background
DESCRIPTION
No. of sample. KRAS WT. KRAS MT. KRAS WT. KRAS WT. KRAS WT. KRAS WT. KRAS MT (G13D). KRAS MT (G13D). KRAS MT (G13D). KRAS MT (G13D). KRAS MT (others). KRAS MT (others). KRAS MT (others). KRAS MT (others). n. %. 95%CI. n. %. 95%CI. All. 5,732. 3,577. 62.4. - PowerPoint PPT PresentationTRANSCRIPT
n KRAS WTKRAS MT (G13D)
KRAS MT (others)
Gender Male 3,475 2,243 (64.5%) 222 ( 6.4%) 1,010 (29.1%)
Female 2,257 1,334 (59.1%) 198 ( 8.8%) 725 (32.1%)
Age < 50 560 389 (69.5%) 42 ( 7.5%) 129 (23.0%)
50-59 1,258 798 (63.4%) 91 ( 7.2%) 369 (29.3%)
60-69 2,081 1,289 (61.9%) 140 ( 6.7%) 652 (31.3%)
70 =< 1,833 1,101 (60.1%) 147 ( 8.0%) 585 (31.9%)
Primary tumor site appendix 25 9 (36.0%) 2 ( 8.0%) 14 (56.0%)
right-sided colon 1,713 887 (51.8%) 169 ( 9.9%) 657 (38.4%)
left-sided colon 2,160 1,528 (70.7%) 102 ( 4.7%) 530 (24.5%)
rectum 1,817 1,142 (62.9%) 147 ( 8.1%) 528 (29.1%)
others* 17 11 (64.7%) 0 ( 0.0%) 6 (35.3%)
Site of the sample obtained
Primary tumor 5,258 3,281 (62.4%) 385 ( 7.3%) 1,592 (30.3%)
Metastasis 474 296 (62.4%) 35 ( 7.4%) 143 (30.2%)
liver 216 146 (67.6%) 13 ( 6.0%) 57 (26.4%)
lung 74 48 (64.9%) 7 ( 9.5%) 19 (25.7%)
lymph node 37 22 (59.5%) 2 ( 5.4%) 13 (35.1%)
local 45 29 (64.4%) 3 ( 6.7%) 13 (28.9%)
dissemination 70 34 (48.6%) 6 ( 8.6%) 30 (42.9%)
others* 32 17 (53.1%) 4 (12.5%) 11 (34.4%)
Clinicopathological features of colorectal cancer patients among KRAS wild type, p.G13D and other mutations: Results from a multicenter, cross-sectional study by the Japan Study Group of KRAS Mutation in Colorectal Cancer
Clinicopathological features of colorectal cancer patients among KRAS wild type, p.G13D and other mutations: Results from a multicenter, cross-sectional study by the Japan Study Group of KRAS Mutation in Colorectal Cancer
Hiroyuki Uetake1, Toshiaki Watanabe2, Takayuki Yoshino3, Kentaro Yamazaki4, Megumi Ishiguro1, Kenichi Sugihara1, Yasuo Ohashi5Hiroyuki Uetake1, Toshiaki Watanabe2, Takayuki Yoshino3, Kentaro Yamazaki4, Megumi Ishiguro1, Kenichi Sugihara1, Yasuo Ohashi5
１ Tokyo Medical and Dental University, Graduate School, Tokyo, Japan, 2Teikyo University School of Medicine, Tokyo, Japan, 3National Cancer Center Hospital East, Chiba, Japan, 4Shizuoka Cancer Center, Shizuoka, Japan, 5Public Health Research Foundation, Tokyo, Japan
１ Tokyo Medical and Dental University, Graduate School, Tokyo, Japan, 2Teikyo University School of Medicine, Tokyo, Japan, 3National Cancer Center Hospital East, Chiba, Japan, 4Shizuoka Cancer Center, Shizuoka, Japan, 5Public Health Research Foundation, Tokyo, Japan
Many studies have reported that 30-40% of CRC patients have KRAS mutations and they lacked in response to anti-epidermal growth factor receptor (EGFR) antibodies.1-3
Recently, improved outcomes for association of KRAS p.G13D mutation (p.G13D MT) in patients with mCRC treated with cetuximab have been reported.4, 5
We have previously reported the correlation between KRAS mutation rate and sample backgrounds;6, 7 however, the clinicopathological features of KRAS p.G13D mutation have not been fully clarified.
