Table 3:
Univariate and multivariate analyses of survival from locally advanced or metastatic disease (excluding patients treated with immunotherapy) (N = 1415 patients)*
| Variable | Group | Patients N (%) | Median survival (weeks) | Hazard ratio OS (95% CI) | p* univariate | |||
|---|---|---|---|---|---|---|---|---|
| Age | <60 years | 826 (58%) | 250 | Reference Group | ||||
| ≥60 years | 589 (42%) | 170 | 1.57 (1.33–1.84) | 3.83×10−8 | ||||
| Sex | Women | 716 (51%) | 189 | Reference Group | ||||
| Men | 699 (49%) | 172 | 1.07 (0.91–1.25) | 0.41 | ||||
| Ethnicity | African-American | 53 (4%) | 257 | 1.03 (0.67–1.60) | 5.1 × 10−3 | |||
| Asian | 137 (10%) | 170 | 1.31 (1.02–1.68) | |||||
| Hispanic | 194 (14%) | 213 | 0.95 (0.75–1.21) | |||||
| Other | 60 (4%) | 92 | 1.80 (1.26–2.58) | |||||
| NHW | 971 (69%) | 212 | Reference Group | |||||
| Smoking History | No | 848 (60%) | 234 | Reference Group | ||||
| Yes | 567 (40%) | 187 | 1.22 (1.05–1.43) | 0.01 | ||||
| Tumor type | Brain** | 150 (11%) | 697 | 0.61 (0.46–0.80) | 1.65 × 10−8 | |||
| Breast | 136 (10%) | 214 | 0.86 (0.67–1.11) | |||||
| Colon/Rectum | 141 (10%) | 174 | 0.91 (0.69–1.19) | |||||
| Hematologic | 201 (14%) | 707 | 0.48 (0.37–0.63) | |||||
| Lung | 160 (11%) | 146 | 1.15 (0.89–1.48) | |||||
| Cutaneous | 90 (6%) | 535 | 0.59 (0.40–0.86) | |||||
| Other | 537 (38%) | 177 | Reference Group | |||||
| TMB Level | Low (≤5 mutations/Mb) | 960 (68%) | 238 | Reference Group | ||||
| Intermediate (≥6 and <20 mutations/Mb) | 348 (25%) | 174 | 1.44 (1.21–1.71) | 1.8 × 10−4 | ||||
| High (≥20 and <50 mutations/Mb) | 58 (4%) | 195 | 1.12 (0.75–1.67) | |||||
| Very High (≥50 mutations/Mb) | 49 (3%) | 350 | 0.73 (0.43–1.25) | |||||
| Variable | Group | Hazard ratio (95% CI) | p* multivariate | Bootstrap*** p multivariate | ||||
| Age | <60 years | Reference Group | ||||||
| ≥60 years | 1.54 (1.30 – 1.84) | 9.42 × 10−7 | 6.1 × 10−4 | |||||
| Smoking history | No | Reference Group | ||||||
| Yes | 1.15 (0.98 – 1.36) | 0.09 | 0.20 | |||||
| Ethnicity | African-American | 1.06 (0.70 – 1.60) | 0.78 | 0.49 | ||||
| Asian | 1.30 (1.00 – 1.67) | 0.05 | 0.15 | |||||
| Hispanic | 1.11 (0.87 – 1.42) | 0.41 | 0.43 | |||||
| Other | 1.71 (1.19 – 2.47) | 3.9 × 10−3 | 0.05 | |||||
| NHW | Reference Group | |||||||
| Tumor type | Brain | 0.61 (0.46 – 0.81) | 7.3 × 10−4 | 0.02 | ||||
| Breast | 0.93 (0.72 – 1.20) | 0.58 | 0.45 | |||||
| Colon/Rectum | 0.94 (0.71 – 1.25) | 0.66 | 0.48 | |||||
| Hematologic | 0.49 (0.37 – 0.64) | 2.2 × 10−7 | 2.2 × 10−4 | |||||
| Lung | 0.97 (0.75 – 1.27) | 0.84 | 0.49 | |||||
| Cutaneous | 0.76 (0.50 – 1.15) | 0.19 | 0.29 | |||||
| Other | Reference Group | |||||||
| TMB Level | Low (≤5 mutations/Mb) | Reference Group | ||||||
| Intermediate (≥6 and <20 mutations/Mb) | 1.29 (1.07 – 1.54) | 5.4 × 10−3 | 0.05 | |||||
| High (≥20 and <50 mutations/Mb) | 0.98 (0.63 – 1.50) | 0.90 | 0.49 | |||||
| Very High (≥50 mutations/Mb) | 0.65 (0.36 – 1.35) | 0.15 | 0.25 | |||||
Abbreviations: CI = confidence interval; OS = survival; TMB = tumor mutational burden; NHW = Non-Hispanic White
Bolded p values represent p ≤ 0.05, or equivalent significance with Bonferroni correction for multiple hypotheses as appropriate in multivariate analysis. Results demonstrated that tiered TMB confers an increased risk of death with intermediate-range TMB, which returns to baseline risk at higher levels, even trending towards a protective effect at “high” and “very high” TMB tier (Supplemental Table 1 is a similar analysis that however includes immunotherapy treated patients). p-value for multi-level factor variables in univariable analysis derived from likelihood ratio test.
All survival data is calculated from the time of advanced disease; patients with local disease only were not included in the analysis unless they had brain tumors or hematologic malignancies which were considered advanced disease at diagnosis.
Brain tumors included 83 high-grade tumors, 70 grade III or less, and 7 non-glial tumors.
Bootstrapped p values were generated using random resampling to create 1000 computer generated datasets