1. 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 Ohashi5
１Tokyo 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
ASCO 2011 #3605
Background
Summary of the previous presentation
Results: KRAS WT, KRAS MT (G13D), KRAS MT (others)
Conclusions
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.
Study profile
Gender
Clinicopathological features: WT, MT (G13D), MT (others)
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 registration, n=5,887
　 from 389 facilities
From Oct to Mar. 2010
Cut-off: Apr. 2010
KRAS WT
KRAS MT
Mutation rate
P<0.0001 n
KRAS　WT
KRAS　MT
(G13D)
(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%) 32
17 (53.1%)
4 (12.5%)
11 (34.4%)
KRAS WT vs. KRAS MT (G13D)
KRAS MT (G13D) vs. KRAS MT (others)
Odds-ratio
95%CI
P value
1.500
<0.0001
0.805
0.0465
0.667
1.243
1.098
0.3549
1.383
0.1992
1.038
1.024
1.127
0.831
0.826
1.059
0.527
0.588
0.0558
0.490
1.105
2.325
0.729
0.871
1.231 -
1.008
0.9673
0.988
0.9514
0.992
1.012
1.332
0.5733
0.940
0.8520
0.803
1.531
1.293
0.634
1.136
0.953
0.662
0.824
0.497
1.507
100%
Excluded, n=97
　 Cancelation 14
　 Ineligible 1
　 Uncollected 82　
90%
80%
　 KRAS test, n=5,790
　　 Direct sequencing ,479
　　 Luminex
70%
1,334
2,243
60%
Undetectable samples, n=58
　 Direct sequencing 56
　 Luminex 2　
Mutation
50%
40.9%
KRAS test detectable, n=5,732
　　 Direct sequencing ,423
　　 Luminex
35.5%
40%
30%
Objective
20%
923
1,232
10%
Sample Background
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). 0% n
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
< 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%)
< 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%)
Male
Female
n=3,475
n=2,257
Age
Methods
KRAS WT
KRAS MT
Mutation rate
P=0.0007
100%
90%
* not included in the logistic regression
Key eligibility criteria
Histologically confirmed colorectal adenocarcinoma
Adequate tumor samples
80%
Gender
Primary tumor site
Comparison of KRAS mutation results
70%
798
1,289
1,101
389
60%
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%)
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%)
6 (37.5%)
2 (33.3%)
1 (14.3%)
KRAS WT
KRAS MT (G13D)
KRAS MT (others)
KRAS WT
KRAS MT (G13D)
KRAS MT (others)
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)
Mutation
50%
39.9%
40%
36.6%
38.1%
appendix
n=25
36.0%
8.0%
56.0%
30.5%
30%
Male
n=3,475
6.4 %
64.5%
29.1%
20%
460
792
732
171
right-sided
colon
n=1,713
10%
51.8%
9.9%
38.4%
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%)
32 ( 6.8%) 0%
<50
50-59
60-69
70=<
n=560
n=1,258
n=2,081
n=1,833
left-sided
colon
n=2,160
70.7%
4.7 %
24.5%
References
Primary tumor site
Female
n=2,257
59.1%
8.8%
32.1%
1. Karapetis CS. et al. N Engl J Med. 2008;359:
2. Amado RG. et al. J Clin Oncol. 2008;26:
3. Van Cutsem E. et al. N Engl J Med. 2009;360:
4. De Roock W. et al. JAMA. 2010;304:
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 WT
KRAS MT
Mutation rate
P<0.0001
100%
rectum
n=1,817
62.9%
8.1%
29.1%
90%
80%
887
70%
1,142
1,528
KRAS mutation
60%
Age
Site of the sample obtained
* G13D vs. G12V P=0.0171, vs. G12C P=0.0399, vs. G12S P=0.0009
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
48.2%
Mutation
50%
No. of sample
KRAS　WT
KRAS　MT n %
95%CI
All
5,732
3,577
62.4
2,155
37.6
　 Codon12
　 Codon13
1,714
441
29.9
7.7
Summary of the results
37.1%
KRAS WT
KRAS MT (G13D)
KRAS MT (others)
KRAS WT
KRAS MT (G13D)
KRAS MT (others)
40%
29.3%
Hospitals
Laboratories
Data center
1. Sample registration
2. Enrollment confirmation
6. Result
3. Sample
2’. Registration information
5. Result
4. KRAS test
KRAS WT
KRAS MT (G13D)
KRAS MT (Others)
Gender
Male > Female
64.5% %
Male < Female
6.4% %
29.1% %
P<
P=0.0465
Age
Young > Old
69.5%/63.4%/61.9%/60.1%*
Young ≒ Old
7.5%/7.2%/6.7%/8.0%*
Young < Old
23.0%/29.3%/31.3%/31.9%*
P=0.3549
P=0.1992
Primary tumor site
Right < Left
51.8% %
Right > Left
9.9% %
38.4% %
P<0.0001
P=0.0558
Site of the sample obtained
Liver ≒ Lung
67.6% %
Liver < Lung
6.0% %
26.4% %
P=0.5733
P=0.8520
Acknowledgement
30%
P=0.0001*
P=0.5285*
P=0.0002*
Primary tumor
n=5,258
62.4%
7.3%
30.3%
826
<50 n=560
20%
69.5%
7.5%
23.0%
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.
