Introduction

Objective

Patient selection criteria

Results

Conclusions

Polymorphisms in fragment C receptor (FcγR) are expected as a predictive biomarker of cetuximab1-3.

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 polymorphisms4,5.

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

References

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 a and FcγR aⅡ Ⅲ 　 was evaluated by Linkdis6 and Genopop7.

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 criteriaHistologically proven metastatic and unresectable

colorectal adenocarcinomaKRAS genotype was examined5-FU/irinotecan/oxaliplatin resistant or intolerance Treated with cetuximab contained regimenBaseline CT scan performed within 28 days before

administrationMeasurable lesion definedAge ≥ 20 years oldECOG performance status 0–2Preserved organ functionWritten informed consent

Key exclusion criteriaUGT1A1 genotype is homozygote of *28 or a

homozygote of *6 or a double of *28 and *6 (cetuximab plus irinotecan therapy only) 

Uncontrollable heart diseaseOther severe complications (renal failure, liver failure,

and intestinal pneumonitis)Symptomatic CNS metastasisMassive ascites or pleural effusion

Acknowledgements

　 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: 2048–20539. 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 Fukushima12, T Yoshino1, K Yamazaki3, T Nishina4, S Yuki2, S Kadowaki5, E Shinozaki6, T Yokota7, S Kajiura8, T Yamanaka9

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.

Methods

No. of pts 93

Gender: Male/Female 57/36

Age (yrs): median (range) 64 (38-80)

ECOG PS: 0/1/2 57/33/3

Primary side: right sided/ left sided/ rectum 19/41/33

No. of metastatic site: 1/2/3≤ 25/34/34

Histology: wel/ mod/ por/ muc/ unknown 19/63/6/4/1

No. of prior chemotherapy: 2/3/4≤ 62/20/11

Usage of prior chemotherapy (%): 5-FU /Oxa / Iri / Bev 100/100/98/68

Treatment regimen: cetuximab + irinotecan/ cetuximab 79/14

KRAS status: wild type/ mutant 87/6

FcγRIIIa-158 VV VF FF Total

FcγRIIa-131HH 3 28 32 63 (68%)

HR 1 9 18 28 (30%)

RR 0 0 2 2 (2%)

Total 4 (4%) 37 (40%) 52 (56%) 93

Abstract

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.

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Distributions of FcγR Polymorphisms

FcγR a-158Ⅲ

V/V V/F F/F

HFcγRIIa-131H/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% 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

FcγRIIa FcγRIIIa

H/H H/R or R/R V/V or V/F F/F

Response rate 37% 36% 39% 35%

p -value p=1.00 p=0.81

FcγR polymorphisms and response

FcγR polymorphisms and PFS

months

Pro

bab

ility

Pro

bab

ility

months

Median follow-up of 10.4 months (2.6-19.2 months)

H/R or R/Rcensored

H/Hcensored

FcγRIIamPFS

(months)

H/H, n=49 6.0

H/R or R/R, n=25 6.9

FcγRI aⅢ mPFS(months)

F/F, n=43 5.8

V/V or V/F, n=31 8.7

V/V or V/Fcensored

F/Fcensored

log-rank test p=0.84

log-rank test p=0.09

Summary

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).

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Zhang1

(2007)Bibeau2

(2009)Pander3

(2010)Paez 8

(2010)Park9

(2010)Zarata10

(2010)Our data

Country U.S. France Netherlands Spain Korea Spain Japan

No. 39 69 127 104 123 66 93

Treatment CmabCmab

+irinotecan

CAPOX+bev

+Cmab

Cmab or Pmab

alone or combined

CmabCmab-based

Cmab+irinotecan

Sample bloodtumor tissue

blood blood bloodtumor tissue

blood

KRAS (WT/MT) NA 37/27 127/0 74/22 90/33 NA 87/6

Association with clinical response

+ + + - - + -

Favorable type ofFcγR polymorphisms

Ⅱa any HⅢa any F

Ⅱa H/H Ⅲa V/V

ⅢaF/F Ⅲa any V

Recent studies of FcγR polymorphisms and clinical response

NA; not applicable, Cmab; cetuximab, Pmab; panitumumab