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EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer

  • Original Article
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Pathology & Oncology Research

Abstract

Genetic variability in KRAS and EGFR predicts response to cetuximab in irinotecan refractory colorectal cancer. Whether these markers or others remain predictive in combination biologic therapies including bevacizumab is unknown. We identified predictive biomarkers from patients with irinotecan refractory metastatic colorectal cancer treated with cetuximab plus bevacizumab. Patients who received cetuximab plus bevacizumab for irinotecan refractory colorectal cancer in either of two Phase II trials conducted were identified. Tumor tissue was available for 33 patients. Genomic DNA was extracted and used for mutational analysis of KRAS, BRAF, and p53 genes. Fluorescence in situ hybridization was performed to assess EGFR copy number. The status of single genes and various combinations were tested for association with response. Seven of 33 patients responded to treatment. KRAS mutations were found in 14/33 cases, and 0 responded to treatment (p = 0.01). EGFR gene amplification was seen in 3/33 of tumors and in every case was associated with response to treatment (p < 0.001). TP53 and BRAF mutations were found in 18/33 and 0/33 tumors, respectively, and there were no associations with response to either gene. EGFR gene amplification and KRAS mutations are predictive markers for patients receiving combination biologic therapy of cetuximab plus bevacizumab for metastatic colorectal cancer. One marker or the other is present in the tumor of half of all patients allowing treatment response to be predicted with a high degree of certainty. The role for molecular markers in combination biologic therapy seems promising.

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Acknowledgement

We thank Dr. Margaret Leversha (Cytogenetic Core Facility Lab, Memorial Sloan-Kettering Cancer Center) for valuable technical assistance for FISH analysis.

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Authors and Affiliations

  1. Department of Surgery, Section of Surgical Oncology, Yale University School of Medicine, 310 Cedar Street, FMB 130, New Haven, CT, 06520, USA

    Sajid A. Khan

  2. Colorectal Service, Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Zhaoshi Zeng & Philip B. Paty

  3. Colorectal Service, Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY, USA

    Jinru Shia

Authors
  1. Sajid A. Khan
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  2. Zhaoshi Zeng
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  3. Jinru Shia
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Corresponding author

Correspondence to Sajid A. Khan.

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Funding

This work was supported by the Program Project Grant PO1-CA65930 and T32 surgical oncology training grant CA 09501 of the National Cancer Institute.

Conflict of Interest

Sajid Khan, Zhaoshi Zeng, Jinru Shia, and Philip Paty declare no conflicts of interest.

Ethical Approval

This retrospective study does not contain any studies with human participants by any of the authors. Tissue was obtained from patients enrolled in clinical trials. These trials were in accordance with the ethical standards of the institutional review board and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Tumor block accrual were approved by the institutional review board.

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Khan, S.A., Zeng, Z., Shia, J. et al. EGFR Gene Amplification and KRAS Mutation Predict Response to Combination Targeted Therapy in Metastatic Colorectal Cancer. Pathol. Oncol. Res. 23, 673–677 (2017). https://doi.org/10.1007/s12253-016-0166-2

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  • DOI: https://doi.org/10.1007/s12253-016-0166-2

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