675
632
Metastasis
n=474
10%
62.4%
7.4%
30.2% n %
Codon12
1,714
GAT (G12D)
GTT (G12V)
TGT (G12C)
AGT (G12S)
GCT (G12A)
CGT
Others
814
493
162
120
107 15 3
47.5
28.8
9.5
7.0
6.2
0.9
0.1
Codon13
441
GAC (G13D)
TGC
CGC
GAG
420 11 6 1
95.2
2.5
1.4
0.2
0.7 0%
others
30.3％
(n=1,735)
right-sided colon
left-sided colon
rectum
50-59
n=1,258
liver
n=216
63.4%
7.2%
29.3%
67.6%
6.0%
26.4%
n=1,713
n=2,160
n=1,817
lung
n=74
64.9%
9.5%
25.7%
KRAS MT
37.6%
(n=2,155)
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.
60-69
n=2,081
61.9%
6.7%
31.3%
lymph node
n=37
59.5%
5.4%
35.1%
KRAS WT
62.4%
(n=3,577)
local
n=45
64.4%
6.7%
28.9%
G13D
7.3％
(n=420)
70=<
n=1,833
60.1%
8.0%
31.9%
dissemination
n=70
48.6%
8.6%
42.9%
*Cochran-Armitage trend test
*< 50/50-59/60-69/70=<

2. 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 Ohashi5
１Tokyo 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
ASCO 2011 #3605
Background
Summary of the previous presentation
Results: KRAS WT, KRAS MT (G13D), KRAS MT (others)
Conclusions
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.
Study profile
Gender
Clinicopathological features: WT, MT (G13D), MT (others)
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 registration, n=5,887
　 from 389 facilities
From Oct to Mar. 2010
Cut-off: Apr. 2010
KRAS WT
KRAS MT
Mutation rate
P<0.0001 n
KRAS　WT
KRAS　MT
(G13D)
(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%) 32
17 (53.1%)
4 (12.5%)
11 (34.4%)
KRAS WT vs. KRAS MT (G13D)
KRAS MT (G13D) vs. KRAS MT (others)
Odds-ratio
95%CI
P value
1.500
<0.0001
0.805
0.0465
0.667
1.243
1.098
0.3549
1.383
0.1992
1.038
1.024
1.127
0.831
0.826
1.059
0.527
0.588
0.0558
0.490
1.105
2.325
0.729
0.871
1.231 -
1.008
0.9673
0.988
0.9514
0.992
1.012
1.332
0.5733
0.940
0.8520
0.803
1.531
1.293
0.634
1.136
0.953
0.662
0.824
0.497
1.507
100%
Excluded, n=97
　 Cancelation 14
　 Ineligible 1
　 Uncollected 82　
90%
80%
　 KRAS test, n=5,790
　　 Direct sequencing ,479
　　 Luminex
70%
1,334
2,243
60%
Undetectable samples, n=58
　 Direct sequencing 56
　 Luminex 2　
Mutation
50%
40.9%
KRAS test detectable, n=5,732
　　 Direct sequencing ,423
　　 Luminex
35.5%
40%
30%
Objective
20%
923
1,232
10%
Sample Background
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). 0% n
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
< 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%)
< 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%)
Male
Female
n=3,475
n=2,257
Age
Methods
KRAS WT
KRAS MT
Mutation rate
P=0.0007
100%
90%
* not included in the logistic regression
Key eligibility criteria
Histologically confirmed colorectal adenocarcinoma
Adequate tumor samples
80%
Gender
Primary tumor site
Comparison of KRAS mutation results
70%
798
1,289
1,101
389
60%
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%)
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%)
