内容紹介
Relationship between Polymorphisms and the Efficacy of Cetuximab
Summary
Background and Objectives: Cetuximab has shown efficacy in patients with metastatic colorectal cancer(mCRC). Recent studies have demonstrated that cetuximab induces antibody-dependent cell-mediated cytotoxicity(ADCC), mediated via the fragment c gamma receptors(FcγR)in mCRC. Since the establishment of KRAS mutations as a major negative predictor of efficacy, additional biomarkers have been found to be useful for the improvement of selection of patients likely to be responsive to cetuximab. We investigated the relationship between polymorphisms and the outcome of mCRC patients treated with cetuximab. Methods: In this study, 57 patients were evaluated. The relationships of FcγR polymorphisms with response rate(RR), progression-free survival(PFS), and overall survival(OS)were analyzed. Results: The FcγR polymorphisms were not significantly related to RR, PFS, and OS. Compared with the other haplotypes, the haplotype containing the 131H and 158V alleles was related to a lower RR(p=0.018). The diplotypes containing 131H and 158V alleles had significantly lower RR than the other diplotypes(p=0.038). Conclusion: Our data suggest that FcγR polymorphisms may be associated with the outcome of mCRC patients treated with cetuximab and FOLFIRI. However, these results are currently controversial, and detailed investigations are needed to confirm the relationship between FcγRs polymorphisms and cetuximab efficacy.
要旨
背景: セツキシマブ(Cmab)は切除不能進行再発大腸癌の予後改善に重要な役割を果たしている。現在,一般臨床ではKRAS遺伝子がCmabの予後予測因子として用いられているがCmabのさらなる効果予測因子の探索が試みられている。目的: Cmabの効果とFcγR遺伝子多型の関連性を検討した。対象と方法: FLIER試験(切除不能進行再発大腸癌に対する二次治療としてのFOLFIRI+Cmab療法: ECRIN)登録症例のうちKRAS(コドン12,13)とBRAF(コドン600)野生型の57例。FcγRⅡa(H131R)/FcγⅢa(V158F)と奏効率,overall survival(OS),progression-free survival(PFS)との関連を検討した。結果: FcγRⅡa(HH/HR/RR),FcγRⅢa(FF/FV/VV)の遺伝子多型は奏効率,OS,PFSのいずれも関連は認めなかった。 haplotype解析ではFcγRⅡa-131H,FcγRⅢa-158Vがそれ以外と比較して奏効率が有意に低く(p=0.018),diplotype解析においてもHV/HVで奏効率が有意に低かった(p=0.038)。考察・結語: 今回の検討ではFcγRⅡa-131HとFcγRⅢa-158VがCmabの予後不良因子になる可能性が示唆された。ADCC活性に関与するFcγR遺伝子多型がCmabの効果予測因子になり得るかについてはさらなる検討が必要と考えられた。
目次
Summary
Background and Objectives: Cetuximab has shown efficacy in patients with metastatic colorectal cancer(mCRC). Recent studies have demonstrated that cetuximab induces antibody-dependent cell-mediated cytotoxicity(ADCC), mediated via the fragment c gamma receptors(FcγR)in mCRC. Since the establishment of KRAS mutations as a major negative predictor of efficacy, additional biomarkers have been found to be useful for the improvement of selection of patients likely to be responsive to cetuximab. We investigated the relationship between polymorphisms and the outcome of mCRC patients treated with cetuximab. Methods: In this study, 57 patients were evaluated. The relationships of FcγR polymorphisms with response rate(RR), progression-free survival(PFS), and overall survival(OS)were analyzed. Results: The FcγR polymorphisms were not significantly related to RR, PFS, and OS. Compared with the other haplotypes, the haplotype containing the 131H and 158V alleles was related to a lower RR(p=0.018). The diplotypes containing 131H and 158V alleles had significantly lower RR than the other diplotypes(p=0.038). Conclusion: Our data suggest that FcγR polymorphisms may be associated with the outcome of mCRC patients treated with cetuximab and FOLFIRI. However, these results are currently controversial, and detailed investigations are needed to confirm the relationship between FcγRs polymorphisms and cetuximab efficacy.
要旨
背景: セツキシマブ(Cmab)は切除不能進行再発大腸癌の予後改善に重要な役割を果たしている。現在,一般臨床ではKRAS遺伝子がCmabの予後予測因子として用いられているがCmabのさらなる効果予測因子の探索が試みられている。目的: Cmabの効果とFcγR遺伝子多型の関連性を検討した。対象と方法: FLIER試験(切除不能進行再発大腸癌に対する二次治療としてのFOLFIRI+Cmab療法: ECRIN)登録症例のうちKRAS(コドン12,13)とBRAF(コドン600)野生型の57例。FcγRⅡa(H131R)/FcγⅢa(V158F)と奏効率,overall survival(OS),progression-free survival(PFS)との関連を検討した。結果: FcγRⅡa(HH/HR/RR),FcγRⅢa(FF/FV/VV)の遺伝子多型は奏効率,OS,PFSのいずれも関連は認めなかった。 haplotype解析ではFcγRⅡa-131H,FcγRⅢa-158Vがそれ以外と比較して奏効率が有意に低く(p=0.018),diplotype解析においてもHV/HVで奏効率が有意に低かった(p=0.038)。考察・結語: 今回の検討ではFcγRⅡa-131HとFcγRⅢa-158VがCmabの予後不良因子になる可能性が示唆された。ADCC活性に関与するFcγR遺伝子多型がCmabの効果予測因子になり得るかについてはさらなる検討が必要と考えられた。