BackgroundBackground
ObjectiveObjective
MethodsMethods
Sample size: 5,000
Data collection:
Sample for KRAS test
– Surgically resected specimen or biopsy from primary tumor or metastases
– Paraffin-embedded tumor blocks or thinly sliced tumor sections
Patients and sample backgrounds
– Gender, age
– Primary tumor site
– Type of sample (surgically resected / biopsy)
– Date of the sample obtained
– Site of the sample obtained (primary tumor / metastases)
– Stage (l / ll / lll / IV / recurrence / unknown)
– Duration of formalin fixation (<24h / 24-48h / 48h< / unknown)
– Formalin concentration (10% / 20% / unknown)
Key eligibility criteriaHistologically confirmed colorectal adenocarcinomaAdequate tumor samples
Send formalin-fixed paraffin-embedded tumor blocks or thinly sliced tumor sections to commercial laboratories （ 10µm 5 slices and 3µm 1 slice for HE staining）
Investigate KRAS point mutations in the codon 12 and 13 by following laboratories’ SOP
Hospitals
LaboratoriesData center
1. Sample registration
2. Enrollment confirmation
6. Result
3. Sample
2’. Registration information
5. Result
4. KRAS test
From Oct. 2009 to Mar. 2010Cut-off: Apr. 2010 Sample registration, n=5,887
from 389 facilitiesExcluded, n=97 Cancelation 14 Ineligible 1 Uncollected 82
Undetectable samples, n=58 Direct sequencing 56 Luminex 2
KRAS test detectable, n=5,732 Direct sequencing 5,423 Luminex 309
KRAS test, n=5,790 Direct sequencing 5,479 Luminex 311
ConclusionsConclusions
This study was funded by Comprehensive Support Project for Oncology Research (CSPOR) of Public Health Research Foundation.
The research institutes are Tokyo Medical and Dental University, Teikyo University School, and National Cancer Center Hospital East.
We would like to thank the 389 sample providing hospitals.
AcknowledgementAcknowledgement
ReferencesReferences1. Karapetis CS. et al. N Engl J Med. 2008;359:1757-1765.
2. Amado RG. et al. J Clin Oncol. 2008;26:1626-1634.
3. Van Cutsem E. et al. N Engl J Med. 2009;360:1408-1417.
4. De Roock W. et al. JAMA. 2010;304:1812-1820.
5. Bando H., Yoshino T. et al. ASCO-GI 2011 #448
6. Yamazaki K. et al. ESMO 2010 #595P
7. Yoshino T. et al. ASCO-GI 2011 #407
KRAS p.G13D mutation was remarkably higher in female (P<0.0001).
KRAS p.G13D mutation occurred at a constant rate regardless of age (P=0.5285); however, KRAS other mutations increased with age (P=0.0002). In contrast, KRAS wild type decreased with age (P=0.0001).
KRAS p.G13D mutation seemed remarkably higher in right-sided colon than left-sided colon (right： 9.9%, left： 4.7%, P=0.0515).
KRAS p.G13D mutation was tend to be higher in lung metastasis (9.5%) compared to other metastatic sites; however, this is uncertain because the sample size has varied through the metastatic sites.
Other KRAS MT had similar trend with KRAS p.G13D in primary tumor site.
This study suggested that clinicopathological features were not similar among KRAS wild type, KRAS p.G13D and other mutations.
It suggests a possibility that KRAS p.G13D mutation might be a different tumor than other KRAS mutations, since some different trends were seen between those mutations.
Presently, any KRAS mutation is regarded to be the same; however, this study suggests that it might be an aggregation from different tumors.
