Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab

Wendy De Roock, Derek J. Jonker, Federica Di Nicolantonio, Andrea Sartore-Bianchi, Dongsheng Tu, Salvatore Siena, Simona Lamba, Sabrina Arena, Milo Frattini, Hubert Piessevaux, Eric Van Cutsem, Chris J. O'Callaghan, Shirin Khambata-Ford, John R. Zalcberg, John Simes, Christos S. Karapetis, Alberto Bardelli, Sabine Tejpar

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Abstract

Context: Patients with metastatic colorectal cancer who have KRAS codon 12- or KRAS codon 13-mutated tumors are presently excluded from treatment with the anti-epidermal growth factor receptor monoclonal antibody cetuximab. Objective: To test the hypothesis that KRAS codon 13 mutations are associated with a better outcome after treatment with cetuximab than observed with other KRAS mutations. Design, Setting, and Patients: We studied the association between KRAS mutation status (p.G13D vs other KRAS mutations) and response and survival in a pooled data set of 579 patients with chemotherapy-refractory colorectal cancer treated with cetuximab between 2001 and 2008. Patients were included in the CO.17, BOND, MABEL, EMR202600, EVEREST, BABEL, or SALVAGE clinical trials or received offstudy treatment. Univariate and multivariate analyses, adjusting for possible prognostic factors and data set, were performed. The effect of the different mutations was studied in vitro by constructing isogenic cell lines with wild-type KRAS, p.G12V, or p.G13D mutant alleles and treating them with cetuximab. Main Outcome Measures: The main efficacy end point was overall survival. Secondary efficacy end points were response rate and progression-free survival. Results: In comparison with patients with other KRAS-mutated tumors, patients with p.G13D-mutated tumors (n=32) treated with cetuximab had longer overall survival (median, 7.6 [95% confidence interval {CI}, 5.7-20.5] months vs 5.7 [95% CI, 4.9-6.8] months; adjusted hazard ratio [HR], 0.50; 95% CI, 0.31-0.81; P=.005) and longer progression-free survival (median, 4.0 [95% CI, 1.9-6.2] months vs 1.9 [95% CI, 1.8-2.8] months; adjusted HR, 0.51; 95% CI, 0.32-0.81; P=.004). There was a significant interaction between KRAS mutation status (p.G13D vs other KRAS mutations) and overall survival benefit with cetuximab treatment (adjusted HR, 0.30; 95% CI, 0.14-0.67; P=.003). In vitro and mouse model analysis showed that although p.G12Vmutated colorectal cells were insensitive to cetuximab, p.G13D-mutated cells were sensitive, as were KRAS wild-type cells. Conclusions: In this analysis, use of cetuximab was associated with longer overall and progression-free survival among patients with chemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS-mutated tumors. Evaluation of cetuximab therapy in these tumors in prospective randomized trials may be warranted.

Original languageEnglish
Pages (from-to)1812-1820
Number of pages9
JournalJournal of the American Medical Association
Volume304
Issue number16
DOIs
Publication statusPublished - Oct 27 2010

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Colorectal Neoplasms
Drug Therapy
Mutation
Confidence Intervals
Codon
Disease-Free Survival
Neoplasms
Survival
Cetuximab
Therapeutics
Epidermal Growth Factor Receptor
Multivariate Analysis
Alleles
Monoclonal Antibodies
Outcome Assessment (Health Care)
Clinical Trials
Cell Line

ASJC Scopus subject areas

  • Medicine(all)

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Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. / De Roock, Wendy; Jonker, Derek J.; Di Nicolantonio, Federica; Sartore-Bianchi, Andrea; Tu, Dongsheng; Siena, Salvatore; Lamba, Simona; Arena, Sabrina; Frattini, Milo; Piessevaux, Hubert; Van Cutsem, Eric; O'Callaghan, Chris J.; Khambata-Ford, Shirin; Zalcberg, John R.; Simes, John; Karapetis, Christos S.; Bardelli, Alberto; Tejpar, Sabine.

In: Journal of the American Medical Association, Vol. 304, No. 16, 27.10.2010, p. 1812-1820.

