Prospective evaluation of candidate SNPs of VEGF/VEGFR pathway in metastatic colorectal cancer (mCRC)
patients (pts) treated with first-line FOLFIRI plus bevacizumab (BV).
C. Cremolini1, F. Loupakis1,2, D. Yang2, L. Salvatore1, W. Zhang2, T. Wakatsuki2, M. Schirripa1, S. Lonardi3, C. Antoniotti1, G. Aprile4, G. Masi1, F. Graziano5, A. Ruzzo6, S. Lucchesi7, M. Ronzoni8,
M.K.H. Maus9, G. Bocci10, G. Tonini11, A. Falcone1 and HJ Lenz2
1.U.O. Oncologia Medica 2, Azienda Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy; 2. University of Southern California Norris Comprehensive Cancer Center, Los Angeles, CA; 3. Istituto Oncologico Veneto, IRCCS, Padova, Italy; 4.Azienda Ospedaliero-Universitaria di Udine, Udine, Italy; 5. UOC Oncologia, A. O., Pesaro, Italy; 6. Section of
Biochemistry and Molecular Biology, Department of Biomolecular Sciences, University of Urbino, Urbino, Italy; 7. U.O. Oncologia Medica, Ospedale , Pontedera, Italy; 8. Dipartimento di Oncologia, Istituto Scientifico San Raffaele, Milano, Italy; 9. Response Genetics Inc. , Los Angeles, CA; 10. Division of Chemotherapy and Pharmacology Department of Internal
Medicine, University of Pisa, Pisa, Italy; 11. Università Campus Bio-Medico, Rome, Italy; University of Pisa, Pisa, Italy
Background
Patients and Methods
Loupakis et al, BMC 2011
No association of VEGF rs833061 C/T variants with PFS was found
100
To detect an HR for PFS of 1.7 for VEGF rs833061 T/T variant compared
to C-, with α and β errors of 0.05 and 0.20 respectively, 199 events were
required.
Finding
Reference
VEGF-A
rs699947
Predictive
Schneider et al. JCO ‘08
VEGF-A
rs699946
Predictive
Lambrechts et al. ESMO ‘11
60
40
20
0
20
40
60
Time
At the univariate analysis, no association of other candidate SNPs with PFS was found,
except for VEGFR2 12505758 C/T variants
CC (N= 11) median PFS: 10.7 mos
CT (N= 107) median PFS: 9.5 mos
TT (N= 306) median PFS: 10.9 mos
Germ-line DNA was extracted by peripheral blood and candidate
SNPs were analyzed by PCR and sequencing
C- (N= 118) median PFS: 9.5 mos
TT (N= 306) median PFS: 10.9 mos
CC
CT
TT
80
60
40
60
40
20
0
0
20
40
60
CC/CT
TT
80
20
0
HR: 1.40 (1.07-1.84)
Log-rank test p=0.015
100
Log-rank test p=0.047
100
Percent survival
rs number
80
0
As secondary endpoint, we planned a confirmatory analysis of the
following candidate SNPs.
• A potential prognostic or predictive role of other VEGF,
VEGFR1 and 2 and EPAS1 SNPs was suggested by other
retrospective series and by the post-hoc analysis of phase III
randomized trials as reported below
Gene
TT
TT (N=
147) median PFS: 10.2 mos
CC- (N= 276) median PFS: 10 mos
HR: 1.17 (0.91-1.50)
Log-rank test p=0.218
Percent survival
• The association of the T/T variant of VEGF rs833061 C/T SNP
with worse PFS and OS was retrospectively reported by our
group in a cohort of 111 pts treated with first-line FOLFIRI plus
BV but not in a historical cohort of pts treated with first-line
FOLFIRI
Based on our retrospective findings, we planned a prospective
validation trial in mCRC patients treated with first-line FOLFIRI+BV
Percent survival
• No predictors of benefit from BV have been so far identified
Results
0
20
40
60
Time
Time
VEGFR-1
rs9582036
Predictive
Lambrechts et al. ECCO ‘09
VEGFR-1
rs7993418
Predictive
Claes et al. AACR ‘12
VEGFR-2
rs11133360
Predictive
Lambrechts et al. ESMO ‘11
VEGFR-2
rs12505758
Prognostic
Lambrechts et al. ESMO ‘11
Sex M/F
VEGFR-2
rs2305948
Predictive
Gerger et al. CCR ‘11
Age (median)
EPAS-1
rs4145836
Prognostic
Lambrechts et al. ESMO ‘11
ECOG PS 0/1/2
357/63/4
84/15/1
Primary site Right/Left/Rectum
110/187/127
26/44/30
Liver-only disease Yes/No
136/288
32/68
The prospective validation is an essential step on biomarkers’ way toward clinical practice.
Number of mts sites 1/>1
194/230
46/54
Future studies on predictors of benefit from BV should provide a comprehensive overlook
on the complexity of tumoral angiogenesis not only from the genetic perspective.
[email protected]
MAIN PATIENTS’ CHARACTERISTICS
N=424
%
252/172
59/41
62
At the multivariate analysis, including Kohne score, mucinous histology, ECOG PS, LDH
levels and primary tumor site as covariates, the association of VEGFR2 12505758 C- variants
with shorter PFS was still significant (HR: 1.402 [1.079-1.822], p=0.012).Significance was lost
when applying multiple testing correction.
Conclusions
This prospective trial does not confirm the predictive impact of VEGF rs833061 C/T SNP
suggested by our retrospective experience. Also previous findings on other candidate SNPs
are not confirmed.