FcγR polymorphisms and clinical outcome in colorectal cancer patients receiving passive or active antibody treatment.
Fcγ receptors (FcγRs) on effector cells are of importance for mediating antibody-dependent cellular cytotoxicity (ADCC). FcγRIIIa158valine (V)/phenylalanine (F) and FcγRIIa131histidine (H)/arginine(R) polymorphisms have been shown to relate to prognosis in antibody-treated patients. The aim of the present study was to analyze the polymorphisms of both FcγRIIIa and FcγRIIa in colorectal carcinoma (CRC) patients receiving either passively administered monoclonal antibodies (MAbs) or antibodies induced by carcinoembryonic antigen (CEA) vaccination. One hundred and thirty CRC patients were included. Thirty-eight patients received adjuvant treatment with an anti-EpCAM monoclonal antibody (edrecolomab) (n=17) or rCEA vaccination therapeutic cancer vaccine (TCV) (n=21) inducing anti-CEA IgG antibodies. Ninety-two patients had metastatic disease and received anti-EpCAM MAb based therapies. FcγR genotypes were analysed using genomic DNA and PCR. ADCC was tested in a standard 18 h Cr51 release assay. In all adjuvant-treated patients, FcγRIIIa158V carriers (V/V and V/F) had a significantly better overall survival compared to F/F homozygous patients (p<0.05), FcγRIIa R carriers vs. H/H (p=0.05) as well as V and R carriers combined compared to the others (p<0.05). Similar findings were obtained when antibody and TCV-treated patients were analysed separately. No impact on the prognosis of FcγR polymorphisms was noted in advanced disease. FcγRIIIa V carriers had a significantly higher ADCC activity compared to F/F patients (p=0.001). Our model study might support the notion that FcγRIIIa V carriers as well as FcγRIIa R carriers receiving adjuvant, passively or actively (TCV)-induced antibody treatment might have a better prognosis than the others. Prospective extended clinical trials are warranted to study the predictive/prognostic impact of FcγR polymorphisms in antibody-treated patients and might be a valuable biomarker to optimize antibody-based treatment strategies.
Immune and Gene Therapy Laboratory, Cancer Centre Karolinska, Department of Oncology-Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden.
Biyun
B
Wang
Parviz
P
Kokhaei
Håkan
H
Mellstedt
Maria
M
Liljefors
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000906:Antibodies / Q000627:therapeutic use*; D002272:Carcinoembryonic Antigen / Q000276:immunology; D002277:Carcinoma / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015179:Colorectal Neoplasms / Q000175:diagnosis* / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D005260:Female; D006801:Humans; D007116:Immunization, Passive / Q000379:methods; D016233:Immunotherapy, Active / Q000379:methods; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000502:physiology; D011379:Prognosis; D017452:Receptors, IgG / Q000235:genetics* / Q000378:metabolism; D016896:Treatment Outcome; D055815:Young Adult
D000906:Antibodies; D002272:Carcinoembryonic Antigen; D017452:Receptors, IgG