Reproductive factors and familial predisposition for breast cancer by age 50 years. A case-control-family study for assessing main effects and possible gene-environment interaction

Background The effect of environmental/lifestyle factors on breast cancer risk may be modified by genetic predisposition. Methods In a population-based case-control-family study performed in Germany including 706 cases by age 50 years, 1381 population, and 252 sister controls, we investigated main effects for environmental/lifestyle factors and genetic susceptibility and gene-environment interaction (G x E). Different surrogate measures for genetic predisposition using pedigree information were used: first-degree family history of breast or ovarian cancer; and gene carrier probability using a genetic model based on rare dominant genes. Possible G x E interaction was studied by (1) logistic regression using cases and population controls including an interaction term; (2) comparing results using sister controls and population controls; (3) case-only analysis with logistic regression and (4) a mixture logistic model. Results Familial predisposition showed the strongest main effect and the estimated gene carrier probability gave the best fit. High parity and longer duration of breastfeeding reduced breast cancer risk significantly, a history of abortions increased risk and age at menarche showed no significant effect. We found significant G x E interaction between parity and genetic susceptibility using different surrogate measures. In women most likely to have a high genetic susceptibility, high parity was less protective. Later age at menarche was protective in women with a positive family history. No evidence for G x E interaction was found for breastfeeding and abortion. Conclusions These findings corroborate results from other studies and provide further evidence that the magnitude of protection from parity is reduced in women most likely to have a genetic risk in spite of the limitations of using surrogate genetic measures.