THE IMPACT OF KRAS MUTATION ON THE PRESENTATION AND PROGNOSIS OF NON-METASTATIC COLON CANCER: AN ANALYSIS FROM THE NATIONAL CANCER DATABASE.
Paolo Goffredo*1, Xiang Gao1, Timothy Ginader2, Jennifer Hrabe1, Irena Gribovskaja-Rupp1, Muneera Kapadia1, Ronald J. Weigel1, Imran Hassan1
1Surgery, University of Iowa, Iowa City, IA; 2Biostatistics, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA
Introduction
Approximately 30-40% of colorectal cancers have a KRAS mutation (mKRAS). Colorectal cancers carrying this mutation are biologically more aggressive and resistant to epidermal growth factor inhibitors compared to wild type KRAS (wKRAS) cancers. The clinical relevance and prognostic significance of mKRAS in patients with non-metastatic colon cancer has not been well elucidated. The aim of the current study was to utilize the National Cancer Database (NCDB) to analyze factors associated with mKRAS as well as its impact on the presentation and survival of patients with stage I-III colon cancer.
Methods
The NCDB was queried to identify patients diagnosed with stage I-III adenocarcinoma of the colon from 2004 to 2015. Patient and tumor related characteristics associated with KRAS mutation and differences in presentation patterns were identified with bivariate and multivariable analysis. The survival impact was analyzed using Kaplan-Meier and Cox proportional hazards regression analyses.
Results
A total of 19,877 patients with known KRAS status were identified: mutation rates were 33% in stage I, 35% in stage II, and 38% in stage III patients (p< 0.01). Within each stage, KRAS mutated cancers were not consistently associated with more advanced disease characteristics at presentations, such as higher T stage, tumor size and grade, or lymphovascular and perineural invasion. On multivariable analysis, African-American race and right-sided location were independently associated with mKRAS cancers (all p <0.01). On univariate analysis for overall survival (OS), mKRAS was not significantly associated with a worse 5-year OS for stage I and II patients (p = 0.60 and 0.88, respectively). Conversely, stage III mKRAS colon cancers had a lower OS as compared to wKRAS cancers both on univariate and multivariable analysis (Figure 1; Table 1; Hazard Ratio = 1.14, Confidence Interval = 1.01-1.28). Right-sided colon cancers were independently associated with a worse prognosis compared to left-sided lesions (p <0.01).
Conclusions
mKRAS colon cancers were more frequently observed in African-Americans, right side locations, and higher stages. mKRAS was not associated with adverse pathologic characteristics in the primary tumor. These mutations had a negative prognostic impact in stage III colon cancer, but not for node negative cancers. The lower OS of right-sided colon cancers independent of KRAS status suggests a role of other potential causative factors that may be responsible for their worse prognosis.
Multivariate Survival Analysis for Stage III patients
| Variables | Hazard Ratio | 95% Confidence Interval | p-value | |
| KRAS mutation | 1.14 | 1.01 - 1.28 | 0.03 | |
| Pathologic T1 | 0.37 | 0.23 - 0.60 | <0.01 | |
| Pathologic T2 | 0.34 | 0.25 - 0.46 | <0.01 | |
| Pathologic T3 | 0.65 | 0.58 - 0.74 | <0.01 | |
| Tumor grade, differentiated | 0.63 | 0.58 - 0.71 | <0.01 | |
| Location, left side | 0.78 | 0.69 - 0.88 | <0.01 | |
| Absence of lymphovascular invasion | 0.65 | 0.57 - 0.74 | <0.01 | |
| Absence of perineural invasion | 0.73 | 0.64 - 0.83 | <0.01 | |
| Age at diagnosis, years | 1.02 | 1.02 - 1.03 | <0.01 | |
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