Table 2. Distribution of CIMP-high or CIMP-low/negative according to
clinicopathologic variables. Logistic regression was used for statistical analysis3.
Variable, N (%)
CIMP-high CRC (N = 45)
CIMP-low/negative CRC (N = 248)
OR (95% CI)
high vs.
low/negative
p-value
Age (years)
< 50 14 (31.1) 75 (30.2) reference
≥ 50 31 (68.9) 173 (69.8) 0.96 (0.48-1.91) 0.91 Sex
Male 22 (48.9) 135 (54.4) reference
Female 23 (51.1) 113 (45.6) 1.25 (0.66-2.36) 0.49 Stage†
1 7 (15.6) 41 (16.5) reference
2 8 (17.8) 72 (29.0) 0.65 (0.22-1.93) 0.44
3 17 (37.8) 96 (37.1) 1.08 (0.42-2.81) 0.87 4 13 (28.9) 39 (17.3) 1.77 (0.64-4.88) 0.27 Histology
Mucinous
adenocarcinoma 3 (6.8) 8 (3.2) reference Not mucinous
adenocarcinoma 42 (93.3) 240 (96.8) 0.41 (0.10-1.64) 0.21 Tumor grade
Low 39 (86.7) 230 (92.7) reference
High 5 (11.1) 13 (5.2) 2.27 (0.77-6.72) 0.14
Missing 1 (2.2) 5 (2.0) NA
Primary tumor side††
Left-sided 18 (40.0) 126 (50.8) reference
Rectum 5 (11.1) 51 (20.6) 0.69 (0.24-1.95) 0.48 Right-sided 22 (48.9) 71 (28.6) 2.17 (1.09-4.31) 0.03 RAS
Wild type 28 (62.2) 158 (63.7) reference
KRAS Mutation 16 (35.5) 83 (33.5) 1.09 (0.56-2.12) 0.81 NRAS Mutation
1 (2.2) 2 (0.8) 2.82
(0.25-32.17) 0.40
Abbreviations: CIMP, CpG island methylator phenotype; OR, odds ratio; CI, confidence interval; MSI, microsatellite instability
† By the American Joint Cancer Committee on Cancer (AJCC) system, 7th edition.
†† The right-sided colon is defined as the cecum to the splenic flexure of the colon. The left-sided colon is defined as the region from the descending colon to sigmoid colon.
Missing 0 (0.0) 5 (2.0) NA
BRAF V600E
Wild type 26 (57.8) 238 (96.0) reference Mutation
18 (40.0) 4 (1.6) 41.19
(12.96-130.95) < 0.01
Missing 1 (2.2) 6 (2.4) NA
MSI
Low/stable 31 (68.9) 229 (93.1) reference High
14 (31.1) 17 (6.9) 6.08
(2.73-13.55) < 0.01
Missing 0 (0.0) 2 (0.8) NA
Table 3.Distribution of CIMP-high or CIMP-low/negative according to clinicopathologic variables stratified by age. Chi-square test, and Fisher’s exact test were used for statistical analysis3.
