Correlation of KRAS Mutation and Villous Adenoma in Colorectal Adenocarcinoma Guides Pretreatment Screening and Targeted Therapy
H Chen, JA Lefferts, GJ Tsongalis, A Suriawinata. Dartmouth-Hitchcock Medical Center, Lebanon, NH
Background: Cetuximab is an EGFR inhibitor effective in treating advanced colorectal adenocarcinoma (CA). However, patients with downstream mutations, such as KRAS mutants at codon 12 or 13, respond poorly to Cetuximab. KRAS mutations had been previously reported in 16-40% of villous adenoma. In this study, we investigate the presence of KRAS mutations in a large number of colon cases, including villous adenoma.
Design: Archived surgical resection specimens of villous adenoma (n=9), CA arising from villous adenoma (n=10), and CA not otherwise specified (NOS) (n=25) were collected from the Pathology files at DHMC. The patient demography, gross, and histopathological features of these lesions were thoroughly reviewed. DNA was extracted from formalin-fixed paraffin-embedded sections. All of the DNA samples were subjected to a Taqman real-time PCR assay designed to detect one of the seven point mutations commonly seen in KRAS at codons 12 and 13. Two-thirds of the DNA samples were also subjected to PCR sequencing to confirm the real time PCR results.
Results: Patients with CA arising from villous adenoma were predominantly female (F:M 4:1) and patients with CA NOS had a M:F ratio of 1:1. KRAS mutations were found in 7 cases (78%) of villous adenoma and 9 cases (90%) of CA arising from villous adenoma. KRAS mutation was undetectable in CA NOS. Interestingly, all villous adenomas and 9 cases (90%) of CA arising from villous adenoma were grossly polypoid, whereas the gross appearance of CA NOS was predominately ulcerated (15/25, 60%). Furthermore, all cases with KRAS mutation showed villous architecture and no other histologic features were associated with KRAS mutation. KRAS mutations (G12D, G12V, G12C, G12S, and G13D) detected in this study were consistent with previously identified mutations that predicted poor response to Cetuximab treatment.
Conclusions: KRAS mutations have a strong association with grossly polypoid lesions especially those with villous architecture such as villous adenoma and CA with persistent preexisting villous adenoma. Patients with a large villous adenoma that progresses to invasive adenocarcinoma may require pretreatment screening for KRAS mutation as these patients may not respond to Cetuximab.
Tuesday, March 23, 2010 1:00 PM
Poster Session IV # 84, Tuesday Afternoon