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Analysis of PTEN, BRAF and PI3K status for determination of benefit from cetuximab therapy in metastatic colorectal cancer patients refractory to chemotherapy with wild-type KRAS

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Tumor Biology

Abstract

We investigated predictive values of BRAF, PI3K and PTEN in cetuximab responses in KRAS wild-type (+) chemotherapy refractory, metastatic colorectal cancer (CRC) patients. Primary tumour tissues of 41 KRAS wild-type mCRC patients receiving cetuximab-based chemotherapy were investigated for PI3K, PTEN, KRAS and BRAF mutations. Progression-free survival (PFS) and overall survival (OS) periods were calculated with Kaplan–Meier method and the Cox proportional hazards model was used. PTEN and PI3K expressions were 63 and 42 %, respectively. BRAF mutation was observed as 9.8 % among patients. Tumours with BRAF mutation had statistically lower response rates (RR) for cetuximab-based treatment than tumours with BRAF wild type (0 vs. 58 %, p = 0.02). PTEN expressing tumours had statistically higher RR for cetuximab-based treatment than tumours with PTEN loss (42 vs. 12 %, p = 0.04). PI3K expression had worse significant effect on cetuximab RR than PI3K non-expressed tumours (15 vs. 44 %, p = 0.023). Median PFS was significantly longer in patients with PTEN expression (14 months) than in patients with PTEN loss (5 months) (HR, 0.4; p = 0.028). Median PFS was significantly longer in patients with PI3K non-expression (15.2 months) than in patients with PI3K expression (4.1 months) (HR, 0.31; p = 0.001). Significant difference in PFS and OS between patients with BRAF mutated and BRAF wild-type tumours was not detected. However, patients with PTEN expression had significantly longer OS (15.1 months) than patients with PTEN loss tumour (9.9 months) (HR, 0.34; p = 0.008). Patients without PI3K expression had significantly longer OS (18.2 months) than patients with PI3K expression (10.1 months) (HR, 0.27; p = 0.001). Multivariate analyses revealed that PTEN expression (HR, 0.48; p = 0.02) and absence of PI3K expression (HR, 0.2; p = 0.001) were independent prognostic factors for increased PFS. Similarly, PTEN overexpression (HR, 0.62; p = 0.03) and absence of PI3K expression (HR, 0.27; p = 0.005) were independent prognostic factors for increased OS. In PTEN loss, PI3K expression may be used as biomarkers to further select KRAS wild-type patients undergoing anti-epidermal growth factor receptor treatment.

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Authors and Affiliations

  1. Division of Medical Oncology, Department of Internal Medicine, Akdeniz Medical School, Akdeniz University, 7058, Antalya, Turkey

    Deniz Tural

  2. Department of Pathology, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey

    Sebnem Batur, Sibel Erdamar & Nuray Kepil

  3. Medical student at Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey

    Emre Akar

  4. Division of Medical Oncology, Department of Internal Medicine, Cerrahpasa Medical School, Istanbul University, Istanbul, Turkey

    Nil Molinas Mandel & Süheyla Serdengeçti

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  1. Deniz Tural
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  2. Sebnem Batur
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  3. Sibel Erdamar
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  4. Emre Akar
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Correspondence to Deniz Tural.

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Tural, D., Batur, S., Erdamar, S. et al. Analysis of PTEN, BRAF and PI3K status for determination of benefit from cetuximab therapy in metastatic colorectal cancer patients refractory to chemotherapy with wild-type KRAS. Tumor Biol. 35, 1041–1049 (2014). https://doi.org/10.1007/s13277-013-1138-8

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  • DOI: https://doi.org/10.1007/s13277-013-1138-8

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