Abstract P1-13-03: Genome wide association study (GWAS) of genetic variants associated with docetaxel toxicity in the ROSE/TRIO-012 trial
Authors: Damaraju S , Gorbunova V , Gelmon K , García-Saenz J , Morales-Murillo S , AbiGerges D , Canon J-L , Kiselev I , Cohen GL , Jerusalem G , Thireau F , Fresco R , Houé V , Press MF , Kumaran M , Mackey JR 
Published: May 2016

Background: Genetic predisposition to docetaxel (Doc) toxicity contributes to unacceptable toxicity and reduced dose intensity, and may influence disease outcomes. We previously reported variants associated with Doc toxicity in candidate gene single nucleotide polymorphism (SNP) associations in a breast cancer treatment setting (Damaraju et al. Eur J Cancer (suppl); Vol 8 (7), page 175, 2010) and the identified variants were confirmed in an independent validation study (Damaraju et al, J Clin Oncol Vol 33, Issue 15 suppl, 2015: 540). Others have reported candidate SNP (Breast Cancer Res Treat, 2011 SWOG 0221 study) and GWAS (Clin Cancer Res 2012 CALGB 40101 study) identified variants associated with paclitaxel mediated peripheral neuropathy. However, the overlap on the variants identified thus far between Doc and paclitaxel are limited, prompting a genome wide search to find variants contributing to Doc specific toxicity.

Methods: TRIO-012 is a double blinded, multinational trial that randomized 1,144 patients with advanced breast cancer to receive first-line Doc in combination with ramucirumab (RAM) or placebo (Mackey et al. J Clin Oncol Jan 10, 2015:141-148). Study subjects (n=719) in the Doc+RAM or Doc+placebo arm with available germline DNA are being genotyped; all subjects provided ethics-committee approved prospective consent for this genetic study. Genotyping are being performed with Affymetrix SNP 6.0 arrays. Genotype data will be filtered for deviations from Hardy Weinberg Equilibrium and minor allele frequency of &gt;0.05. Doc-induced adverse events (AEs) are based on CTCAE (Common Terminology Criteria for Adverse Events v4.1) toxicity grades. Toxicities &gt;2 scored for fatigue (n=96), myalgia (n=22), peripheral neuropathy (n=17) will be analysed as individual phenotypes in comparison with the no toxicity group (toxicity grades 0-1) and in a combined analysis of all Doc induced toxicities (0-1, n=599 vs. &gt;2, n=120). Dominant genotypic model is assumed; Chi-square test, FDR and/or 10000 permutations were employed using SVS v8.3 and p&lt;0.05 considered statistically significant. We will identify population stratification using EIGENSTRAT method and will correct the association statistics using the Eigenvectors along with age and BMI as covariates. Fine mapping of the identified loci will be attempted using imputation tools. We will interrogate the data for cumulative dose to toxicity and correlate SNPs identified with survival outcomes.

Results and conclusions: We expect to reconfirm the associations of loci reported in candidate SNP and previous GWAS studies; XKR4 (rs4737264) for peripheral neuropathy, CYP3A5*3 (rs776746) with fatigue, and FACND2 (rs7637888) with myalgia in addition to the potential novel variants distinct from paclitaxel AE GWAS studies. Fine mapping around these loci may help identify potential causal variants. Both candidate SNP and GWAS identified variants may aid in developing risk stratification models. The GWAS identified loci and the flanking genes will be interrogated using the ingenuity pathway analysis for insights in to the biological roles in the drug metabolism. We expect to complete the analysis by mid-November 2015.

Citation Format: Damaraju S, Gorbunova V, Gelmon K, García-Saenz J, Morales-Murillo S, AbiGerges D, Canon J-L, Kiselev I, Cohen GL, Jerusalem G, Thireau F, Fresco R, Houé V, Press MF, Kumaran M, Mackey JR. Genome wide association study (GWAS) of genetic variants associated with docetaxel toxicity in the ROSE/TRIO-012 trial. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-13-03.