Sample Backgroundn
Gender Male 3,475 (60.6%)Female 2,257 (39.4%)
Age < 50 560 ( 9.8%)
Median:65 （ 12-92）
50-59 1,258 (21.9%)60-69 2,081 (36.3%)70 =< 1,833 (32.0%)
Type of sample Surgically resected 5,364 (93.6%)Biopsy 368 ( 6.4%)
Year Surgically resected
< 2006 748 (13.0%)2006 445 ( 7.8%)2007 761 (13.3%)2008 1,255 (21.9%)2009 1,843 (32.2%)2010 312 ( 5.4%)
Biopsy < 2009 110 ( 1.9%)2009 =< 258 ( 4.5%)
Stage I 166 ( 2.9%) II 814 (14.2%)III 1,765 (30.8%)IV 2,805 (48.9%)recurrence 152 ( 2.7%)unknown 30 ( 0.5%)
Primary tumor site appendix 25 ( 0.4%)right-sided colon 1,713 (29.9%)left-sided colon 2,160 (37.7%)rectum 1,817 (31.7%)others 17 ( 0.3%)
Site of the sample obtained
Primary tumor 5,258 (91.7%)Metastasis 474 ( 8.3%)
liver 216 (45.6%)lung 74 (15.6%)lymph node 37 ( 7.8%)local 45 ( 9.5%)dissemination 70 (14.8%)others 32 ( 6.8%)
Results: Results: KRASKRAS WT, WT, KRASKRAS MT (G13D), MT (G13D), KRASKRAS MT (others) MT (others)
KRAS mutation
n %
Codon12 1,714
GAT (G12D)GTT (G12V)TGT (G12C)AGT (G12S)GCT (G12A)CGTOthers
814493162120107153
47.528.89.57.06.20.90.1
Codon13 441
GAC (G13D)TGCCGCGAGOthers
42011613
95.22.51.40.20.7
No. of sample
KRAS WT KRAS MT
n % 95%CI n % 95%CI
All 5,732 3,577 62.4 61.1-63.7 2,155 37.6 36.3-38.9
Codon12 Codon13
1,714 441
29.9 7.7
28.7-31.17.0-8.4
KRAS WT62.4%(n=3,577)
KRAS MT37.6%
(n=2,155)
G13D7.3％(n=420)
others30.3％(n=1,735)
The frequency of KRAS mutation (37.6%) in Japanese CRC patients is similar to those reported in previous studies from western countries.
There are the significant difference of the frequency of KRAS mutation between
male (35.5%) and female (40.9%) left-sided colon (29.3%) and right-sided colon (48.2%). As the age is higher there is more frequent KRAS mutation.
* not included in the logistic regression
KRAS WT vs. KRAS MT (G13D) KRAS MT (G13D) vs. KRAS MT (others)
Odds-ratio 95%CI P value Odds-ratio 95%CI P value
1.500 1.224 - 1.838 <0.0001 0.805 0.650 - 0.997 0.0465
0.667 0.544 - 0.817 1.243 1.003 - 1.539
1.098 0.785 - 1.536 0.3549 1.383 0.960 - 1.994 0.1992
1.038 0.813 - 1.327 1.024 0.790 - 1.327
1.127 0.910 - 1.396 0.831 0.663 - 1.040
0.826 0.668 - 1.022 1.059 0.846 - 1.324
0.527 0.114 - 2.448 <0.0001 0.588 0.133 - 2.598 0.0558
0.490 0.397 - 0.604 1.105 0.889 - 1.374
2.325 1.842 - 2.934 0.729 0.571 - 0.932
0.871 0.704 - 1.077 1.231 0.983 - 1.542
- - - - - -
1.008 0.699 - 1.453 0.9673 0.988 0.672 - 1.454 0.9514
0.992 0.688 - 1.431 1.012 0.688 - 1.489
1.332 0.749 - 2.371 0.5733 0.940 0.510 - 1.734 0.8520
0.803 0.361 - 1.785 1.531 0.639 - 3.666
1.293 0.303 - 5.520 0.634 0.143 - 2.819
1.136 0.345 - 3.746 0.953 0.270 - 3.359
0.662 0.276 - 1.587 0.824 0.341 - 1.992
0.497 0.166 - 1.483 1.507 0.478 - 4.756
ASCO 2011 #3605ASCO 2011 #3605
Clinicopathological features: WT, MT (G13D), MT (others)
Gender
Femalen=2,257
Malen=3,475
59.1%
64.5%
8.8%
6.4%
32.1%
29.1%
Primary tumor site
62.9%
70.7%
51.8%
36.0%
8.1%
4.7%
9.9%
8.0%
29.1%
24.5%
38.4%
56.0%
rectumn=1,817
left-sided colonn=2,160
right-sided colonn=1,713
appendixn=25
Age
*Cochran-Armitage trend test
70=<n=1,833
60-69n=2,081
50-59n=1,258
<50n=560
60.1%
61.9%
63.4%
69.5%
8.0%
6.7%
7.2%
7.5%
31.9%
31.3%
29.3%
23.0%
P=0.0001* P=0.5285* P=0.0002*
KRAS WT KRAS MT (G13D) KRAS MT (others)
Site of the sample obtained
48.6%
64.4%
59.5%
64.9%
67.6%
62.4%
62.4%
8.6%
6.7%
5.4%
9.5%
6.0%
7.4%
7.3%
42.9%
28.9%
35.1%
25.7%
26.4%
30.2%
30.3%
disseminationn=70
localn=45
lymph noden=37
lungn=74
livern=216
Metastasisn=474
Primary tumorn=5,258
This study aimed to examine whether the clinicopathological features of tumors with p.G13D MT is more similar to those of KRAS wild type or other KRAS mutations in large-scale Japanese population (n=5,887).
