BACKGROUND

1. Correlation of ERCC1 mRNA expression with KRAS mutation status in colorectal, pancreatic, and lung adenocarcinoma Diana L. Hanna1, Martin K. H. Maus2,3, Craig Stephens3, Peter Philipp Grimminger2, Stephanie H. Astrow3, Dongyun Yang1, Fotios Loupakis1, Jack Hsiang1, GaryZeger4,Afsaneh Barzi1, Heinz-Josef Lenz1 Abstract ID: 116082 1USC Norris Comprehensive Cancer Center, Los Angeles, CA; 2Department of General, Visceral, and Tumor Surgery, University of Cologne, Cologne, Germany; 3Response Genetics, Inc., Los Angeles, CA; 4Keck School of Medicine, Department of Pathology, University of Southern California, Los Angeles, CA BACKGROUND RESULTS Table 1: ERCC1 mRNA Expression by KRAS/BRAF Mutation Status in Colorectal, Pancreatic,Lung Cancer Mutant KRAS tumors had significantly lower ERCC1 mRNA levels relative to wildtypeKRAS tumors in both colorectal (0.89 vs. 1.06; p<0.001) and pancreatic (1.20 vs. 1.80; p=0.006) cancer patients. While mutant KRAS lung tumors showed decreased ERCC1 expression (1.25 vs. 1.39), the trend did not meet significance (p=0.069). Within the colorectal subset, mutant BRAF cancers trended towards less ERCC1 expression than tumors harboring both wildtype KRAS/BRAF genes (0.96 vs. 1.06; p=0.25). KRAS is mutated in about 40% of colorectal cancers; it is the only validated predictive marker used in patients with metastatic CRC1. It is also a negative prognosticator in NSCLC. BRAF missense V600E mutations are present in approximately 10–15% of colorectal cancers, are more common in right-sided colon tumors and are prognostic of decreased tumor response and overall survival2. ERCC1 is a critical enzyme in nucleotide excision repair and is associated with disease response, progression free and overall survival in patients with NSCLC, colorectal, and gastric cancer treated with platinum-based chemotherapy3. Resistance to EGFR-directed antibodies in KRAS-wildtype metastatic colorectal cancer patients may be related to interactions with the concurrent cytotoxic chemotherapy used (e.g. oxaliplatin, fluoropyrimidine)4,5. In NSCLC patients, KRAS mutations predict lack of benefit from platinum-based chemotherapy and worse outcomes in those treated with a combination of platinum agents and EGFR-TKIs6. The EGFR targeted tyrosine kinase inhibitor, erlotinib, in combination with gemcitabine improves survival in patients with metastatic pancreatic cancer7. The role of EGFR antibodies combined with platinum chemotherapy is under investigation. Understanding the interactions between the EGFR and ERCC1 molecular pathways will help individualize cancer therapy and identify targets for drug development. Figure3: Oncogenic Activation of KRAS, BRAF, MAPK Pathways Figure2: ERCC1 mRNA Expression by KRASMutation Status in PancreaticCancer Figure1: ERCC1 mRNA Expression by KRAS Mutation Status in ColorectalCancer Adapted from: Nature Reviews Cancer 4, 718-727 (September 2004) CONCLUSIONS & DISCUSSION This is one of the first reports linking KRAS mutation status with ERCC1 gene expression in colon, pancreatic and lung adenocarcinoma. KRAS mutation status may predict sensitivity to platinum based therapy in colon and pancreatic cancer. Colorectal tumors with either the BRAF or KRAS mutation have decreased ERCC1 expression, relative to those that carry both wildtype genes. CRCpatientswhose tumors have both wildtype BRAF and KRAS genes may have a decreased response to oxaliplatin based regimens. The uniform downregulation of ERCC1 amongst mutant KRAS and BRAF cancers suggests that ERCC1 expression may be driven by MAPK activation. Concomitant use of MEK inhibitors may thereforeimprove the efficacy of oxaliplatin based chemotherapy in patients with mutant KRAS or BRAF tumors. Prospective biomarker driven studies should explore these hypotheses, guide clinical decision making and improve patient outcomes. OBJECTIVE We tested whether ERCC1 mRNA expression correlateswith KRAS and BRAF mutation status in patients with colorectal, pancreatic, and lung adenocarcinoma. METHODS Formalin fixed paraffin embedded tumor specimens from 1,514 patients (573 colorectal; 91 pancreatic; 850 lung) were microdissected; DNA and RNA were extracted. Specifically designed primers and probes were used to detect 7 different base substitutions in codons 12 and 13 of KRAS (GLy12Ala; GLy12Asp; Gly12Arg; Gly12Cys; Gly12Ser; Gly12Val; Gly13Asp) and the V600E BRAF mutation. ERCC1 mRNA expression levels were measured by quantitative RT-PCR in a CLIA approved laboratory. 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