Journal Name:European Journal of Epidemiology

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Title: Associations of red and processed meat intakewith major molecular pathological features of colorectal cancer

Journal name:European Journal of Epidemiology

Author names:Prudence R Carr1, Lina Jansen1, Stefanie Bienert1, Wilfried Roth2,3, Esther Herpel3,4, Matthias Kloor5, Hendrik Bläker6, Jenny Chang-Claude7, Hermann Brenner1,8,9, Michael Hoffmeister1

Affiliations:
1Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany
2Institute of Pathology, University Medical Center Mainz, Mainz, Germany.
3Institute of Pathology, Heidelberg University Hospital, Heidelberg, Germany
4 NCT Tissue Bank, National Center for Tumor Diseases (NCT), Heidelberg, Germany
5Department of Applied Tumor Biology, Institute of Pathology, Heidelberg University Hospital, Germany
6Institute of Pathology, Charité University Medicine, Berlin, Germany
7Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany
8Division of Preventive Oncology, German Cancer Research Center (DKFZ), Heidelberg, Germany
9German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany

Corresponding author:
Michael Hoffmeister

Supplementary Table 1.Re-classification of red meat and processed meat into 4 categories of red and processed meat combined based on responses from the DACHS study food frequency questionnaire.

Processed Meat
Red Meat / Multiple times per day / Once per day / Multiple times per week / Once per week / Less than once per week / Never
Multiple times per day / 4 / 4 / 4 / 4 / 4 / 4
Once per day / 4 / 4 / 4 / 3 / 3 / 3
Multiple times per week / 4 / 4 / 3 / 2 / 2 / 2
Once per week / 4 / 3 / 2 / 1 / 1 / 1
Less than once per week / 4 / 3 / 2 / 1 / 1 / 1
Never / 4 / 3 / 2 / 1 / 1 / 1

1= ≤1 time/week (including never)
2= Multiple times/week
3= 1 time/day
4= >1 time/day
Red meat = fresh pork, beef, lamb and sausages made from beef, pork
Processed meat = all luncheon meats (e.g. sliced sausage, salami) and ham

Supplementary Table 2. Conversion of FFQ categories - “times” per day to “servings” per day

FFQ categories / Conversion “servings/day”
Multiple times per day / 2 servings/day
Once per day / 1 serving/day
Multiple times per week / 4/7 (0.56) servings/day
Once per week / 1/7 (0.14) servings/day
Less than once per week / 0.5/7 (0.07) servings/day
Never / 0 servings/day

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Supplementary Table 3.Association of red meat intake and colorectal cancer risk by molecular pathological features in the DACHS study

Red meat intake
<1 time/week / 1 time/week / Multiple times/week / ≥1 time/day / Ptrend2 / Per serving/day / P
Heterogeneity3
ncases(%)/ncontrols(%) / ncases(%)/ncontrols(%) / ncases(%)/ncontrols(%) / ncases(%)/ncontrols(%)
OR1 (95% CI) / OR1 (95% CI) / OR1 (95% CI) / OR1 (95% CI) / OR1 (95% CI)
Colorectal cancer / 190(42)/266(58) / 504(48)/557(53) / 1613(51)/1552(49) / 142(58)/104(42)
1.00 (Ref.) / 1.23 (0.96-1.57) / 1.30 (1.04-1.62) / 1.54 (1.09-2.17) / 0.01 / 1.38 (1.07-1.78)
Proximal colon cancer / 69(21)/266(79) / 207(27)/557(73) / 549(27)/1552(74) / 38(27)/104(73)
1.00 (Ref.) / 1.43 (1.03-1.98) / 1.30 (0.96-1.75) / 1.37 (0.84-2.22) / 0.39 / 1.09 (0.78-1.54)
0.06
Distal colon cancer / 57(18)/266(82) / 117(17)/557(83) / 454(23)/1552(77) / 45(30)/104(70)
1.00 (Ref.) / 0.92 (0.63-1.33) / 1.18 (0.85-1.64) / 1.54 (0.94-2.52) / 0.03 / 1.70 (1.16-2.50)
Colon Cancer / 126(32)/266(68) / 324(37)/557(63) / 1007(39)/1552(61) / 83(44)/104(56)
1.00 Ref. / 1.23 (0.94-1.61) / 1.28 (1.00-1.64) / 1.53 (1.04-2.25) / 0.04 / 1.35 (1.02-1.80)
0.64
Rectal cancer / 64(19)/266(81) / 180(24)/557(76) / 606(28)/1552(72) / 59(36)/104(64)
1.00 (Ref.) / 1.21 (0.85-1.72) / 1.28 (0.93-1.76) / 1.46 (0.91-2.35) / 0.11 / 1.36 (0.96-1.94)
Stage I / 29/266 / 91/557 / 295/1552 / 32/104
1.00 (Ref.) / 1.46 (0.92-2.31) / 1.54 (1.01-2.35) / 2.19 (1.22-3.91) / 0.02 / 1.62 (1.04-2.52)
Stage II / 61/266 / 176/557 / 551/1552 / 48/104
1.00 (Ref.) / 1.34 (0.94-1.90) / 1.34 (0.97-1.85) / 1.61(0.99-2.61) / 0.07 / 1.35 (0.94-1.93)
Stage III / 70/266 / 166/557 / 546/1552 / 38/104
1.00 (Ref.) / 1.03 (0.74-1.44) / 1.15 (0.85-1.55) / 1.11(0.68-1.81) / 0.51 / 1.21 (0.85-1.73)
Stage IV / 30/266 / 71/557 / 221/1552 / 24/104
1.00 (Ref.) / 1.02 (0.64-1.65) / 1.05(0.68-1.61) / 1.33(0.71-2.50) / 0.49 / 1.35 (0.84-2.18)

