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The Interaction Between Kras Mutation, Microsatellite Instability, And Tumor Laterality And The Impact On Prognosis In Non-metastatic Colorectal Cancer
*Paolo Goffredo1, *Catherine G. Tran2, *Sarah L. Mott3, *Sajida Ahad2, *Y. Nancy You4, *Jean Nicolas Vauthey4, Ronald J. Weigel2, *Imran Hassan2
1Division of Colon & Rectal Surgery, University of Minnesota, Minneapolis, MN;2Department of Surgery, University of Iowa, Iowa City, IA;3Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA;4Department of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX

Objectives: KRAS mutations (mKRAS), microsatellite instability (MSI), and right-sided tumor location are independent prognostic factors in colorectal cancer. However, the interaction between these variables and its effect on prognosis not been well elucidated. This study evaluated their impact on overall survival (OS) in patients with stage I-III colon cancer.
Methods: The National Cancer Database (2010-2016) was queried for patients with non-metastatic colon cancer and known MSI and KRAS status who underwent resection.
Results: A total of 5,292 patients were identified: 60.4% had right-sided cancers, 36.4% had mKRAS, and 15.6% had MSI. Patients with mKRAS did not have significantly worse pathologic features at presentation than those with wild-type tumors. MSI patients had larger and more poorly differentiated cancers, but lower rates of nodal metastasis and tumor deposits (all p<.01). Compared to left-sided cancers, right-sided tumors were more likely to have MSI (20.5 vs. 8.0%, p<.01) and mKRAS (39.9 vs. 31.1%, p<.01). On univariable analysis, neither mKRAS nor MSI was associated with differences in survival, while right-sided cancers had worse OS compared to left-sided cancers (HR: 1.32, 95% CI:1.18-1.47). On multivariable analysis, right-sided location, mKRAS, and MSI were not independent prognostic factors. However, a significant interaction between laterality and KRAS status was observed. Among patients with mKRAS, left-sided tumors were at 1.30 times increased risk of death relative to right-sided tumors (95% CI:1.03-1.63), while in patients with wild-type KRAS, left-sided tumors were at 0.81 times risk of mortality relative to right-sided cancers (95% CI:0.67-0.97).
Conclusion: In patients with stage I-III colon cancer, right-sided tumors were associated with higher rates of mKRAS and MSI, but these mutations were not independently prognostic. However, the effect of laterality on survival was diametrically opposite based on KRAS status, with left-sided (compared to right-sided) tumors associated with worse OS in mKRAS patients and better OS in wild-type KRAS individuals. Therefore, laterality itself may not be an independent prognostic factor, but rather a reflection of differing genetic profiles within the colon.

Multivariable survival analysis of patients with stage I-III colon cancer treated with resection
Overall Survival
CovariateLevelHazard Ratio95% CIP-value
Age70+1.641.401.94<.01
<70Ref--
SexMale1.291.131.47<.01
FemaleRef--
Interaction Between KRAS and SideMutated vs Wild Type at Left Side1.511.201.91<.01
Mutated vs Wild Type at Right Side0.940.801.12
GradeModerately differentiated1.220.931.62<.01
Poorly differentiated1.711.262.32
Undifferentiated1.761.192.61
Well differentiatedRef--
AJCC Pathologic T21.280.841.96<.01
31.390.942.06
4A2.051.343.13
4B2.841.824.45
1Ref--
Pathologic N1A1.981.582.47<.01
1B1.961.572.45
2A3.052.423.84
2B3.993.165.04
0Ref--
Surgical MarginsPositive1.841.402.42<.01
NegativeRef--
ChemotherapyMulti Agent0.430.360.52<.01
Single Agent0.510.400.66
NoneRef--


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