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RAS Mutations Beyond KRAS Exon 2: A Review and Discussion of Clinical Trial Data

  • Lower Gastrointestinal Cancers (AB Benson, Section Editor)
  • Published:
Current Treatment Options in Oncology Aims and scope Submit manuscript

Opinion Statement

The addition of targeted therapy to a 5-FU chemotherapy backbone is now a standard of care in metastatic colorectal cancer. Epidermal growth factor receptor (EGFR) inhibitors have been demonstrated to improve progression-free survival (PFS) and overall survival (OS) in the first line for patients with tumors that do not harbor KRAS exon 2 mutations. Eligibility criteria for most clinical trials involving EGFR inhibitors in recent years have used the absence of KRAS exon 2 mutation as the sole criteria for entry, as this specific mutation has been consistently shown to be predictive of a poor response to EGFR inhibitors. However, expanded analyses of first-line metastatic trials reveal that other RAS mutations, such as other KRAS mutations in exons 3 and 4, along with NRAS mutations, are predictive of poor responses to EGFR inhibitors as well. Testing for a full panel of these RAS mutations should be done prior to initiating treatment with an EGFR inhibitor. Further clinical trials are required to determine the predictive impact of each of these individual mutations. To date, they have been analyzed in the aggregate. The addition of targeted therapy, bevacizumab or an EGFR inhibitor, to a chemotherapy backbone should be considered for all appropriate patients. The relevant clinical trials that evaluated patients without any RAS mutation and compared an EGFR inhibitor to chemotherapy alone show a distinct advantage in overall survival and progression-free survival to the groups that received EGFR inhibition. The largest trial that compared bevacizumab with an EGFR inhibitor in the first line, CALGB/SWOG 80405, did not show a statistically significant difference between the two groups, making the use of bevacizumab, cetuximab, or panitumumab reasonable in the first line.

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References and Recommended Reading

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Timothy L. Cannon, Megan A. Kokon, Sara Shafaqat, and John Deeken declare that they have no conflict of interest.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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Authors and Affiliations

  1. INOVA Medical Group, 8505 Arlington Blvd. Suite 100, Fairfax, VA, 22031, USA

    Timothy L. Cannon M.D. & Megan A. Kokon R.N.

  2. 8505 Arlington Blvd. Suite 100, Fairfax, VA, 22031, USA

    Sara Shafqat M.D.

  3. Virginia Commonwealth University, 8505 Arlington Blvd. Suite 100, Fairfax, VA, 22031, USA

    John F. Deeken M.D.

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  1. Timothy L. Cannon M.D.
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Correspondence to Timothy L. Cannon M.D..

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This article is part of the Topical Collection on Lower Gastrointestinal Cancers

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Cannon, T.L., Kokon, M.A., Shafqat, S. et al. RAS Mutations Beyond KRAS Exon 2: A Review and Discussion of Clinical Trial Data. Curr. Treat. Options in Oncol. 16, 33 (2015). https://doi.org/10.1007/s11864-015-0350-8

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