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

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish
Pages (from-to)5705-5712
Number of pages8
JournalJournal of Clinical Oncology
Volume26
Issue number35
DOIs
Publication statusPublished - Dec 10 2008

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Colorectal Neoplasms
Mutation
panitumumab
Cetuximab
Alleles
Survival
Protein-Serine-Threonine Kinases
Therapeutic Uses
Therapeutics
Epidermal Growth Factor Receptor
Reaction Time
Disease-Free Survival
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. / Di Nicolantonio, Federica; Martini, Miriam; Molinari, Francesca; Sartore-Bianchi, Andrea; Arena, Sabrina; Saletti, Piercarlo; De Dosso, Sara; Mazzucchelli, Luca; Frattini, Milo; Siena, Salvatore; Bardelli, Alberto.

In: Journal of Clinical Oncology, Vol. 26, No. 35, 10.12.2008, p. 5705-5712.

Research output: Contribution to journalArticle

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 2008, 'Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer', Journal of Clinical Oncology, vol. 26, no. 35, pp. 5705-5712. https://doi.org/10.1200/JCO.2008.18.0786
Di Nicolantonio, Federica ; Martini, Miriam ; Molinari, Francesca ; Sartore-Bianchi, Andrea ; Arena, Sabrina ; Saletti, Piercarlo ; De Dosso, Sara ; Mazzucchelli, Luca ; Frattini, Milo ; Siena, Salvatore ; Bardelli, Alberto. / Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer. In: Journal of Clinical Oncology. 2008 ; Vol. 26, No. 35. pp. 5705-5712.
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abstract = "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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T1 - Wild-type BRAF is required for response to panitumumab or cetuximab in metastatic colorectal cancer

AU - Di Nicolantonio, Federica

AU - Martini, Miriam

AU - Molinari, Francesca

AU - Sartore-Bianchi, Andrea

AU - Arena, Sabrina

AU - Saletti, Piercarlo

AU - De Dosso, Sara

AU - Mazzucchelli, Luca

AU - Frattini, Milo

AU - Siena, Salvatore

AU - Bardelli, Alberto

PY - 2008/12/10

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N2 - 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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