PIK3CA, BRAF, and PTEN Status and Benefit from Cetuximab in the Treatment of Advanced Colorectal Cancer-Results from NCIC CTG/AGITG CO.17

Christos Karapetis, Derek Jonker, Manijeh Daneshmand, Jennifer Hanson, Christopher O'Callaghan, Celia Marginean, John Zalcberg, R. Simes, Malcolm Moore, Niall Tebbutt, Timothy Price, Jeremy Shapiro, Nick Pavlakis, Peter Gibbs, Guy van Hazel, U Lee, Rashida Haq, Shakeel Virk, Dongsheng Tu, Ian Lorimer

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    96 Citations (Scopus)

    Abstract

    Purpose: Cetuximab improves survival in patients with K-ras wild-type advanced colorectal cancer. We examined the predictive and prognostic significance of additional biomarkers in this setting, in particular BRAF, PIK3CA, and PTEN. Experimental Design: Available colorectal tumor samples were analyzed from the CO.17 study. BRAF mutations were identified in tumor-derived DNA by direct sequencing and PIK3CA mutations were identified using a high-resolution melting screen with confirmation by sequencing. PTEN expression by immunohistochemistry (IHC) was performed on tissue microarrays. For each biomarker, prognostic and predictive effects were examined using a Cox model with tests for treatment-biomarker interaction. Results: A total of 572 patients with pretreated colorectal cancer were randomly assigned to receive cetuximab or best supportive care (BSC). Of 401 patients assessed for BRAF status, 13 (3.2%) had mutations. Of 407 patients assessed for PIK3CA status, 61 (15%) had mutations. Of 205 patients assessed for PTEN, 148 (72%) were negative for IHC expression. None of BRAF, PIK3CA, or PTEN was prognostic for overall or progression-free survival in the BSC arm. None was predictive of benefit from cetuximab, either in the whole study population or the K-ras wild-type subset. In the K-ras wild-type subgroup, the overall survival adjusted HR according to BRAF mutation status was 1.39 (interaction P = 0.69), PIK3CA mutation status HR = 0.79 (interaction P = 0.63), and PTEN expression HR = 0.75 (interaction P = 0.61). Conclusions: In chemotherapy-refractory colorectal cancer, neither PIK3CA mutation status nor PTEN expression were prognostic, nor were they predictive of benefit from cetuximab. Evaluation of predictive significance of BRAF mutations requires a larger sample size.

    Original languageEnglish
    Pages (from-to)744-753
    Number of pages10
    JournalClinical Cancer Research
    Volume20
    Issue number3
    DOIs
    Publication statusPublished - 2014

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    Karapetis, C., Jonker, D., Daneshmand, M., Hanson, J., O'Callaghan, C., Marginean, C., Zalcberg, J., Simes, R., Moore, M., Tebbutt, N., Price, T., Shapiro, J., Pavlakis, N., Gibbs, P., van Hazel, G., Lee, U., Haq, R., Virk, S., Tu, D., & Lorimer, I. (2014). PIK3CA, BRAF, and PTEN Status and Benefit from Cetuximab in the Treatment of Advanced Colorectal Cancer-Results from NCIC CTG/AGITG CO.17. Clinical Cancer Research, 20(3), 744-753. https://doi.org/10.1158/1078-0432.CCR-13-0606