Age<50 Age≧50
Variable, N (%) CIMP-high CRC CIMP-low/negative CRC p-value CIMP-high CRC CIMP-low/negative CRC p-value
(N =14) (N = 75) (N = 31) (N =173 )
Sex
Male 8 (57.1) 47 (62.7) 14 (45.2) 88 (50.9)
Female 6 (42.9) 28 (37.3) 0.70 17 (54.8) 85 (49.1) 0.56
Stage†
1-3 5 (35.7) 59 (74.7) 27 (87.1) 149 (86.1)
4 9 (64.3) 16 (25.3) < 0.01F 4 (12.9) 24 (13.9) 1.00F
Histology
Mucinous adenocarcinoma 1 (7.1) 2 (2.7) 2 (6.5) 5 (2.9)
Not Mucinous adenocarcinoma 13 (92.9) 73 (97.3) 0.41F 29 (93.6) 167 (97.1) 0.29F
Tumor grade
Low 11 (78.6) 69 (92.0) 28 (90.3) 161 (93.1)
High 2 (14.3) 4 (5.3) 0.22 F 3 (9.7) 9 (5.2) 0.40 F
Missing 1 (7.1) 2 (2.7) 0 (0.0) 3 (1.7)
Primary tumor side††
Left-sided + rectum 9 (64.3) 60 (80.0) 14 (45.2) 117 (67.6)
Right-sided 5 (35.7) 15 (20.0) 0.29 F 17 (54.8) 56 (32.4) 0.02
RAS
Wild type 9 (64.3) 50 (66.7) 19 (61.3) 108 (62.4)
Mutation 5 (35.7) 23 (30.7) 0.76 F 12 (38.7) 62 (35.8) 0.81
Missing 0 (0.0) 2 (2.7) 0 (0.0) 3 (1.7)
BRAF V600E
Wild type 8 (57.1) 71 (94.7) 18 (58.1) 167 (96.5)
Mutation 6 (42.9) 2 (2.7) <0.01 F 12 (38.7) 2 (1.2) <0.01 F
Missing 0 (0.0) 2 (2.7) 0 (0.0) 3 (1.7)
MSI
Low/stable 11 (78.6) 69 (92.0) 20 (64.5) 160 (93.6)
High 3 (21.4) 6 (8.0) 0.15F 11 (35.5) 11 (6.4) <0.01 F
Missing 0 (0.0) 0 (0.0) 0 (0.0) 2 (1.2)
Abbreviations: CIMP, CpG island methylator phenotype; OR, odds ratio; CI, confidence interval; MSI, microsatellite instability.
FFisher’s exact test
Table 4. Distribution of CIMP-high or CIMP-low/negative according to risk factors of CRC in overall patients and stratified by age. Logistic regression was used for statistical analysis3.
Overall Age<50 Age≧50
Variable, N (%)
CIMP-high CRC CIMP-low/negative
CRC
OR (95% CI) p-value
CIMP-high CRC
CIMP-low/negative CRC
OR (95% CI)
p-value CIMP-high CRC
CIMP-low/negative CRC
OR (95% CI)
p-value
(N =45) (N =248) high vs. low/negative
(N =14) (N =75 )
high vs.
low/negative
(N = 31) (N = 173)
high vs.
low/negative Family history
None 42 (93.3) 218 (87.9) reference 13 (92.9) 68 (90.7) reference 29 (93.55) 150 (86.7) reference
Yes
3 (6.7) 30 (12.1) 0.52 (0.15-1.7
8)
0.30
1 (7.1) 7 (9.3) 0.75 (0.09-6.60)
0.79
2 (6.45) 23 (13.3) 0.45 (0.10-2.01) 0.30
Colorectal polyp
0 32 (71.1) 209 (85.3) reference 12 (85.7) 70 (93.3) reference 20 (64.5) 139 (81.8) reference
≥ 1 13 (28.9) 36 (14.7) 2.36 (1.13-4.92) 0.02 2 (14.3) 5 (6.7) 2.33 (0.41-13.43) 0.34 11 (35.5) 31 (18.2) 2.47 (1.07-5.67) 0.03
BMI at diagno sis (kg/m2), WHO criteria
< 25 29 (64.4) 162 (65.7) reference 7 (50.0) 51 (68.0) reference 22 (71.0) 112 (64.7) reference
25-29 14 (31.1) 70 (28.2) 1.12 (0.56-2.26) 0.74 6 (42.9) 18 (24.0) 2.43 (0.72-8.19) 0.15 8 (25.8) 52 (30.1) 0.78 (0.33-1.88) 0.58
