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Background:  The standard treatment for epithelial ovarian cancer (EOC) patients with advanced disease is carboplatin-paclitaxel combination therapy following initial debulking surgery, yet there is wide inter-patient variation in clinical response. We sought to identify pharmacogenomic markers related to carboplatin-paclitaxel therapy.   Methods:  The lymphoblastoid cell lines, derived from 74 invasive EOC patients seen at the Mayo Clinic, were treated with increasing concentrations of carboplatin and/or paclitaxel and assessed for  in vitro  drug response using MTT viability and caspase3/7 apoptosis assays. Drug response phenotypes IC50 (effective dose at which 50% of cells are viable) and EC50 (dose resulting in 50% induction of caspase 3/7 activity) were estimated for each patient to paclitaxel and carboplatin (alone and in combination). For each of the six drug response phenotypes, a genome-wide association study was conducted.   Results:  Statistical analysis found paclitaxel  in vitro  drug response phenotypes to be moderately associated with time to EOC recurrence ( p  = 0.008 IC50;  p  = 0.058 EC50). Although no pharmacogenomic associations were significant at  p  < 5 × 10 −8 , seven genomic loci were associated with drug response at  p  < 10 −6 , including at 4q21.21 for carboplatin, 4p16.1 and 5q23.2 for paclitaxel, and 3q24, 10q, 1q44, and 13q21 for combination therapy. Nearby genes of interest include  FRAS1, MGC32805, SNCAIP, SLC9A9, TIAL1, ZNF731P , and  PCDH20 .   Conclusions:  These results suggest the existence of genetic loci associated with response to platinum-taxane therapies. Further research is needed to understand the mechanism by which these loci may impact EOC clinical response to this commonly used regimen.

frontiers in genetics

Genome-Wide Study of Response to Platinum, Taxane, and Combination Therapy in Ovarian Cancer: In vitro Phenotypes, Inherited Variation, and Disease Recurrence