BRAF wild-type is required for response to panitumumab or cetuximab in metastatic colorectal cancer
Federica Di Nicolantonio,1,* Miriam Martini,1,* Francesca Molinari,2,* Andrea Sartore-Bianchi,3 Sabrina Arena,1 Piercarlo Saletti,4 Sara De Dosso,
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Luca
Mazzucchelli,2,4 Milo Frattini,2† Salvatore Siena,3† and Alberto Bardelli1,5† 1
Laboratory of Molecular Genetics, The Oncogenomics Center, Institute for
Cancer Research and Treatment (IRCC), University of Torino Medical School, Candiolo, Italy; 2Laboratory of Molecular Diagnostic, Istituto Cantonale di Patologia, Locarno, Switzerland; 3The Falck Division of Medical Oncology, Ospedale Niguarda Ca’ Granda, Milan, Italy; 4Oncology Institute of Southern Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland; and 5FIRC Institute of Molecular Oncology (IFOM), Milan, Italy
* These authors equally contributed to this work † Co-Senior authors
RESEARCH SUPPORT: This work was supported by grants from Italian Association for Cancer Research (AIRC), Italian Ministry of Health, Regione Piemonte, Italian Ministry of University and Research, Association for International Cancer Research (AICR-UK), EU FP6 MCSCs contract 037297, CRT Progetto Alfieri, Oncosuisse grant OCS-01921-08-2006, Fondazione Ticinese per la Ricerca sul Cancro (Tessin Foundation for Cancer Research), and OCGO (Oncologia Ca’ Granda Onlus) Fondazione.
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Address correspondence to: Milo Frattini PhD Laboratory of Molecular Diagnostic, Institute of Pathology, Via in Selva, 24 6600 Locarno, Switzerland
[email protected]
Salvatore Siena MD Divisione Oncologia Falck Ospedale Niguarda Ca’ Granda Piazza Ospedale Maggiore 3 20162 Milan, Italy
[email protected]
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 (TO), Italy
[email protected]
Financial Disclosures: None
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RUNNING HEAD: BRAF mutations and response to cetuximab or panitumumab
ABBREVIATIONS: IHC, immunohistochemistry; mCRC, metastatic colorectal cancer; MoAb, Monoclonal Antibody; MSI, microsatellite instability; NR, non responder; OS, overall survival; PD, progressive disease; PFS, progressionfree survival; PR, partial response; RECIST, response evaluation criteria in solid tumors; SD, stable disease.
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Abstract
Purpose Cetuximab or panitumumab are effective in 10-20% unselected metastatic colorectal cancer (mCRC) patients. KRAS mutations account for about 30-40% of the non-responsive cases. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wildtype patients, BRAF mutations could have a predictive/prognostic value. Patients and Methods We retrospectively analyzed objective tumor responses, time to progression, overall survival and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated mCRC 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 11/79 patients who had wild-type KRAS. None of the BRAF mutated patients responded to treatment, while none of the responders carried BRAF mutations (P=.029). BRAF mutated patients had significantly shorter progression-free survival (PFS) (P=.011) and overall survival (OS) (P
