Puberty and genetic susceptibility to breast cancer in a case-control study in twins

BACKGROUND: Breast cancer is thought to result from excessive cumulative exposure to ovarian hormones. Different predictors of hereditary and sporadic breast cancer suggest different pathogenic mechanisms. Affected twin pairs may help to illustrate such differences. METHODS: We obtained information from 1811 pairs of female twins, one or both of whom had breast cancer. The pairs were stratified according to concordance or discordance for breast cancer, zygosity, the presence or absence of a family history of breast cancer, and the presence of bilateral or unilateral disease. Disease-concordant monozygotic pairs were assumed to have a higher genetic susceptibility than other subgroups of pairs. Paired twins were compared with respect to age at puberty and other factors. We calculated adjusted odds ratios for the diagnosis of breast cancer when only one twin was affected and for the first of the two diagnoses when both were affected. RESULTS: Within disease-discordant monozygotic pairs, the twin with an earlier onset of puberty did not have an increased risk of breast cancer (adjusted odds ratio, 0.8; 95 percent confidence interval, 0.6 to 1.2). Within disease-concordant monozygotic pairs, the twin with earlier puberty was much more likely to receive the diagnosis first (adjusted odds ratio, 5.4; 95 percent confidence interval, 2.0 to 14.5). In contrast, a later first pregnancy, lower parity, and later menopause within the pair were associated with an increased risk of breast cancer when one twin was affected but did not predict an earlier diagnosis when both were affected. CONCLUSIONS: Within the most genetically susceptible subgroup of twin pairs, the strong influence of earlier puberty on the age at the diagnosis of breast cancer and the absence of linkage to hormonal milestones later in life suggest that most cases of hereditary breast cancer are not related to cumulative hormone exposure and that they may instead result from an unusual sensitivity to pubertal hormones. Associations between breast cancer and early menarche and those with reproductive milestones in adulthood may reflect different genotypes.