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

Wendy De Roock, Bart Claes, David Bernasconi, Jef De Schutter, Bart Biesmans, George Fountzilas, Konstantine T. Kalogeras, Vassiliki Kotoula, Demetris Papamichael, Pierre Laurent-Puig, Frédérique Penault-Llorca, Philippe Rougier, Bruno Vincenzi, Daniele Santini, Giuseppe Tonini, Federico Cappuzzo, Milo Frattini, Francesca Molinari, Piercarlo Saletti, Sara De DossoMiriam Martini, Alberto Bardelli, Salvatore Siena, Andrea Sartore-Bianchi, Josep Tabernero, Teresa Macarulla, Frédéric Di Fiore, Alice Oden Gangloff, Fortunato Ciardiello, Per Pfeiffer, Camilla Qvortrup, Tine Plato Hansen, Eric Van Cutsem, Hubert Piessevaux, Diether Lambrechts, Mauro Delorenzi, Sabine Tejpar

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Abstract

Background: Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era. Methods: 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. Findings: 40·0% (299/747) of the tumours harboured a KRAS mutation, 14·5% (108/743) harboured a PIK3CA mutation (of which 68·5% [74/108] were located in exon 9 and 20·4% [22/108] in exon 20), 4·7% (36/761) harboured a BRAF mutation, and 2·6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6·7% (17/253) versus 35·8% (126/352; odds ratio [OR] 0·13, 95% CI 0·07-0·22; p

Original languageEnglish
Pages (from-to)753-762
Number of pages10
JournalThe Lancet Oncology
Volume11
Issue number8
DOIs
Publication statusPublished - Aug 2010

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Colorectal Neoplasms
Drug Therapy
Mutation
Neoplasms
Exons
Neoplasm Antibodies
DNA
Mutation Rate
Epidermal Growth Factor Receptor
Paraffin
Formaldehyde
Disease-Free Survival
Cetuximab
Mass Spectrometry
Odds Ratio
Survival

ASJC Scopus subject areas

  • Oncology

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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. / De Roock, Wendy; Claes, Bart; Bernasconi, David; De Schutter, Jef; Biesmans, Bart; Fountzilas, George; Kalogeras, Konstantine T.; Kotoula, Vassiliki; Papamichael, Demetris; Laurent-Puig, Pierre; Penault-Llorca, Frédérique; Rougier, Philippe; Vincenzi, Bruno; Santini, Daniele; Tonini, Giuseppe; Cappuzzo, Federico; Frattini, Milo; Molinari, Francesca; Saletti, Piercarlo; De Dosso, Sara; Martini, Miriam; Bardelli, Alberto; Siena, Salvatore; Sartore-Bianchi, Andrea; Tabernero, Josep; Macarulla, Teresa; Di Fiore, Frédéric; Gangloff, Alice Oden; Ciardiello, Fortunato; Pfeiffer, Per; Qvortrup, Camilla; Hansen, Tine Plato; Van Cutsem, Eric; Piessevaux, Hubert; Lambrechts, Diether; Delorenzi, Mauro; Tejpar, Sabine.

In: The Lancet Oncology, Vol. 11, No. 8, 08.2010, p. 753-762.

