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EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetuximab

  • Original Article - Cancer Research
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Abstract

Introduction

Cetuximab is a monoclonal epidermal growth factor receptor (EGFR)-targeting antibody, used in the treatment of colon cancer. KRAS mutation status is strongly predictive of cetuximab efficacy, but more predictive factors are needed for better patient selection. PTEN is a downstream inhibitor of the EGFR pathway and has been evaluated as a predictive factor of cetuximab efficacy in colorectal cancer.

Patients and methods

Formalin-fixed paraffin-embedded tumor tissue samples were collected from 226 patients with advanced or metastatic colorectal cancer that had been treated with cetuximab. Clinical information was collected retrospectively from the patients’ medical records. After central evaluation, 147 cases with adequate material were eligible for further evaluation. EGFR and PTEN status was evaluated with immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). Data were associated with cetuximab treatment outcome. Additional analysis was performed with previously published data on PIK3CA, BRAF and KRAS mutation status and EGFR ligand amphiregulin (AREG) and epiregulin intratumoral mRNA expression levels. PIK3CA mutation status and PTEN protein expression were also analyzed as a single complex parameter, to evaluate the predictive value of PI3K/PTEN axis dysfunction as one entity.

Results

Analysis showed a borderline association of overall response rate (ORR) and time to progression (TTP) with EGFR protein overexpression by IHC (p = 0.059 and p = 0.057, respectively) and a positive association of EGFR gain by FISH (found in only five cases) with longer TTP (p = 0.026). No association was found between ORR or TTP and PTEN IHC or FISH status. Comparative analysis with previously published data showed that PTEN protein expression is associated with longer TTP in patients with wild-type (WT) KRAS (p = 0.036) and especially in the ones with elevated AREG levels (p = 0.046), as well as in patients with both KRAS and BRAF WT (p = 0.019). Patients with both PIK3CA WT and PTEN protein expression had significantly longer TTP (p = 0.010) versus all others, in the absence of BRAF and KRAS mutations, a finding which persisted in the KRAS WT/AREG high subgroup (p = 0.046).

Conclusions

In this cetuximab-treated colorectal cancer population, EGFR gain was associated with better outcome and PTEN protein expression with longer TTP in KRAS WT, KRAS WT/AREG high and KRAS/BRAF WT subpopulations. Cetuximab efficacy is greater with intact and activated EGFR signaling, without activating mutations of KRAS/BRAF and in the presence of preserved PTEN inhibitory activity upon the PI3K/AKT pathway. These results reflect a solid biological rationale and warrant further evaluation of the predictive role of PTEN in prospective studies.

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Acknowledgments

We would like to thank Ms. Thalia Spinari for tissue collection, Ms. Dimitra Katsala for monitoring the study and Ms. Maria Moschoni for coordinating the data management. The study was supported by a Hellenic Cooperative Oncology Group grant HER_6ER/05.

Conflict of interest

The authors declare that they have no conflicts of interest, that they have full control of all primary data and that they agree to allow the journal to review their data if requested.

Ethical standard

The translational research protocol was approved by the Institutional Review Board (IRB) of “Papageorgiou” Hospital in Thessaloniki (Protocol # 193) and “Hygeia” Hospital in Athens, Greece, under the general title “Association of PTEN and EGFR with cetuximab response in colorectal cancer” and has therefore been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. Waiver of consent was obtained from the IRB for patients included in the study before 2005. All patients included in the study after 2005 provided written informed consent for the provision of biological material for future research studies, before receiving any treatment.

Author information

Authors and Affiliations

  1. Third Department of Medical Oncology, “Hygeia” Hospital, Athens, Greece

    Evangelia Razis & George Rigakos

  2. Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

    George Pentheroudakis

  3. Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

    Mattheos Bobos & Eleftheria Tsolaki

  4. Health Data Specialists Ltd, Athens, Greece

    George Kouvatseas

  5. Department of Pathology, Metaxas Cancer Hospital, Piraeus, Greece

    Olympia Tzaida

  6. Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece

    Thomas Makatsoris

  7. Department of Medical Oncology, “Hippokration” Hospital, Athens, Greece

    Pavlos Papakostas

  8. Department of Pathology, Ioannina University Hospital, Ioannina, Greece

    Maria Bai & Anna Goussia

  9. Third Department of Medical Oncology, “Agii Anargiri” Cancer Hospital, Athens, Greece

    Epaminontas Samantas

  10. Bank of Cyprus Oncology Center, Nicosia, Cyprus, Greece

    Demetrios Papamichael

  11. Department of Medical Oncology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki School of Medicine, Thessaloniki, Greece

    Ourania Romanidou, Konstantine T. Kalogeras & George Fountzilas

  12. Department of Pathology, “Papageorgiou” Hospital, Thessaloniki, Greece

    Ioannis Efstratiou

  13. Division of Oncology, Second Department of Internal Medicine, Attikon University Hospital, Athens, Greece

    Amanda Psyrri

  14. Department of Oncology, Ziekenhuis Oost-Limburg, Genk, Belgium

    Wendy De Roock

  15. First Department of Medical Oncology, “Metropolitan” Hospital, Piraeus, Greece

    Dimitrios Bafaloukos

  16. Second Department of Medical Oncology, “Metropolitan” Hospital, Piraeus, Greece

    George Klouvas

  17. Centre for Human Genetics, KU Leuven, Louvain, Belgium

    Sabine Tejpar

  18. Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece

    Konstantine T. Kalogeras

  19. Oncology Section, Second Department of Internal Medicine, “Hippokration” Hospital, Athens, Greece

    Dimitrios Pectasides

  20. First Department of Medical Oncology, Hygeia Hospital, Er. Stavrou and Kifissias Av., 151 23, Maroussi, Athens, Greece

    Evangelia Razis

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  1. Evangelia Razis
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  2. George Pentheroudakis
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  3. George Rigakos
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  19. George Klouvas
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  21. Konstantine T. Kalogeras
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  22. Dimitrios Pectasides
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  23. George Fountzilas
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Corresponding author

Correspondence to Evangelia Razis.

Additional information

Maria Bai: Deceased.

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432_2014_1626_MOESM1_ESM.tif

Supplementary Figure 1. Percent of PTEN categories evaluated by FISH and IHC according to the line of treatment. (TIFF 81 kb)

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Razis, E., Pentheroudakis, G., Rigakos, G. et al. EGFR gene gain and PTEN protein expression are favorable prognostic factors in patients with KRAS wild-type metastatic colorectal cancer treated with cetuximab. J Cancer Res Clin Oncol 140, 737–748 (2014). https://doi.org/10.1007/s00432-014-1626-2

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