1 ORs are adjusted for matching factors age and sex, and in addition, for school education, BMI, family history of colorectal cancer, history of large-bowel endoscopy, participation in health checkup, smoking, ever regular use of NSAIDs, fruit intake, and wholegrain intake.
2 Test for trend were conducted using red meat as a continuous variable in the regression model
3 Test for heterogeneity was conducted to show the significance of differential association of red meat intake with colorectal cancer risk by subsites.

Supplementary Table 4.Association of red meat intake and colorectal cancer risk by molecular pathological features in the DACHS study

Red meat intake
Molecular features / ≤1 time/week / 1 time/week / Multiple times/week / ≥1 time/day / Per serving/day3
(case/controls) / Per serving/day4
(case/case) / P
Heterogeneity5
ncases(%)/ncontrols(%) / ncases(%)/ncontrols(%) / ncases(%)/ncontrols(%) / ncases(%)/ncontrols(%)
OR1 (95% CI) / OR1 (95% CI) / OR1 (95% CI) / OR1 (95% CI) / Ptrend2 / OR (95% CI) / OR (95% CI)
MSS / 152(36)/266(64) / 401(42)/557(58) / 1297(45)/1552(55) / 116(53)/104(47)
1.00 (Ref.) / 1.21 (0.93-1.57) / 1.29 (1.02-1.63) / 1.55 (1.07-2.23) / 0.02 / 1.41 (1.08-1.84) / 1.00 (Ref.)
MSI-high / 21(7)/266(93) / 54(9)/557(91) / 150(9)/1552(91) / 11(10)/104(90) / 0.50
1.00 (Ref.) / 1.19 (0.69-2.05) / 1.22 (0.74-2.01) / 1.26 (0.57-2.80) / 0.39 / 1.17 (0.65-2.07) / 0.82 (0.47-1.46)
CIMP-low/negative / 158(37)/266(63) / 399(42)/557(58) / 1344(46)/1552(54) / 126(55)/104(45)
1.00 (Ref.) / 1.18 (0.92-1.53) / 1.28 (1.01-1.62) / 1.58 (1.10-2.27) / 0.02 / 1.42 (1.09-1.85) / 1.00 (Ref.)
CIMP-high / 29(10)/266(90) / 101(15)/557(85) / 257(14)/1552(86) / 13(11)/104(89) / 0.33
1.00 (Ref.) / 1.57 (0.99-2.48) / 1.45 (0.94-2.22) / 1.13 (0.54-2.34) / 0.45 / 1.13 (0.70-1.80) / 0.79 (0.49-1.27)
BRAF-wildtype / 161(38)/266(62) / 424(43)/557(57) / 1382(47)/1552(53) / 118(53)/104(47)
1.00 (Ref.) / 1.22 (0.95-1.58) / 1.30 (1.03-1.64) / 1.48 (1.03-2.13) / 0.02 / 1.37 (1.05-1.78) / 1.00 (Ref.)
BRAF-mutated / 14(5)/266(95) / 41(7)/557(93) / 116(7)/1552(93) / 4(4)/104(96) / 0.92
1.00 (Ref.) / 1.32 (0.69-2.52) / 1.49 (0.82-2.70) / 0.83 (0.26-2.68) / 0.36 / 1.22 (0.62-2.40) / 1.03 (0.51-2.08)
KRAS-wildtype / 107(29)/266(71) / 315(36)/557(64) / 1005(39)/1552(61) / 92(47)/104(53)
1.00 (Ref.) / 1.35 (1.02-1.79) / 1.41 (1.09-1.83) / 1.70 (1.15-2.52) / 0.006 / 1.44 (1.08-1.92) / 1.00 (Ref.)
KRAS-mutated / 66(20)/266(80) / 148(21)/557(79) / 488(24)/1552(76) / 35(25)/104(75) / 0.27
