Contribution of Immunoscore and Molecular Features to Survival Prediction in Stage III Colon Cancer

Abstract

Background: The American Joint Committee on Cancer staging and other prognostic tools fail to account for stage-independent variability in outcome. We developed a prognostic classifier adding Immunoscore to clinicopathological and molecular features in patients with stage III colon cancer.

Methods: Patient (n = 559) data from the FOLFOX arm of adjuvant trial NCCTG N0147 were used to construct Cox models for predicting disease-free survival (DFS). Variables included age, sex, T stage, positive lymph nodes (+LNs), N stage, performance status, histologic grade, sidedness, KRAS/BRAF, mismatch repair, and Immunoscore (CD3⁺, CD8⁺ T-cell densities). After determining optimal functional form (continuous or categorical) and within Cox models, backward selection was performed to analyze all variables as candidate predictors. All statistical tests were two-sided.

Results: Poorer DFS was found for tumors that were T4 vs T3 (hazard ratio [HR] = 1.76, 95% confidence interval [CI] = 1.19 to 2.60; P = .004), right- vs left-sided (HR = 1.52, 95% CI = 1.14 to 2.04; P = .005), BRAF ^V600E (HR = 1.74, 95% CI = 1.26 to 2.40; P < .001), mutant KRAS (HR = 1.66, 95% CI = 1.08 to 2.55; P = .02), and low vs high Immunoscore (HR = 1.69, 95% CI = 1.22 to 2.33; P = .001) (all P < .02). Increasing numbers of +LNs and lower continuous Immunoscore were associated with poorer DFS that achieved significance (both Ps< .0001). After number of +LNs, T stage, and BRAF/KRAS, Immunoscore was the most informative predictor of DFS shown multivariately. Among T_1-3 N₁ tumors, Immunoscore was the only variable associated with DFS that achieved statistical significance. A nomogram was generated to determine the likelihood of being recurrence-free at 3 years.

Conclusions: The Immunoscore can enhance the accuracy of survival prediction among patients with stage III colon cancer.

Figure 1.

Representative hematoxylin-stained tissue sections showing CD3⁺ and CD8⁺ T cells and CD20⁺ B cells in stage III human colon cancers. The core tumor (CT) and the invasive margin (IM) are shown with the demarcation of the IM (red line; see "Methods") separating malignant glands/cells from peritumoral stroma.

Figure 2.

Association of the two-level categorical Immunoscore with patient 3-year disease-free survival (DFS) in 559 patients with stage III colon cancers as shown in a Kaplan-Meier (KM) plot. Immunoscore was dichotomized into predetermined low (0–1) vs high (2–4) values, as evaluated in an international validation study (5). Adj HR = adjusted hazard ratio; CI = confidence interval; Est = estimated.

Figure 3.

Relative contributions (%) of the 10 variables included in the multivariable Cox model to disease-free survival in patients with stage III colon cancer treated with adjuvant FOLFOX chemotherapy. LN = lymph node.

Figure 4.

Nomogram for 3-year disease-free survival (DFS). An example of an individual patient's prediction may be obtained from the nomogram as follows. First, risk points associated with each variable are obtained via vertical translation of the patient's variable value e.g., Immunosore, to the scale labeled “Points” in the nomogram (i.e., having Immunoscore of 46 contributes 42 points to recurrence/death risk). Next, the points associated with each variable value for the patient are totaled across the variables. This total is then located on the scale “Total Points” (e.g., 185) and then vertically mapped to obtain the 3-year DFS probability. As an example, a patient with an Immunoscore of 46.0%, one positive LN, T3, and mutant KRAS would have 185 total points corresponding to a 3 yr DFS of 78.0%.