KSR1 gene polymorphism in mCRC patients treated with first-line FOLFIRI and bevacizumab Marta Schirripa1, Fotios Loupakis1, Chiara Cremolini1, Dongyun Yang2, Melissa Janae Labonte2, Wu Zhang2, Lisa Salvatore1, Takeru Wakatsuki2, Rita El-Khoueiry2, Carlotta Antoniotti1, Giuseppe Aprile3, Martin Karl Herbert Maus4, Sara Lucchesi5, Giacomo Allegrini5, Fernando De Vita6, Hua Zhang7, Georgios Giamas7, Justin Stebbing7, Alfredo Falcone1 and Heinz-Josef 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. Policlinico Universitario, Oncologia Medica, Udine, Italy 4. Response Genetics Inc. , Los Angeles, CA 5. U.O. Oncologia Medica Azienda USL-5, Istituto Toscano Tumori, Pontedera, Italy 6. Medical Oncology Division, Second University of Naples, Naples, Italy 7. Imperial College Healthcare NHS Trust, London, United Kingdom Abstract ID: 3546 Introduction Results Kinase suppressor of Ras (KSR) 1 is a scaffolding protein that regulates the Raf/Mek/ERK cascade. Hughes et al, Cell ’95 In vitro studies suggest that KSR1 activity differs according to KRAS and BRAF mutational status. Oikonomou et al, Neoplasia ’09 Preclinical data show that KSR1 might increase estrogen receptor transcriptional activity after exposure to estrogens. Fisher et al, Mol Cell Biol ’11 Recent retrospective analyses suggest a possible role for KSR1 rs2241906 C/T SNP in predicting mCRC patients’ prognosis. MAIN PATIENTS’ CHARACTERISTICS PRE-PLANNED SUBGROUP ANALYSIS IN KRAS and BRAF WT POPULATION N=287 % Sex Females 112 39 Males 175 61 Age Median 62 Range 26-79 Time to metastases Synchr. 213 74 Metachr. 26 Köhne Score Low 122 43 Intermediate 129 45 High 22 8 NA 14 4 KRAS-BRAF wt-wt 123 mut-wt 146 51 wt-mut 18 6 KSR1 rs2241906 C/C 165 57 C/T 108 38 T/T 5 Female Population (N=50) Females T/- (N=22) median PFS=15.9 months C/C (N=28) median PFS= 8.8 months HR=0.44 [95%CI 0.21-0.91], p=0.010 Male Population (N=73) Males T/- (N=34) median PFS=11.1 months C/C (N=39) median PFS=16.1 months HR=1.92 [95%CI 1.05-3.53], p=0.021 No association of KSR1 rs2241906 C/T allelic variants with PFS was observed in the overall population (log-rank=1.055, p=0.590) Also in KRAS and BRAF wt population, KSR1 polymorphism did not affect PFS (log-rank=1.815, p=0.404) Methods mCRC patients, prospectively enrolled in a translational research program, were selected on the basis of KRAS and BRAF mutational status availability. All of them received first-line FOLFIRI plus bevacizumab. Germ-line DNA was extracted from peripheral blood. KSR1 rs2241906 allelic variants were determined by means of PCR and direct sequencing. Taking into account the connection between estrogen pathway and KSR1, subgroup analyses according to gender were pre-planned. In the multivariate model, including ECOG PS, Köhne score and primary tumor’s side as covariates, the association of KSR1 variants with PFS was still significant. A significant interaction of KSR1 allelic variants with PFS according to gender was demonstrated (p=0.004). Conclusions This prospectively conceived pharmacogenetic study confims the role of KSR1 rs2241906 C/T SNP in affecting the outcome of KRAS and BRAF wt mCRC patients. Present results indirectly indicate that estrogenic stimulation might affect the proliferation of KRAS and BRAF wt CRC cells through an interaction with KSR1. Preclinical investigations to further explore this preliminary hypothesis are ongoing. martaschirripa@gmail.com