KRAS MT G13D
KRAS MT (others)
G12D G12V G12C G12S G12A
Gender Male 205 (52.0%)
424 (56.8%)
270 (59.0%)
102 (67.1%)
61 (54.5%)
55 (54.5%)
Female 189 (48.0%)
323 (43.2%)
188 (41.0%)
50 (32.9%)
51 (45.5%)
46 (45.5%)
Age < 60 127 (32.2%)
206 (27.6%)
141 (30.8%)
40 (26.3%)
33 (29.5%)
28 (27.7%)
60-69 128 (32.5%)
279 (37.3%)
172 (37.6%)
61 (40.1%)
42 (37.5%)
43 (42.6%)
70 =< 139 (35.3%)
262 (35.1%)
145 (31.7%)
51 (33.6%)
37 (33.0%)
30 (29.7%)
Primary tumor site*
right-sided colon
158 (40.1%)
316 (42.3%)
155 (33.8%)
76 (50.0%)
32 (28.6%)
32 (31.7%)
left-sided colon
98 (24.9%)
215 (28.8%)
154 (33.6%)
39 (25.7%)
48 (42.9%)
36 (35.6%)
rectum 138 (35.0%)
216 (28.9%)
149 (32.5%)
37 (24.3%)
32 (28.6%)
33 (32.7%)
Site of the sample obtained
Primary tumor
362 (91.9%)
683 (91.4%)
427 (93.2%)
136 (89.5%)
106 (94.6%)
94 (93.1%)
Metastasis 32 ( 8.1%)
64 ( 8.6%)
31 ( 6.8%)
16 (10.5%)
6 ( 5.4%)
7 ( 6.9%)
liver 11 (34.4%)
26 (40.6%)
13 (41.9%)
8 (50.0%)
3 (50.0%)
4 (57.1%)
lung 7 (21.9%)
4 ( 6.3%)
5 (16.1%)
2 (12.5%)
1 (16.7%)
2 (28.6%)
others 14 (43.8%)
34 (53.1%)
13 (41.9%)
6 (37.5%)
2 (33.3%)
1 (14.3%)
Comparison of KRAS mutation results
* G13D vs. G12V P=0.0171, vs. G12C P=0.0399, vs. G12S P=0.0009
KRAS WT KRAS MT (G13D) KRAS MT (Others)
GenderMale > Female
64.5% 59.1%
Male < Female
6.4% 8.8%
Male < Female
29.1% 32.1%
P< 0.0001 P=0.0465
Age Young > Old69.5%/63.4%/61.9%/60.1%*
Young Old≒7.5%/7.2%/6.7%/8.0%*
Young < Old23.0%/29.3%/31.3%/31.9%*
P=0.3549 P=0.1992
Primary tumor site
Right < Left
51.8% 70.7%
Right > Left
9.9% 4.7%
Right > Left
38.4% 24.5%
P<0.0001 P=0.0558
Site of the sample obtained
Liver Lung≒67.6% 64.9%
Liver < Lung
6.0% 9.5%
Liver Lung≒26.4% 25.7%
P=0.5733 P=0.8520
Summary of the results
*< 50/50-59/60-69/70=<
Summary of the previous presentationSummary of the previous presentation
Study profile Gender
Age
Primary tumor site
Mutation
Male Female
1,232 923
2,243 1,334
35.5%40.9%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
n=3,475 n=2,257
KRAS WT KRAS MT Mutation rate P<0.0001
<50 50-59 60-69 70=<
389
171
30.5%
460
798
36.6%
792
1,289
38.1%
732
1,101
39.9%
n=560 n=1,258 n=2,081 n=1,833
KRAS WT KRAS MT Mutation rate P=0.0007
Mutation
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
826
887
48.2%
632
1,528
29.3%
left-sided colonn=2,160
right-sided colonn=1,713
675
1,142
37.1%
rectumn=1,817
KRAS WT KRAS MT Mutation rate P<0.0001
Mutation
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
KRAS WT KRAS MT (G13D) KRAS MT (others)
KRAS WT KRAS MT (G13D) KRAS MT (others)
KRAS WT KRAS MT (G13D) KRAS MT (others)
n KRAS WTKRAS MT (G13D)
KRAS MT (others)
Gender Male 3,475 2,243 (64.5%) 222 ( 6.4%) 1,010 (29.1%)
