Impact of the specific mutation in KRAS codon 12 mutated tumors on treatment efficacy in patients with metastatic colorectal cancer receiving cetuximab-based first-line therapy: a pooled analysis of three trials

Dominik P Modest; Thomas Brodowicz; Sebastian Stintzing; Andreas Jung; Jens Neumann; Ruediger P Laubender; Janja Ocvirk; Galina Kurteva; Zsuzsanna Papai; Regina Knittelfelder; Thomas Kirchner; Volker Heinemann; Christoph C Zielinski

doi:10.1159/000339534

Impact of the specific mutation in KRAS codon 12 mutated tumors on treatment efficacy in patients with metastatic colorectal cancer receiving cetuximab-based first-line therapy: a pooled analysis of three trials

Oncology. 2012;83(5):241-7. doi: 10.1159/000339534. Epub 2012 Aug 29.

Authors

Dominik P Modest¹, Thomas Brodowicz, Sebastian Stintzing, Andreas Jung, Jens Neumann, Ruediger P Laubender, Janja Ocvirk, Galina Kurteva, Zsuzsanna Papai, Regina Knittelfelder, Thomas Kirchner, Volker Heinemann, Christoph C Zielinski

Affiliation

¹ Department of Medicine III, University Hospital Grosshadern, University of Munich, Munich, Germany. [email protected]

PMID: 22948721
DOI: 10.1159/000339534

Abstract

Purpose: This study investigated the impact of specific mutations in codon 12 of the Kirsten-ras (KRAS) gene on treatment efficacy in patients with metastatic colorectal cancer (mCRC).

Patients: Overall, 119 patients bearing a KRAS mutation in codon 12 were evaluated. All patients received cetuximab-based first-line chemotherapy within the Central European Cooperative Oncology Group (CECOG), AIO KRK-0104 or AIO KRK-0306 trials.

Results: Patients with KRAS codon 12 mutant mCRC showed a broad range of outcome when treated with cetuximab-based first-line regimens. Patients with tumors bearing a KRAS p.G12D mutation showed a strong trend to a more favorable outcome compared to other mutations (overall survival 23.3 vs. 14-18 months; hazard ratio 0.66, range 0.43-1.03). An interaction model illustrated that KRAS p.G12C was associated with unfavorable outcome when treated with oxaliplatin plus cetuximab.

Conclusion: The present analysis suggests that KRAS codon 12 mutation may not represent a homogeneous entity in mCRC when treated with cetuximab-based first-line therapy.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Aged, 80 and over
Antibodies, Monoclonal / administration & dosage
Antibodies, Monoclonal, Humanized
Antineoplastic Combined Chemotherapy Protocols / administration & dosage
Antineoplastic Combined Chemotherapy Protocols / adverse effects
Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
Camptothecin / administration & dosage
Camptothecin / analogs & derivatives
Capecitabine
Cetuximab
Codon / drug effects
Colorectal Neoplasms / drug therapy*
Colorectal Neoplasms / genetics
Colorectal Neoplasms / pathology*
Deoxycytidine / administration & dosage
Deoxycytidine / analogs & derivatives
Drug Administration Schedule
Female
Fluorouracil / administration & dosage
Fluorouracil / analogs & derivatives
Germany
Humans
Irinotecan
Leucovorin / administration & dosage
Male
Middle Aged
Multicenter Studies as Topic
Mutation*
Odds Ratio
Organoplatinum Compounds / administration & dosage
Oxaliplatin
Prognosis
Proto-Oncogene Proteins / drug effects
Proto-Oncogene Proteins / genetics*
Proto-Oncogene Proteins p21(ras)
Randomized Controlled Trials as Topic
Treatment Outcome
ras Proteins / drug effects
ras Proteins / genetics*

Substances

Antibodies, Monoclonal
Antibodies, Monoclonal, Humanized
Codon
KRAS protein, human
Organoplatinum Compounds
Proto-Oncogene Proteins
Oxaliplatin
Deoxycytidine
Capecitabine
Irinotecan
Proto-Oncogene Proteins p21(ras)
ras Proteins
Cetuximab
Leucovorin
Fluorouracil
Camptothecin

Supplementary concepts

Folfox protocol
IFL protocol
capecitabine-irinotecan combination