≥ 30 2 (4.4) 15 (6.1) 0.75 (0.16-3.45) 0.71 1 (7.1) 6 (8.0) 1.21 (0.13-11.63) 0.87 1 (3.2) 9 (5.2) 0.57 (0.07-4.69) 0.60
BMI at diagno sis (kg/m2)
< 27.5 37 (82.2) 205 (82.7) reference 9 (64.3) 63 (84.0) reference 28 (90.3) 142 (82.1) reference
≥ 27.5 8 (17.8) 43 (17.3) 1.03 (0.45-2.37) 0.94 5 (35.7) 12 (16.0) 2.92 (0.83-10.24) 0.09 3 (9.7) 31 (17.9 0.49 (0.14-1.72) 0.27
DM
None 37 (82.2) 201 (81.4) reference 14 (100.0) 72 (96.0) reference 23 (74.2) 129 (75.0) reference
Yes 8 (17.8) 46 (18.6) 0.95 (0.41-2.16) 0.89 0 (0.0) 3 (4.0) NA 0.98 8 (25.8) 43 (25.0) 1.04 (0.43-2.51) 0.92
Hyperlipidemia
None 31 (68.9) 189 (76.2) reference 13 (92.9) 64 (85.3) reference 18 (58.1) 125 (72.25) reference
Yes 14 (31.1) 59 (23.8) 1.45 (0.72-2.90) 0.30 1 (7.1) 11 (14.7) 0.45 (0.05-3.77) 0.46 13 (41.9) 48 (27.75) 1.88 (0.86-4.13) 0.12
NSAIDs use
None 41 (91.1) 234 (94.7) reference 13 (92.9) 75 (100.0) reference 28 (90.3) 159 (92.4) reference
Yes 4 (8.9) 13 (5.3) 1.76 (0.55-5.65) 0.35 1 (7.1) 0 (0.0) NA 0.99 3 (9.7) 13 (7.6) 1.31 (0.35-4.90) 0.69
HRT
None 45 (100.0) 243 (98.4) reference 14 (100.0) 75 (100.0) reference 31 (100.0) 168 (97.7) reference
Yes 0 (0.0) 4 (1.6) NA NA 0 (0.0) 0 (0.0) NA NA 0 (0.0) 4 (2.3) NA 0.98
Abbreviations: CIMP, CpG island methylator phenotype; OR, odds ratio; CI, confidence interval; BMI, body mass index; DM, diabetes mellitus; NSAIDs, non-steroidal anti-inflammatory drugs; HRT, hormone replacement therapy; WHO, world health organization.
Table 5. Multivariate analysis for the association between CIMP-high CRC and clinicopathological variables in overall patients, patients with age < 50y and age ≥ 50y3.
Overall Age < 50y Age ≥ 50y
Variable, N (%) OR (95% CI) p-value OR (95% CI) p-value OR (95% CI) p-value
high vs. low/negative high vs. low/negative high vs. low/negative Primary tumor site as
right-sided 1.55 (0.67-3.60) 0.30 1.62 (0.69-3.82) 0.27
MSI-high 5.64 (2.06-15.45) <0.01 5.86 (2.07-16.60) <0.01
Colorectal polyp 1.33 (0.49-3.61) 0.58 1.38 (0.54-3.58) 0.50
BRAF V600E 38.86 (11.60-130.12) <0.01
Stage IV at diagnosis 10.021 (2.430-41.326) <0.01
BMI (≥ 27.5 kg/m2) 5.657 (1.211-26.418) 0.03
BRAF V600E mutation was excluded in multivariate logistic regression in patients with age <50y and age ≥ 50y because of few events were noted.
Abbreviations: CIMP, CpG island methylator phenotype; OR, odds ratio; CI, confidence interval; BMI, body mass index.
Table 6.Distribution of CIMP-high or CIMP-low/negative according to clinicopathologic variables stratified by gender. Chi-square test, and Fisher’s exact test were used for statistical analysis3.