Female 2,257 1,334 (59.1%) 198 ( 8.8%) 725 (32.1%)
Age < 50 560 389 (69.5%) 42 ( 7.5%) 129 (23.0%)
50-59 1,258 798 (63.4%) 91 ( 7.2%) 369 (29.3%)
60-69 2,081 1,289 (61.9%) 140 ( 6.7%) 652 (31.3%)
70 =< 1,833 1,101 (60.1%) 147 ( 8.0%) 585 (31.9%)
Primary tumor site appendix 25 9 (36.0%) 2 ( 8.0%) 14 (56.0%)
right-sided colon 1,713 887 (51.8%) 169 ( 9.9%) 657 (38.4%)
left-sided colon 2,160 1,528 (70.7%) 102 ( 4.7%) 530 (24.5%)
rectum 1,817 1,142 (62.9%) 147 ( 8.1%) 528 (29.1%)
others* 17 11 (64.7%) 0 ( 0.0%) 6 (35.3%)
Site of the sample obtained
Primary tumor 5,258 3,281 (62.4%) 385 ( 7.3%) 1,592 (30.3%)
Metastasis 474 296 (62.4%) 35 ( 7.4%) 143 (30.2%)
liver 216 146 (67.6%) 13 ( 6.0%) 57 (26.4%)
lung 74 48 (64.9%) 7 ( 9.5%) 19 (25.7%)
lymph node 37 22 (59.5%) 2 ( 5.4%) 13 (35.1%)
local 45 29 (64.4%) 3 ( 6.7%) 13 (28.9%)
dissemination 70 34 (48.6%) 6 ( 8.6%) 30 (42.9%)
others* 32 17 (53.1%) 4 (12.5%) 11 (34.4%)
Clinicopathological features of colorectal cancer patients among KRAS wild type, p.G13D and other mutations: Resultsfrom a multicenter, cross-sectional study by the Japan Study Group of KRAS Mutation in Colorectal Cancer
Clinicopathological features of colorectal cancer patients among KRAS wild type, p.G13D and other mutations: Resultsfrom a multicenter, cross-sectional study by the Japan Study Group of KRAS Mutation in Colorectal Cancer
Hiroyuki Uetake1, Toshiaki Watanabe2, Takayuki Yoshino3, Kentaro Yamazaki4, Megumi Ishiguro1, Kenichi Sugihara1, Yasuo Ohashi5Hiroyuki Uetake1, Toshiaki Watanabe2, Takayuki Yoshino3, Kentaro Yamazaki4, Megumi Ishiguro1, Kenichi Sugihara1, Yasuo Ohashi5
１ Tokyo Medical and Dental University, Graduate School, Tokyo, Japan, 2Teikyo University School of Medicine, Tokyo, Japan, 3National Cancer Center Hospital East, Chiba, Japan, 4Shizuoka Cancer Center, Shizuoka, Japan, 5Public Health Research Foundation, Tokyo, Japan
１ Tokyo Medical and Dental University, Graduate School, Tokyo, Japan, 2Teikyo University School of Medicine, Tokyo, Japan, 3National Cancer Center Hospital East, Chiba, Japan, 4Shizuoka Cancer Center, Shizuoka, Japan, 5Public Health Research Foundation, Tokyo, Japan
Many studies have reported that 30-40% of CRC patients have KRAS mutations and they lacked in response to anti-epidermal growth factor receptor (EGFR) antibodies.1-3
Recently, improved outcomes for association of KRAS p.G13D mutation (p.G13D MT) in patients with mCRC treated with cetuximab have been reported.4, 5
We have previously reported the correlation between KRAS mutation rate and sample backgrounds;6, 7 however, the clinicopathological features of KRAS p.G13D mutation have not been fully clarified.
