Prognostic value of KRAS mutation status in colorectal cancer patients: a population-based competing risk analysis

Abstract

Background: To use competing analyses to estimate the prognostic value of KRAS mutation status in colorectal cancer (CRC) patients and to build nomogram for CRC patients who had KRAS testing.

Method: The cohort was selected from the Surveillance, Epidemiology, and End Results database. Cumulative incidence function model and multivariate Fine-Gray regression for proportional hazards modeling of the subdistribution hazard (SH) model were used to estimate the prognosis. An SH model based nomogram was built after a variable selection process. The validation of the nomogram was conducted by discrimination and calibration with 1,000 bootstraps.

Results: We included 8,983 CRC patients who had KRAS testing. SH model found that KRAS mutant patients had worse CSS than KRAS wild type patients in overall cohort (HR = 1.10 (95% CI [1.04-1.17]), p < 0.05), and in subgroups that comprised stage III CRC (HR = 1.28 (95% CI [1.09-1.49]), p < 0.05) and stage IV CRC (HR = 1.14 (95% CI [1.06-1.23]), p < 0.05), left side colon cancer (HR = 1.28 (95% CI [1.15-1.42]), p < 0.05) and rectal cancer (HR = 1.23 (95% CI [1.07-1.43]), p < 0.05). We built the SH model based nomogram, which showed good accuracy by internal validation of discrimination and calibration. Calibration curves represented good agreement between the nomogram predicted CRC caused death and actual observed CRC caused death. The time dependent area under the curve of receiver operating characteristic curves (AUC) was over 0.75 for the nomogram.

Conclusion: This is the first population based competing risk study on the association between KRAS mutation status and the CRC prognosis. The mutation of KRAS indicated a poor prognosis of CRC patients. The current competing risk nomogram would help physicians to predict cancer specific death of CRC patients who had KRAS testing.

Keywords: Colorectal cancer; Competing risk; KRAS; Nomograms; Prognosis; SEER.

Figure 1. CSS of CRC patients with different stages according to KRAS status by CIF plot.

CIF plots of KRAS status and the prognosis of CRC in overall population (A) and stage I–IV CRC patients (B–E).

Figure 2. CSS of CRC patients with differed location according to KRAS status by CIF plot.

CIF plots of KRAS status and the prognosis of CRC in locations of unknown (A), left colon (B), right colon (C) and rectum (D) NOS, not otherwise specified.

Figure 3. Nomogram for predicting 1-year, 2-year and 3-year CSS of CRC patients who had KRAS testing.

The nomogram is used by summing the points identified on the top scale for each independent variable and drawing a vertical line from the total points scale to the 1-year, 2-year and 3-year CSS to obtain the probability of survival. The total points projected to the bottom scale indicate the % probability of the 3-year survival. Age: 2, 20–29 years, 3, 30–39 years, 4, 40–49 years, 5, 50–59 years, 6, 60–69 years and 7, 70–79 years; Race: 1, Caucasian, 2, African American, 3, Other race and N, Unknown race; Tumor size: 2, “0–2 cm”, 4, “2–4 cm”, 6, “4–6 cm”, >6 = “>6 cm”, N, Unknown size; Tumor stage, 0, 0 stage (Tumor in situ), 1, I stage, 2, II stage, 3, III stage, 4, IV stage and N, Unknown stage; No. Nodes, the number of positive regional lymph nodes; KRAS status: 0, Wild type and 1, Mutation; Chemotherapy, 0, none/unknown and 1, yes; Radiotherapy, 0, none/unknown or refused, 1, beam radiation or combination of beam with implants or isotopes or radiation with method or source not specified or radioactive implants or radioisotopes and N, Recommended, unknown if administered.

Figure 4. Calibration curves for cox-based and SH based nomograms.

(A–C) The calibration plots for predicting 1-year, 2-year and 3-year CSS of CRC patients; (D) the AUC plots for SH-based nomogram.