Endocrine Abstracts

Autopsy studies report a reservoir of small, occult, and undiagnosed breast cancers in up to 15.6% of 40–80-year-old women dying from unrelated causes. Modeling of the biologic behavior of these occult tumors facilitates interpretation of the effects of hormone therapy in menopausal women. We used iterative and mathematical techniques to develop a model of occult tumor growth (OTG) whose parameters included prevalence, effective doubling time (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 our OTG model as judged by comparison with Surveillance Epidemiology and End Results (SEER) population incidence rates in the USA. We further 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 menopausal hormone therapy (MHT) predominantly causes existing, occult tumors to grow more rapidly (i.e. 150 rather than 200 days doubling time) and to exceed the diagnostic threshold earlier. The model also suggests that only 6% of tumors arise de novo during the first 5 years of MHT. From these data we conclude that occult, undiagnosed tumors are prevalent, grow slowly, and are the biologic targets of hormone therapy for menopausal women. In addition, the results suggest that breast cancer prevention with anti-estrogens or aromatase inhibitors represents early treatment of occult breast tumors and not true prevention. From these perspectives, we envision that a key approach for the future is to identify these occult tumors early, to distinguish those that are aggressive, and to initiate treatment in the appropriate tumors at an earlier stage.