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Journal Article

PMID

(19001320)

Authors

Di Nicolantonio F, Martini M, Molinari F, Sartore-Bianchi A, Arena S, Saletti P, De Dosso S, Mazzucchelli L, Frattini M, Siena S, Bardelli A

Title

Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Journal of clinical oncology : official journal of the American Society of Clinical Oncology	26	35	2008 Dec 10	5705-12	J Clin Oncol

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Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	colorectal cancer	resistant	Panitumumab	Clinical Study	Actionable	In a retrospective analysis, metastatic colorectal cancer patients harboring BRAF V600E demonstrated shorter progression-free survival (p=0.0107) and overall survival (p<0.0001) compared to patients with wild-type BRAF following Vectibix (panitumumab) or Erbitux (cetuximab) therapy with or without chemotherapy, and in a preclinical study, colorectal cancer cell lines harboring BRAF V600E were resistant to Vectibix (panitumumab) in culture (PMID: 19001320).	19001320
BRAF V600E	colorectal cancer	resistant	Cetuximab	Clinical Study	Actionable	In a retrospective analysis, metastatic colorectal cancer patients harboring BRAF V600E demonstrated shorter progression-free survival (p=0.0107) and overall survival (p<0.0001) compared to patients with wild-type BRAF following Vectibix (panitumumab) or Erbitux (cetuximab) therapy with or without chemotherapy, and in a preclinical study, colorectal cancer cell lines harboring BRAF V600E were resistant to Erbitux (cetuximab) in culture (PMID: 19001320).	19001320

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