P-235 - Retrospective evaluation of ADCC activity and cetuximab response in KRAS wild-type metastatic colorectal cancer patients (mCRC)

Date 04 July 2015
Event WorldGI 2015
Session Posters
Topics Anti-Cancer Agents & Biologic Therapy
Colon Cancer
Rectal Cancer
Translational Research
Presenter V. Ricci
Citation Annals of Oncology (2015) 26 (suppl_4): 1-100. 10.1093/annonc/mdv233
Authors V. Ricci1, D. Vivenza1, M. Monteverde1, G. Strola2, C. Granetto3, C. Lo Nigro1, M.C. Merlano4
  • 1S. Croce & Carle Teaching Hospital Cuneo, Cuneo/IT
  • 2Laboratory Department S. Croce & Carle Teaching Hospital Cuneo, Cuneo/IT
  • 3Azienda Sanitaria Ospedaliera S. Croce e Carle, Cuneo/IT
  • 4S. Croce General Hospital, Cuneo/IT

Abstract

Introduction

Cetuximab is a IgG1 monoclonal antibody against epidermal growth factor receptor (EGFR) used in mCRC and in Head and Neck Cancer treatment. The proposed working mechanism of cetuximab is thought to include antibody-dependent cell-mediated cytotoxicity (ADCC). Cetuximab has been restricted to mCRC patients (pts) with wild-type RAS. Whether ADCC is associated with EGFR expression and/or mutational status of RAS and BRAF in mCRC remains unclear.

Methods

We retrospectively identified, from March 2008 to September 2014, 41 mCRC pts who received chemotherapy with cetuximab (9 received cetuximab in first, 26 in second and 6 in third line). Peripheral blood samples were collected at start of therapy and during treatment.

ADCC was evaluated over time of ex vivo NK-dependent activity measuring LDH release by a non radioactive cytotoxicity assay.

Genotyping of FcgRII, FcgRIII and rs61764370 SNPs was done on DNA extracted from total peripheral blood using the appropriate “allelic discrimination assay”. RAS (codon 12-13-59-61-146) and BRAF (V600E) genotypes were determined by pyrosequencing in patients' tumoral Formalin Fixed Paraffin Embedded (FFPE) tissues archived at diagnosis.

Results

Median ADCC activity at treatment start for all 41 mCRC pts was 68.5% (range 10-99%). Correlation with OS and PFS was evaluated only in the sub-group of 26 pts treated with cetuximab in second line. All pts resulted KRAS wt. For this latter group, median follow-up was 13 months (range 3-37) for OS and 5.5 months (range 2-37) for PFS. Pts performing ADCC activity above the median value showed an improved OS compared to pts with ADCC activity below this value (median 21 vs 12 months; p = 0.045; Long-rank Mantel-Cox Test).

Correlation in terms of OS and PFS with FcgR and rs61764370 genotypes resulted significant for FcgRII in PFS where allele frequencies were 52% for A and 48% for G. Pts carrying alleles with A presented a longer PFS in comparison with GG genotype (median 8 vs 3 months; p = 0.04; Long-rank Mantel-Cox Test). This effect resulted even amplified when PFS was evaluated in FcgRII favourable alleles stratified for FcgRIII. Pts presented with both FcgRII AA/AG and FcgRIII TT performed better than all the other subgroups (median 11 vs 5 months; p= 0.03; Long-rank Mantel-Cox Test).

Conclusion

These results indicate a link between ADCC activity, FcgR genotypes and efficacy of cetuximab in KRAS wild-type mCRC pts. Our results should be confirmed by further large prospective studies.