Biological and endocrinological insights into the possible breast cancer risk from menopausal estrogen replacement therapy.

The question of whether estrogen therapy increases the risk of breast cancer is reviewed. Despite more than 60 epidemiological studies and several meta-analyses over a five-decade period, there is no consensus about the answer. At present, the majority of investigators agree that short-term or medium-term therapy (less than 10 years) poses no measurable risk; some, but not all, investigators feel that there is a modest risk with long-term therapy (more than 15 years). Even this semi-consensus is clouded by the startling and clear-cut finding of the largest ever epidemiological study, the Nurses Surveillance Study, that a small increase in risk with estrogen therapy occurred only in women who also ingested alcohol, itself a known risk factor for breast cancer; women who did not ingest alcohol were at no increased risk. Because virtually none of the other epidemiological studies has controlled for alcohol ingestion, the conclusions of all of them are placed in doubt. To try to shed light on this problem, the 60-year-old studies of Lacassagne et al. on the induction of breast cancer in mice by estrogens were reviewed. They found that the magnitude and timing of the inducing effect of estrogen depended on the spontaneous breast cancer incidence in the mouse strain studied: in no-incidence strains, no cancer was induced; in high-incidence strains, induction was rapid and universal; in low-incidence strains, only a low percentage of animals had cancer induced, and it required prolonged estrogen administration.(ABSTRACT TRUNCATED AT 250 WORDS)