Male Female
Variable, N (%) CIMP-high CRC CIMP-low/negative CRC p-value CIMP-high CRC CIMP-low/negative CRC p-value
(N =22) (N = 135) (N = 23) (N =113)
Age
<50 8 (36.4) 47 (34.8) 6 (26.1) 28 (24.8)
≧50 14 (63.6) 88 (65.2) 0.89 17 (73.9) 85 (75.2) 0.89
Stage†
1-3 15 (68.2) 115 (85.2) 17 (73.9) 94 (83.2)
4 7 (31.8) 20 (14.8) 0.07F 6 (26.1) 19 (16.8) 0.37F
Histology
Mucinous adenocarcinoma 2 (9.1) 5 (3.7) 1 (4.4) 2 (1.8)
Not Mucinous adenocarcinoma 20 (90.9) 130 (96.3) 0.25F 22 (95.7) 110 (98.2) 0.43F
Tumor grade
Low 19 (86.4) 124 (91.9) 20 (87.0) 106 (93.8)
High 2 (9.1) 6 (4.4) 0.31 F 3 (13.0) 7 (6.2) 0.37 F
Missing 1 (4.5) 5 (3.7) 0 (0.0) 0 (0.0)
Primary tumor side††
Left-sided and rectum 12 (54.6) 98 (72.6) 11 (47.8) 79 (30.1)
Right-sided 10 (45.5) 37 (27.4) 0.13 12 (52.2) 34 (69.9) 0.04
RAS
Wild type 10 (45.5) 89 (65.9) 18 (78.3) 69 (61.1)
Mutation 12 (54.6) 42 (31.1) 0.04 5 (21.7) 43 (38.1) 0.13
Missing 0 (0.0) 4 (3.0) 0 (0.0) 1 (0.9)
BRAF V600E
Wild type 14 (63.6) 127 (94.1) 12 (52.2) 111 (98.2)
Mutation 7 (31.8) 3 (2.2) <0.01 F 11 (47.8) 1 (0.9) <0.01 F
Missing 1 (4.5) 5 (3.7) 0 (0.0) 1 (0.9)
MSI
Low/stable 16 (72.7) 125 (92.6) 15 (65.2) 104 (92.0)
High 6 (27.3) 8 (5.9) <0.01F 8 (34.8) 9 (8.0) <0.01 F
Missing 0 (0.0) 2 (1.5) 0 (0.0) 0 (0.0)
Abbreviations: CIMP, CpG island methylator phenotype; OR, odds ratio; CI, confidence interval; MSI, microsatellite instability.
FFisher’s exact test.
Table 7. Distribution of CIMP-high or CIMP-low/negative according to risk factors of CRC stratified by gender. Logistic regression was used for statistical analysis3.
Male Female
Variable, N (%) CIMP-high CRC CIMP-low/negative CRC OR (95% CI) p-value CIMP-high CRC CIMP-low/negative CRC OR (95% CI) p-value
(N =14) (N =75) high vs. low/negative (N = 31) (N = 173) high vs. low/negative
Family history
None 21
(95.5) 113 (83.7) reference 21 (91.3) 105 (92.9) reference
Yes 1 (4.6) 22 (16.3) 0.25 (0.03-1.91) 0.18 2 (8.7) 8 (7.08) 1.25 (0.25-6.31) 0.79
Colorectal polyp
0 16 (72.7) 110 (82.7) reference 16 (69.6) 99 (88.4) reference
≥ 1 6 (27.3) 23 (17.3) 1.79 (0.63-5.08) 0.27 7 (30.4) 13 (11.6) 3.33 (1.16-9.62) 0.03
BMI (kg/m2) at diagnosis, WHO criteria
< 25 13 (59.1) 78 (57.8) reference 16 (69.6) 85 (75.2) reference
25-29 7 (31.8) 49 (36.3) 0.857 0.76 7 (30.4) 21 (18.6) 1.771 0.27
≥ 30 2 (9.1) 8 (5.9) 1.500 0.63 0 (0.0) 7 (6.2) NA NA
BMI (kg/m2) at diagnosis
< 27.5 17 (77.3) 109 (80.7) reference 20 (87.0) 96 (85.0) reference
≥ 27.5 5 (22.7) 26 (19.3) 1.233 0.70 3 (13.0) 17 (15.0) 0.847 0.80
DM
None 17 (77.3) 114 (85.1) reference 20 (87.0) 87 (77.0) reference
Yes 5 (22.7) 20 (14.9) 1.68 (0.56-2.06) 0.36 3 (13.0) 26 (23.0) 0.50 (0.14-1.82) 0.30
Hyperlipidemia
None 16 (72.7) 104 (77.0) reference 15 (65.2) 85 (75.2) reference
