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 Age50

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 Age50

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

In document 大腸直腸癌預後學之研究- 著重表觀遺傳學和腫瘤微環境之解析 (Page 85-102)

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