6 (37.5%)
2 (33.3%)
1 (14.3%)
KRAS WT
KRAS MT (G13D)
KRAS MT (others)
KRAS WT
KRAS MT (G13D)
KRAS MT (others)
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)
Mutation
50%
39.9%
40%
36.6%
38.1%
appendix
n=25
36.0%
8.0%
56.0%
30.5%
30%
Male
n=3,475
6.4 %
64.5%
29.1%
20%
460
792
732
171
right-sided
colon
n=1,713
10%
51.8%
9.9%
38.4%
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%)
32 ( 6.8%) 0%
<50
50-59
60-69
70=<
n=560
n=1,258
n=2,081
n=1,833
left-sided
colon
n=2,160
70.7%
4.7 %
24.5%
References
Primary tumor site
Female
n=2,257
59.1%
8.8%
32.1%
1. Karapetis CS. et al. N Engl J Med. 2008;359:
2. Amado RG. et al. J Clin Oncol. 2008;26:
3. Van Cutsem E. et al. N Engl J Med. 2009;360:
4. De Roock W. et al. JAMA. 2010;304:
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 WT
KRAS MT
Mutation rate
P<0.0001
100%
rectum
n=1,817
62.9%
8.1%
29.1%
90%
80%
887
70%
1,142
1,528
KRAS mutation
60%
Age
Site of the sample obtained
* G13D vs. G12V P=0.0171, vs. G12C P=0.0399, vs. G12S P=0.0009
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
48.2%
Mutation
50%
No. of sample
KRAS　WT
KRAS　MT n %
95%CI
All
5,732
3,577
62.4
2,155
37.6
　 Codon12
　 Codon13
1,714
441
29.9
7.7
Summary of the results
KRAS WT
KRAS MT (G13D)
KRAS MT (others)
KRAS WT
KRAS MT (G13D)
KRAS MT (others)
40%
37.1%
29.3%
Hospitals
Laboratories
Data center
1. Sample registration
2. Enrollment confirmation
6. Result
3. Sample
2’. Registration information
5. Result
4. KRAS test
KRAS WT
KRAS MT (G13D)
KRAS MT (Others)
Gender
Male > Female
64.5% %
Male < Female
6.4% %
29.1% %
P<
P=0.0465
Age
Young > Old
69.5%/63.4%/61.9%/60.1%*
Young ≒ Old
7.5%/7.2%/6.7%/8.0%*
Young < Old
23.0%/29.3%/31.3%/31.9%*
P=0.3549
P=0.1992
Primary tumor site
Right < Left
51.8% %
Right > Left
9.9% %
38.4% %
P<0.0001
P=0.0558
Site of the sample obtained
Liver ≒ Lung
67.6% %
Liver < Lung
6.0% %
26.4% %
P=0.5733
P=0.8520
Acknowledgement
30%
P=0.0001*
P=0.5285*
P=0.0002*
Primary tumor
n=5,258
62.4%
7.3%
30.3%
826
<50 n=560
20%
69.5%
7.5%
23.0%
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.
675
632
Metastasis
n=474
10%
62.4%
7.4%
30.2% n %
Codon12
1,714
GAT (G12D)
GTT (G12V)
TGT (G12C)
AGT (G12S)
GCT (G12A)
CGT
Others
814
493
162
120
107 15 3
47.5
28.8
9.5
7.0
6.2
0.9
0.1
Codon13
441
GAC (G13D)
TGC
CGC
GAG
420 11 6 1
95.2
2.5
1.4
0.2
0.7 0%
others
30.3％
(n=1,735)
right-sided colon
left-sided colon
rectum
50-59
n=1,258
liver
n=216
63.4%
7.2%
29.3%
67.6%
6.0%
26.4%
n=1,713
n=2,160
n=1,817
lung
n=74
64.9%
9.5%
25.7%
KRAS MT
37.6%
(n=2,155)
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.
60-69
n=2,081
61.9%
6.7%
31.3%
lymph node
n=37
59.5%
5.4%
35.1%
KRAS WT
62.4%
(n=3,577)
local
n=45
64.4%
6.7%
28.9%
G13D
7.3％
(n=420)
70=<
n=1,833
60.1%
8.0%
31.9%
dissemination
n=70
48.6%
8.6%
42.9%
*Cochran-Armitage trend test
*< 50/50-59/60-69/70=<