Table 3.
Pack-years of cigarettes at diagnosis and colorectal cancer mortality in strata of levels of lymphocytic reaction patterns
| Characteristics | Colorectal cancer–specific mortalitya,b |
Overall mortalitya,b |
|||||
|---|---|---|---|---|---|---|---|
| No. of cases | No. of events | Univariate HR (95% CI) | Multivariable HR (95% CI)c | No. of events | Univariate HR (95% CI) | Multivariable HR (95% CI)c | |
| TIL (n = 1430) | |||||||
| Negative or low | |||||||
| Pack-years = 0 | 458 | 141 | 1.00 (referent) | 1.00 (referent) | 262 | 1.00 (referent) | 1.00 (referent) |
| Pack-years = 1-19 | 260 | 71 | 0.81 (0.60 to 1.10) | 0.75 (0.54 to 1.03) | 135 | 0.87 (0.68 to 1.10) | 0.81 (0.64 to 1.03) |
| Pack-years = 20-39 | 180 | 61 | 1.07 (0.78 to 1.47) | 0.98 (0.73 to 1.31) | 116 | 1.18 (0.91 to 1.52) | 1.22 (0.96 to 1.54) |
| Pack-years ≥40 | 169 | 68 | 1.40 (1.04 to 1.88) | 1.17 (0.86 to 1.58) | 130 | 1.66 (1.31 to 2.09) | 1.47 (1.16 to 1.86) |
| Intermediate or high | |||||||
| Pack-years = 0 | 142 | 36 | 1.00 (referent) | 1.00 (referent) | 80 | 1.00 (referent) | 1.00 (referent) |
| Pack-years = 1-19 | 81 | 11 | 0.51 (0.24 to 1.08) | 0.49 (0.22 to 1.08) | 36 | 0.81 (0.53 to 1.23) | 0.79 (0.52 to 1.21) |
| Pack-years = 20-39 | 69 | 12 | 0.50 (0.25 to 1.02) | 0.60 (0.28 to 1.29) | 40 | 0.88 (0.61 to 1.27) | 0.85 (0.59 to 1.22) |
| Pack-years ≥40 | 71 | 13 | 0.57 (0.29 to 1.11) | 0.49 (0.24 to 1.01) | 54 | 1.23 (0.88 to 1.71) | 1.10 (0.76 to 1.60) |
| Pinteractiond | .006 | .02 | .08 | .07 | |||
| Intratumoral periglandular reaction (n = 1430) | |||||||
| Negative or low | |||||||
| Pack-years = 0 | 80 | 41 | 1.00 (referent) | 1.00 (referent) | 54 | 1.00 (referent) | 1.00 (referent) |
| Pack-years = 1-19 | 35 | 13 | 0.58 (0.29 to 1.14) | 0.66 (0.34 to 1.31) | 18 | 0.92 (0.48 to 1.76) | 0.74 (0.41 to 1.34) |
| Pack-years = 20-39 | 34 | 17 | 1.01 (0.57 to 1.77) | 0.91 (0.52 to 1.60) | 24 | 1.76 (1.04 to 2.97) | 1.41 (0.87 to 2.26) |
| Pack-years ≥40 | 35 | 11 | 0.60 (0.29 to 1.23) | 0.61 (0.29 to 1.28) | 19 | 0.98 (0.50 to 1.92) | 0.78 (0.40 to 1.50) |
| Intermediate or high | |||||||
| Pack-years = 0 | 519 | 136 | 1.00 (referent) | 1.00 (referent) | 288 | 1.00 (referent) | 1.00 (referent) |
| Pack-years = 1-19 | 306 | 68 | 0.80 (0.59 to 1.10) | 0.70 (0.50 to 0.98) | 152 | 0.86 (0.69 to 1.06) | 0.79 (0.63 to 0.99) |
| Pack-years = 20-39 | 215 | 56 | 0.92 (0.66 to 1.28) | 0.87 (0.63 to 1.20) | 132 | 1.04 (0.83 to 1.30) | 1.05 (0.85 to 1.30) |
| Pack-years ≥40 | 206 | 71 | 1.34 (1.00 to 1.80) | 1.13 (0.82 to 1.55) | 166 | 1.63 (1.33 to 2.00) | 1.45 (1.16 to 1.80) |
| Pinteractiond | .13 | .22 | .54 | .33 | |||
| Peritumoral lymphocytic reaction (n = 1425) | |||||||
| Negative or low | |||||||
| Pack-years = 0 | 92 | 48 | 1.00 (referent) | 1.00 (referent) | 66 | 1.00 (referent) | 1.00 (referent) |
| Pack-years = 1-19 | 40 | 20 | 0.87 (0.49 to 1.54) | 1.11 (0.61 to 2.05) | 27 | 1.32 (0.75 to 2.34) | 1.04 (0.64 to 1.68) |
| Pack-years = 20-39 | 32 | 15 | 0.88 (0.48 to 1.59) | 1.08 (0.59 to 1.99) | 21 | 1.25 (0.71 to 2.20) | 1.36 (0.83 to 2.22) |
| Pack-years ≥40 | 38 | 18 | 0.77 (0.42 to 1.41) | 0.76 (0.42 to 1.35) | 25 | 0.91 (0.48 to 1.74) | 0.84 (0.48 to 1.47) |
