Microsatellite Instability and KRAS Mutation in Stage IV Colorectal Cancer: Prevalence, Geographic Discrepancies, and Outcomes From the National Cancer Database

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  • 1 Section of Interventional Radiology, Yale School of Medicine, New Haven, Connecticut;
  • 2 Department of Diagnostic and Interventional Radiology, University Medical Center Goettingen, Goettingen, Germany; and
  • 3 Section of Medical Oncology, Yale School of Medicine, and
  • 4 Yale Cancer Center, Yale School of Medicine, New Haven, Connecticut.
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Background: This study sought to assess microsatellite and KRAS status, prevalence, and impact on outcome in stage IV colorectal cancer (CRC). Materials and Methods: The 2010 to 2016 US National Cancer Database was queried for adult patients with stage IV CRC. Prevalence of microsatellite status (microsatellite instability–high [MSI-H] or microsatellite stable [MSS]) and KRAS status (KRAS mutation or wild-type) of the primary CRC was assessed. Overall survival (OS) was evaluated using multivariable Cox proportional hazards models in patients with complete data on both microsatellite and KRAS status and information on follow-up. Results: Information on microsatellite and KRAS status was available for 10,844 and 25,712 patients, respectively, and OS data were available for 5,904 patients. The overall prevalence of MSI-H status and KRAS mutation was 3.1% and 42.4%, respectively. Prevalence of MSI-H ranged between 1.6% (rectosigmoid junction) and 5.2% (transverse colon), and between 34.7% (sigmoid colon) and 58.2% (cecum) for KRAS mutation. MSI-H rates were highest in East North Central US states (4.1%), and KRAS mutation rates were highest in West South Central US states (44.1%). Multivariable analyses revealed longer OS for patients with KRAS wild-type versus mutation status (hazard ratio [HR], 0.91; 95% CI, 0.85–0.97; P=.004), those with MSS versus MSI-H status (HR, 0.75; 95% CI, 0.62–0.9; P=.003), and those with left-sided versus right-sided CRC (multivariable HR, 0.65; 95% CI, 0.6–0.7; P<.001). The effect of KRAS mutation further varied with CRC site and microsatellite status (P=.002 for interaction). Conclusions: Depending on the primary site and US geography, stage IV CRC shows distinct mutational behavior. KRAS mutation, MSI-H, and primary CRC sidedness independently affect OS and interact with distinct prognostic profiles. Generically classifying adenocarcinomas at different sites as CRC might deprecate this diversity.

Submitted April 16, 2020; accepted for publication July 14, 2020. Published online February 2, 2021.

Author contributions: Study concept: Uhlig, Kim. Data curation: All authors. Formal analysis: Uhlig. Investigation: All authors. Methodology: Uhlig. Project administration: Kim. Resources: Uhlig, Cecchini, Stein, Lacy, Kim. Supervision: Kim. Validation: Uhlig, Sheth, Kim. Visualization: Uhlig. Writing – original draft: All authors.

Disclosures: Dr. Uhlig has disclosed that he was a speaker for Bayer Healthcare. Dr. Kim has disclosed that he is a scientific advisor for Boston Scientific, SIRTex, Genentech, Eisai, Amgen, and Bayer, and has received research support from Galil and Flatiron. The remaining authors have disclosed that they have no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors.

Funding: Dr. Kim is supported by a grant from the US Department of Defense (CA160741). The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Correspondence: Hyun S. Kim, MD, MHS, University of Maryland School of Medicine, 22 South Greene Street, Suite G2K14, Baltimore, MD 21201. Email: kevin.kim@umm.edu

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