724P - Significant association between VEGF-a and ABCB1 polymorphisms and survival in metastatic pancreatic adenocarcinoma (MPA) patients (pts) treated wit...

Date 30 September 2012
Event ESMO Congress 2012
Session Poster presentation II
Topics Pancreatic Cancer
Translational Research
Presenter Michele Reni
Authors M. Reni1, E. Giovannetti2, S. Cereda1, C. Belli3, A. Passardi4, G. Di Lucca5, L. Ferrari6, F. Bergamo7, A. Novarino8, H.M. Verheul2
  • 1Oncologia, IRCCS San Raffaele, 20132 - Milano/IT
  • 2Department Of Medical Oncology, VU University Medical Center, Amsterdam/NL
  • 3Oncology, IRCCS San Raffaele, 20132 - Milano/IT
  • 4Oncology, Istituto Tumori della Romagna I.R.S.T., IT-47014 - Meldola/IT
  • 5Struttura Complessa Di Oncologia Medica, Ospedale di Saronno, IT-21047 - Saronno/IT
  • 6Oncology, University Hospital, Udine/IT
  • 7U.o.oncologia Medica, Istituto Oncologico Veneto IOV-IRCCS, IT-35128 - Padova/IT
  • 8Oncology, Centro Oncoematologico Subalpino Molinette, Turin/IT

Abstract

A randomised multi-centre phase II trial explored the role of MS in pts with MPA without progressive disease (PD) after induction chemotherapy (CT), using an observation only group (O) as calibration arm [Reni et al. Proc ASCO 2012]. The aim of this present study was to identify genetic polymorphisms related to pharmacokinetics and pharmacodynamics of sunitinib that are associated with outcome. Adult pts with pathologic diagnosis of MPA, performance status (PS) >50%, no PD after 6 months of CT were randomized to O (arm A) or MS at 37.5 mg daily until PD or a maximum of 6 months (arm B). Functional polymorphisms of 6 genes involved in sunitinib activity, metabolism and transport (VEGFA, VEGFR-2, CYP3A5, CYP1A1, ABCB1, ABCG2) were studied in genomic DNA from baseline blood samples, using PCR Taqman®-probes-based assays. Associations of genotypes with overall survival (OS) and progression-free survival (PFS) were evaluated by Log-rank test. Genotyping was successfully performed in all the DNA samples of 43 consenting pts of 55 enrolled in the trial (78%; arm A/B: 83%/73%; p = 0.39). Significantly longer OS was observed in 7 pts harbouring the ABCB1 3435TT genotype (group-1; median OS 20 months) as compared to 36 pts with 3435CC/CT genotype (group-2; median OS 7 months; p = 0.027). Median OS was 26 months in 4 group-1 arm B pts, 7 months in 15 group-2 arm B pts (p = 0.12); 16 months in 3 group-1 arm A pts and 9 months in 21 group-2 arm A pts (p = 0.67). No OS difference was observed in 28 pts harbouring the VEGFA -634GC-CC genotype (group-3; median OS 10 months) as compared to 15 pts with -634GG genotype (group-4; median OS 8 months; p = 0.15). However, median OS was 13 months in 13 group-3 arm B pts, 6 months in 6 group-4 arm B pts (p = 0.016); 9 months in 15 group 3 arm A pts and 11 months in 9 group 4 arm A pts (p = 0.67). These results suggest that polymorphisms of genes involved in expression of the main ligand for VEGFR2 (VEGFA 634G > C) and of efflux transporters (ABCB1 3435C > T) are promising candidates as predictive marker for selecting pts with MPA who may benefit of MS. Given the small sample size of these analyses, a larger confirmatory trial is necessary and appears worthwhile.

Disclosure

All authors have declared no conflicts of interest.