Introduction

Patients and Methods

Results

Conclusion

Pericytes are a key component in the maturation of the VEGF driven tumor angiogenic process1. Bevacizumab (BV), a humanized monoclonal antibody, is used to target this process in patients with metastatic colorectal cancer (mCRC)2. However, a differential patient response to the addition of BV to a FOLFIRI chemotherapeutic backbone urges the use of biomarkers to personalize drug therapy3. We performed an exploratory analysis in patients enrolled in either a phase 3 (TRIBE NCT00719797) or phase 2 trial (PROVETTA NCT01363739) treated with FOLFIRI+BV to identify potential predictive markers of outcome in genes related to the early steps of vessel maturation driven by pericytes.

DNA was extracted from 424 patients’ blood or tissue treated with first-line FOLFIRI+BV and prospectively enrolled in a prospective pharmacogenomic translational study. Median follow up is 45.1 months and median PFS and OS were 10.4 and 27.3 months, respectively. Eight functionally significant SNPs; RGS5 (rs1056515, rs2661280), PDGFRB (rs2229562, rs2302273), CSPG4 (rs8023621, rs1127648), and RALBP1 (rs10989, rs329007) were analyzed by PCR-based direct sequencing. All candidate SNPs were analyzed for association with tumor response rate (RR), progression free survival (PFS), and overall survival (OS). The associations between genetic variants and clinical outcome were examined using χ2 test, log-rank test, and Cox regression models whenever appropriate. All tests were 2-sided and p values were not adjusted for multiple testing.

Table 1. Baseline characteristics of the 424 patients included in the biomarker analysis.

Objectives

The aim of this study was to identify molecular predictors of response and survival to FOLFIRI+BV by evaluating single nucleotide polymorphisms (SNPs) in genes involved in the pericyte driven maturation of tumor vasculature to personalize treatment.

Genetic variants in pericyte driven tumor vessel maturation genes predict treatment efficacy in mCRC patients treated with FOLFIRI/bevacizumab

Nico B Volz1, Wu Zhang1, Dongyun Yang1, Sebastian Stintzing1, Yan Ning1, Takeru Wakatsuki1 ,Rita E El-Khoueiry1, Joseph E Li1, Adel Kardosh1, Fotios Loupakis2, Federica Marmorino2, Carlotta Antoniotti2, Heinz-Josef Lenz1

1USC/Norris Comprehensive Cancer Center, Los Angeles, CA; 2U.O. Oncologia Medica 2 – Aziendo Ospedaliero-Universitaria Pisana, Pisa, Italy

Patient Characteristics

Abstract ID: 3566

Results

•P value was based on Cochran-Mantel-Haenszel test for response, log-rank test for PFS and OS in the univariate analysis (†) and Wald test for PFS and OS in the multivariable Cox regression model (‡). Abbreviations: HR – hazard ratio

Our initial results suggest that the PDGFRB polymorphism rs2302273 and the CSPG4 polymorphism rs1127648 may serve as a prognostic marker for the efficacy of FOLFIRI + BV treatment in patients with mCRC. Studies to confirm these preliminary findings are warranted.

References1. Weis, S. M. and D. A. Cheresh (2011). "Tumor angiogenesis: molecular pathways and therapeutic targets." Nat Med 17(11): 1359-1370. 2. Lambrechts, D., et al., Markers of Response for the Antiangiogenic Agent Bevacizumab. J Clin Oncol, 2013. 3. He, K., et al., The effect of anti-VEGF drugs (bevacizumab and aflibercept) on the survival of patients with metastatic colorectal cancer (mCRC). Onco Targets Ther, 2012. 5: p. 59-65. 4. Fukushi, J., I.T. Makagiansar, and W.B. Stallcup, NG2 proteoglycan promotes endothelial cell motility and angiogenesis via engagement of galectin-3 and alpha3beta1 integrin. Mol Biol Cell, 2004. 15(8): p. 3580-90. 5. Weis, S. M. and D. A. Cheresh (2011). "Tumor angiogenesis: molecular pathways and therapeutic targets." Nat Med 17(11): 1359-1370. 6. Carmeliet, P. and R. K. Jain (2011). "Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases." Nat Rev Drug Discov 10(6): 417-427.

Figure 2. In RGS5, rs2661280, the hazard ratio in OS for patients with a GG genotype was significantly higher than in patients carrying any C allele (CC /CG). (HR: 1.43; 95% CI: 1.00 – 2.05; p = 0.044).

Figure 1. Relevant Genes Involved

Table 2. Significant polymorphisms and clinical outcome in first-line FOLFIRI+BV therapy.

N % N %Age, years Lung mets Median (range) 62 (25-81) Yes 135 31.8

≤65 274 64.6 No 289 68.2> 65 150 35.4 Mst site, n

Sex 1 194 45.8M 252 59.4 >1 230 54.3F 172 40.6 Time to mets

ECOGPS Synchronous 311 73.40 357 84.2 Metachronous 113 26.7

1-2 67 15.8 Kohne Score Primary tumor site Low 194 45.8

Right colon 107 25.2 Intermediate 180 42.5Left colon 180 42.5 High 35 8.3Rectum 122 28.8 NA 15 3.5

Colon, rectum 1 0.2 Primary tumor resected Unknown 14 3.3 Yes 320 75.5

Liver-only disease No 103 24.3Yes 136 32.1 Unknown 1 0.2No 288 67.9

OS

SNP N Median, mo (95%CI) HR (95%CI)† HR (95%CI)‡

RGS5 rs2661280 p – value = 0.044 p – value = 0.48

Any C 375 28.6 (24.8, 32.1) 1 (Reference) 1 (Reference)

G/G 45 23.5 (19.8. 28.8) 1.43 (1.00, 2.05) 1.14 (0.79, 1.65)

PFS

SNP N Median, mo (95%CI) HR (95%CI)† HR (95%CI)‡

PDGFRB rs2302273 p – value = 0.11 p – value = 0.033

C/C 218 9.9 (9.3, 10.6) 1 (Reference) 1 (Reference)

C/T 158 11.1 (10.0, 12.3) 0.80 (0.63, 1.00) 0.73 (0.57, 0.92)

T/T 32 11.9 (8.3, 14.0) 0.79 (0.53, 1.17) 0.88 (0.59, 1.32)

p – value = 0.035 p – value = 0.013

Any T 190 11.1 (10.2, 12.3) 0.79 (0.64, 0.99) 0.75 (0.60, 0.94)

CSPG4 rs1127648 p – value = 0.043 p – value = 0.14

C/C 119 11.0 (10.1, 12.1) 1 (Reference) 1 (Reference)

C/T 215 10.0 (9.2, 10.6) 1.23 (0.96, 1.57) 1.20 (0.93, 1.54)

T/T 79 10.2 (9.4, 12.7) 0.88 (0.63, 1.22) 0.91 (0.64, 1.28)

Tumor Response

SNP N CR+PR SD+PD

RALBP1 rs329007 p – value = 0.034A/A 258 160 (63%) 96 (38%)

A/G 140 73 (54%) 63 (46%)

G/G 18 6 (35%) 11 (65%) A/A A/G G/G0%

20%

40%

60%

80%

63% 54%35%

Resp

onse

Rat

e %

Figure 3. PDGFRB rs2302273 concluded patients with any T (CT/TT) allele were significantly associated with longer PFS compared to those with CC genotypes (median 9.9 vs 11.1 months, HR=0.79 [95%CI: 0.64-.99], p=0.035, log-rank test) which remained significant upon multivariate analysis (HR=0.75 [95% CI: 0.60-0.94], p=0.013, log-rank test).

Genotype