Originally published as JCO Early Release 10.1200/JCO.2008.18.0786 on November 10 2008

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Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer

Federica Di Nicolantonio, Miriam Martini, Francesca Molinari, Andrea Sartore-Bianchi, Sabrina Arena, Piercarlo Saletti, Sara De Dosso, Luca Mazzucchelli, Milo Frattini, Salvatore Siena, Alberto Bardelli

From the Laboratory of Molecular Genetics, The Oncogenomics Center, Institute for Cancer Research and Treatment, University of Torino Medical School, Candiolo; The Falck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda; Italian Foundation for Cancer Research–Institute of Molecular Oncology, Milan, Italy; Laboratory of Molecular Diagnostic, Istituto Cantonale di Patologia, Locarno; and Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland

Corresponding author: Alberto Bardelli, PhD, Laboratory of Molecular Genetics, The Oncogenomics Center, Institute for Cancer Research and Treatment, University of Torino, Medical School, Str prov 142 Km 3.95, 10060 Candiolo, Torino, Italy; e-mail: a.bardelli{at}unito.it

Purpose Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value.

Patients and Methods We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC.

Results KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele.

Conclusion BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.

published online ahead of print at www.jco.org on November 10, 2008

Supported by the Italian Association for Cancer Research, Italian Ministry of Health, Regione Piemonte, Italian Ministry of University and Research, Association for International Cancer Research, EU FP6 MCSCs Contract No. 037297, CRT Progetto Alfieri, Oncosuisse Grant No. OCS-01921-08-2006, Fondazione Ticinese per la Ricerca sul Cancro, and Oncologia Ca’ Granda Onlus Fondazione.

F.D.N., M.M., and F.M. contributed equally to this work.

M.F., S.S., and A.B. are co-senior authors.

Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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