回顾，以评估不同等级乳腺肿瘤的Ki和MI之间的可变相关性，以及（ii）建立通过平均MI/平均值KI比替换MI的建立，可以提高肿瘤级的预后准确性。 AIM 2将确定大量1级（n = 200）和2级（n = 200）乳腺癌样本的有丝分裂频率风险指数（MFRI），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协助1级肿瘤和2级肿瘤的患者分层为个性化医学的低风险类别来改变与风险预测有关的当前临床实践范例。新型风险指数MFRI可能还可以提供深刻的提示，说明为什么一些低级，无创乳腺癌的癌症转变为具有转移到遥远部位的侵袭性肿瘤。