TABLE 4.
Univariable and multivariable‐adjusted hazard ratios for associations between Warburg‐subtypes and survival of colorectal cancer patients within the Netherlands Cohort Study (NLCS, 1986‐2006) in mutational subgroups
| N | CRC‐specific survival | Overall survival | |||||
|---|---|---|---|---|---|---|---|
| CRC deaths n (%) | HR (95% CI) | Deaths n (%) | HR (95% CI) | ||||
| Univariable | Multivariable‐adjusted * | Univariable | Multivariable‐adjusted * | ||||
| Total | |||||||
| Warburg‐low | 646 | 241 (37.3) | 1.00 (ref) | 1.00 (ref) | 393 (60.8) | 1.00 (ref) | 1.00 (ref) |
| Warburg‐moderate | 820 | 343 (41.8) | 1.15 (0.98‐1.36) | 1.07 (0.91‐1.26) | 526 (64.1) | 1.09 (0.96‐1.24) | 1.05 (0.92‐1.20) |
| Warburg‐high | 802 | 346 (43.1) | 1.26 (1.07‐1.49) | 1.16 (0.98‐1.37) | 550 (68.6) | 1.25 (1.10‐1.43) | 1.20 (1.05‐1.36) |
| All‐wild‐type+pMMR | |||||||
| Warburg‐low | 285 | 97 (34.0) | 1.00 (ref) | 1.00 (ref) | 173 (60.7) | 1.00 (ref) | 1.00 (ref) |
| Warburg‐moderate | 300 | 112 (37.3) | 1.07 (0.82‐1.41) | 0.99 (0.75‐1.31) | 177 (59.0) | 0.95 (0.77‐1.17) | 0.94 (0.76‐1.16) |
| Warburg‐high | 242 | 93 (38.4) | 1.22 (0.92‐1.62) | 0.98 (0.72‐1.32) | 163 (67.4) | 1.22 (0.98‐1.51) | 1.10 (0.88‐1.38) |
| KRAS mut + pMMR | |||||||
| Warburg‐low | 128 | 55 (43.0) | 1.00 (ref) | 1.00 (ref) | 81 (63.3) | 1.00 (ref) | 1.00 (ref) |
| Warburg‐moderate | 226 | 104 (46.0) | 1.08 (0.78‐1.50) | 1.06 (0.76‐1.48) | 149 (65.9) | 1.06 (0.81‐1.39) | 1.00 (0.76‐1.32) |
| Warburg‐high | 200 | 105 (52.5) | 1.39 (1.00‐1.92) | 1.31 (0.94‐1.84) | 147 (73.5) | 1.35 (1.03‐1.78) | 1.27 (0.96‐1.68) |
| KRAS mut + PIK3CA mut + pMMR | |||||||
| Warburg‐low | 48 | 22 (45.8) | 1.00 (ref) | 1.00 (ref) | 30 (62.5) | 1.00 (ref) | 1.00 (ref) |
| Warburg‐moderate | 69 | 31 (44.9) | 1.04 (0.60‐1.80) | 1.25 (0.70‐2.23) | 46 (66.7) | 1.11 (0.70‐1.76) | 1.30 (0.81‐2.11) |
| Warburg‐high | 51 | 21 (41.2) | 0.95 (0.52‐1.72) | 0.95 (0.48‐1.88) | 32 (62.7) | 1.03 (0.63‐1.70) | 1.07 (0.62‐1.86) |
| PIK3CA mut + pMMR | |||||||
| Warburg‐low | 43 | 16 (37.2) | 1.00 (ref) | 1.00 (ref) | 22 (51.2) | 1.00 (ref) | 1.00 (ref) |
| Warburg‐moderate | 36 | 14 (38.9) | 1.14 (0.56‐2.34) | 0.63 (0.28‐1.43) | 25 (69.4) | 1.57 (0.88‐2.79) | 1.22 (0.65‐2.27) |
| Warburg‐high | 39 | 12 (30.8) | 0.88 (0.41‐1.85) | 0.92 (0.39‐2.17) | 27 (69.2) | 1.50 (0.86‐2.64) | 1.59 (0.85‐2.97) |
| BRAF mut + pMMR | |||||||
| Warburg‐low | 24 | 12 (50.0) | 1.00 (ref) | 1.00 (ref) | 18 (75.0) | 1.00 (ref) | 1.00 (ref) |
| Warburg‐moderate | 38 | 27 (71.1) | 1.49 (0.76‐2.95) | 1.22 (0.59‐2.50) | 31 (81.6) | 1.15 (0.64‐2.05) | 0.99 (0.53‐1.83) |
| Warburg‐high | 82 | 51 (62.2) | 1.16 (0.62‐2.18) | 1.42 (0.74‐2.71) | 61 (74.4) | 0.92 (0.54‐1.55) | 1.13 (0.65‐1.95) |
| BRAF mut + dMMR | |||||||
| Warburg‐low | 32 | 10 (31.3) | 1.00 (ref) | 1.00 (ref) | 16 (50.0) | 1.00 (ref) | 1.00 (ref) |
| Warburg‐moderate | 39 | 13 (33.3) | 1.03 (0.45‐2.35) | 1.46 (0.61‐3.54) | 24 (61.5) | 1.18 (0.63‐2.22) | 1.52 (0.78‐2.96) |
| Warburg‐high | 61 | 21 (34.4) | 1.13 (0.53‐2.40) | 1.41 (0.60‐3.31) | 42 (68.9) | 1.44 (0.81‐2.56) | 1.54 (0.83‐2.87) |
| Other + pMMR | |||||||
| Warburg‐low | 63 | 28 (44.4) | 1.00 (ref) | 1.00 (ref) | 42 (66.7) | 1.00 (ref) | 1.00 (ref) |
| Warburg‐moderate | 75 | 33 (44.0) | 1.06 (0.64‐1.75) | 1.18 (0.70‐1.99) | 54 (72.0) | 1.19 (0.79‐1.78) | 1.30 (0.85‐1.97) |
| Warburg‐high | 73 | 30 (41.1) | 0.91 (0.55‐1.53) | 0.95 (0.55‐1.64) | 48 (65.8) | 0.98 (0.65‐1.48) | 1.02 (0.66‐1.58) |
| Other + dMMR | |||||||
| Warburg‐low | 23 | 1 (4.3) | 1.00 (ref) | 1.00 (ref) | 11 (47.8) | 1.00 (ref) | 1.00 (ref) |
| Warburg‐moderate | 37 | 9 (24.3) | 7.18 (0.91‐56.75) | 5.03 (0.59‐42.62) | 20 (54.1) | 1.55 (0.74‐3.24) | 1.37 (0.63‐2.99) |
| Warburg‐high | 54 | 13 (24.1) | 7.09 (0.93‐54.27) | 8.13 (0.93‐71.34) | 30 (55.6) | 1.61 (0.80‐3.21) | 1.65 (0.78‐3.50) |
Abbreviations: CI, confidence interval; CRC, colorectal cancer; HR, hazard ratio; pMMR, mismatch repair proficient; dMMR, mismatch repair deficient.
*
Adjusted for age at diagnosis (years), sex (men/women), tumor location (colon/rectosigmoid/rectum), pTNM stage (I/II/III/IV/unknown), differentiation grade (well/moderate/poor/unknown), and adjuvant therapy (yes/no/unknown).