Objective: A pilot study to examine accrual rates, efficiency of data capture approaches, study design and genotyping capacity for a future genetic validation study was undertaken.
Design: The process pilot evaluated feasibility of applying a matched case-control design to validate association of two candidate estrogen receptor (ER) single nucleotide polymorphisms (SNPs) with incidence of venothromboembolic events (VTE) in breast cancer patients treated with tamoxifen where criteria included frequency matching by age, number of years diagnosed with breast cancer within 4-year intervals, and geographic residency.
Setting: The study was conducted at Marshfield Clinic, in central Wisconsin.
Participants: Study-eligible cases with a breast cancer diagnosis between 1994 and 2006 who experienced a VTE within 5 years of last tamoxifen exposure were matched at a ratio of 1:4 to controls with a breast cancer diagnosed between 1994 and 2006 with no VTE history following tamoxifen exposure for ≥2 years.
Methods: Feasibility of enrolling, phenotyping, and genotyping 20% of the total number of validated eligible cases and controls was tested in order to project enrollment rates and assess probability of enrolling the projected sample size for the prospective validation study and adequacy of planned data capture. Conditional logistic regression analysis was conducted for the matched case-control study design.
Results: Enrollment accruals included 19 of 24 targeted cases (79%), and 74 of 96 (77%) targeted controls. Electronic data capture for most variables was nearly 100%. No unexpected statistically significant differences were observed between cases and controls. Capacity to conduct in-house screening for rs2234689 (ER1 PvuII), rs9340799 (ER1 XbaI), rs13146272 (CYP4V2), rs2227589 (SERPINC 1) and rs1613662 (GP6) was successfully established. Association of GP6 with VTE was further validated (P=0.0403; OR, 0.19).
Conclusion: Accrual rates to the larger prospective study will require a multi-center design to ensure enrollment of adequate numbers of cases and controls for achieving the projected sample size required to validate association of the ER SNPs. To prevent study failure due to poor accrual, the importance of conducting feasibility studies before launching large scale validation studies of genetic association and adverse drug events, is discussed.