Yes 6 (27.3) 31 (23.0) 1.26 (0.45-3.497) 0.66 8 (34.8) 28 (24.8) 1.62 (0.62-4.22) 0.32
NSAIDs use
None 21 (95.5) 128 (94.8) reference 20 (87.0) 106 (94.6) reference
Yes 1 (4.6) 7 (5.2) 0.87 (0.10-7.44) 0.90 3 (13.0) 6 (5.4) 2.65 (0.61-11.48) 0.19
Yes 0 (0.0) 0 (0.0) NA NA 0 (0.0) 4 (3.6) NA 0.98 Abbreviations: CIMP, CpG island methylator phenotype; OR, odds ratio; CI, confidence interval; BMI, body mass index; DM, diabetes mellitus; NSAIDs, non-steroidal anti-inflammatory drugs; HRT, hormone replacement therapy; WHO, world health organization.
Table 8. Clinicopathological features in patients with BRAF V600E-mutated colorectal cancer124.
Abbreviations: MSS: microsatellite stable; NA: not available
†One patient had adenocarcinoma rich in signet ring cells.
Characteristic De novo metastatic MSS, N= 54 (100%) Age (years)
Median 51
Range 26-79
Sex
Male 30 (55.6)
Female 24 (44.4)
Stage
1-3 0 (0)
4 54 (100)
Histology
Adenocarcinoma† 54 (100) Mucinous adenocarcinoma 0 (0) Tumor grade
Low 43 (79.6)
High 10 (18.5)
Missing 1 (1.9)
Location of primary tumor
Left-sided 20 (37.0)
Right-sided 34 (63.0)
Metastatic site
Liver-limited 14 (25.9)
Peritoneum 23 (42.6)
First-line chemotherapy
Triplet 8 (14.8)
Doublet 41 (75.9)
Fluoropyrimidine
monotherapy 3 (5.6)
No 2 (3.7)
First-line targeted therapy
Bevacizumab 29 (53.7)
Cetuximab 8 (14.8)
Table 9. Immune cells in Cox proportional hazard model for hazard ratios of progression-free survival and overall survival in patients with de novo metastatic MSS BRAF V600E-mutated CRC124.
Progression-free survival Overall survival
Immune cell HR (95% CI) p -value HR (95% CI) p -value
B cell 0.72 (0.52-0.98) 0.039 1.08 (0.78-1.50) 0.631 CD4 T cell 0.61 (0.43-0.86) 0.005 0.83 (0.59-1.16) 0.276 CD8 T cell 1.03 (0.77-1.39) 0.842 0.96 (0.68-1.37) 0.832 Cytotoxic cell 1.19 (0.89-1.59) 0.251 1.01 (0.75-1.37) 0.937 Dendritic cell 1.19 (0.86-1.64) 0.290 1.41 (0.98-2.02) 0.061 Exhausted CD8 1.11 (0.82-1.51) 0.500 1.08 (0.77-1.52) 0.653 Macrophage 1.14 (0.87-1.47) 0.340 1.11 (0.84-1.48) 0.463 Mast cell 0.99 (0.71-1.37) 0.944 1.20 (0.87-1.67) 0.270 Neutrophil 1.08 (0.81-1.43) 0.602 1.05 (0.76-1.44) 0.781 NK CD56dim cell 1.05 (0.74-1.48) 0.793 1.06 (0.75-1.52) 0.725 NK cell 1.05 (0.79-1.38) 0.746 1.15 (0.86-1.55) 0.350 T cell 0.91 (0.66-1.25) 0.552 0.90 (0.64-1.26) 0.536 Th1 cell 1.03 (0.76-1.40) 0.848 0.99 (0.71-1.38) 0.968
Treg 0.90 (0.64-1.27) 0.538 0.98 (0.73-1.32) 0.918
Abbreviation: CI: confidence interval; HR: hazard ratio. NK: natural killer; Th1: T helper 1; Treg: T regulatory cell
Table 10. Immune checkpoints link to B and T cell signaling in Cox proportional hazard model for hazard ratios of progression-free survival and overall survival in patients with de novo metastatic MSS BRAF V600E-mutated CRC124.
