Guanylyl cyclase C as a biomarker

Abstract

Metastasis is the primary cause of death from colorectal cancer. In that context, overall survival and therapeutic response to adjuvant chemotherapy are most significantly governed by the presence of metastatic tumor cells in regional lymph nodes. Although histopathologic analysis of lymph nodes is central to all colorectal cancer staging paradigms, its prognostic and predictive value is limited. Indeed, up to 30 % of patients with histopathology-negative lymph nodes (pN0) die from metastatic disease, reflected by microscopic lymph node metastases that are overlooked by standard techniques. These occult tumor cells are especially important when considering racial disparities in outcomes in colorectal cancer patients, where blacks with lymph node-negative disease have the largest discrepancies in outcomes, with more than 40 % excess mortality compared to Caucasian patients. However, the predictive impact of tumor cells in regional lymph nodes remains uncertain, and approximately 50 % of colorectal cancer patients with nodal metastases detected by histopathology remain free of recurrent disease. Accurate identification of occult metastases in regional lymph nodes and certifying their value as a prognostic marker of recurrence risk or a predictive marker of response to adjuvant chemotherapy remain to be a challenge in the management of colorectal cancer patients. Guanylyl cyclase C (GUCY2C), a receptor which is normally expressed in intestinal cells, but is universally overexpressed by colorectal cancer cells, has been validated to detect prognostically significant occult metastases using quantitative RT-PCR (RT-qPCR). This biomarker was validated by a prospective, multicenter, blinded clinical trial. In that trial, occult tumor burden estimated across all regional lymph nodes by GUCY2C RT-qPCR predicted clinical outcomes. Specifically, the biomarker was able to distinguish node-negative patients with a low (near zero) risk, from those with >80 % risk of developing disease recurrence. Moreover, there was disproportionately higher occult tumor burden in black patients compared to white ones. This difference is a contributing factor of racial disparities in outcomes in colorectal cancer. The diagnostic paradigm quantifying occult tumor burden using GUCY2C RT-qPCR is positioned to reduce racial disparities in colorectal cancer deaths.