| Intermediate or high | |||||||
| Pack-years = 0 | 506 | 129 | 1.00 (referent) | 1.00 (referent) | 276 | 1.00 (referent) | 1.00 (referent) |
| Pack-years = 1-19 | 298 | 61 | 0.75 (0.54 to 1.04) | 0.64 (0.46 to 0.91) | 142 | 0.82 (0.66 to 1.02) | 0.75 (0.60 to 0.95) |
| Pack-years = 20-39 | 216 | 58 | 0.96 (0.69 to 1.34) | 0.87 (0.63 to 1.20) | 135 | 1.09 (0.87 to 1.37) | 1.07 (0.87 to 1.33) |
| Pack-years ≥40 | 203 | 64 | 1.28 (0.94 to 1.74) | 1.08 (0.78 to 1.50) | 160 | 1.68 (1.38 to 2.04) | 1.45 (1.16 to 1.81) |
| Pinteractiond | .20 | .45 | .11 | .13 | |||
| Crohn’s-like lymphoid reaction (n = 1174) | |||||||
| Negative/low | |||||||
| Pack-years = 0 | 391 | 131 | 1.00 (referent) | 1.00 (referent) | 235 | 1.00 (referent) | 1.00 (referent) |
| Pack-years = 1-19 | 215 | 61 | 0.77 (0.55 to 1.06) | 0.73 (0.52 to 1.04) | 108 | 0.77 (0.59 to 1.01) | 0.79 (0.61 to 1.04) |
| Pack-years = 20-39 | 135 | 46 | 1.03 (0.73 to 1.46) | 1.06 (0.77 to 1.45) | 88 | 1.14 (0.85 to 1.52) | 1.25 (0.97 to 1.60) |
| Pack-years ≥40 | 148 | 54 | 1.14 (0.83 to 1.58) | 1.01 (0.72 to 1.42) | 113 | 1.44 (1.10 to 1.87) | 1.33 (1.01 to 1.75) |
| Intermediate/high | |||||||
| Pack-years = 0 | 98 | 20 | 1.00 (referent) | 1.00 (referent) | 53 | 1.00 (referent) | 1.00 (referent) |
| Pack-years = 1-19 | 70 | 6 | 0.33 (0.12 to 0.90) | 0.29 (0.10 to 0.84) | 30 | 0.75 (0.50 to 1.13) | 0.61 (0.40 to 0.94) |
| Pack-years = 20-39 | 58 | 9 | 0.58 (0.25 to 1.35) | 0.66 (0.28 to 1.55) | 31 | 0.91 (0.60 to 1.36) | 0.90 (0.60 to 1.35) |
| Pack-years ≥40 | 59 | 11 | 0.60 (0.28 to 1.31) | 0.54 (0.25 to 1.18) | 43 | 1.32 (0.93 to 1.86) | 1.13 (0.78 to 1.64) |
| Pinteractiond | .13 | .15 | .56 | .69 | |||
IPW was applied to reduce a bias due to the availability of tumor tissue after cancer diagnosis (see “Statistical Analysis” subsection for details). AJCC = American Joint Committee on Cancer; CI = confidence interval; HR = hazard ratio; IPW = inverse probability weighting; TIL = tumor-infiltrating lymphocytes.
Hazard ratios were estimated for each stratum on the basis of the patients with pack-years of cigarettes at diagnosis, using a reparameterization of the interaction term in a single regression model for the stratified analyses.
The multivariable Cox regression model initially included age, sex, year of diagnosis, family history of colorectal cancer, body mass index at diagnosis, alcohol consumption at diagnosis, physical activity at diagnosis, processed meat intake at diagnosis, total fiber intake at diagnosis, tumor location, tumor differentiation, AJCC disease stage, microsatellite instability, CpG island methylator phenotype, long interspersed nucleotide element-1 methylation level, KRAS mutation, BRAF mutation, and PIK3CA mutation. A backward elimination with a threshold of P = .05 was used to select variables in the final models.
P interaction was calculated using the Wald test for the cross-product of pack-years of cigarettes at diagnosis (ordinal; 0, 1-19, 20-39, and ≥40) and lymphocytic reaction status (binary; negative or low and intermediate or high) in Cox regression model.