Prevalence of DNA Biomarkers in Fecal Immunochemical Test Positive and Negative Colorectal Cancers: Presidential Poster

Abstract

Introduction: While fecal immunochemical test (FIT) screening identifies the majority of patients with asymptomatic colorectal cancer (CRC), the addition of stool DNA biomarkers to FIT has been shown to significantly improve the CRC detection rate. This study’s objective was to determine if DNA biomarker expression by CRCs detected through a FIT-positive result differs from that of CRCs where FIT was falsely negative (FIT-negative). Methods: This study was conducted in the Kaiser Permanente Northern California CRC screening program in patients who were 50-77 years old on the date of diagnosis with CRC between 2009 and 2010 and had received a FIT (OC FIT CHEK, Polymedco) in the 24-month period prior to the diagnosis date. We selected a total of 251 FIT-positive patients and matched them 1:1 to FIT-negative patients on age (in 5-year intervals), sex, and tumor stage. Colorectal neoplasia-associated DNA biomarkers were assessed on DNA isolated from formalin-fixed, paraffin-embedded CRC tissue, blinded to FIT positivity status, using quantitative allele specific real-time target and signal amplification (QuARTS) assays for KRAS mutations and aberrant methylation (NDRG4 and BMP3). Patients whose tissue blocks could not be analyzed were excluded from the analysis. DNA biomarker expression in FIT-positive CRCs was compared to those of FIT-negative CRCs using the Chi-square test. Results: Four hundred ninety CRC patients had tissue available (239 FIT-positive, 251 FIT-negative); the average age was 65.0 years (range: 55-77 years), 51.3% were female, and 67.4% were of white race. About 58.1% of tumors were diagnosed at localized stage and 73.2% were moderately differentiated. These characteristics were similar between the FIT-positive and FIT-negative CRCs. However, the 2 groups differed in CRC location: the majority of FIT-positive CRCs (59.8%) was in the distal colon while most FITnegative CRCs (51.4%) were in the proximal colon (p<0.01). Overall, 87.7% of CRCs expressed at least 1 DNA biomarker; the majority (83.9%) expressed aberrant NDRG4 or BMP3 methylation, and 38.1% had a KRAS mutation. When the methylation markers were considered separately, 78.4% of CRCs were positive for NDRG4 and 58.4% for BMP3. Slightly more FIT-negative than FIT-positive CRCs expressed DNA biomarkers, but the differences were not statistically significant (p=0.29-0.74). Conclusion: Colorectal neoplasia associated DNA biomarkers were present in the majority of CRCs, both in those detected and undetected by FIT screening. Our findings provide a potential biological basis for increased CRC detection observed when DNA biomarkers are combined with FIT. Disclosure - Rebecca Oldham-Haltom, Hatim Allawi, Graham P. Lidgard, and Barry M. Berger are employees of Exact Sciences.