Occult lymph node metastases and racial disparities in colon cancer outcomes

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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.

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