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Journal of Clinical Oncology, Vol 26, No 13 (May 1), 2008: pp. 2228-2230 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.9186
KRAS Mutation Signature in Colorectal Tumors Significantly Overlaps With the Cetuximab Response SignatureLigue Nationale Contre le Cancer, Paris, France
Institut Gustave Roussy Villejuif, Villejuif, France
Institut Antoine Lacassagne Nice, Nice, France
Université de Bourgogne; Centre Hospitalier Universitaire Dijon, Dijon, France
Université Paris Descartes; Assistance Publique-Hôpitaux de Paris; L'Institut National de la Santé et de la Recherche Médicale U775, Paris, France To the Editor: The mutation of KRAS has been shown to be highly predictive of the response to anti–epidermal growth factor receptor antibody in colorectal cancer.1-3 Recently, a pharmaceutical company generated the expression signature of the response to cetuximab monotherapy in colorectal cancer patients4 (Affymetrix HG U133 plus 2.0 arrays, Santa Clara, CA). After a filtering step, they retained 17,137 probe sets, corresponding to 10,931 distinct HUGO gene symbols, and proposed a list of 2,341 probe sets, corresponding to 1,845 distinct HUGO gene symbols, significantly differentially expressed in tumor tissues of responding and nonresponding patients (t test P value < .05). We hypothesized that there may be a significant overlap between this list and the signature differentiating KRAS wild type and mutant colorectal cancers. To test this hypothesis, we analyzed the expression of 130 colorectal cancers (stage II and III) with Affymetrix HG U133 plus 2.0 arrays. RNA and DNA from these tumors were extracted from frozen tissues before any treatment by chemotherapy or radiotherapy. These tumors were also characterized for KRAS mutation by sequencing (40 mutated, 90 wild type). Using the same 17,137 probe sets analyzed in the Khambata-Ford series,4 we found 1,543 probe sets, corresponding to 1220 distinct HUGO gene symbol, differentially expressed between the mutated and nonmutated tumors (t test P value < .05). We ordered the two gene lists according to the ascending P value of each comparison (ie, responder v nonresponder to cetuximab therapy, and KRAS-mutated and nonmutated patients). We found that the overlap between the two lists was highly significant (Fisher's exact test P values are listed in Table 1). Notably the two top genes of each list are the same, NT5E and PHLDA1 (5'-nucleotidase, ecto [CD73] and pleckstrin homology-like domain, family A, member 1).
We also tested the performance of the top genes of the cetuximab response signature for their ability to separate KRAS wild type from mutant tumors. When selecting the most significant genes from the response signature (P value < 5 x 10–5; 16 probe sets; 13 distinct HUGO gene symbol), and clustering our colorectal cancer Affymetrix data using the corresponding expression profiles, we obtained clusters of samples highly associated to KRAS and BRAF mutation (  2 test P value < 10–5 and 10–4, respectively), showing that these genes are highly discriminant for these two activating mutations of the MAP kinase pathway (Fig 1).
Although the definition of a predictive expression signature using mRNA is an interesting approach, we think that the selection of genes predicting survival or response to anti–epidermal growth factor receptor therapy should take into account the role of KRAS or BRAF mutations, which are easy tumors parameter to determine from DNA. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: Gérard Milano, Merck Lipha Santé (C), Amgen France (C); Pierrre Laurent-Puig, Merck (C), Amgen (C) Stock Ownership: None Honoraria: Gérard Milano, Merck Lipha Santé, Amgen; Pierrre Laurent-Puig, Merck, Amgen Research Funding: Pierrre Laurent-Puig, Merck Lipha Santé, Amgen France Expert Testimony: None Other Remuneration: Valérie Boige, Merck; Gérard Milano, Amgen; Pierrre Laurent-Puig, Amgen
REFERENCES
1. De Roock W, Piessevaux H, De Schutter J, et al: KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol 19:508-515, 2008 2. Di Fiore F, Blanchard F, Charbonnier F, et al: Clinical relevance of KRAS mutation detection in metastatic colorectal cancer treated by Cetuximab plus chemotherapy. Br J Cancer 96:1166-1169, 2007[CrossRef][Medline] 3. Lièvre A, Bachet JB, Le Corre D, et al: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res 66:3992-3995, 2006 4. Khambata-Ford S, Garrett CR, Meropol NJ, et al: Expression of epiregulin and amphiregulin and KRAS mutation status predict disease control in metastatic colorectal cancer patients treated with cetuximab. J Clin Oncol 25:3230-3237, 2007
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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