1.00 (Ref.) / 1.00 (0.71-1.42) / 1.10 (0.81-1.51) / 1.10 (0.67-1.82) / 0.69 / 1.16 (0.80-1.69) / 0.82 (0.56-1.18)
ER-β high/moderate / 36(12)/266(88) / 114(17)/557(83) / 375(20)/1552(80) / 36(26)/104(74)
1.00 (Ref.) / 1.44 (0.94-2.19) / 1.59 (1.08-2.34) / 2.01 (1.16-3.49) / 0.01 / 1.73 (1.16-2.59) / 1.00 (Ref.)
ER-β negative / 44(14)/266(86) / 100(15)/557(85) / 340(18)1552(82) / 47(31)/104(69) / 0.92
1.00 (Ref.) / 1.01 (0.67-1.52) / 1.19 (0.82-1.72) / 2.32 (1.39-3.87) / 0.01 / 1.91 (1.26-2.91) / 1.03 (0.63-1.67)
P53 normal / 71(21)/266(79) / 168(23)/557(77) / 565(27)/1552(73) / 63(38)/104(62)
1.00 (Ref.) / 1.07 (0.77-1.50) / 1.21 (0.89-1.64) / 1.82 (1.16-2.84) / 0.02 / 1.60 (1.13-2.26) / 1.00 (Ref.)
P53 mutated / 20(7)/266(93) / 56(9)/557(91) / 204(12)/1552(88) / 20(16)/104(84) / 0.98
1.00 (Ref.) / 1.21 (0.69-2.10) / 1.48 (0.90-2.43) / 1.96 (0.98-3.98) / 0.02 / 1.90 (1.12-3.25) / 1.00 (0.58-1.72)

1 ORs are adjusted for matching factors age and sex, school education, BMI, family history of colorectal cancer, history of large-bowel endoscopy, participation in health checkup, smoking, ever regular use of NSAIDs, fruit intake, and wholegrain intake.
2 Test for trend were conducted using red meat as a continuous variable in the regression model
3 Results are presented as per serving/day for case/control analysis. ORs are adjusted for matching factors age and sex, and in addition, for school education, BMI, family history of colorectal cancer, history of large-bowel endoscopy, participation in health checkup, smoking, ever regular use of NSAIDs, fruit intake and wholegrain intake.
4 Results are presented as per serving/day for case/case analysis. ORs are adjusted for matching factors age and sex, and in addition, for CRC location, school education, BMI, family history of colorectal cancer, history of large-bowel endoscopy, participation in health checkup, smoking, ever regular use of NSAIDs, fruit intake, and wholegrain intake.
5 Test for heterogeneity was conducted to show the significance of differential association of red meat intake with colorectal cancer risk by molecular features (ie. MSI-high vs MSS; CIMP high vs CIMP low/negative; BRAF mutated vs BRAF wildtype; KRAS mutated vs KRAS wildtype; ER β high/moderate vs ER β negative; P53 mutated vs P53 normal)

Supplementary Table 5.Association of processed meat intake and colorectal cancer risk by molecular pathological features in the DACHS study

