Occult lymph node metastases and racial disparities in colon cancer outcomes

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，非洲裔美国人在结直肠癌的具体阶段结果上存在既定的差异，结直肠癌是美国第三大最常见的癌症事件，也是美国癌症死亡的第三大原因。事实上，没有转移的非洲裔美国人表现出40%的额外死亡率可归因于种族。导致这些结果上的种族差异的因素，以及量化过度风险的方法，仍未明确。虽然结直肠癌最重要的生存预后指标和治疗反应预测指标是组织学检测到的区域淋巴结中的肿瘤细胞，但约30%的组织学阴性淋巴结（I期、II期、pN0期）患者死于复发性疾病，反映了未分期和隐匿性淋巴结转移未被检测到。最近，在一项前瞻性、多中心、盲法临床试验中，GUCY2C蛋白在正常情况下仅在肠细胞中表达，但在结直肠癌细胞中普遍表达，该蛋白通过定量RT-PCR （qRT-PCR）被临床证实可用于检测预后重要的隐性转移。此外，除了使用隐匿性转移作为分类变量（是/否）之外，通过GUCY2C qRT-PCR分层风险估计的隐匿性肿瘤负担（多少），确定pN0患者接近零风险和>80%风险的不良结果。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性肿瘤负担，与不利的临床结果相关。本研究的工作假设表明，pN0结直肠癌分期特异性结局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，这可以通过GUCY2C qRT-PCR检测到。在这里，我们提出了一项回顾性分析pN0非裔美国人和白种人结肠癌患者超过分期50年，具有确定的临床结果，量化隐匿性转移对结果的种族差异的贡献。本提案将检验GUCY2C qRT-PCR作为分类变量（是/否）的效用，以确定淋巴结隐匿转移导致pN0结肠癌患者因种族导致的过度风险。此外，我们将量化隐性肿瘤负担（多少）对pN0患者结局的种族差异的贡献。总之，淋巴结隐匿性转移性肿瘤细胞对结肠癌分期特异性结局的种族差异的贡献将被定义，包括GUCY2C qRT-PCR的预后模式将被临床验证并定位为翻译，以量化非裔美国人的隐匿性肿瘤负担和过度风险。项目描述：非裔美国人结肠癌的死亡率比白种人高，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。目前的研究考察了通过新的分子技术检测到的隐匿性转移对非洲裔美国人和高加索人结肠癌患者预后的种族差异的贡献。

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.