Modeling of the growth kinetics of occult breast tumors: role in interpretation of studies of prevention and menopausal hormone therapy.

Abstract

Autopsy studies report a reservoir of small, occult, undiagnosed breast cancers in up to 15.6% of women dying from unrelated causes. The effective doubling times (EDT) of these occult neoplasms range from 70 to 350 days and mammographic detection threshold diameters from 0.88 to 1.66 cm. Modeling of the biologic behavior of these occult tumors facilitates interpretation of tamoxifen breast cancer prevention and menopausal hormone therapy studies. We used iterative and mathematical techniques to develop a model of occult tumor growth (OTG) whose parameters included prevalence, EDT, and detection threshold. The model was validated by comparing predicted with observed incidence of breast cancer in several populations. Iterative analysis identified a 200-day EDT, 7% prevalence and 1.16 cm detection threshold as optimal parameters for an OTG model as judged by comparison with Surveillance Epidemiology and End Results (SEER) population incidence rates in the United States. We validated the model by comparing predicted incidence rates with those observed in five separate population databases, in three long-term contralateral breast cancer detection studies, and with data from a computer-simulated tumor growth (CSTG) model. Our model strongly suggests that breast cancer prevention with anti-estrogens or aromatase inhibitors represents early treatment not prevention. In addition, menopausal hormone therapy does not primarily induce de novo tumors but promotes the growth of occult lesions. Our OGTG model suggests that occult, undiagnosed tumors are prevalent, grow slowly, and are the biologic targets of anti-estrogen therapy for prevention and hormone therapy for menopausal women.