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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, Gary
Zeger4, Afsaneh Barzi1, Heinz-Josef Lenz1
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
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Table 1: ERCC1 mRNA Expression by KRAS/BRAF Mutation Status in Colorectal, Pancreatic, Lung Cancer
KRAS/BRAF Mutation Status
Median ERCC1 Expression (Range)
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.
Colorectal Cancer
KRAS Mutant/
BRAF Wildtype
KRAS Wildtype/
BRAF Wildtype
KRAS Wildtype/
BRAF Mutant
0.89 (0.23-2.96)
N = 263
1.06 (0.17-6.71)
N = 310
0.96 (0.28-3.75)
P < 0.001
Pancreatic Cancer
1.20 (0.36-3.29)
N = 80
P = 0.25
RESULTS
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1.80 (0.87-3.53)
N = 11
Lung Cancer
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.
1.25 (0.28-5.09)
N = 236
Figure 3:
Oncogenic
Activation of
KRAS, BRAF,
MAPK
Pathways
1.39 (0.22-27.31)
N = 614
P = 0.069
Figure 1: ERCC1 mRNA Expression by KRAS
Mutation Status in Colorectal Cancer
Figure 2: ERCC1 mRNA Expression by KRAS
Mutation Status in Pancreatic Cancer
Adapted from:
Nature Reviews
Cancer 4, 718-727
(September 2004)
CONCLUSIONS & DISCUSSION
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OBJECTIVE
Understanding the interactions between the EGFR and
We
tested
whetherpathways
ERCC1 mRNA
expression
correlates
ERCC1
molecular
will help
individualize
cancer
with
KRAS
BRAF
mutation
status
in patients with
therapy
andand
identify
targets
for drug
development.
colorectal, pancreatic, and lung adenocarcinoma.
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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.
Differences in mRNA ERCC1 levels by mutation status
were tested using Wilcoxon two-sample tests.
Mutant KRAS tumors had significantly lower ERCC1
mRNA levels relative to wildtype KRAS 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).
P = 0.006
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METHODS
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Abstract ID: 116082
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REFERENCES
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7.
Neumann, J., et al., Frequency and type of KRAS mutations in routine diagnostic analysis of metastatic colorectal cancer. Pathol Res Pract, 2009. 205(12): p. 858-62.
De Roock, W., et al., Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal
cancer: a retrospective consortium analysis. Lancet Oncol, 2010. 11(8): p. 753-62.
Shirota, Y., et al., ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J
Clin Oncol, 2001. 19(23): p. 4298-304.
Tveit, K.M., et al., Phase III trial of cetuximab with continuous or intermittent fluorouracil, leucovorin, and oxaliplatin (Nordic FLOX) versus FLOX alone in first-line treatment of
metastatic colorectal cancer: the NORDIC-VII study. J Clin Oncol, 2012. 30(15): p. 1755-62.
Maughan, T.S., et al., Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase
3 MRC COIN trial. Lancet, 2011. 377(9783): p. 2103-14.
Eberhard, D.A., et al., Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated
with chemotherapy alone and in combination with erlotinib. J Clin Oncol, 2005 Sep 1;23(25):5900-9.
Moore, M.J., et al., Erlotinib plus gemcitabine compared with gemcitabine alone in patients with advanced pancreatic cancer: a phase III trial of the National Cancer Institute of
Canada Clinical Trials Group. J Clin Oncol, 2007 May 20;25(15):1960-6. Epub 2007 Apr 23.
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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.
CRC patients whose 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 therefore improve
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.