1. IntroductionIntroduction ObjectiveObjective Patient selection criteria ResultsResults ConclusionsConclusions Polymorphisms in fragment C receptor (FcγR) are expected as a predictive biomarker of cetuximab 1-3. Previous studies have convincingly confirmed the distributions of FcγR polymorphisms in Western population and shown the existence of linkage disequilibrium (LD) between FcγRIIa and FcγRIIIa polymorphisms 4,5. The distributions in Asian population have been unknown but a few studies for non-cancer patients have suggested the difference in distributions between Asian and Western populations. Patient Characteristics ReferencesReferences We are grateful to the participating patients and their families and to all other co investigators who contributed and registered to the study. This study was supported by the Grant-in-Aid for Cancer Research (21 S4-5) from the Ministry of Health, Labour and Welfare of Japan. A119 We retrospectively registered mCRC patients according to the selection criteria from 8 centers in Japan. FcγR polymorphisms were determined from genomic DNA extracted from peripheral blood samples based on the Multiplex allele-specific PCR method. LD between FcγR Ⅱ a and FcγR Ⅲ a was evaluated by Linkdis 6 and Genopop 7. Comparisons according to FcγR polymorphisms were evaluated using Fisher’s exact test for response rate (RR) and log-rank test for progression-free survival curves (PFS). Eligibility criteria Histologically proven metastatic and unresectable colorectal adenocarcinoma KRAS genotype was examined 5-FU/irinotecan/oxaliplatin resistant or intolerance Treated with cetuximab contained regimen Baseline CT scan performed within 28 days before administration Measurable lesion defined Age ≥ 20 years old ECOG performance status 0–2 Preserved organ function Written informed consent Key exclusion criteria UGT1A1 genotype is homozygote of *28 or a homozygote of *6 or a double of *28 and *6 (cetuximab plus irinotecan therapy only) Uncontrollable heart disease Other severe complications (renal failure, liver failure, and intestinal pneumonitis) Symptomatic CNS metastasis Massive ascites or pleural effusion AcknowledgementsAcknowledgements This study clarified an ethnic difference in the frequencies of FcγR polymorphisms in mCRC patients. Associations between the polymorphisms and clinical response to cetuximab did not reach a statistical significance. 1.Zhang W, et al. J Clin Oncol 2007; 25: 3712-3718. 2.Bibeau F, et al. J Clin Oncol 2009; 27: 1122-1129. 3.Pander J, et al. Eur J Cnacer 2010; 46: 1829-1834. 4.Lehrnbecher T, et al. Blood 1999; 94: 4220-4232. 5.van der Pol WL, et al. Immunogenetics 2003; 55: 240-246. 6.Black WC, et al. Theor Appl Genet 1985; 70:491-496. 7.Raymond M, et al. J Heredity 2003; 86:248-249. 8.Paez E, et al. Cancer Sci 2010; 9: 2048–2053 9.Park S.J., et al. Ann Oncol 2010; 21: suppl.8 (#605P) 10.Zarata R, et al. J Clin Oncol 2010; 28: suppl. #e13523 Of 74 patients with KRAS wild-type and treated by cetuximab plus irinotecan were analyzed for clinical response. Distributions of FcγRIIa-131 and FcγRIIIa-158 polymorphisms and clinical response to cetuximab in Japanese patients with metastatic colorectal cancer (mCRC) H Fukushima 12, T Yoshino 1, K Yamazaki 3, T Nishina 4, S Yuki 2, S Kadowaki 5, E Shinozaki 6, T Yokota 7, S Kajiura 8, T Yamanaka 9 1 National Cancer Center Hospital East, 2 Hokkaido University Hospital, 3 Shizuoka Cancer Center, 4 Shikoku Cancer Center, 5 Saitama Cancer Center, 6 Cancer Institute Hospital, 7 Aichi Cancer Center Hospital, 8 Toyama University Hospital, 9 Kyushu Cancer center Hospital, Japan Distributions of FcγRIIa-131 and FcγRIIIa-158 polymorphisms and clinical response to cetuximab in Japanese patients with metastatic colorectal cancer (mCRC) H Fukushima 12, T Yoshino 1, K Yamazaki 3, T Nishina 4, S Yuki 2, S Kadowaki 5, E Shinozaki 6, T Yokota 7, S Kajiura 8, T Yamanaka 9 1 National Cancer Center Hospital East, 2 Hokkaido University Hospital, 3 Shizuoka Cancer Center, 4 Shikoku Cancer Center, 5 Saitama Cancer Center, 6 Cancer Institute Hospital, 7 Aichi Cancer Center Hospital, 8 Toyama University Hospital, 9 Kyushu Cancer center Hospital, Japan Abstract # 565 This retrospective analysis was to investigate the distributions of FcγR polymorphisms and their association with clinical response to cetuximab in Japanese mCRC patients. MethodsMethods No. of pts93 Gender: Male/Female57/36 Age (yrs): median (range)64 (38-80) ECOG PS: 0/1/257/33/3 Primary