Research output: Contribution to journalArticle

De Roock, W, Claes, B, Bernasconi, D, De Schutter, J, Biesmans, B, Fountzilas, G, Kalogeras, KT, Kotoula, V, Papamichael, D, Laurent-Puig, P, Penault-Llorca, F, Rougier, P, Vincenzi, B, Santini, D, Tonini, G, Cappuzzo, F, Frattini, M, Molinari, F, Saletti, P, De Dosso, S, Martini, M, Bardelli, A, Siena, S, Sartore-Bianchi, A, Tabernero, J, Macarulla, T, Di Fiore, F, Gangloff, AO, Ciardiello, F, Pfeiffer, P, Qvortrup, C, Hansen, TP, Van Cutsem, E, Piessevaux, H, Lambrechts, D, Delorenzi, M & Tejpar, S 2010, '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', The Lancet Oncology, vol. 11, no. 8, pp. 753-762. https://doi.org/10.1016/S1470-2045(10)70130-3
De Roock, Wendy ; Claes, Bart ; Bernasconi, David ; De Schutter, Jef ; Biesmans, Bart ; Fountzilas, George ; Kalogeras, Konstantine T. ; Kotoula, Vassiliki ; Papamichael, Demetris ; Laurent-Puig, Pierre ; Penault-Llorca, Frédérique ; Rougier, Philippe ; Vincenzi, Bruno ; Santini, Daniele ; Tonini, Giuseppe ; Cappuzzo, Federico ; Frattini, Milo ; Molinari, Francesca ; Saletti, Piercarlo ; De Dosso, Sara ; Martini, Miriam ; Bardelli, Alberto ; Siena, Salvatore ; Sartore-Bianchi, Andrea ; Tabernero, Josep ; Macarulla, Teresa ; Di Fiore, Frédéric ; Gangloff, Alice Oden ; Ciardiello, Fortunato ; Pfeiffer, Per ; Qvortrup, Camilla ; Hansen, Tine Plato ; Van Cutsem, Eric ; Piessevaux, Hubert ; Lambrechts, Diether ; Delorenzi, Mauro ; Tejpar, Sabine. / 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. In: The Lancet Oncology. 2010 ; Vol. 11, No. 8. pp. 753-762.
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abstract = "Background: Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era. Methods: 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. Findings: 40·0{\%} (299/747) of the tumours harboured a KRAS mutation, 14·5{\%} (108/743) harboured a PIK3CA mutation (of which 68·5{\%} [74/108] were located in exon 9 and 20·4{\%} [22/108] in exon 20), 4·7{\%} (36/761) harboured a BRAF mutation, and 2·6{\%} (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6·7{\%} (17/253) versus 35·8{\%} (126/352; odds ratio [OR] 0·13, 95{\%} CI 0·07-0·22; p",
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TY - JOUR

T1 - Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer

T2 - A retrospective consortium analysis

AU - De Roock, Wendy

AU - Claes, Bart

AU - Bernasconi, David

AU - De Schutter, Jef

AU - Biesmans, Bart

AU - Fountzilas, George

AU - Kalogeras, Konstantine T.

AU - Kotoula, Vassiliki

AU - Papamichael, Demetris

AU - Laurent-Puig, Pierre

AU - Penault-Llorca, Frédérique

AU - Rougier, Philippe

AU - Vincenzi, Bruno

AU - Santini, Daniele

AU - Tonini, Giuseppe

AU - Cappuzzo, Federico

AU - Frattini, Milo

AU - Molinari, Francesca

AU - Saletti, Piercarlo

AU - De Dosso, Sara

AU - Martini, Miriam

AU - Bardelli, Alberto

AU - Siena, Salvatore

AU - Sartore-Bianchi, Andrea

AU - Tabernero, Josep

AU - Macarulla, Teresa

AU - Di Fiore, Frédéric

AU - Gangloff, Alice Oden

AU - Ciardiello, Fortunato

AU - Pfeiffer, Per

AU - Qvortrup, Camilla

AU - Hansen, Tine Plato

AU - Van Cutsem, Eric

AU - Piessevaux, Hubert

AU - Lambrechts, Diether

AU - Delorenzi, Mauro

AU - Tejpar, Sabine

PY - 2010/8

Y1 - 2010/8

N2 - Background: Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era. Methods: 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. Findings: 40·0% (299/747) of the tumours harboured a KRAS mutation, 14·5% (108/743) harboured a PIK3CA mutation (of which 68·5% [74/108] were located in exon 9 and 20·4% [22/108] in exon 20), 4·7% (36/761) harboured a BRAF mutation, and 2·6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6·7% (17/253) versus 35·8% (126/352; odds ratio [OR] 0·13, 95% CI 0·07-0·22; p

AB - Background: Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era. Methods: 1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy. Findings: 40·0% (299/747) of the tumours harboured a KRAS mutation, 14·5% (108/743) harboured a PIK3CA mutation (of which 68·5% [74/108] were located in exon 9 and 20·4% [22/108] in exon 20), 4·7% (36/761) harboured a BRAF mutation, and 2·6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6·7% (17/253) versus 35·8% (126/352; odds ratio [OR] 0·13, 95% CI 0·07-0·22; p

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U2 - 10.1016/S1470-2045(10)70130-3

DO - 10.1016/S1470-2045(10)70130-3

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JO - The Lancet Oncology

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