BackgroundBackground
ObjectiveObjective
MethodsMethods
Sample size: 5,000
Data collection:
Sample for KRAS test
– Surgically resected specimen or biopsy from primary tumor or metastases
– Paraffin-embedded tumor blocks or thinly sliced tumor sections
Patients and sample backgrounds
– Gender, age
– Primary tumor site
– Type of sample (surgically resected / biopsy)
– Date of the sample obtained
– Site of the sample obtained (primary tumor / metastases)
– Stage (l / ll / lll / IV / recurrence / unknown)
– Duration of formalin fixation (<24h / 24-48h / 48h< / unknown)
– Formalin concentration (10% / 20% / unknown)
Key eligibility criteriaHistologically confirmed colorectal adenocarcinomaAdequate tumor samples
Send formalin-fixed paraffin-embedded tumor blocks or thinly sliced tumor sections to commercial laboratories （ 10µm 5 slices and 3µm 1 slice for HE staining）
Investigate KRAS point mutations in the codon 12 and 13 by following laboratories’ SOP
Hospitals
LaboratoriesData center
1. Sample registration
2. Enrollment confirmation
6. Result
3. Sample
2’. Registration information
5. Result
4. KRAS test
From Oct. 2009 to Mar. 2010Cut-off: Apr. 2010 Sample registration, n=5,887
from 389 facilitiesExcluded, n=97 Cancelation 14 Ineligible 1 Uncollected 82
Undetectable samples, n=58 Direct sequencing 56 Luminex 2
KRAS test detectable, n=5,732 Direct sequencing 5,423 Luminex 309
KRAS test, n=5,790 Direct sequencing 5,479 Luminex 311
ConclusionsConclusions
This study was funded by Comprehensive Support Project for Oncology Research (CSPOR) of Public Health Research Foundation.
The research institutes are Tokyo Medical and Dental University, Teikyo University School, and National Cancer Center Hospital East.
We would like to thank the 389 sample providing hospitals.
AcknowledgementAcknowledgement
ReferencesReferences1. Karapetis CS. et al. N Engl J Med. 2008;359:1757-1765.
2. Amado RG. et al. J Clin Oncol. 2008;26:1626-1634.
3. Van Cutsem E. et al. N Engl J Med. 2009;360:1408-1417.
4. De Roock W. et al. JAMA. 2010;304:1812-1820.
5. Bando H., Yoshino T. et al. ASCO-GI 2011 #448
6. Yamazaki K. et al. ESMO 2010 #595P
7. Yoshino T. et al. ASCO-GI 2011 #407
KRAS p.G13D mutation was remarkably higher in female (P<0.0001).
KRAS p.G13D mutation occurred at a constant rate regardless of age (P=0.5285); however, KRAS other mutations increased with age (P=0.0002). In contrast, KRAS wild type decreased with age (P=0.0001).
KRAS p.G13D mutation seemed remarkably higher in right-sided colon than left-sided colon (right： 9.9%, left： 4.7%, P=0.0515).
KRAS p.G13D mutation was tend to be higher in lung metastasis (9.5%) compared to other metastatic sites; however, this is uncertain because the sample size has varied through the metastatic sites.
Other KRAS MT had similar trend with KRAS p.G13D in primary tumor site.
This study suggested that clinicopathological features were not similar among KRAS wild type, KRAS p.G13D and other mutations.
It suggests a possibility that KRAS p.G13D mutation might be a different tumor than other KRAS mutations, since some different trends were seen between those mutations.
Presently, any KRAS mutation is regarded to be the same; however, this study suggests that it might be an aggregation from different tumors.