Research output: Contribution to journalArticle

De Roock, W, Jonker, DJ, Di Nicolantonio, F, Sartore-Bianchi, A, Tu, D, Siena, S, Lamba, S, Arena, S, Frattini, M, Piessevaux, H, Van Cutsem, E, O'Callaghan, CJ, Khambata-Ford, S, Zalcberg, JR, Simes, J, Karapetis, CS, Bardelli, A & Tejpar, S 2010, 'Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab', Journal of the American Medical Association, vol. 304, no. 16, pp. 1812-1820. https://doi.org/10.1001/jama.2010.1535
De Roock, Wendy ; Jonker, Derek J. ; Di Nicolantonio, Federica ; Sartore-Bianchi, Andrea ; Tu, Dongsheng ; Siena, Salvatore ; Lamba, Simona ; Arena, Sabrina ; Frattini, Milo ; Piessevaux, Hubert ; Van Cutsem, Eric ; O'Callaghan, Chris J. ; Khambata-Ford, Shirin ; Zalcberg, John R. ; Simes, John ; Karapetis, Christos S. ; Bardelli, Alberto ; Tejpar, Sabine. / Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab. In: Journal of the American Medical Association. 2010 ; Vol. 304, No. 16. pp. 1812-1820.
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title = "Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab",
abstract = "Context: Patients with metastatic colorectal cancer who have KRAS codon 12- or KRAS codon 13-mutated tumors are presently excluded from treatment with the anti-epidermal growth factor receptor monoclonal antibody cetuximab. Objective: To test the hypothesis that KRAS codon 13 mutations are associated with a better outcome after treatment with cetuximab than observed with other KRAS mutations. Design, Setting, and Patients: We studied the association between KRAS mutation status (p.G13D vs other KRAS mutations) and response and survival in a pooled data set of 579 patients with chemotherapy-refractory colorectal cancer treated with cetuximab between 2001 and 2008. Patients were included in the CO.17, BOND, MABEL, EMR202600, EVEREST, BABEL, or SALVAGE clinical trials or received offstudy treatment. Univariate and multivariate analyses, adjusting for possible prognostic factors and data set, were performed. The effect of the different mutations was studied in vitro by constructing isogenic cell lines with wild-type KRAS, p.G12V, or p.G13D mutant alleles and treating them with cetuximab. Main Outcome Measures: The main efficacy end point was overall survival. Secondary efficacy end points were response rate and progression-free survival. Results: In comparison with patients with other KRAS-mutated tumors, patients with p.G13D-mutated tumors (n=32) treated with cetuximab had longer overall survival (median, 7.6 [95{\%} confidence interval {CI}, 5.7-20.5] months vs 5.7 [95{\%} CI, 4.9-6.8] months; adjusted hazard ratio [HR], 0.50; 95{\%} CI, 0.31-0.81; P=.005) and longer progression-free survival (median, 4.0 [95{\%} CI, 1.9-6.2] months vs 1.9 [95{\%} CI, 1.8-2.8] months; adjusted HR, 0.51; 95{\%} CI, 0.32-0.81; P=.004). There was a significant interaction between KRAS mutation status (p.G13D vs other KRAS mutations) and overall survival benefit with cetuximab treatment (adjusted HR, 0.30; 95{\%} CI, 0.14-0.67; P=.003). In vitro and mouse model analysis showed that although p.G12Vmutated colorectal cells were insensitive to cetuximab, p.G13D-mutated cells were sensitive, as were KRAS wild-type cells. Conclusions: In this analysis, use of cetuximab was associated with longer overall and progression-free survival among patients with chemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS-mutated tumors. Evaluation of cetuximab therapy in these tumors in prospective randomized trials may be warranted.",
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TY - JOUR

T1 - Association of KRAS p.G13D mutation with outcome in patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab

AU - De Roock, Wendy

AU - Jonker, Derek J.

AU - Di Nicolantonio, Federica

AU - Sartore-Bianchi, Andrea

AU - Tu, Dongsheng

AU - Siena, Salvatore

AU - Lamba, Simona

AU - Arena, Sabrina

AU - Frattini, Milo

AU - Piessevaux, Hubert

AU - Van Cutsem, Eric

AU - O'Callaghan, Chris J.

AU - Khambata-Ford, Shirin

AU - Zalcberg, John R.

AU - Simes, John

AU - Karapetis, Christos S.

