Article Figures & Data
Figures
- Figure 1.
Kaplan–Meier estimates, TOP1 FISH stage III. A and B, RFS and OS for treatment group by TOP1 gene status, stage III. TOP1 gain: TOP1/CEN20 ≥ 1.5; TOP1 normal: TOP1/CEN20 < 1.5. C and D, RFS and OS for treatment group by TOP1 gene status, stage III. TOP1 gain: ≥ 4 TOP1 signals per cell; TOP1 normal: < 4 TOP1 signals per cell.
- Figure 2.
Kaplan–Meier estimates, TOP1 mRNA expression stage III. A and B, RFS and OS for treatment group by TOP1 mRNA status. TOP1 high: TOP1 mRNA expression ≥ third quartile of the observed TOP1 expression values; TOP1 normal: TOP1 mRNA expression < third quartile of the observed TOP1 expression values.
- Figure 3.
Treatment-effect plots. Multivariable fractional polynomial interaction (MFPI) treatment-effect plots for treatment effect by TOP1 mRNA expression status in the TOP1 mRNA expression stage III population. The curves show the relative hazard (hazard ratio) on a logarithmic scale for 5FU/FA + irinotecan versus 5FU/FA at different values of TOP1 mRNA gene expression. The shaded areas represent the point-wise 95% confidence intervals. The plots were generated from MFPI second-degree fractional polynomial functions. The RFS model was adjusted for N stage, KRAS status, and MSI status (n = 521). The OS model was adjusted for N stage, KRAS status, and BRAF status (n = 519). The adjusting covariates were selected based on significant prognostic effects in full models, including: N stage, tumor localization, and status of: TOP1, BRAF, KRAS, and MSI. P values for interaction: RFS, P = 0.34; OS, P = 0.26. RFS: recurrence-free survival.
Tables
- Table 1.
Univariate combined prognostic and predictive effects of TOP1 status in relation to recurrence-free survival and OS
Recurrence-free survival OS No. HR (95% CI) P HR (95% CI) P TOP1 FISH stage II + III 534 TOP1 signals per cell Continuous 0.96 (0.76–1.22) 0.76 0.84 (0.62–1.12) 0.22 Gain vs. normal 0.86 (0.60–1.22) 0.40 0.75 (0.49–1.16) 0.20 TOP1/CEN20 Continuous 0.90 (0.75–1.09) 0.28 0.74 (0.58–0.95) 0.01 Gain vs. normal 1.00 (0.72–1.39) 0.99 0.67 (0.44–1.01) 0.06 TOP1 FISH stage III 368 TOP1 signals per cell Continuous 0.96 (0.73–1.27) 0.79 0.81 (0.58–1.13) 0.20 Gain vs. normal 0.83 (0.56–1.23) 0.35 0.69 (0.43–1.12) 0.14 TOP1/CEN20 Continuous 0.91 (0.74–1.12) 0.35 0.74 (0.56–0.97) 0.02 Gain vs. normal 1.04 (0.73–1.48) 0.82 0.70 (0.45–1.09) 0.11 TOP1 mRNA expression stage III 580 TOP1 mRNA expression Continuous 0.85 (0.70–1.03) 0.10 0.74 (0.60–0.92) 0.007 High vs. normal 0.84 (0.61–1.15) 0.28 0.85 (0.59–1.23) 0.38 NOTE: The analyses are made without stratifying for treatment arm. Cutoff values for TOP1 gene gain: ≥ 4 TOP1 signals per cell, TOP1/CEN20 ratio ≥ 1.5. Cutoff value for high TOP1 mRNA expression: ≥ third quartile of the observed TOP1 expression values. The variables are handled linearly in the continuous models.
- Table 2.
Univariate predictive effects of TOP1 status in relation to recurrence-free survival
Recurrence-free survival Patients, n Events, n 5-year rate 95% CI HR (95% CI) PWald Plog rank TOP1 FISH stage II + III 534 TOP1 signals per cell ≥ 4 142 5FU/FA 70 20 0.73 0.63–0.84 5FU/FA + irinotecan 72 21 0.70 0.60–0.81 1.07 (0.58–1.97) 0.83 0.83 TOP1 signals per cell < 4 392 5FU/FA 188 60 0.70 0.63–0.76 5FU/FA + irinotecan 204 65 0.69 0.63–0.76 1.02 (0.72–1.45) 0.90 0.90 TOP1/CEN20 ≥ 1.5 167 5FU/FA 83 26 0.70 0.60–0.80 5FU/FA + irinotecan 84 26 0.69 0.60–0.80 1.03 (0.59–1.77) 0.93 0.93 TOP1/CEN20 < 1.5 367 5FU/FA 175 54 0.71 0.64–0.78 5FU/FA + irinotecan 192 60 0.69 0.63–0.76 1.04 (0.72–1.50) 0.84 0.84 TOP1 FISH stage III 368 TOP1 signals per cell ≥ 4 95 5FU/FA 47 16 0.65 0.53–0.81 5FU/FA + irinotecan 48 17 0.63 0.51–0.79 1.08 (0.55–2.14) 0.82 0.82 TOP1 signals per cell < 4 273 5FU/FA 132 49 0.64 0.57–0.73 5FU/FA + irinotecan 141 58 0.60 0.52–0.68 1.16 (0.79–1.69) 0.46 0.45 TOP1/CEN20 ≥ 1.5 120 5FU/FA 61 23 0.65 0.57–0.74 5FU/FA + irinotecan 59 24 0.61 0.53–0.70 1.13 (0.64–2.01) 0.67 0.67 TOP1/CEN20 < 1.5 248 5FU/FA 118 42 0.64 0.53–0.77 5FU/FA + irinotecan 130 51 0.60 0.48–0.74 1.15 (0.76–1.72) 0.51 0.51 TOP1 mRNA expression stage III 580 TOP1 high 140 5FU/FA 73 29 0.60 0.49–0.72 5FU/FA + irinotecan 67 18 0.73 0.63–0.84 0.64 (0.35–1.15) 0.13 0.13 TOP1 normal 440 5FU/FA 206 80 0.63 0.57–0.70 5FU/FA + irinotecan 234 92 0.62 0.56–0.68 1.02 (0.76–1.38) 0.88 0.88 NOTE: The relative treatment effects (hazard ratios) are for 5FU/FA + irinotecan vs. 5FU/FA. The P values from the Wald test relate to the hazard ratios, whereas the P values from the log rank test relate to the estimated Kaplan–Meier functions for the two treatment groups within each TOP1 subgroup. Cutoff value for high TOP1 mRNA expression: ≥ third quartile of the observed TOP1 expression values.