Processed meat intake
<1 time/week / 1 time/week / Multiple times/week / ≥1 time/day / Ptrend2 / Per serving/day / P
Heterogeneity3
ncases(%)/ncontrols(%) / ncases(%)/ncontrols(%) / ncases(%)/ncontrols(%) / ncases(%)/ncontrols(%)
OR1 (95% CI) / OR1 (95% CI) / OR1 (95% CI) / OR1 (95% CI) / OR1 (95% CI)
Colorectal cancer / 258(41)/377(59) / 297(45)/358(55) / 1110(50)/1128(50) / 784(56)/616(44)
1.00 (Ref.) / 1.17 (0.92-1.49) / 1.39 (1.14-1.69) / 1.83 (1.48-2.26) / <0.0001 / 1.64 (1.38-1.94)
Proximal colon cancer / 103(22)/377(78) / 120(25)/358(75) / 413(27)/1128(73) / 227(27)/616(73)
1.00 (Ref.) / 1.21 (0.88-1.66) / 1.36 (1.05-1.76) / 1.45 (1.09-1.93) / 0.01 / 1.30 (1.04-1.62)
0.13
Distal colon cancer / 73(16)/377(84) / 89(20)/358(80) / 271(19)/1128(81) / 240(28)/616(72)
1.00 (Ref.) / 1.36 (0.95-1.96) / 1.26 (0.93-1.71) / 2.05 (1.49-2.83) / <0.0001 / 1.68 (1.32-2.15)
Colon Cancer / 176(32)/377(68) / 209(37)/358(63) / 687(38)/1128(62) / 468(43)/616(57)
1.00 (Ref.) / 1.23 (0.95-1.61) / 1.31 (1.05-1.63) / 1.70 (1.34-2.15) / <0.0001 / 1.48 (1.23-1.79)
0.03
Rectal cancer / 82(17.9)/377(82) / 88(20)/358(80) / 423(27)/1128(73) / 316(34)/616(66)
1.00 (Ref.) / 1.16 (0.81-1.66) / 1.70 (1.27-2.27) / 2.30 (1.70-3.13) / <0.0001 / 1.98 (1.57-2.50)
Stage I / 42/377 / 54/358 / 208/1128 / 143/616
1.00 (Ref.) / 1.40 (0.90-2.18) / 1.66 (1.15-2.40) / 2.09 (1.42-3.08) / 0.0001 / 1.63 (1.23-2.15)
Stage II / 81/377 / 100/358 / 390/1128 / 265/616
1.00 (Ref.) / 1.27 (0.89-1.81) / 1.61 (1.20-2.14) / 1.95 (1.43-2.65) / <0.0001 / 1.64 (1.30-2.07)
Stage III / 98/377 / 101/358 / 359/1128 / 262/616
1.00 (Ref.) / 1.13 (0.81-1.57) / 1.27(0.97-1.66) / 1.74 (1.31-2.32) / <0.0001 / 1.61 (1.28-2.01)
Stage IV / 37/377 / 42/358 / 153/1128 / 114/616
1.00 (Ref.) / 1.24 (0.76-2.02) / 1.34 (0.90-2.00) / 1.88 (1.24-2.87) / 0.001 / 1.54 (1.12-2.12)

1 ORs are adjusted for matching factors age and sex, and in addition, for school education, BMI, family history of colorectal cancer, history of large-bowel endoscopy, participation in health checkup, smoking, ever regular use of NSAIDs, fruit intake, and wholegrain intake.
2 Test for trend were conducted using processed meat as a continuous variable in the regression model
3 Test for heterogeneity was conducted to show the significance of differential association of processed meat intake with colorectal cancer risk by subsites.

Supplementary Table 6.Association of processed meat intake and colorectal cancer risk by molecular pathological features in the DACHS study