Abbreviation: CI: confidence interval; HR: hazard ratio.
Progression-free survival Overall survival
Checkpoints HR (95% CI) p-value HR (95% CI) p-value
CD40LG 0.73 (0.49-1.10) 0.136 0.62 (0.43-0.89) 0.01
CD40 1.12 (0.81-1.56) 0.503 1.61 (0.87-1.56) 0.319
CD80 1.09 (0.78-1.51) 0.631 1.01 (0.75-1.36) 0.946
CD86 1.1 (0.81-1.50) 0.541 1.11 (0.84-1.47) 0.476
ICOS 0.92 (0.68-1.24) 0.589 0.71 (0.51-0.977) 0.035 ICOSLG 0.69 (0.49-0.97) 0.034 1.03 (0.73-1.45) 0.888 CD274 1.25 (0.87-1.77) 0.224 1.19 (0.86-1.66) 0.301 PDCD1 0.81 (0.56-1.18) 0.273 0.93 (0.68-1.28) 0.661
CD28 0.93 (0.63-1.37) 0.705 0.99 (0.72-1.39) 0.992
CTLA4 0.82 (0.6-1.12) 0.215 0.74 (0.53-1.04) 0.086
Table 11. Complement genes in the Cox proportional hazards model for hazard ratios of progression-free survival and overall survival in patients with de novo metastatic MSS BRAF V600E mutant CRC124.
Progression-free survival Overall survival
Complement genes HR (95% CI) p -value HR (95% CI) p -value
Classical pathway
C1S 1.54 (1.10, 2.14) 0.010 1.18 (0.81, 1.72) 0.378
C1R 1.46 (1.03, 2.06) 0.030 1.15 (0.77, 1.70) 0.490
C1QA 1.35 (0.99, 1.84) 0.050 1.52 (1.04, 2.22) 0.029
C1QB 1.33 (0.98, 1.80) 0.062 1.37 (0.97, 1.91) 0.068
C1QBP 0.84 (0.62, 1.14) 0.279 0.85 (0.60, 1.19) 0.352
C2 1.00 (0.75, 1.32) 0.984 1.28 (0.96, 1.70) 0.090
C4B 1.00 (0.74, 1.35) 0.971 1.06 (0.77, 1.44) 0.732
Lectin pathway
MBL2 1.26 (0.93, 1.72) 0.129 1.46 (1.04, 2.04) 0.027
MASP1 1.09 (0.78, 1.43) 0.507 1.24 (0.73, 1.45) 0.154
MASP2 0.76 (0.54, 1.05) 0.106 0.96 (0.65, 1.40) 0.845
Alternative pathway
CFB 0.93 (0.69, 1.26) 0.679 1.07 (0.77, 1.46) 0.684
CFD 0.75 (0.54, 1.03) 0.077 1.02 (0.76, 1.37) 0.875
Complement regulators
CD46 0.93 (0.69, 1.26) 0.657 0.82 (0.58, 1.15) 0.264
CD55 0.97 (0.70, 1.34) 0.876 0.68 (0.46, 1.00) 0.053
CFI 1.20 (0.91, 1.60) 0.187 1.02 (0.75, 1.39) 0.884
CFP 1.01 (0.53, 1.03) 0.967 0.78 (0.65, 1.41) 0.226
SERPING1 1.64 (1.18, 2.27) 0.003 1.20 (0.83, 1.72) 0.331
CD59 1.09 (0.82, 1.45) 0.537 1.47 (1.61, 2.02) 0.020
CR1 1.01 (0.69, 1.46) 0.976 1.54 (0.51, 1.17) 0.009
C4BPA 0.68 (0.84, 1.44) 0.013 0.92 (0.92, 1.66) 0.611
Terminal pathway
C3 1.28 (0.91, 1.79) 0.147 1.29 (0.87, 1.90) 0.198
