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Prognostic Value of BRAF, PI3K, PTEN, EGFR Copy Number, Amphiregulin and Epiregulin Status in Patients with KRAS Codon 12 Wild-Type Metastatic Colorectal Cancer Receiving First-Line Chemotherapy with Anti-EGFR Therapy

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Abstract

Introduction

Mutational analysis of RAS is required for anti-epidermal growth factor receptor (EGFR) treatment for patients with metastatic colorectal cancer (mCRC). However, most patients with KRAS wild-type tumors still do not respond. Other molecules downstream of the EGFR may also play a role in resistance to EGFR therapies.

Objective

Our objective was to investigate the clinical importance of biomarkers in relation to response, progression-free survival, and overall survival in patients with mCRC receiving first-line treatment with anti-EGFR therapy plus chemotherapy.

Methods

We studied the EGFR pathway [EGFR, NRAS, BRAF, PIK3CA, phosphatase and tensin homolog (PTEN), amphiregulin (AREG), and epiregulin (EREG)] in 105 patients with mCRC KRAS codon 12 wild type. We analysed objective response, progression-free survival, and overall survival in molecularly defined subgroups of the patients receiving anti-EGFR therapy plus chemotherapy as first-line treatment.

Results

We found a significant association between RAS wild-type, BRAF wild-type, EREG, and AREG overexpression and response to anti-EGFR therapy (p = 0.003, p = 0.015, p = 0.05, and p = 0.009, respectively). Progression-free survival and overall survival were lower in patients with RAS (p = 0.36 and p ≤ 0.001, respectively) or BRAF (p = 0.003 and p = 0.002, respectively) mutant tumors. Patients with EREG and AREG messenger RNA (mRNA) expression had longer survival than those with low-expression tumors; progression-free survival and overall survival were significant for AREG (p = 0.001 and p = 0.05, respectively). Patients with EGFR amplification tumors responded better to treatment and had better survival rates, although this was not significant. PIK3CA and PTEN were not associated with either response or survival. The multivariate logistic regression model for response showed only BRAF as a significant predictor after adjustment for the other covariates (p = 0.04, odds ratio 8.3, 95 % confidence interval 0.81–86.0).

Conclusions

RAS, BRAF, AREG, and EREG predict for efficacy of first-line anti-EGFR therapy in patients with mCRC.

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Authors and Affiliations

  1. Laboratory of Molecular Oncology, Medical Oncology Department, Hospital Clínico San Carlos, Madrid, Spain

    Patricia Llovet, Inmaculada Bando & Trinidad Caldés

  2. Medical Oncology Department, Fundación Investigación Biomédica, Hospital Clínico San Carlos, c/ Martin Lagos s/n, 28040, Madrid, Spain

    Javier Sastre, Bárbara Sanchíz & Eduardo Díaz-Rubio

  3. Department of Medicine, Facultad de Medicina, Universidad Complutense, Madrid, Spain

    Javier Sastre, Bárbara Sanchíz & Eduardo Díaz-Rubio

  4. Department of Pathology, Hospital Clínico San Carlos, Madrid, Spain

    Julián Sanz Ortega & Milagros Ferrer

  5. Department of Medical Oncology, Hospital Gregorio Marañón, Madrid, Spain

    Pilar García-Alfonso

  6. Department of Medical Oncology, Hospital La Princesa, La Paz, Madrid, Spain

    Olga Donnay

  7. Department of Medical Oncology, Hospital Ramón y Cajal, Madrid, Spain

    Alfredo Carrato

  8. Department of Medical Oncology, Hospital Getafe, Madrid, Spain

    Ana Jiménez

  9. Department of Medical Oncology, Hospital Reina Sofía, Córdoba, Spain

    Enrique Aranda

  10. Department of Medical Oncology, Fundación Jiménez Díaz, Madrid, Spain

    Ana León

  11. Department of Medical Oncology, Hospital 12 de Octubre, Madrid, Spain

    Cristina Grávalos

  12. Department of Medical Oncology, Hospital Alcorcón, Madrid, Spain

    Juan Carlos Cámara

  13. Department of Medical Oncology, Hospital La Paz, Madrid, Spain

    Jaime Feliú

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  1. Patricia Llovet
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Corresponding author

Correspondence to Eduardo Díaz-Rubio.

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Funding

JS, JSO, TC, ED-R, AC and EA belong to Centres affiliated to the Red Tematica de Investigacion Cooperativa (RD12/0036/006, RD12/0036/0038/, RD12/0036/0073), Instituto Carlos III, Spanish Ministry of Economy and Competitivity, Madrid, Spain.

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All authors state they have no conflicts of interest.

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Ethical approval was received from the Comité ético de investigación Clínica Hospital Clínico San Carlos (CEIC), E-09/124.

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Llovet, P., Sastre, J., Ortega, J.S. et al. Prognostic Value of BRAF, PI3K, PTEN, EGFR Copy Number, Amphiregulin and Epiregulin Status in Patients with KRAS Codon 12 Wild-Type Metastatic Colorectal Cancer Receiving First-Line Chemotherapy with Anti-EGFR Therapy. Mol Diagn Ther 19, 397–408 (2015). https://doi.org/10.1007/s40291-015-0165-0

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