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)：健康差异和预防以及特定挑战主题 09-CA-101：癌症发病率差异的基础。与白人相比，非裔美国人的特定阶段结果存在明显差异，结直肠癌是美国第三大常见癌症，也是癌症死亡的第三大原因。事实上，没有转移的非裔美国人因种族而导致的死亡率高出 40%。导致这些种族结果差异的因素以及量化过度风险的方法仍然不确定。虽然结直肠癌最重要的生存预后标志物和治疗反应的预测标志物是组织学检测到的区域淋巴结中的肿瘤细胞，但约 30% 组织学阴性淋巴结（I、II 期；pN0）的患者死于复发性疾病，反映出分期不足和逃避检测的隐匿性淋巴结转移。最近，在一项前瞻性、多中心、盲法临床试验中，GUCY2C（一种通常表达仅限于肠道细胞，但在结直肠癌细胞中普遍表达的蛋白质）通过定量 RT-PCR (qRT-PCR) 进行了临床验证，可用于检测对预后重要的隐匿性转移。此外，除了隐匿性转移作为分类变量（是/否）的效用之外，GUCY2C qRT-PCR 还评估了隐匿性肿瘤负荷（多少），对风险进行了分层，识别出风险接近零的 pN0 患者，以及不良结果风险 >80% 的患者。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荷，与不利的临床结果相关。这里的工作假设表明，pN0 结直肠癌分期特异性结果的种族差异部分反映了淋巴结中不成比例的分期不足和隐匿性转移，这些转移可以通过 GUCY2C qRT-PCR 检测到。在这里，我们建议对分期超过 5 年的 pN0 非裔美国人和白种人结肠癌患者进行回顾性分析，并确定临床结果，以量化隐匿性转移对结果种族差异的影响。该提案将检查 GUCY2C qRT-PCR 作为分类变量（是/否）的效用，该分类变量可识别淋巴结中的隐匿性转移，从而导致 pN0 结肠癌患者因种族导致的过度风险。此外，我们将量化隐匿性肿瘤负荷（多少）对 pN0 患者结局种族差异的影响。最后，将定义淋巴结中隐匿性转移肿瘤细胞对结肠癌特定阶段结果的种族差异的贡献，并且包括 GUCY2C qRT-PCR 在内的用于量化非裔美国人隐匿性肿瘤负担和过度风险的预后范式将得到临床验证并进行转化。项目叙述：与白种人相比，患有结肠癌的非洲裔美国人的死亡率更高，但原因尚不清楚。在这种情况下，最近的工作揭示了常规技术无法检测到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。目前的研究探讨了通过新分子技术检测到的隐匿性转移对非裔美国人和白种人结肠癌预后的种族差异的影响。