Sample Backgroundn
Gender Male 3,475 (60.6%)Female 2,257 (39.4%)
Age < 50 560 ( 9.8%)
Median:65 （ 12-92）
50-59 1,258 (21.9%)60-69 2,081 (36.3%)70 =< 1,833 (32.0%)
Type of sample Surgically resected 5,364 (93.6%)Biopsy 368 ( 6.4%)
Year Surgically resected
< 2006 748 (13.0%)2006 445 ( 7.8%)2007 761 (13.3%)2008 1,255 (21.9%)2009 1,843 (32.2%)2010 312 ( 5.4%)
Biopsy < 2009 110 ( 1.9%)2009 =< 258 ( 4.5%)
Stage I 166 ( 2.9%) II 814 (14.2%)III 1,765 (30.8%)IV 2,805 (48.9%)recurrence 152 ( 2.7%)unknown 30 ( 0.5%)
Primary tumor site appendix 25 ( 0.4%)right-sided colon 1,713 (29.9%)left-sided colon 2,160 (37.7%)rectum 1,817 (31.7%)others 17 ( 0.3%)
Site of the sample obtained
Primary tumor 5,258 (91.7%)Metastasis 474 ( 8.3%)
liver 216 (45.6%)lung 74 (15.6%)lymph node 37 ( 7.8%)local 45 ( 9.5%)dissemination 70 (14.8%)others 32 ( 6.8%)
Results: Results: KRASKRAS WT, WT, KRASKRAS MT (G13D), MT (G13D), KRASKRAS MT (others) MT (others)
KRAS mutation
n %
Codon12 1,714
GAT (G12D)GTT (G12V)TGT (G12C)AGT (G12S)GCT (G12A)CGTOthers
814493162120107153
47.528.89.57.06.20.90.1
Codon13 441
GAC (G13D)TGCCGCGAGOthers
42011613
95.22.51.40.20.7
No. of sample
KRAS WT KRAS MT
n % 95%CI n % 95%CI
All 5,732 3,577 62.4 61.1-63.7 2,155 37.6 36.3-38.9
Codon12 Codon13
1,714 441
29.9 7.7
28.7-31.17.0-8.4
KRAS WT62.4%(n=3,577)
KRAS MT37.6%
(n=2,155)
G13D7.3％(n=420)
others30.3％(n=1,735)
The frequency of KRAS mutation (37.6%) in Japanese CRC patients is similar to those reported in previous studies from western countries.
There are the significant difference of the frequency of KRAS mutation between
male (35.5%) and female (40.9%) left-sided colon (29.3%) and right-sided colon (48.2%). As the age is higher there is more frequent KRAS mutation.
* not included in the logistic regression
KRAS WT vs. KRAS MT (G13D) KRAS MT (G13D) vs. KRAS MT (others)
Odds-ratio 95%CI P value Odds-ratio 95%CI P value
1.500 1.224 - 1.838 <0.0001 0.805 0.650 - 0.997 0.0465
0.667 0.544 - 0.817 1.243 1.003 - 1.539
1.098 0.785 - 1.536 0.3549 1.383 0.960 - 1.994 0.1992
1.038 0.813 - 1.327 1.024 0.790 - 1.327
1.127 0.910 - 1.396 0.831 0.663 - 1.040
0.826 0.668 - 1.022 1.059 0.846 - 1.324
0.527 0.114 - 2.448 <0.0001 0.588 0.133 - 2.598 0.0558
0.490 0.397 - 0.604 1.105 0.889 - 1.374
2.325 1.842 - 2.934 0.729 0.571 - 0.932
0.871 0.704 - 1.077 1.231 0.983 - 1.542
- - - - - -
1.008 0.699 - 1.453 0.9673 0.988 0.672 - 1.454 0.9514
0.992 0.688 - 1.431 1.012 0.688 - 1.489
1.332 0.749 - 2.371 0.5733 0.940 0.510 - 1.734 0.8520
0.803 0.361 - 1.785 1.531 0.639 - 3.666
1.293 0.303 - 5.520 0.634 0.143 - 2.819
1.136 0.345 - 3.746 0.953 0.270 - 3.359
0.662 0.276 - 1.587 0.824 0.341 - 1.992
0.497 0.166 - 1.483 1.507 0.478 - 4.756
Clinicopathological features: WT, MT (G13D), MT (others)
Gender
Femalen=2,257
Malen=3,475
59.1%
64.5%
8.8%
6.4%
32.1%
29.1%
Primary tumor site
62.9%
70.7%
51.8%
36.0%
8.1%
4.7%
9.9%
8.0%
29.1%
24.5%
38.4%
56.0%
rectumn=1,817
left-sided colonn=2,160
right-sided colonn=1,713
appendixn=25
Age
*Cochran-Armitage trend test
70=<n=1,833
60-69n=2,081
50-59n=1,258
<50n=560
60.1%
61.9%
63.4%
69.5%
8.0%
6.7%
7.2%
7.5%
31.9%
31.3%
29.3%
23.0%
P=0.0001* P=0.5285* P=0.0002*
KRAS WT KRAS MT (G13D) KRAS MT (others)
Site of the sample obtained
48.6%
64.4%
59.5%
64.9%
67.6%
62.4%
62.4%
8.6%
6.7%
5.4%
9.5%
6.0%
7.4%
7.3%
42.9%
28.9%
35.1%
25.7%
26.4%
30.2%
30.3%
disseminationn=70
localn=45
lymph noden=37
lungn=74
livern=216
Metastasisn=474
Primary tumorn=5,258
This study aimed to examine whether the clinicopathological features of tumors with p.G13D MT is more similar to those of KRAS wild type or other KRAS mutations in large-scale Japanese population (n=5,887).