Processed meat intake
Molecular features / ≤1 time/week / 1 time/week / Multiple times/week / ≥1 time/day / Per serving/day3
(case/controls) / Per serving/day4
(case/case) / P
Heterogeneity5
ncases(%)/ncontrols(%) / ncases(%)/ncontrols(%) / ncases(%)/ncontrols(%) / ncases(%)/ncontrols(%)
OR1 (95% CI) / OR1 (95% CI) / OR1 (95% CI) / OR1 (95% CI) / Ptrend2 / OR (95% CI) / OR (95% CI)
MSS / 210(36)/377(64) / 246(41)/358(59) / 879(44)/1128(56) / 631(51)/616(49)
1.00 (Ref.) / 1.24 (0.96-1.61) / 1.38 (1.12-1.70) / 1.85 (1.47-2.31) / <0.0001 / 1.61 (1.34-1.92) / 1.00 (Ref.)
MSI-high / 22(6)/377(94) / 30(8)/358(92) / 111(9)/1128(91) / 73(11)/616(89) / 0.53
1.00 (Ref.) / 1.49 (0.83-2.67) / 1.84 (1.13-3.00) / 2.29 (1.37-3.85) / 0.001 / 1.71 (1.18-2.46) / 1.39 (0.93-2.08)
CIMP-low/negative / 214(36)/377(64) / 242(40)/358(60) / 913(45)/1128(55) / 658(52)/616(48)
1.00 (Ref.) / 1.18 (0.91-1.52) / 1.38 (1.12-1.70) / 1.84 (1.47-2.30) / <0.0001 / 1.63 (1.37-1.95) / 1.00 (Ref.)
CIMP-high / 41(10)/377(90) / 52(13)/358(87) / 188(14)/1128(86) / 119(16)/616(84) / 0.88
1.00 (Ref.) / 1.38 (0.87-2.18) / 1.63 (1.11-2.39) / 1.98 (1.32-2.98) / 0.0006 / 1.63 (1.20-2.21) / 1.17 (0.85-1.60)
BRAF-wildtype / 222(37)/377(63) / 241(40)/358(60) / 946(46)/1128(54) / 676(52)/616(48)
1.00 (Ref.) / 1.09 (0.85-1.41) / 1.37 (1.12-1.68) / 1.79 (1.43-2.23) / <0.0001 / 1.64 (1.38-1.96) / 1.00 (Ref.)
BRAF-mutated / 16(4)/377(96) / 26(7)/358(93) / 87(7)/1128(93) / 46(7)/616(93) / 0.50
1.00 (Ref.) / 1.92 (0.99-3.72) / 2.01 (1.14-3.56) / 2.12 (1.15-3.92) / 0.06 / 1.42 (0.92-2.20) / 1.07 (0.66-1.72)
KRAS-wildtype / 149(28)/377(72) / 170(32)/358(68) / 701(38)/1128(62) / 499(45)/616(55)
1.00 (Ref.) / 1.19 (0.89-1.58) / 1.54 (1.22-1.93) / 2.03 (1.59-2.60) / <0.0001 / 1.82 (1.50-2.20) / 1.00 (Ref.)
KRAS-mutated / 87(19)/377(81) / 93(21)/358(79) / 322(22)/1128(78) / 235(28)/616(72) / 0.04
1.00 (Ref.) / 1.18 (0.83-1.67) / 1.28 (0.96-1.70) / 1.70 (1.26-2.30) / 0.0002 / 1.39 (1.09-1.77) / 0.77 (0.60-0.99)
ER-β high/moderate / 75(17)/377(83) / 81(18)/358(82) / 237(17)/1128(83) / 168(21)/616(79)
1.00 (Ref.) / 1.15 (0.80-1.65) / 1.09 (0.81-1.48) / 1.43 (1.03-1.98) / 0.02 / 1.35 (1.04-1.74) / 1.00 (Ref.)
ER-β negative / 60(14)/377(86) / 67(16)/358(84) / 251(18)/1128(82) / 153(20)/616(80) / 0.97
1.00 (Ref.) / 1.22 (0.82-1.82) / 1.51 (1.09-2.10) / 1.73 (1.21-2.46) / 0.003 / 1.47 (1.12-1.93) / 1.04 (0.75-1.44)
P53 normal / 112(23)/377(77) / 118(25)/358(75) / 394(26)/1128(74) / 243(28)/616(72)
1.00 (Ref.) / 1.13 (0.82-1.55) / 1.21 (0.93-1.57) / 1.39 (1.05-1.85) / 0.02 / 1.26 (1.01-1.59) / 1.00 (Ref.)
P53 mutated / 33(8)/377(92) / 41(10)/358(90) / 132(10)/1128(90) / 94(13)/616(87) / 0.35
1.00 (Ref.) / 1.32 (0.80-2.18) / 1.38 (0.90-2.09) / 1.79 (1.15-2.79) / 0.009 / 1.58 (1.14-2.19) / 1.19 (0.83-1.71)