- Table 3.
Univariate predictive effects of TOP1 status in relation to OS
OS Patients, n Events, n 5-Year rate 95% CI HR (95% CI) PWald Plog rank TOP1 FISH stage II + III 534 TOP1 signals per cell ≥ 4 142 5FU/FA 70 15 0.86 0.78–0.94 5FU/FA + irinotecan 72 12 0.84 0.76–0.93 0.78 (0.63–1.66) 0.51 0.51 TOP1 signals per cell < 4 392 5FU/FA 188 44 0.77 0.72–0.84 5FU/FA + irinotecan 204 49 0.77 0.71–0.83 1.06 (0.70–1.59) 0.79 0.79 TOP1/CEN20 ≥ 1.5 167 5FU/FA 83 15 0.85 0.78–0.93 5FU/FA + irinotecan 84 14 0.83 0.75–0.91 0.95 (0.46–1.96) 0.88 0.88 TOP1/CEN20 < 1.5 367 5FU/FA 175 44 0.77 0.71–0.83 5FU/FA + irinotecan 192 47 0.77 0.71–0.83 0.99 (0.66–1.49) 0.96 0.96 TOP1 FISH stage III 368 TOP1 signals per cell ≥ 4 95 5FU/FA 47 12 0.83 0.73–0.94 5FU/FA + irinotecan 48 9 0.83 0.73–0.94 0.72 (0.30–1.70) 0.45 0.45 TOP1 signals per cell < 4 273 5FU/FA 132 36 0.73 0.66–0.81 5FU/FA + irinotecan 141 44 0.70 0.63–0.78 1.20 (0.77–1.86) 0.42 0.42 TOP1/CEN20 ≥ 1.5 120 5FU/FA 61 15 0.80 0.70–0.91 5FU/FA + irinotecan 59 12 0.79 0.70–0.91 0.83 (0.39–1.78) 0.63 0.63 TOP1/CEN20 < 1.5 248 5FU/FA 118 33 0.73 0.66–0.82 5FU/FA + irinotecan 130 41 0.70 0.63–0.79 1.17 (0.74–1.84) 0.51 0.51 TOP1 mRNA expression stage III 580 TOP1 high 140 5FU/FA 73 24 0.72 0.62–0.83 5FU/FA + irinotecan 67 12 0.83 0.75–0.93 0.51 (0.25–1.02) 0.056 0.049 TOP1 normal 440 5FU/FA 206 61 0.74 0.68–0.80 5FU/FA + irinotecan 234 69 0.71 0.66–0.77 1.04 (0.74–1.46) 0.83 0.83 NOTE: The relative treatment effects (hazard ratios) are for 5FU/FA + irinotecan vs. 5FU/FA. The P values from the Wald test relate to the hazard ratios, whereas the P values from the log rank test relate to the estimated Kaplan–Meier functions for the two treatment groups within each TOP1 subgroup. Cutoff value for high TOP1 mRNA expression: ≥ third quartile of the observed TOP1 expression values.
Supplementary Data
- Supplementary Tables S1-S8 and Figures S1-S3 - Supplementary Table S1: Baseline characteristics of biomarker stage III vs PETACC3 stage III. Supplementary Table S2: Baseline characteristics of biomarker stage II + III vs PETACC3 stage II + III. Supplementary Table S3: Treatment effects in the biomarker populations vs PETACC3. Supplementary Table S4: Associations between the TOP1 gene copy number and baseline characteristics, stage II + III. Supplementary Table S5: Associations between the TOP1 gene copy number and baseline characteristics, stage III. Supplementary Table S6: Associations between the TOP1/CEN20 ratio and baseline characteristics, stage II + III. Supplementary Table S7: Associations between the TOP1/CEN20 ratio and baseline characteristics, stage III. Supplementary Table S8: Associations between TOP1 mRNA expression and baseline characteristics, stage III. Supplementary Figure S1: CONSORT diagram Supplementary Figure S2: Inter-observer agreement of FISH counting, Bland-Altman plots. Supplementary Figure S3: Correlation between TOP1 FISH and TOP1 mRNA expression.
Volume 22, Issue 7