AU - Bardelli, Alberto

AU - Tejpar, Sabine

PY - 2010/10/27

Y1 - 2010/10/27

N2 - Context: Patients with metastatic colorectal cancer who have KRAS codon 12- or KRAS codon 13-mutated tumors are presently excluded from treatment with the anti-epidermal growth factor receptor monoclonal antibody cetuximab. Objective: To test the hypothesis that KRAS codon 13 mutations are associated with a better outcome after treatment with cetuximab than observed with other KRAS mutations. Design, Setting, and Patients: We studied the association between KRAS mutation status (p.G13D vs other KRAS mutations) and response and survival in a pooled data set of 579 patients with chemotherapy-refractory colorectal cancer treated with cetuximab between 2001 and 2008. Patients were included in the CO.17, BOND, MABEL, EMR202600, EVEREST, BABEL, or SALVAGE clinical trials or received offstudy treatment. Univariate and multivariate analyses, adjusting for possible prognostic factors and data set, were performed. The effect of the different mutations was studied in vitro by constructing isogenic cell lines with wild-type KRAS, p.G12V, or p.G13D mutant alleles and treating them with cetuximab. Main Outcome Measures: The main efficacy end point was overall survival. Secondary efficacy end points were response rate and progression-free survival. Results: In comparison with patients with other KRAS-mutated tumors, patients with p.G13D-mutated tumors (n=32) treated with cetuximab had longer overall survival (median, 7.6 [95% confidence interval {CI}, 5.7-20.5] months vs 5.7 [95% CI, 4.9-6.8] months; adjusted hazard ratio [HR], 0.50; 95% CI, 0.31-0.81; P=.005) and longer progression-free survival (median, 4.0 [95% CI, 1.9-6.2] months vs 1.9 [95% CI, 1.8-2.8] months; adjusted HR, 0.51; 95% CI, 0.32-0.81; P=.004). There was a significant interaction between KRAS mutation status (p.G13D vs other KRAS mutations) and overall survival benefit with cetuximab treatment (adjusted HR, 0.30; 95% CI, 0.14-0.67; P=.003). In vitro and mouse model analysis showed that although p.G12Vmutated colorectal cells were insensitive to cetuximab, p.G13D-mutated cells were sensitive, as were KRAS wild-type cells. Conclusions: In this analysis, use of cetuximab was associated with longer overall and progression-free survival among patients with chemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS-mutated tumors. Evaluation of cetuximab therapy in these tumors in prospective randomized trials may be warranted.

AB - Context: Patients with metastatic colorectal cancer who have KRAS codon 12- or KRAS codon 13-mutated tumors are presently excluded from treatment with the anti-epidermal growth factor receptor monoclonal antibody cetuximab. Objective: To test the hypothesis that KRAS codon 13 mutations are associated with a better outcome after treatment with cetuximab than observed with other KRAS mutations. Design, Setting, and Patients: We studied the association between KRAS mutation status (p.G13D vs other KRAS mutations) and response and survival in a pooled data set of 579 patients with chemotherapy-refractory colorectal cancer treated with cetuximab between 2001 and 2008. Patients were included in the CO.17, BOND, MABEL, EMR202600, EVEREST, BABEL, or SALVAGE clinical trials or received offstudy treatment. Univariate and multivariate analyses, adjusting for possible prognostic factors and data set, were performed. The effect of the different mutations was studied in vitro by constructing isogenic cell lines with wild-type KRAS, p.G12V, or p.G13D mutant alleles and treating them with cetuximab. Main Outcome Measures: The main efficacy end point was overall survival. Secondary efficacy end points were response rate and progression-free survival. Results: In comparison with patients with other KRAS-mutated tumors, patients with p.G13D-mutated tumors (n=32) treated with cetuximab had longer overall survival (median, 7.6 [95% confidence interval {CI}, 5.7-20.5] months vs 5.7 [95% CI, 4.9-6.8] months; adjusted hazard ratio [HR], 0.50; 95% CI, 0.31-0.81; P=.005) and longer progression-free survival (median, 4.0 [95% CI, 1.9-6.2] months vs 1.9 [95% CI, 1.8-2.8] months; adjusted HR, 0.51; 95% CI, 0.32-0.81; P=.004). There was a significant interaction between KRAS mutation status (p.G13D vs other KRAS mutations) and overall survival benefit with cetuximab treatment (adjusted HR, 0.30; 95% CI, 0.14-0.67; P=.003). In vitro and mouse model analysis showed that although p.G12Vmutated colorectal cells were insensitive to cetuximab, p.G13D-mutated cells were sensitive, as were KRAS wild-type cells. Conclusions: In this analysis, use of cetuximab was associated with longer overall and progression-free survival among patients with chemotherapy-refractory colorectal cancer with p.G13D-mutated tumors than with other KRAS-mutated tumors. Evaluation of cetuximab therapy in these tumors in prospective randomized trials may be warranted.

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