536P - Amphiregulin and epiregulin polymorphisms as pharmacogenetic predictive factors for response to irinotecan plus anti-EGFR treatment

Date 01 October 2012
Event ESMO Congress 2012
Session Poster presentation III
Topics Anti-Cancer Agents & Biologic Therapy
Colon Cancer
Rectal Cancer
Presenter Ana Sebio Garcia
Authors A. Sebio Garcia1, D. Páez1, J. Salazar Blanco2, M. Tobeña Puyal1, M. Martín-Richard1, A. Barnadas1, M. Baiget3
  • 1Medical Oncology, Santa Creu i Sant Pau Hospital, 08041 - BARCELONA/ES
  • 2Genetics, Santa Creu i Sant Pau Hospital, 08041 - Barcelona/ES
  • 3Deparment Of Genetics, Hospital de la Santa Creu i Sant Pau, 08041 - Barcelona/ES

Abstract

Background

EGF (epidermal growth factor) pathway is the main target of anti-EGFR (epidermal growth factor receptor) drugs in colorectal cancer. Although K-Ras mutation has been identified as a strong predictor of resistance to anti-EGFR therapy in mCRC (metastatic colorectal cancer), not all wild type patients respond to treatment. Several ligands have been proved to bind to EGFR such as amphiregulin (AREG) and epiregulin (EREG). The aim of this study is to analyze the role of polymorphisms in these ligands as pharmacogenetic markers for anti-EGFR treatment.

Methods

A total of 75 refractory mCRC patients were analyzed. All patients were K-Ras and B-Raf wild type and treatment consisted of anti-EGFR antibody (cetuximab or panitumumab) plus irinotecan. DNA was extracted from peripheral blood. Tag SNPs (single nucleotide polymorphisms) for the two ligands were seleted using Hap Map database (Browser realease #27) and Haploview 4.2 Software following these criteria: MAF (minor allele frecuency) 0.1 and a r2 of 0.8. A total of 11 Tag SNPs were studied: 2 for EREG, and 9 for AREG. Genotype was performed using the BioMarkTM System (Fluidgm). Response rate was evaluated following RECIST criteria 1.1.

Results

Two polymorphisms in the AREG gene were found to be predictive of response to irinotecan plus anti-EGFR treatment. For the polymorphism g.75422078C > A, overall response rate (partial reponse and stable disease) was 25% for the patients with the A/A genotype, 73% for the C/A genotype and 85% for C/C (p = 0.032). Progression free survival (PFS) was 2.5 months for patients harbouring the A/A genotype compare to 8 months for the patients with A/C and C/C genotypes (p = 0.0001); overall survival was also superior for patients containing the allele C genotypes (5 months for AA and 18 months for C/A and C/C); p = 0.001. For the polymorphism g.75395312G > A, the G/G genotype overall response rate was 100% compare to 69% for the A/G and A/A genotypes (p = 0.048). PFS did not reach statistical significance for this polymorphism. None of the two Tag SNPs for the EREG ligand were found to correlate with response.

Conclusions

AREG polimorphisms may help to identify refractory mCRC patients who will benefit from irinotecan plus anti-EGFR treatment.

Disclosure

All authors have declared no conflicts of interest.