KRAS mutations in non-small-cell lung cancer and colorectal cancer: implications for EGFR-targeted therapies

M K H Maus; P P Grimminger; P C Mack; S H Astrow; C Stephens; G Zeger; J Hsiang; J Brabender; M Friedrich; H Alakus; A H Hölscher; P Lara; K D Danenberg; H J Lenz; D R Gandara

doi:10.1016/j.lungcan.2013.11.010

KRAS mutations in non-small-cell lung cancer and colorectal cancer: implications for EGFR-targeted therapies

Lung Cancer. 2014 Feb;83(2):163-7. doi: 10.1016/j.lungcan.2013.11.010. Epub 2013 Nov 21.

Authors

M K H Maus¹, P P Grimminger², P C Mack³, S H Astrow⁴, C Stephens⁴, G Zeger⁵, J Hsiang⁴, J Brabender², M Friedrich⁶, H Alakus⁴, A H Hölscher², P Lara⁷, K D Danenberg⁸, H J Lenz⁷, D R Gandara³

Affiliations

¹ Department of General, Visceral and Tumor Surgery, University of Cologne, Germany; Response Genetics, Inc., Los Angeles, CA, USA. Electronic address: mausman@gmx.at.
² Response Genetics, Inc., Los Angeles, CA, USA.
³ Department of Molecular Biology and Biochemistry, University of California, Davis, Sacramento, USA.
⁴ Department of General, Visceral and Tumor Surgery, University of Cologne, Germany.
⁵ Department of General, Visceral and Tumor Surgery, University of Cologne, Germany; Department of Pathology, Keck School of Medicine, University of Southern California, USA.
⁶ Department of Thoracic, Vascular and Heart Surgery, University of Göttingen, Germany.
⁷ Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, USA.
⁸ Formerly Response Genetics, Inc., Los Angeles, CA, USA.

PMID: 24331409
DOI: 10.1016/j.lungcan.2013.11.010

Abstract

Background: KRAS mutations are associated with diverse biologic functions as well as prognostic and predictive impact in non-small cell-lung cancer (NSCLC) and colorectal cancer (CRC). In CRC, benefit from monoclonal antibody therapies targeting EGFR is generally limited to patients whose tumors have wild-type (WT) KRAS, whereas data suggest that this association is not present for NSCLC. We hypothesized that the unique tobacco-related carcinogenesis of NSCLC results in a divergence of KRAS MT genotype compared with CRC, contributing to differences in outcomes from EGFR-targeted therapies.

Material and methods: Tumor from 2603 patients (838 CRC and 1765 NSCLC) was analyzed for KRAS mutations. DNA was extracted from microdissected formalin-fixed-paraffin-embedded specimens (FFPE) and 7 different base substitutions in codons 12 and 13 of KRAS were determined.

Results: KRAS mutation genotype differed significantly between NSCLC and CRC in frequency (25% vs. 39%; p<0.001), smoking-associated G>T transversions (73% versus 27%; p<0.001), and ratio of transversions to transitions (3.5 vs. 0.79; p<0.001). In NSCLC GLY12Cys mutations, resulting from a codon 12 GGT>TGT substitution, were observed in 44% compared to 10% for CRC. In contrast, codon 12 or 13 GLY>ASP substitutions (resulting in a G>A transition) were more frequent in CRC (42%) compared with NSCLC (21%).

Conclusion: In this large dataset, KRAS mutation patterns are quantitatively and qualitatively distinct between NSCLC and CRC, reflecting in part differences in tobacco-related carcinogenesis. In light of differences in predictive value for EGFR-directed monoclonal antibody therapy and prognosis for specific KRAS mutations between NSCLC and CRC, these data provide an underlying biologic rationale.

Keywords: Colorectal cancer (CRC); EGFR-targeted therapy; KRAS mutations; Molecular genetics; Non-small-cell lung cancer (NSCLC); Personalized medicine; Predictive biomarkers.

Publication types

Comparative Study

MeSH terms

Antibodies, Monoclonal / therapeutic use
Carcinogenesis / genetics
Carcinoma, Non-Small-Cell Lung / genetics*
Carcinoma, Non-Small-Cell Lung / therapy
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / therapy
DNA Mutational Analysis
ErbB Receptors / immunology
Gene Frequency
Genotype
Humans
Lung Neoplasms / genetics*
Lung Neoplasms / therapy
Molecular Targeted Therapy
Mutation / genetics*
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins p21(ras)
Smoking / adverse effects
Smoking / genetics
Treatment Outcome
ras Proteins / genetics*

Substances

Antibodies, Monoclonal
KRAS protein, human
Proto-Oncogene Proteins
EGFR protein, human
ErbB Receptors
Proto-Oncogene Proteins p21(ras)
ras Proteins