side: right sided/ left sided/ rectum19/41/33 25/34/34 Histology: wel/ mod/ por/ muc/ unknown19/63/6/4/1 62/20/11 Usage of prior chemotherapy (%): 5-FU /Oxa / Iri / Bev100/100/98/68 Treatment regimen: cetuximab + irinotecan/ cetuximab79/14 KRAS status: wild type/ mutant87/6 FcγRIIIa-158 VVVFFF Total FcγRIIa-131 HH 3283263 (68%) HR191828 (30%) RR0022 (2%) Total4 (4%)37 (40%)52 (56%)93 AbstractAbstract Background: Polymorphisms in fragment C receptor (FcγR) are expected as a predictive biomarker of cetuximab (Cmab). Previous studies have convincingly confirmed the distributions (dists) of FcγR polymorphisms in Western population and shown the existence of linkage disequilibrium (LD) between FcγRIIa and FcγRIIIa polymorphisms. Meanwhile, the dists in Asian population have been unknown but a few studies for non-cancer patients have suggested the difference in dists between Asian and Western populations. We investigated the dists of FcγR polymorphisms and their association with clinical response to Cmab in Japanese metastatic colorectal cancer (mCRC) patients. Patients and Methods: Ninety-three patients with irinotecan/oxaliplatin/5-FU- refractory mCRC and treated by Cmab plus irinotecan or Cmab monotherapy were retrospectively registered from 8 centers in Japan. FcγR polymorphisms were determined from genomic DNA extracted from peripheral blood samples based on the Multiplex allele-specific PCR method. Comparisons according to FcγR polymorphisms were evaluated using Fisher’s exact test for response rate (RR) and log-rank test for progression- free survival curves (PFS). Results: The dists of FcγRIIa HH/HR/RR and FcγRIIIa VV/VF/FF were 68/30/2% and 4/40/56%, respectively. The absence of LD between FcγRIIa and FcγRIIIa polymorphisms was confirmed (GENEPOP, p=0.526; Linkdis, p=0.146). Of 74 patients with KRAS wild-type and treated by Cmab plus irinotecan, no difference according to FcγR polymorphisms was observed in either RR (IIa: HH 37% vs. HR/RR 36%, p=1.00; IIIa: VV/VF 39% vs. FF 35%, p= 0.81) or PFS curves (IIa: HH vs. HR/RR, p=0.84; IIIa: VV/VF vs. FF, p=0.09). Similar results were seen in patients treated by cetuximab monotherapy. Conclusions: This study clarified an ethnic difference in the frequencies of FcγR polymorphisms. Associations between the polymorphisms and clinical response to Cmab did not reach a statistical significance. ● ● ● ● ● ● ● ● ● ● ● Distributions of FcγR Polymorphisms FcγR Ⅲ a-158 V/VV/FF/F HFcγRIIa-131 H/H This study(N=93)4.8%44.4%50.8% White(N=180) 4 19.6%42.9%37.5% White(N=514) 5 22.9%51.1%26.0% African American(N=150) 4 15.0%45.0%40.0% H/R This study(N=93)3.6%32.1%64.3% White(N=180)8.6%39.5%51.9% White(N=514)12.9%49.6%37.5% African American(N=150)7.8%54.7%37.5% R/R This study(=N=93)0% 100% White(N=180)2.3%34.9%62.8% White(N=514)8.1%38.2%53.7% African American(N=150)2.2%47.8%50.0% Clinical response to cetuximab GENOPOP p=0.526, Linkdis p=0.146 FcγRIIaFcγRIIIa H/HH/R or R/RV/V or V/FF/F Response rate37%36%39%35% p -valuep=1.00p=0.81 FcγR polymorphisms and response FcγR polymorphisms and PFS months Probability months Median follow-up of 10.4 months (2.6-19.2 months) H/R or R/R censored H/H censored FcγRIIa mPFS (months) H/H, n=496.0 H/R or R/R, n=256.9 FcγRI Ⅲ a mPFS (months) F/F, n=435.8 V/V or V/F, n=318.7 V/V or V/F censored F/F censored log-rank test p=0.84 log-rank test p=0.09 SummarySummary The dists of FcγRIIa HH/HR/RR and FcγRIIIa VV/VF/FF were 68/30/2% and 4/40/56%, respectively. The absence of LD between FcγRIIa and FcγRIIIa polymorphisms was confirmed (GENEPOP, p=0.526; Linkdis, p=0.146). Of 74 patients with KRAS wild-type and treated by cetuximab plus irinotecan, no difference according to FcγR polymorphisms was observed in either RR (IIa: HH 37% vs. HR/RR 36%, p=1.00; IIIa: VV/VF 39% vs. FF 35%, p= 0.81) or PFS curves (IIa: HH vs. HR/RR, p=0.84; IIIa: VV/VF vs. FF, p=0.09). ● ● ● ● Zhang 1 (2007) Bibeau 2 (2009) Pander 3 (2010) Paez 8 (2010) Park 9 (2010) Zarata 10 (2010) Our data CountryU.S.FranceNetherlandsSpainKoreaSpainJapan No.39691271041236693 TreatmentCmab +irinotecan CAPOX +bev +Cmab Cmab or Pmab alone or combined Cmab -based Cmab +irinotecan Sampleblood tumor tissue blood tumor tissue blood KRAS (WT/MT)NA37/27127/074/2290/33NA87/6 Association with clinical response +++--+- Favorable type of FcγR polymorphisms Ⅱ a any H Ⅲ a any F Ⅱ a H/H Ⅲ a V/V Ⅲ aF/F Ⅲ a any V Recent studies of FcγR polymorphisms and clinical response NA; not applicable, Cmab; cetuximab, Pmab; panitumumab