Genetic variants predict clinical outcome clinical outcome in patients (pts) with metastatic colorectal cancer (mCRC)
treated with first line 5-FU or capecitabine in combination with oxaliplatin and bevacizumab (FOLFOX/BV or XELOX/BV)
Harpreet Singh, Alexandra Pohl, Anthony El-Khoueiry, Georg Lurje, Wu Zhang, Dongyun Yang, Yan Ning, Jabi Shriki, Syma Iqbal, Heinz-Josef Lenz
University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA, USA
Results
Introduction
Recent studies have suggested that germline
polymorphisms involved in angiogenesis were associated
with clinical outcome in patients treated with the VEGFinhibitor bevacizumab. (Schneider et al. JCO 2008,
Manegold et al ASCO 2008). We tested whether functional
polymorphisms involved in genes in angiogenesis- (VEGF,
KDR, IL-6, CXCR1 and-2), apoptosis (p53) and cellproliferation (MMP2,-7 and-9, ICAM)-related pathways in
an expanded patient cohort of 79 patients with mCRC,
treated with FOLFOX or Xelox and BV predict
progression-free survival (PFS) or response (RR).
PFS by MMP-9 -1562C>T
79 patients (47 men, 32 women) with a median age of 56 years
(range 29-81) were treated with with either FOLFOX/BV (33
patients) or XELOX/BV (46 patients). Radiologic response: 2/79
pts (3%) CR, 41/77 pts (52%) PR, 32/77 pts (41%) SD and 3/79
pts (4%) DP. At a median follow-up of 32.0 months (range: 1.447.8 months), the median time to progression was 10.8 months
(95% CI: 8.1-14.9), whereas median overall survival hasn’t been
reached yet. We found IL-6 G-174C (p=0.025, Fisher’s exact test)
and p53 codon 72 (p=0.029, Fisher’s exact test) polymorphisms
associated with response to BV -therapy. The multivariate logistic
regression of IL6 -174G>C and p53 codon 72 showed a borderline
significance for IL6 -174G>C (p=0.065) and a significant
assocation with RR for p53 (p=0 .023), respectively. Furthermore,
there were statistically significant associations between MMP-9 1572C>T, CXCR-1 2607G>C and PFS (p=0.023 and p=0.014,
respectively, log-rank test). In multivariate analysis, MMP-9
1572C>T demonstrated to be an independent prognostic factor for
PFS (adjusted p=0.002); whereas CXCR-1 2607G>C showed only
borderline significance (adjusted p=0.055).
Material and Methods
Whole blood samples were obtained from 79 patients, who
received first-line treatment for mCRC with FOLFOX ( or
XELOX and BV at University of Southern California medical
facilities. All patients signed informed consent; patient
information was collected through prospective database
and chart review. Statistical endpoints of this study were
Progression Free Survival (PFS) and Response Rate (RR).
Genomic DNA was extracted from white blood cells using
the QiaAmp kit (Qiagen, Valencia, CA). Genotyping was
performed using PCR-RFLP technique, direct sequencing
and 5’-end [ϒ-33P] labeled PCR-protocols.
PFS by CXCR-1 2607G>C
Conclusions
These are the first data to predict clinical outcome in mCRC patients treated with
FOLFOX/BV or XELOX/BV. Our data demonstrate that functional polymorphisms in
MMP-9 and CXCR-1, leading to alteration of transcription, predict PFS in patients
treated with the angiogenesis-inhibitor BV. Furthermore, polymorphisms in IL6 and
p53 have demonstrated to predict response to BV-treatment. However, confirmation of
these findings in larger, prospective genotype-guided clinical trials is warranted.
References
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