Introduction Patient baseline characteristics

Conclusion

The process of EGFR recycling is important mechanism of resistance of cetuximab in colorectal cancer. This is the first report suggesting that germline polymorphisms in the degradation process may predict efficacy of cetuximab in patients with metastatic colorectal cancer. The pathways involved in EGFR turnover may be new targets in the treatment of colorectal cancer.

Patients and MethodsGenomic DNA was isolated from blood from 108 patients treated with cetuximab of two clinical trials. All patients were KRAS and BRAF wildtype. 20 SNPs were selected based on the involvement in receptor endocytosis, ubiquitation/neddylation, recycling and degradation. Minor allele frequency had to be higher than 10%. PCR and product sequencing were done using standard procedures. Uni- and multivariate analyses, adjusting for age, gender, rash and racial background, were carried out. After logistic regression analyses, baseline characteristics showing a p of <0.1 were included in the multivariate analysis. Kaplan-Meier estimation with log-rank testing for differences were carried out.This study tested:1. Are germline single nucleotide polymorphisms (SNPs) in genes involved in EGFR turnover capable

of predictive value in cetuximab treated patients with mCRC.

Abstract ID: 3557

References

ResultsAs many transmembrane receptors, the epithelial growth factor receptor (EGFR) has a highly regulated turnover leading to inactivation and recycling or degradation after activation. This process can be divided into four different phases: receptor endocytosis, ubiquitation/neddylation, recycling and degradation. We tested whether functional significant single nucleotide polymorphisms in genes involved in the degradation pathway will predict clinical outcome (PFS and OS) in 108 patients with metastatic colorectal cancer (mCRC) enrolled in two clinical trials and treated with cetuximab.

1. Schmidt M.H., Dicic I. Sci. STKE 2006, pe50 (2006).2. Oved S., Mosesson Y., Santonico E. et al J Biol Chem (2006)281:31 2164-216513. Soubeyran P, Kowanetz K, Szymkiewicz I, Langdon WY, Dikic I. Nature 416, 183-187

(2002)

Kaplan-Meier curves of PFS and OS by UBC12 rs895374 polymorphism

Results

Genes involved in EGFR-degradation are predictive for efficacy in metastatic colorectal cancer patients treated with cetuximab

Sebastian Stintzing1, Wu Zhang1, Takeru Wakatsuki1, Yan Ning1, Dongyun Yang1, Nico Volz1, Joseph E. Li1, Melissa J. LaBonte2, Peter M. Wilson1, Adel Kardosh1, Fotios Loupakis3, Lisa Salvatore3, Martha Schirripa3 and Heinz-Josef Lenz1

1USC/Norris Comprehensive Cancer Center, Los Angeles, CA, 2Azusa Pacific University, Azusa, CA; 3Ospedaliero-Universitaria Pisana, Istituto Toscano Tumori, Pisa, Italy

supported by

EGFR turnover:The process of EGFR turnover can be divided into three different stages:- receptor endocytosis- neddylation or ubiquitation- recycling or degradation

Baseline characteristics (N= 108)

Age: median(range)

64 years(35 – 110)

Gender male: 60%female: 40%

Primary outcome data (N = 108)

Overall response rate (ORR) 20.0 % Progression free survival (PFS) 3.7 months(2.8 – 4.6)

Disease control rate (DCR) 62.9 % Overall survival (OS) 10.5 months(7.7 – 13.3)

PFS OS PFS OSn HR p* HR p* n HR p* HR p*

CBL rs7105971

GGAGAA

523214

1.541.39

0.27 1.541.20

0.42CIN85 rs7051590

CCCGGG

79108

1.14na

0.66 1.24na

0.54

CBL rs4938637

GGAGAA

74242

0.96na

0.88 1.01na

0.97CIN85rs5955820

TTCTCC

701314

1.061.01

0.99 0.981.39

0.71

CBL rs4938638

AAAGGG

454116

0.910.66

0.45 0.950.77

0.76CIN85rs1017874

GGAGAA

7699

0.80na

0.46 1.09na

0.81

CBL rs251837

CCCTTT

315217

0.720.70

0.40 1.090.92

0.89CIN85rs11795873

AAAGGG

351636

1.091.01

0.96 1.231.05

0.87

EPS15 rs17567

TTCTCC

65355

0.69na

0.07 0.79na

0.38Endophilinrs604737

GGAGAA

70215

1.13na

0.67 0.93na

0.82

EPS15 rs7308

TTCTCC

64316

0.70na

0.09 0.82na

0.47Endophilinrs6570808

GGAGAA

305211

0.830.59

0.41 0.730.41

0.14

EPS15 rs1065754

TTCTCC

434814

0.991.22

0.76 0.981.17

0.89Endophilinrs7526812

AAAGGG

71213

0.69na

0.19 0.83na

0.56

NEDD8rs363169

TTTAAA

265118

1.181.07

0.64 0.891.21

0.68UBC12rs895374

CCACAA

265221

2.072.11

0.02# 1.431.60

0.41

NEDD8rs363170

AAAGGG

71220

1.34na

0.32 1.38na

0.34UBC12rs895374

TTCTCC

60354

0.97na

0.90 0.83na

0.49

NEDD8rs363172

GGAGAA

315213

0.820.94

0.73 0.600.91

0.21UBCH7rs5754216

GGGTTT

71213

0.70na

0.25 0.63na

0.25

Results of multivariate analysis on SNPs of genes involved in the process EGFR turnover

Legend: PFS = progression free survival; OS = overall survival; HR = Hazard ratio; p = logrank´s p; na: not applicable due to small number, # indicates significant value