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G12V and G12A KRAS mutations are associated with poor outcome in patients with metastatic colorectal cancer treated with bevacizumab

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Tumor Biology

Abstract

The v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) mutations are found in 35–45 % of colorectal cancer (CRC) cases. Although the association between the RAS signaling and angiogenesis is well known, the negative predictive value of KRAS mutation has not been established in patients treated with bevacizumab. The aim of this study was to evaluate the association between specific KRAS mutation types and outcome of patients with metastatic CRC treated with bevacizumab. The study included 404 patients with metastatic CRC (mCRC) treated with bevacizumab. Clinical data obtained from the clinical registry CORECT were retrospectively analyzed. The shortest survival was observed in patients with tumors harboring G12V or G12A KRAS mutation (G12V/A). The median progression-free survival (PFS) and overall survival (OS) for patients with tumors harboring G12V/A KRAS mutation was 6.6 and 16.8 compared to 11.6 and 26.3 months for patients with tumors harboring other KRAS mutation type (p < 0.001 and p < 0.001), while the survival of patients harboring other KRAS mutation types was comparable to those with tumors harboring wild-type KRAS gene. In the Cox multivariable analysis, KRAS G12V/A mutation type remains a significant factor predicting both PFS (HR = 2.18, p < 0.001) and OS (HR = 2.58, p < 0.001). In conclusion, the results of the present study indicate that there is a significant difference in biological behavior between tumors harboring G12V/A and other KRAS mutations. Moreover, comparison of the survival of patients with tumors harboring G12V/A KRAS mutations with those harboring wild-type KRAS gene revealed that G12V/A KRAS mutations are prognostic biomarker for inferior PFS and OS in patients with mCRC treated with bevacizumab in univariate as well as multivariable analyses.

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Acknowledgements

The authors would like to thank all patients voluntarily taking part in the observational, population-based registry CORECT. This study was supported by the National Sustainability Program I (NPU I) Nr. LO1503 provided by the Ministry of Education Youth and Sports of the Czech Republic.

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Authors and Affiliations

  1. Department of Oncology and Radiotherapy, Medical School and Teaching Hospital Pilsen, Charles University in Prague, alej Svobody 80, CZ-304 60, Pilsen, Czech Republic

    Ondrej Fiala, Vit Martin Matejka, Lubos Holubec, Jana Kulhankova & Jindrich Finek

  2. Biomedical Center, Faculty of Medicine in Pilsen, Charles University in Prague, Plzeň, Czech Republic

    Ondrej Fiala & Vaclav Liska

  3. Department of Oncology and First Faculty of Medicine, Charles University and Thomayer Hospital, Prague, Czech Republic

    Tomas Buchler

  4. Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic

    Beatrice Mohelnikova-Duchonova, Bohuslav Melichar & Marie Bartouskova

  5. Institute of Biostatistics and Analyses, Faculty of Medicine, Masaryk University, Brno, Czech Republic

    Zbynek Bortlicek

  6. Department of Surgery, Medical School and Teaching Hospital Pilsen, Charles University in Prague, Pilsen, Czech Republic

    Vaclav Liska

  7. Department of Nuclear Medicine, Medical School and Teaching Hospital Pilsen, Charles University in Prague, Pilsen, Czech Republic

    Ondrej Topolcan

  8. Bioptic Laboratory, Ltd., Molecular Pathology Laboratory, Plzeň, Czech Republic

    Monika Sedivcova

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  1. Ondrej Fiala
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Correspondence to Ondrej Fiala.

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Conflicts of interest

JF has received honoraria from Astra Zeneca, Roche, and Novartis for consultations and lectures unrelated to this project. BM has received honoraria from Astra Zeneca, Roche, Merck, Amgen, and Novartis for consultations and lectures unrelated to this project. TB has received honoraria from Roche for consultations and lectures unrelated to this project. OF, VMM, LH, JK, ZB, MB, VL, OT, and MS declare that they have no actual or potential conflict of interest including any financial, personal, or other relationships with other people or organizations that could inappropriately influence this work.

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Fiala, O., Buchler, T., Mohelnikova-Duchonova, B. et al. G12V and G12A KRAS mutations are associated with poor outcome in patients with metastatic colorectal cancer treated with bevacizumab. Tumor Biol. 37, 6823–6830 (2016). https://doi.org/10.1007/s13277-015-4523-7

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