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Background

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.

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Background

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  1. No. of sample KRASWT KRASMT 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 61.1-63.7 2,155 37.6 36.3-38.9 Codon12 Codon13 1,714 441 29.9 7.7 28.7-31.1 7.0-8.4 Hospitals 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 1. Sample registration 3. Sample 2. Enrollment confirmation 6. Result 4. KRAS test Codon13 441 2’. Registration information GAC (G13D) TGC CGC GAG Others 420 11 6 1 3 95.2 2.5 1.4 0.2 0.7 5. Result Data center Laboratories 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. From Oct. 2009 to Mar. 2010 Cut-off: Apr. 2010 Sample registration, n=5,887 from 389 facilities KRAS WT KRAS MT Mutation rate P<0.0001 100% Excluded, n=97 Cancelation 14 Ineligible 1 Uncollected 82 90% 80% KRAS test, n=5,790 Direct sequencing 5,479 Luminex 311 1,334 70% 2,243 60% Undetectable samples, n=58 Direct sequencing 56 Luminex 2 Mutation 50% 40.9% 35.5% KRAS test detectable, n=5,732 Direct sequencing 5,423 Luminex 309 40% 30% 923 20% Objective 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% Male Female n=3,475 n=2,257 Age KRAS WT KRAS MT Mutation rate P=0.0007 Methods 100% * not included in the logistic regression 90% • Key eligibility criteria • Histologically confirmed colorectal adenocarcinoma • Adequate tumor samples 80% Gender Primary tumor site Comparison of KRAS mutation results 70% 1,101 1,289 798 389 60% 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% 38.1% 36.6% appendix n=25 40% 36.0% 8.0% 56.0% 30.5% 30% Male n=3,475 6.4 % 64.5% 29.1% 20% 732 792 460 right-sided colon n=1,713 171 10% 51.8% 9.9% 38.4% 0% <50 50-59 60-69 70=< n=1,833 n=560 n=1,258 n=2,081 left-sided colon n=2,160 4.7 % 70.7% 24.5% References Primary tumor site Female n=2,257 1. 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 59.1% 8.8% 32.1% KRAS WT KRAS MT Mutation rate P<0.0001 rectum n=1,817 100% 62.9% 8.1% 29.1% 90% 80% 887 70% 1,142 1,528 Age 60% * G13D vs. G12V P=0.0171, vs. G12C P=0.0399, vs. G12S P=0.0009 Site of the sample obtained KRAS mutation 48.2% • 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 Mutation 50% Summary of the results 37.1% 40% 29.3% Acknowledgement P=0.5285* P=0.0002* P=0.0001* 30% Primary tumor n=5,258 62.4% 30.3% 7.3% 826 <50n=560 69.5% 7.5% 23.0% 20% • 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 Metastasis n=474 632 62.4% 30.2% 7.4% 10% 0% others 30.3％ (n=1,735) liver n=216 right-sided colon left-sided colon rectum 50-59 n=1,258 67.6% 26.4% 6.0% 63.4% 7.2% 29.3% n=1,713 n=2,160 n=1,817 lung n=74 64.9% 25.7% 9.5% 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 lymph node n=37 61.9% 6.7% 31.3% 59.5% 35.1% 5.4% KRAS WT 62.4% (n=3,577) local n=45 64.4% 28.9% 6.7% 70=< n=1,833 G13D 7.3％ (n=420) 60.1% 8.0% 31.9% dissemination n=70 48.6% 42.9% 8.6% *Cochran-Armitage trend test *< 50/50-59/60-69/70=<

  2. No. of sample KRASWT KRASMT 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 61.1-63.7 2,155 37.6 36.3-38.9 Codon12 Codon13 1,714 441 29.9 7.7 28.7-31.1 7.0-8.4 Hospitals 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 1. Sample registration 3. Sample 2. Enrollment confirmation 6. Result 4. KRAS test Codon13 441 2’. Registration information GAC (G13D) TGC CGC GAG Others 420 11 6 1 3 95.2 2.5 1.4 0.2 0.7 5. Result Data center Laboratories 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 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. From Oct. 2009 to Mar. 2010 Cut-off: Apr. 2010 Sample registration, n=5,887 from 389 facilities KRAS WT KRAS MT Mutation rate P<0.0001 100% Excluded, n=97 Cancelation 14 Ineligible 1 Uncollected 82 90% 80% KRAS test, n=5,790 Direct sequencing 5,479 Luminex 311 1,334 70% 2,243 60% Undetectable samples, n=58 Direct sequencing 56 Luminex 2 Mutation 50% 40.9% 35.5% KRAS test detectable, n=5,732 Direct sequencing 5,423 Luminex 309 40% 30% 923 20% Objective 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% Male Female n=3,475 n=2,257 Age KRAS WT KRAS MT Mutation rate P=0.0007 Methods 100% * not included in the logistic regression 90% • Key eligibility criteria • Histologically confirmed colorectal adenocarcinoma • Adequate tumor samples 80% Gender Primary tumor site Comparison of KRAS mutation results 70% 1,101 1,289 798 389 60% 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% 38.1% 36.6% appendix n=25 40% 36.0% 8.0% 56.0% 30.5% 30% Male n=3,475 6.4 % 64.5% 29.1% 20% 732 792 460 right-sided colon n=1,713 171 10% 51.8% 9.9% 38.4% 0% <50 50-59 60-69 70=< n=1,833 n=560 n=1,258 n=2,081 left-sided colon n=2,160 4.7 % 70.7% 24.5% References Primary tumor site Female n=2,257 1. 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 59.1% 8.8% 32.1% KRAS WT KRAS MT Mutation rate P<0.0001 rectum n=1,817 100% 62.9% 8.1% 29.1% 90% 80% 887 70% 1,142 1,528 Age 60% * G13D vs. G12V P=0.0171, vs. G12C P=0.0399, vs. G12S P=0.0009 Site of the sample obtained KRAS mutation 48.2% • 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 Mutation 50% Summary of the results 37.1% 40% 29.3% Acknowledgement P=0.5285* P=0.0002* P=0.0001* 30% Primary tumor n=5,258 62.4% 30.3% 7.3% 826 <50n=560 69.5% 7.5% 23.0% 20% • 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 Metastasis n=474 632 62.4% 30.2% 7.4% 10% 0% others 30.3％ (n=1,735) liver n=216 right-sided colon left-sided colon rectum 50-59 n=1,258 67.6% 26.4% 6.0% 63.4% 7.2% 29.3% n=1,713 n=2,160 n=1,817 lung n=74 64.9% 25.7% 9.5% 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 lymph node n=37 61.9% 6.7% 31.3% 59.5% 35.1% 5.4% KRAS WT 62.4% (n=3,577) local n=45 64.4% 28.9% 6.7% 70=< n=1,833 G13D 7.3％ (n=420) 60.1% 8.0% 31.9% dissemination n=70 48.6% 42.9% 8.6% *Cochran-Armitage trend test *< 50/50-59/60-69/70=<

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