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In Reply

Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ

The correspondence by de Reynies et al raises an important point with respect to the distinctness of KRAS status and gene expression levels. As reflected in the title of our recent article, "Expression of Epiregulin and Amphiregulin and KRAS Mutation Status Predict Disease Control in Metastatic Colorectal Cancer Patients Treated With Cetuximab,"¹ we have addressed the issue of the predictive value of KRAS. Indeed, it is presented as one of the key findings. Specifically, we have shown that the disease control (complete responder, partial responder, stable disease) population in our study is significantly enriched for patients whose tumors are characterized by wild-type KRAS status relative to the nonresponder population. As such, it is not unexpected that overlap exists between sets of genes that are associated with disease control after cetuximab treatment and sets of genes that are differentially expressed as a function of KRAS status.

More importantly, however, the exclusive use of either KRAS status or gene expression profiles (as defined in our article) does not result in the selection of identical patient populations likely to benefit from treatment with cetuximab. For example, we find that patients with wild-type KRAS tumors are much more likely to experience disease control than those exhibiting mutations of KRAS. However, within this KRAS wild-type population, patients whose tumors express high levels of amphiregulin (AREG) or epiregulin (EREG) are likely to experience disease control, whereas patients whose tumors express low levels of these genes are not (Figs 1A and 1B). Similarly, the population of patients whose tumors are classified as both KRAS wild-type and high expressers of either AREG or EREG shows improved progression-free survival relative to populations that lack either or both of these characteristics (Figs 2A and 2B).

View larger version (14K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 1. Best clinical response, KRAS status, and gene expression from Khambata-Ford et al.1 (A) KRAS status and EREG expression are plotted for the 70 patients for whom results were available. Patients with wild-type KRAS status are randomly distributed within the left two quadrants; patients with mutant KRAS are randomly distributed within the right two quadrants. EREG expression values are plotted on the logarithmic y-axis, with a horizontal line representing the median expression level. Patients who experienced disease control are indicated in blue (DC); those who experienced progressive disease or who died before their first radiographic assessment are indicated in yellow (PD). (B) Results for AREG expression are shown as in (A).

View larger version (13K): [in this window] [in a new window] [PowerPoint Slide for Teaching]   Fig 2. Progression-free survival, KRAS status, and gene expression. Kaplan-Meier curves are shown for four groups as defined by KRAS status (wild-type [WT] or mutant [MT]) and EREG or AREG expression (classified as high or low relative to median gene expression level). (A) Median times to progression for MT/low EREG, WT/low EREG, MT/high EREG, and WT/high EREG groups are 59, 56, 59.5, and 123 days, respectively (P =.001, df = 3). (B) Median times to progression for MT/low AREG, WT/low AREG, MT/high AREG, and WT/high AREG groups are 59, 56, 59.5, and 156 days, respectively (P <.0001, df = 3).

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: Christopher T. Harbison, Bristol-Myers Squibb (C); David J. Mauro, Bristol-Myers Squibb (C); Edwin A. Clark, Bristol-Myers Squibb (C); Shirin Khambata-Ford, Bristol-Myers Squibb (C) Consultant or Advisory Role: None Stock Ownership: David J. Mauro, Bristol-Myers Squibb; Edwin A. Clark, Bristol-Myers Squibb; Shirin Khambata-Ford, Bristol-Myers Squibb Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None

REFERENCE

1. 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[Abstract/Free Full Text]

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Related Correspondence

• KRAS Mutation Signature in Colorectal Tumors Significantly Overlaps With the Cetuximab Response Signature
  Aurélien de Reyniès, Valérie Boige, Gérard Milano, Jean Faivre, and Pierre Laurent-Puig
  JCO 2008 26: 2228-2230 [Full Text]

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