1 ORs are adjusted for matching factors age and sex, school education, BMI, family history of colorectal cancer, history of large-bowel endoscopy, participation in health checkup, smoking, ever regular use of NSAIDs, fruit intake, and wholegrain intake.
2 Test for trend were conducted using processed meat as a continuous variable in the regression model
3 Results are presented as per serving/day for case/control analysis. ORs are adjusted for matching factors age and sex, and in addition, for school education, BMI, family history of colorectal cancer, history of large-bowel endoscopy, participation in health checkup, smoking, ever regular use of NSAIDs, fruit intake, and wholegrain intake.
4 Results are presented as per serving/day for case/case analysis. ORs are adjusted for matching factors age and sex, and in addition, for CRC location, school education, BMI, family history of colorectal cancer, history of large-bowel endoscopy, participation in health checkup, smoking, ever regular use of NSAIDs, fruit intake, and wholegrain intake.
5 Test for heterogeneity was conducted to show the significance of differential association of processed meat intake with colorectal cancer risk by molecular features (ie. MSI-high vs MSS; CIMP high vs CIMP low/negative; BRAF mutated vs BRAF wildtype; KRAS mutated vs KRAS wildtype; ER β high/moderate vs ER β negative; P53 mutated vs P53 normal)

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Supplementary Table 7.Association of red and processed meat intake and colorectal cancer risk by combined molecular pathological features in the DACHS study

Combination of molecular features / Per serving/day
OR1 (95% CI)
CIMP-low/negative / MSS (n=1739) / 1.43 (1.25-1.65)
MSI-high (n=93) / 1.40 (0.91-2.15)
CIMP-high / MSS (n=227) / 1.31 (0.97-1.78)
MSI-high (n=143) / 1.48 (1.02-2.17)
MSS / BRAF- wildtype (n=1729) / 1.45 (1.26-1.67)
BRAF- mutated (n=69) / 0.91 (0.52-1.60)
MSI-high / BRAF- wildtype (134) / 1.50 (1.04-2.17)
BRAF- mutated (n=92) / 1.59 (1.01-2.50)
MSS / KRAS- wildtype (n=1203) / 1.57 (1.34-1.83)
KRAS- mutated (n=622) / 1.20 (0.98-1.46)
MSI-high / KRAS- wildtype (n=182) / 1.53 (1.10-2.13)
KRAS- mutated (n=42) / 1.59 (0.85-2.97)
KRAS -wildtype / BRAF- wildtype (n=1259) / 1.57 (1.35-1.84)
BRAF- mutated (158) / 1.33 (0.93-1.92)
KRAS-mutated / BRAF- wildtype (n=685) / 1.26 (1.03-1.53)
BRAF- mutated (n=8) / n/a
KRAS -wildtype / CIMP-low/negative (n=1250) / 1.58 (1.36-1.85)
CIMP-high (n=269) / 1.43 (1.08-1.91)
KRAS-mutated / CIMP-low/negative (n=616) / 1.26 (1.03-1.54)
CIMP-high (n=121) / 1.18 (0.79-1.76)
CIMP-low/negative / BRAF- wildtype (n=1807) / 1.46 (1.27-1.69)
BRAF- mutated (n=52) / 1.04 (0.56-1.92)
CIMP-high / BRAF- wildtype (n=260) / 1.36 (1.02-1.80)
BRAF- mutated (n=121) / 1.43 (0.95-2.16)
CIMP-low/negative/MSS / BRAF- wildtype (n=1545) / 1.40 (0.88-2.25)
BRAF- mutated (n=40) / 0.68 (0.32-1.43)
CIMP-low/negative/MSI-high / BRAF- wildtype (n=77) / 1.47 (1.27-1.70)
BRAF- mutated (n=11) / 2.45 (0.86-6.97)
CIMP-high/MSS / BRAF- wildtype (n=184) / 1.29 (0.93-1.79)
BRAF- mutated (n=29) / 1.29 (0.57-2.91)
CIMP-high/MSI-high / BRAF- wildtype (n=57) / 1.62 (0.91-2.87)
BRAF- mutated (n=81) / 1.45 (0.88-2.37)