Metastatic disease is the principle cause of death from
colorectal cancer. In that context, the most significant
indicator of overall survival and therapeutic response to
adjuvant chemotherapy is 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, about 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 unrecognized
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 significance 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 defining their value as prognostic markers of recurrence risk and predictive markers of response to
adjuvant chemotherapy remains one challenge in the management of
colorectal cancer patients.
Guanylyl cyclase C (GUCY2C), a receptor which is expressed primarily in intestinal cells normally, but is universally over-expressed by
colorectal cancer cells, has been validated to detect prognostically significant occult
metastases using quantitative RT-PCR (RT-qPCR).
Biomarker validation was achieved through 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, identifying node-negative patients with a low (near zero) risk, and those with >80% risk, of developing disease recurrence. Moreover, there was disproportionately higher occult
tumor burden in black, compared to white, patients which contributes to racial disparities in outcomes in
colorectal cancer. The diagnostic paradigm quantifying occult
tumor burden using GUCY2C qRT-PCR is positioned to reduce racial disparities in
colorectal cancer mortality.