Prognostic and Predictive Value of Immunoscore in Stage III Colorectal Cancer: Pooled Analysis of Cases From the SCOT and IDEA-HORG Studies

Abstract

Purpose: Immunoscore (IS) is prognostic in stage III colorectal cancer (CRC) and may predict benefit of duration (6 v 3 months) of adjuvant infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) chemotherapy. We sought to determine IS prognostic and predictive value in stage-III CRC treated with adjuvant FOLFOX or oral capecitabine and infusional oxaliplatin (CAPOX) in the SCOT and IDEA-HORG trials.

Methods: Three thousand sixty-one cases had tumor samples, of which 2,643 (1,792 CAPOX) were eligible for IS testing. Predefined cutoffs (IS-Low and IS-High) were used to classify cases into two groups for analysis of disease-free survival (3-year DFS) and multivariable-adjusted hazard ratios (mvHRs) by Cox regression.

Results: IS was determined in 2,608 (99.5%) eligible cases, with 877 (33.7%) samples classified as IS-Low. IS-Low tumors were more commonly high-risk (T4 and/or N2; 52.9% IS-Low v 42.2% IS-High; P < .001) and in younger patients (P = .024). Patients with IS-Low tumors had significantly shorter DFS in the CAPOX, FOLFOX, and combined cohorts (mvHR, 1.52 [95% CI, 1.28 to 1.82]; mvHR, 1.58 [95% CI, 1.22 to 2.04]; and mvHR, 1.55 [95% CI, 1.34 to 1.79], respectively; P < .001 all comparisons), regardless of sex, BMI, clinical risk group, tumor location, treatment duration, or chemotherapy regimen. IS prognostic value was greater in younger (≤65 years) than older (>65 years) patients in the CAPOX cohort (mvHR, 1.92 [95% CI, 1.50 to 2.46] v 1.28 [95% CI, 1.01 to 1.63], P_INTERACTION = .026), and in DNA mismatch repair proficient than deficient mismatch repair disease (mvHR, 1.68 [95% CI, 1.41 to 2.00] v 0.67 [95% CI, 0.30 to 1.49], P_INTERACTION = .03), although these exploratory analyses were uncorrected for multiple testing. Adding IS to a model containing all clinical variables significantly improved prediction of DFS (likelihood ratio test, P < .001) regardless of MMR status.

Conclusion: IS is prognostic in stage III CRC treated with FOLFOX or CAPOX, including within clinically relevant tumor subgroups. Possible variation in IS prognostic value by age and MMR status, and prediction of benefit from extended adjuvant therapy merit validation.

FIG 1.

Prognostic value of IS as two groups by univariable and multivariable analyses in the SCOT-HORG trials. Kaplan-Meier plots showing DFS according to IS as two groups for (A) patients treated with FOLFOX, (B) patients treated with CAPOX, and (C) patients treated with either regimen in the pooled SCOT and IDEA-HORG population. (D-F) Harrell C indices obtained from multivariable Cox proportional hazards models of the patient groups shown in A-C including prespecified baseline and prognostic factors* before and after the addition of IS as two groups. Estimates were obtained by internal bootstrap (n = 1,000 samples). (G-I) Pie charts showing contribution of individual variables to goodness of model fit before and after the addition of IS as two groups. Statistical comparison between groups in A-C was made by using the log-rank test. Comparison of bootstrapped C-indices for base model and base model plus IS2 in D-F was by unpaired Wilcoxon test. *Variables included in Cox models include age, sex, PS, pT stage (pT1-3 v pT4), N stage (1 v 2), treatment regimen (in the case of combined population only), and chemotherapy duration. DFS, disease-free survival; dMMR, deficient mismatch repair; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; IS, Immunoscore; MMR, mismatch repair; PS, performance status.

FIG 2.

Predictive value of IS for chemotherapy duration in the SCOT-HORG trials. Kaplan-Meier plots showing DFS according to chemotherapy duration (3 v 6 months) for (A) FOLFOX in IS-High group; (B) FOLFOX in IS-Low group; (C) CAPOX in IS-High group; and (D) CAPOX in IS-Low group. Statistical comparison between groups in A-C was made by using the log-rank test. DFS, disease-free survival; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; IS, Immunoscore.

FIG 3.

Prognostic value of IS according to clinical risk group in the SCOT-HORG trials. Kaplan-Meier plots showing DFS according to clinical risk score and two-group IS for (A) patients treated with FOLFOX, (B) patients treated with CAPOX, and (C) patients treated with either regimen. Statistical comparison between groups was made by using the log-rank test. DFS, disease-free survival; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; IS, Immunoscore.

FIG 4.

Prognostic value of IS within subgroups in the SCOT-HORG trials. Forest plots showing HR for DFS across patient and tumor subgroups according to two-group IS for (A) patients treated with FOLFOX and(B) patients treated with CAPOX. (C and D) Corresponding Kaplan-Meier plots of DFS according to patient age and two-group IS for respective cohorts. Interaction testing in A and B was obtained from the IS × subgroup cross-product term from univariable analysis. Statistical comparison between groups in C and D was made by using the log-rank test. DFS, disease-free survival; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; HR, hazard ratio; IS, Immunoscore.

FIG 5.

Prognostic value of IS within subgroups in patients with DNA MMR status in SCOT-HORG studies. (A) Forest plot showing HR for DFS across patient and tumor subgroups according to two-group IS for patients treated with FOLFOX or CAPOX with available tumor DNA MMR status. (B and C) Corresponding Kaplan-Meier plots of DFS according to two-group IS for cases with (B) pMMR and (C) dMMR. DFS, disease-free survival; dMMR, deficient mismatch repair; FOLFOX, infusional fluorouracil, leucovorin, and oxaliplatin; HR, hazard ratio; IS, Immunoscore; MMR, mismatch repair; pMMR, mismatch repair proficient.