C5 1.24 (0.90, 1.70) 0.181 1.01 (0.74, 1.32) 0.925
C6 1.06 (0.68, 1.18) 0.701 1.03 (0.66, 1.25) 0.851
C7 1.19 (0.87, 1.63) 0.250 0.90 (0.62, 1.27) 0.538
C8A 1.11 (0.81, 1.54) 0.493 1.00 (0.65, 1.52) 0.988
C8B 0.92 (0.63, 1.35) 0.696 0.86 (0.55, 1.32) 0.497
C9 0.89 (0.65, 1.24) 0.521 0.96 (0.67, 1.36) 0.834
Complement receptors
ITGB2 0.99 (0.73, 1.33) 0.957 1.11 (0.80, 1.52) 0.518
ITGAX 0.90 (0.68, 1.18) 0.458 0.91 (0.66, 1.25) 0.563
ITGAM 1.13 (0.86, 1.49) 0.364 1.16 (0.86, 1.55) 0.334
C3AR1 1.07 (0.81, 1.41) 0.617 1.27 (0.93, 1.71) 0.119
CR2 0.74 (0.50, 0.92) 0.081 0.96 (0.65, 1.28) 0.829
Abbreviation: CI: confidence interval; CRC: colorectal cancer. HR: hazard ratio. OS: overall survival. PFS:
progression-free survival.
Table 12. Univariate and multivariate analyses through a Cox proportional hazards model for hazard ratios of progression-free survival and overall survival in patients with de novo metastatic MSS BRAF V600E mutant CRC124.
Progression-free survival Overall survival
Variable Univariate analysis Multivariate analysis Univariate analysis Multivariate analysis
HR (95% CI) p -value HR (95% CI) p -value (BH correction)
HR (95% CI) p -value HR (95% CI) p -value (BH correction) Complement score (High) 1.91 (1.06-3.44)) 0.032 1.62 (0.88-2.98) 0.123
(0.123)
2.35 (1.24-4.48) 0.009 2.44 (1.26-4.70) 0.008 (0.008)
Sex (Male) 1.56 (0.85-2.97) 0.15 1.18 (0.62-2.23) 0.61
Primary tumor site (Right) 0.81 (0.42-1.56) 0.52 0.97 (0.48-1.99) 0.94
Tumor grade (High) 1.90 (0.86-4.17) 0.11 4.52 (1.99-10.3) < 0.001 5.00 (2.14-11.7) < 0.001
(0.002)
Liver-limited metastasis 0.90 (0.49-1.63) 0.72 1.04 (0.55-1.98) 0.89
Peritoneum metastasis 0.83 (0.35-1.99) 0.68 0.42 (0.15-1.22) 0.11
First-line chemotherapy doublet vs.
fluoropyrimidine monotherapy
2.14 (1.10-4.14) 0.02 2.08 (1.03-4.17) 0.040 (0.067)
1.24 (0.61-2.49) 0.55
First-line chemotherapy triplet vs.
fluoropyrimidine monotherapy
0.81 (0.44-1.49) 0.50 1.05 (0.56-1.99) 0.88
First-line targeted therapy – Bevacizumab
0.37 (0.11-1.25) 0.11 0.28 (0.08-1.00) 0.050 (0.067)
0.44 (0.13-1.48) 0.18
First-line targeted 0.26 (0.06-1.08) 0.063 0.20 (0.05-0.90) 0.035 0.37 (0.09-1.60) 0.18
Benjamini & Hochberg multiple testing correction method