Occult lymph node metastases and racial disparities in colon cancer outcomes

结肠癌结果中的隐匿性淋巴结转移和种族差异

• 批准号: 7941015
• 负责人: SCOTT A WALDMAN
• 金额: $ 49.86万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7941015
• 关键词: Address; Adjuvant Chemotherapy; African American; Area; Blinded; Cancer Etiology; Cancer Patient; Caucasians; Caucasoid Race; Cells; Cessation of life; Clinical; Clinical Trials; Colon Carcinoma; Colorectal; Colorectal Cancer; Colorectal Neoplasms; Coupled; Curative Surgery; Detection; Diagnosis; Diagnostic Neoplasm Staging; Disease Outcome; Disease-Free Survival; Distant Metastasis; Epithelial Cells; Excess Mortality; Exhibits; Gastrointestinal tract structure; Goals; Histologic; Histology; Incidence; Intestines; Malignant Neoplasms; Messenger RNA; Methods; Molecular; Neoplasm Metastasis; Nodal; Normal tissue morphology; Nucleic Acids; Outcome; Pathology; Patients; Population; Positioning Attribute; Prevention; Prognostic Marker; Proteins; Race; Recurrence; Recurrent disease; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Stage at Diagnosis; Staging; Subgroup; Techniques; Time; Translations; Tumor Burden; Unfavorable Clinical Outcome; Work; base; burden of illness; cancer cell; chemotherapy; cohort; defined contribution; disorder risk; health disparity; lymph nodes; metastatic colorectal; mortality; neoplastic cell; prognostic; prospective; racial difference; response; response marker; tumor

DESCRIPTION (provided by applicant): This application addresses Broad Challenge Area (09): Health Disparities and Prevention and Specific Challenge Topic, 09-CA-101: The Basis for Differences in Cancer Incidence. There is an established disparity in stage-specific outcomes in African Americans, compared to Caucasians, with colorectal cancer, the 3rd most common incident cancer and the 3rd leading cause of cancer death in the U.S. Indeed, African Americans who are free of metastases exhibit a 40% excess mortality attributable to race. Factors contributing to these racial disparities in outcomes, and methods that quantify excess risk, remain undefined. While the most important prognostic marker of survival and predictive marker of response to therapy in colorectal cancer are tumor cells in regional lymph nodes detected histologically, ~30% of patients with histology-negative nodes (stage I, II; pN0) die of recurrent disease, reflecting under-staging and occult nodal metastases that escape detection. Recently, GUCY2C, a protein whose expression is restricted to intestinal cells normally, but is universally expressed by colorectal cancer cells, was clinically validated for detection of prognostically important occult metastases, by quantitative RT-PCR (qRT-PCR), in a prospective, multicenter, blinded clinical trial. Further, beyond the utility of occult metastases as a categorical variable (yes/no), occult tumor burden (how much) estimated by GUCY2C qRT-PCR stratified risk, identifying pN0 patients with near-zero risk, and those with >80% risk, of unfavorable outcomes. Importantly, subgroup analysis suggests that African Americans exhibit disproportionate occult tumor burden in lymph nodes associated with unfavorable clinical outcomes. The working hypothesis here suggests that racial disparities in stage-specific outcomes in pN0 colorectal cancer, in part, reflect disproportionate under-staging and occult metastases in lymph nodes which can be detected by GUCY2C qRT-PCR. Here, we propose a retrospective analysis of pN0 African American and Caucasian colon cancer patients >5 y beyond staging, with established clinical outcomes, to quantify the contribution of occult metastases to racial disparities in outcomes. This proposal will examine the utility of GUCY2C qRT-PCR as a categorical variable (yes/no) that identifies occult metastases in lymph nodes contributing to excess risk attributable to race in patients with pN0 colon cancer. Moreover, we will quantify the contribution of occult tumor burden (how much) to racial differences in outcomes in pN0 patients. At the conclusion, the contribution of occult metastatic tumor cells in lymph nodes to racial disparities in stage-specific outcomes in colon cancer will be defined, and a prognostic paradigm comprising GUCY2C qRT-PCR to quantify occult tumor burden and excess risk in African Americans will be clinically validated and positioned for translation. PROJECT NARRATIVE: African Americans with colon cancer exhibit increased mortality compared to Caucasians, although the reasons are unknown. In that context, recent work revealed the importance of occult metastases in lymph nodes that are undetected by routine techniques in defining the risk of disease recurrence in patients with colon cancer. The present studies examine the contribution of occult metastases, detected by new molecular techniques, to racial disparities in outcomes in African Americans and Caucasians with colon cancer.

描述（由申请人提供）：此申请解决广泛的挑战领域（09）：健康差异和预防和特定挑战主题，09-CA-101：癌症发病率差异的基础。与高加索人相比，非洲裔美国人的阶段特异性结果存在既定差异40％归因于种族的过剩死亡率。导致这些种族差异的因素以及量化多余风险的方法仍然不确定。虽然结直肠癌的生存期和对治疗反应的预测标志物是在组织学上检测到的区域淋巴结中的肿瘤细胞，但在组织学阴性淋巴结（I期I，II； PN0）中，约有30％的肿瘤细胞死于经常性疾病，反映了逃脱检测的分期和神秘的淋巴结转移。最近，Gucy2c是一种蛋白质，其表达仅限于肠细胞正常的肠道细胞，但由结直肠癌细胞普遍表达，在临床上通过定量RT-PCR（QRT-PCR）在临床上进行了验证，以检测预后重要的可隐匿转移酶，该前瞻性在前多中心，盲目的临床试验。此外，除了神秘转移的效用以外，GUCY2C QRT-PCR分层的风险估计的神秘肿瘤负担（是/否），隐匿性肿瘤负担（多少），识别具有接近零风险的PN0患者，以及具有> 80％风险的PN0患者，不利的结果。重要的是，亚组分析表明，非洲裔美国人在与不利的临床结果相关的淋巴结中表现出不成比例的神秘性肿瘤负担。这里的工作假设表明，PN0结直肠癌的阶段特异性结果中的种族差异部分反映了淋巴结中不成比例的分期差异和隐匿性转移，可以通过GuCy2C QRT-PCR检测到。在这里，我们提出了对PN0非裔美国人和高加索结肠癌患者进行的回顾性分析，该患者的分期超出5 Y，并具有既定的临床结果，以量化神秘转移酶对结果中种族差异的贡献。该提案将研究GuCy2C QRT-PCR作为一个分类变量（是/否）的效用，该变量识别出淋巴结中的神秘转移，这导致PN0结肠癌患者的种族造成过多风险。此外，我们将量化隐匿性肿瘤负担（多少）对PN0患者结果的种族差异的贡献。最后，将定义淋巴结中隐匿性转移性肿瘤细胞对阶段特异性结局中种族差异的贡献，并定义包括GUCY2C QRT-PCR的预后范式，包括gucy2c Qrt-pcr量化非裔美国人的肿瘤负担和多余的风险在临床上进行验证并定位用于翻译。项目叙述：与高加索人相比，患有结肠癌的非裔美国人死亡率增加，尽管原因尚不清楚。在这种情况下，最近的工作揭示了淋巴结中神秘转移的重要性，这些淋巴结中未经常规技术未发现，在定义结肠癌患者疾病复发的风险方面没有发现。本研究研究了由新分子技术检测到的神秘转移酶对非裔美国人和结肠癌高加索人结果的种族差异的贡献。