Study design: evaluating gene-environment interactions in the etiology of breast cancer - the WECARE study

Abstract

Introduction: Deficiencies in cellular responses to DNA damage can predispose to cancer. Ionizing radiation can cause cluster damage and double-strand breaks (DSBs) that pose problems for cellular repair processes. Three genes (ATM, BRCA1, and BRCA2) encode products that are essential for the normal cellular response to DSBs, but predispose to breast cancer when mutated.

Design: To examine the joint roles of radiation exposure and genetic susceptibility in the etiology of breast cancer, we designed a case-control study nested within five population-based cancer registries. We hypothesized that a woman carrying a mutant allele in one of these genes is more susceptible to radiation-induced breast cancer than is a non-carrier. In our study, 700 women with asynchronous bilateral breast cancer were individually matched to 1400 controls with unilateral breast cancer on date and age at diagnosis of the first breast cancer, race, and registry region, and counter-matched on radiation therapy. Each triplet comprised two women who received radiation therapy and one woman who did not. Radiation absorbed dose to the contralateral breast after initial treatment was estimated with a comprehensive dose reconstruction approach that included experimental measurements in anthropomorphic and water phantoms applying patient treatment parameters. Blood samples were collected from all participants for genetic analyses.

Conclusions: Our study design improves the potential for detecting gene-environment interactions for diseases when both gene mutations and the environmental exposures of interest are rare in the general population. This is particularly applicable to the study of bilateral breast cancer because both radiation dose and genetic susceptibility have important etiologic roles, possibly by interactive mechanisms. By using counter-matching, we optimized the informativeness of the collected dosimetry data by increasing the variability of radiation dose within the case-control sets and enhanced our ability to detect radiation-genotype interactions.

Figure 1

Range of quadrant doses (cGy) expected in the WECARE Study. Doses were calculated from phantom-derived measurements. Range limits were chosen to correspond to the techniques being used among the WECARE subjects that would result in the lowest and highest doses to each quadrant and the nipple area of the contralateral breast.

Figure 2

Counter-matching (CM) on registry radiation therapy (RRT) status. This figure shows a hypothetical and idealized implementation of the CM 1:2 samples for this study. The solid and dashed lines represent the time on study for RRT-unexposed (RRT-) and RRT-exposed (RRT+) subjects in a matching stratum. Symbols: Filled circle, contralateral breast cancer case; short vertical line, women 'at risk' at the case's time of contralateral breast cancer who may serve as controls; open circle, counter-matched controls sampled from those at risk; number RRT+, number of RRT+ women in the risk set; number RRT-, number of RRT- women in the risk set.