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)：本申请涉及广泛的挑战领域(09)：健康差距和预防，以及具体的挑战主题，09-CA-101：癌症发病率差异的基础。与高加索人相比，非裔美国人在特定阶段的结果上存在着明显的差异，结直肠癌是美国第三大常见癌症，也是导致癌症死亡的第三大原因。事实上，没有转移的非裔美国人表现出40%以上的可归因于种族的死亡率。造成这些结果种族差异的因素以及量化过度风险的方法仍未确定。虽然最重要的生存预后指标和治疗反应的预测标志是组织学检测到的区域淋巴结中的肿瘤细胞，但组织学阴性的患者(I、II期；pN0期)中约30%的患者死于复发，反映了未被发现的分期不足和隐匿性的淋巴结转移。最近，在一项前瞻性、多中心、盲法临床试验中，GUCY2C--一种正常仅在肠道细胞表达，但在结直肠癌细胞中普遍表达的蛋白--通过定量RT-PCR(qRT-PCR)在临床上被证实可用于检测预后重要的隐匿性转移。此外，除了将隐匿性转移作为分类变量(是/否)之外，GUCY2C QRT-PCR估计的隐匿性肿瘤负担(多少)具有分层的风险，识别那些几乎为零风险的pN0患者和那些具有80%风险的pN0患者预后不良。重要的是，亚组分析表明，非裔美国人在淋巴结中表现出不成比例的隐匿性肿瘤负担，这与不良的临床结果有关。这里的工作假设表明，pN0结直肠癌不同阶段预后的种族差异在一定程度上反映了淋巴转移不成比例的分期不足和隐匿性转移，这可以通过GUCY2C qRT-PCR检测到。在这里，我们建议对pN0非裔美国人和高加索人结肠癌患者进行回顾性分析，以确定临床结果，以量化隐性转移对预后种族差异的贡献。这项建议将检验GUCY2C qRT-PCR作为一个分类变量(是/否)的效用，以确定淋巴结中的隐匿性转移导致pN0结肠癌患者因种族而产生的额外风险。此外，我们将量化隐匿性肿瘤负担(多少)对pN0患者预后的种族差异的影响。在结论中，将确定淋巴结中的隐匿性转移肿瘤细胞对结肠癌不同阶段预后的种族差异的贡献，并将临床验证和定位为翻译包括GUCY2C qRT-PCR的预后范例，以量化非裔美国人的隐匿性肿瘤负担和额外风险。项目简介：与高加索人相比，患有结肠癌的非裔美国人的死亡率更高，尽管原因尚不清楚。在这种背景下，最近的工作揭示了常规技术无法发现的淋巴结隐匿性转移在确定结肠癌患者疾病复发风险方面的重要性。目前的研究检验了通过新的分子技术检测到的隐性转移对患有结肠癌的非裔美国人和高加索人预后的种族差异的贡献。