Genetic variants of kinases suppressors of Ras (KSR)in KRAS-BRAF Genetic variants of kinases suppressors of Ras (KSR)in KRAS-BRAF wild-type metastatic colorectal cancer patients treated with cetuximab and irinotecan wild-type metastatic colorectal cancer patients treated with cetuximab and irinotecan

Benhaim L1*, Loupakis F1,2, Zhang W1, Gerger A1, Bohanes P1, Paez D1, Cremolini C2, Wakatsuki T1, Yang D1, LaBonte MJ1, Ning Y1, El-Khoueiry R1, Zhang Hua3, Salvatore L2, Schirripa M2, Falcone A2, Stebbing J3, Giamas G3, Lenz HJ 1

1. Department of Medical Oncology, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, CA 2. Department of Oncology, Transplants and New Technologies in Medicine, Division of Medical Oncology, University of Pisa, Pisa

3. Department of Surgery and Cancer, Division of Cancer, Imperial College London, London,UK

Germline DNA was obtained from peripheral blood of patients with mCRC KRAS and BRAF wild- type resistant to irinotecan treated with a combination of cetuximab and irinotecan. Seven functionally relevant SNP were selected on the basis of public literature resources and databases, 4 in the KSR1 and 3 in the KSR2 genes and analyzed by PCR followed by direct sequencing.

Scaffold proteins kinase suppressor of ras (KSRs) have emerged as critical modulators of the EGFR pathway that binds to RAS promoting ERK activation. KSR1 and KSR2 have been shown to be over expressed in various solid tumours including colon cancer. In-vitro, the down-regulation of KSR results in reduction of cells proliferation and tumour growth independently to KRAS status. Moving from this biological rational we investigated the correlation between functional polymorphisms in the KSR genes and clinical outcomes in patients with KRAS and BRAF wild-type mCRC treated with cetuximab and irinotecan.

Beyond KRAS and BRAF, some proteins including KSR are involved in modulating the level of activation of the EGFR pathway. Our results show that the functionally relevant KSR2 rs11068551 could affect PFS in advanced mCRC patients treated with cetuximab and irinotecan. Preclinical studies to confirm and further explain these preliminary findings are ongoing.

A total of 66 patients were included. After a median follow-up of 13.3 months, median PFS and OS were 4.7 and 11.3 months respectively. Seventeen out of 66 patients (26%) achieved a RECIST response. In univariate analysis, KSR2 rs11068551 any G (AG/GG) genotype was significantly associated with shorter PFS compared to that of A/A carriers (median 3.5 vs. 7.4 months, HR=1.74 [95%CI: 1-3.04] p=0.049, log-rank test). This result remained significant in a multivariate model (HR=2.13 [95%CI: 1.15-3.95], p=0.017, log-rank test). None of the other tested SNPs were significantly associated with outcomes.

Abstract ID: 3597

Results

Conclusions

Introduction

Methods Treatment Outcome – Overall population

Baseline patient’s characteristicsFigure 1. Progression-free Survival Curves according to KSR2 rs11068551 status

Figure 2. Overall Survival Curves according to KSR2 rs11068551 status.

Median PFS AA: 7.4 monthsx/G: 3.5 months

Median OS AA: 15.8 monthsx/G: 9.1 months

N=66

n %

Age, median (range) 62.5 (37-80) -

ECOG PS (0/1/2) 39/25/2 59%/38%/3%

Sex (M/F) 47/19 71%/29%

Previous CT lines, median (range)

2 (1-5) -

Previous CT lines (2/>2) 56/10 85%/15%

Site of primary (Extraperitoneal Rectum vs. Colon)

16/50 24%/76%

Time to metastatic disease (Synchronous vs. Metachronous)

44/22 67%/33%

No of metastatic sites (1 vs. >1)

14/52 215/79%

Liver only metastases 9 14%

N=66

n %

Cetuximab-related cutaneuos rash

G0/1 2/29 3%/44%

G2/3 24/11 36%/17%

Activity

CR/PR 0/17 0%/25.8%

SD6 3 4.5%

SD 21 31.8%

PD 25 37.9%

median PFS (months) 4.7

median OS (months) 11.3

*Traveling Grant from ASSOCIATION POUR LA RECHERCHE EN ONCOLOGIE DIGESTIVE (A.R.O.L.D.)

Gene rs number Functional association

KSR1 rs2241906* miRNA KSR1 rs1075952* miRNA KSR1 rs940010 tagSNP KSR1 rs2293180 missense KSR2 rs11068551 splicing site KSR2 rs11068502 miRNA KSR2 rs7955803 splicing site

All candidate SNPs were evaluated for association with response rate, PFS and OS.