Fast track — ArticlesEffects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis
Introduction
There has been a recent and rapid development in biological agents targeted against components of receptor tyrosine kinase signalling cascades in the treatment of cancer. In the field of metastatic colorectal cancer the use of monoclonal antibodies against the epidermal growth factor receptor (EGFR), such as cetuximab or panitumumab, has been implemented in clinical practice since 2004. Experience with anti-EGFR monoclonal antibodies has been a textbook example of how genetic profiling of individual tumours can lead to personalised medicine. Although initial response rates of about 10% were seen with cetuximab monotherapy in patients with heavily pretreated metastatic colorectal cancer,1 it subsequently became clear that tumours without mutations in codon 12 or 13 of the KRAS gene responded in 13–17% of cases, whereas only 0–1·2% of the KRAS mutant tumours did.2, 3 Although the KRAS wild-type state seems to be a condition for response, most patients with KRAS codon 12 and 13 wild-type tumours do not respond to anti-EGFR monoclonal antibodies.4 Mutations in other downstream effectors of the EGFR signalling pathway, such as BRAF, NRAS, and PI3 kinase, might also have a negative effect on response to anti-EGFR antibodies.5, 6, 7
We designed a study to centrally genotype tumour samples for mutations in four downstream components of the EGFR signalling pathway (KRAS, PIK3CA [which encodes the catalytic subunit of PI3 kinase], BRAF, and NRAS) using high-throughput mass spectrometric mutation profiling in what is, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab and chemotherapy. Since all patients were treated in the pre-KRAS selection era, patients were unselected, avoiding any bias of over-representation or under-representation of molecular subgroups. We aimed to use the results of this mutation profiling to provide a clear picture of the efficacy of cetuximab in metastatic colorectal cancer in the chemotherapy-refractory setting according to the presence or absence of activating mutations in KRAS, PIK3CA, BRAF, and NRAS. We intended that the algorithms we used would help physicians to predict the efficacy of cetuximab before treatment.
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Data collection
European investigators who had published data for series of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab were contacted to provide tumour DNA or one slide of formalin-fixed paraffin-embedded (FFPE) tissue. Clinical data were collected in a standardised format. This retrospective study was undertaken after approval by the local ethics review boards.
1022 tumour DNA samples (73 from fresh-frozen and 949 from FFPE tumour tissue) were gathered from 11
Results
KRAS mutation status could not be assigned to 26 of 773 (3·4%) primary tumour samples with sufficient quality DNA. 40·0% (299/747) harboured a KRAS mutation (webappendix pp 9–10): 36·3% (271/747) in codon 12 or 13, 2·1% (16/747) in codon 61, and 2·0% (15/747) in codon 146. We also identified one codon 59 mutant tumour. Four tumours had a double KRAS mutation (p.G12V+p.G12S, p.A146T+p.Q61L, and twice p.G12V+p.A146T).
PIK3CA mutation status could not be assigned to 30 of 773 (3·9%) samples. 14·5%
Discussion
Following the discovery that mutant KRAS is associated with resistance to anti-EGFR monoclonal antibodies, tumours of all patients with metastatic colorectal cancer are now profiled for seven KRAS codon 12 and 13 mutations before receiving cetuximab or panitumumab.4, 18, 19 However, up to 65% of patients with KRAS wild-type tumours are resistant to anti-EGFR monoclonal antibodies.4 In, to our knowledge, the largest series to date, we studied the effects of not only KRAS, but also of BRAF, NRAS,
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