214P - Beta 4 integrin polymorphism mediate an alternative resistance pathway in HER-3 negative, K-RAS wild type metastatic colorectal patients receiving i...

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Colon Cancer
Rectal Cancer
Translational Research
Presenter Mario Scartozzi
Authors M. Scartozzi1, R. Giampieri1, C. Loretelli2, A. Mandolesi3, L. Faloppi1, M. Bianconi1, S. Biagetti3, S. Alfonsi3, I. Bearzi3, S. Cascinu4
  • 1Clinica Di Oncologia Medica, AOU Ospedali Riuniti Ancona Università Politecnica delle Marche, 60126 - Ancona/IT
  • 2AOU Ospedali Riuniti Ancona Università Politecnica delle Marche, 60126 - Ancona/IT
  • 3Anatomia Patologica, AOU Ospedali Riuniti Ancona Università Politecnica delle Marche,, Ancona/IT
  • 4Dipartimento Di Medicina Clinica E Biotecnologie A, AOU Ospedali Riuniti Ancona Università Politecnica delle Marche, 60126 - Ancona/IT

Abstract

Previous data suggested that HER-3 positive, K-RAS wild type colorectal tumours are resistant to anti-EGFR monoclonal antibodies. However a not negligible proportion of HER-3 negative colorectal cancer patients still does not seem to benefit from such a treatment. Integrins up-regulation may mediate an alternative survival pathway in HER-3 negative tumour cells by activation of PI3K-K/Akt. In particular an alpha-6 and beta-4 integrin altered expression has been demonstrated in HER-3 negative tumours and may be responsible of anti-HER treatment resistance. Our study evaluated the interaction between polymorphisms (SNPs) of alpha-6 and beta-4 integrins and clinical outcome in HER-3 negative, K-RAS wild type colorectal cancer patients receiving third-line irinotecan cetuximab. HER-3 expression was evaluated by immunohistochemistry, whereas genotyping of alpha-6 (rs17664 G > A, rs2293649, A > G) and beta-4 (rs743554, C > T, rs8669, C > G, rs871443, T > C, rs9367, T > C) integrins was performed by real-time PCR. Among 128 K-RAS wild type metastatic colorectal cancer patients treated with third-line irinotecan cetuximab 62 (48%) were HER-3 negative and were included in the present study. At univariate analysis the beta-4 rs8669, rs871443 and rs9367 polymorphisms correlated with both median progression free survival and overall survival, whereas only the beta-4 rs8669 genotype showed a trend for a statistically significant correlation with response (partial remission rate for genotype G vs. C-G/C = 20% vs. 48%, p = 0.059). At multivariate analysis only the same allelic variant of beta-4 (rs8669 G vs. C-G/C) maintained an independent role in negatively influencing median PFS (HR = 0.13, 95%CI 0.051-0.35, p < 0.0001) and OS (HR = 0.29, 95%CI 0.10-0.81, p < 0.0001). We believe that beta-4 rs8669 genotyping may help identifying a sub-group of HER-3 negative, K-RAS wild type colorectal cancer patients less likely to benefit from anti-EGFR treatment. Our findings could be also relevant in planning future trials testing treatment strategies against the integrins-activated molecular pathway.

Disclosure

All authors have declared no conflicts of interest.