KRAS MT G13D
KRAS MT (others)
G12D G12V G12C G12S G12A
Gender Male 205 (52.0%)
424 (56.8%)
270 (59.0%)
102 (67.1%)
61 (54.5%)
55 (54.5%)
Female 189 (48.0%)
323 (43.2%)
188 (41.0%)
50 (32.9%)
51 (45.5%)
46 (45.5%)
Age < 60 127 (32.2%)
206 (27.6%)
141 (30.8%)
40 (26.3%)
33 (29.5%)
28 (27.7%)
60-69 128 (32.5%)
279 (37.3%)
172 (37.6%)
61 (40.1%)
42 (37.5%)
43 (42.6%)
70 =< 139 (35.3%)
262 (35.1%)
145 (31.7%)
51 (33.6%)
37 (33.0%)
30 (29.7%)
Primary tumor site*
right-sided colon
158 (40.1%)
316 (42.3%)
155 (33.8%)
76 (50.0%)
32 (28.6%)
32 (31.7%)
left-sided colon
98 (24.9%)
215 (28.8%)
154 (33.6%)
39 (25.7%)
48 (42.9%)
36 (35.6%)
rectum 138 (35.0%)
216 (28.9%)
149 (32.5%)
37 (24.3%)
32 (28.6%)
33 (32.7%)
Site of the sample obtained
Primary tumor
362 (91.9%)
683 (91.4%)
427 (93.2%)
136 (89.5%)
106 (94.6%)
94 (93.1%)
Metastasis 32 ( 8.1%)
64 ( 8.6%)
31 ( 6.8%)
16 (10.5%)
6 ( 5.4%)
7 ( 6.9%)
liver 11 (34.4%)
26 (40.6%)
13 (41.9%)
8 (50.0%)
3 (50.0%)
4 (57.1%)
lung 7 (21.9%)
4 ( 6.3%)
5 (16.1%)
2 (12.5%)
1 (16.7%)
2 (28.6%)
others 14 (43.8%)
34 (53.1%)
13 (41.9%)
6 (37.5%)
2 (33.3%)
1 (14.3%)
Comparison of KRAS mutation results
* G13D vs. G12V P=0.0171, vs. G12C P=0.0399, vs. G12S P=0.0009
KRAS WT KRAS MT (G13D) KRAS MT (Others)
GenderMale > Female
64.5% 59.1%
Male < Female
6.4% 8.8%
Male < Female
29.1% 32.1%
P< 0.0001 P=0.0465
Age Young > Old69.5%/63.4%/61.9%/60.1%*
Young Old≒7.5%/7.2%/6.7%/8.0%*
Young < Old23.0%/29.3%/31.3%/31.9%*
P=0.3549 P=0.1992
Primary tumor site
Right < Left
51.8% 70.7%
Right > Left
9.9% 4.7%
Right > Left
38.4% 24.5%
P<0.0001 P=0.0558
Site of the sample obtained
Liver Lung≒67.6% 64.9%
Liver < Lung
6.0% 9.5%
Liver Lung≒26.4% 25.7%
P=0.5733 P=0.8520
Summary of the results
*< 50/50-59/60-69/70=<
Summary of the previous presentationSummary of the previous presentation
Study profile Gender
Age
Primary tumor site
Mutation
Male Female
1,232 923
2,243 1,334
35.5%40.9%
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
n=3,475 n=2,257
KRAS WT KRAS MT Mutation rate P<0.0001
<50 50-59 60-69 70=<
389
171
30.5%
460
798
36.6%
792
1,289
38.1%
732
1,101
39.9%
n=560 n=1,258 n=2,081 n=1,833
KRAS WT KRAS MT Mutation rate P=0.0007
Mutation
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
826
887
48.2%
632
1,528
29.3%
left-sided colonn=2,160
right-sided colonn=1,713
675
1,142
37.1%
rectumn=1,817
KRAS WT KRAS MT Mutation rate P<0.0001
Mutation
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
KRAS WT KRAS MT (G13D) KRAS MT (others)
KRAS WT KRAS MT (G13D) KRAS MT (others)
KRAS WT KRAS MT (G13D) KRAS MT (others)
ASCO 2011 #3605ASCO 2011 #3605