GUCY2C reverse transcriptase PCR to stage pN0 colorectal cancer patients

Abstract

The most important prognostic marker of survival and predictive marker of response to adjuvant chemotherapy in colon cancer patients is tumor cells in regional lymph nodes. Despite their importance, standard techniques to assess nodal metastases remain imperfect, as approximately 30% of patients with histology-negative lymph nodes (pN0) die of recurrent disease, reflecting occult metastases that escape detection. These observations highlight the clinical need for novel, accurate approaches to detect occult lymph node metastases in patients with colon cancer. GUCY2C is a biomarker whose expression normally is restricted to intestinal cells, but is near universally overexpressed by colorectal cancer cells. Recently, a prospective, multicenter, blinded clinical trial demonstrated for the first time that the prognostic utility of GUCY2C quantitative reverse transcriptase (qRT)-PCR to detect occult lymph node metastases in pN0 colorectal cancer patients. Molecular staging revealed that approximately 13% of pN0 patients were free of tumor cells, while approximately 87% had GUCY2C results that suggested occult metastases. The presence of occult lymph node metastases was the strongest independent predictor of time to recurrence and disease-free survival. These observations establish the utility of molecular detection of occult lymph node metastases for estimating prognostic risk in pN0 colorectal cancer patients. Advancing this molecular diagnostic into staging paradigms in clinical laboratories will require validation in independent patient populations, definition of the relationship between the quantity of occult tumor metastases and risk, and determination of the utility of GUCY2C qRT-PCR to identify pN0 patients who might benefit from adjuvant chemotherapy.

Keywords::

• colorectal cancer
• guanylyl cyclase c
• GUCY2C
• lymph node
• metastatic disease
• predictive marker
• prognostic marker
• quantitative reverse transcriptase PCR
• staging

Financial & competing interests disclosure

Scott A Waldman is a paid consultant to Merck, and the Chair (uncompensated) of the Scientific Advisory Board of Targeted Diagnostics and Therapeutics, Inc., which provided research funding that, in part, supported this study and which has a license to commercialize inventions related to this work. David S Weinberg is a shareholder in Targeted Diagnostics and Therapeutics, Inc. This work was supported by funding from the National Institutes of Health (CA75123, CA95026 to Scott A Waldman and CA112147 to Terry Hyslop) and Targeted Diagnostic & Therapeutics, Inc. (to Scott A Waldman). Alex Mejia was enrolled in the NIH-supported institutional K30 Training Program In Human Investigation (K30 HL004522) and was supported by NIH institutional award T32 GM08562 for Postdoctoral Training in Clinical Pharmacology. Scott A Waldman is the Samuel MV Hamilton Endowed Professor. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.