For some women, the major correlation between hormones and increased risk for breast cancer may be through a genetic sensitivity that is manifested as early puberty rather than a cumulative exposure over the lifespan, according to an article in the June 5th issue of the New England Journal of Medicine.

The American research team analyzed information from 1811 pairs of female twins, one or both of whom had breast cancer, including zygosity, concordance or discordance for breast cancer, presence or absence of family history, and presence of unilateral or bilateral disease.

One major assumption in the case-control study was that cancer concordant, monozygotic twins were assumed to have the highest genetic susceptibility for disease among the twin subgroups. For these women, the first twin to reach puberty was 5.4 times as likely to develop the disease first. The link was even stronger when menstruation began early, before age 12 years. For disease-discordant monozygotic twins, earlier onset of puberty had no effect on risk.

Other potential hormonal differences between monozygotic twins, including age at first pregnancy, lower parity, and age at menopause was associated with higher risk in twin pairs when only 1 sibling had breast cancer. The same factors did not alter risk (seen as earlier development of disease) for disease-concordant, monozygotic twins.

The authors hypothesize that the disease-concordant, monozygotic twins represent women with a genotype that makes them unusually sensitive to pubertal hormones. As the age at onset of puberty continues to decrease, the number of women with this hormonal association is likely to increase, as well.

In an editorial, Patricia Hartge, Sc.D., of the National Cancer Institute notes that the “intriguing observations” from the twin study add information to the body of evidence on genes, hormones, and pathways to breast cancer, but she also asserts that it very premature to accept the authors’ interpretation of the data until it is replicated in future research.

Hartge points out the apparent inconsistency between the authors’ interpretations of the twin data and data drawn from studies of women with BRCA1 or BRCA2 mutations or studies of women from strongly affected families and concludes, “Continuing thoughtful exploration of data from twins will enhance the understanding we can gain from consortiums of clinics for women at high genetic risk, surveys of unique populations, and case-control and cohort studies in the population. As studies succeed in finding gene-hormone interactions, we can expect to illuminate the pathways to breast cancer and reduce the changes that it will develop.”