Effects of menopausal hormonal therapy on occult breast tumors

Highlights

• MHT primarily exerts effects on occult breast tumors rather than causing de novo cancer.

• MHT with estrogen alone reduces the incidence of breast cancer, likely by inducing apoptosis.

• A understanding of the effects of MHT requires assessment of attributable risk and not relative risk.

Abstract

An estimated 7% of 40–80 year old women dying of unrelated causes harbor occult breast tumors at autopsy. These lesions are too small to be detected by mammography, a method which requires tumors to be approximately 1 cm in diameter to be diagnosed. Tumor growth rates, as assessed by “effective doubling times” on serial mammography range from 10 to >700 days with a median of approximately 200 days. We previously reported two models, based on iterative analysis of these parameters, to describe the biologic behavior of undiagnosed, occult breast tumors. One of our models is biologically based and includes parameters of a 200 day effective doubling time, 7% prevalence of occult tumors in the 40-80 aged female population and a detection threshold of 1.16 cm and the other involves computer based projections based on age related breast cancer incidence. Our models facilitate interpretation of the Women's Health Initiative (WHI) and anti-estrogen prevention studies.

The biologically based model suggests that menopausal hormone therapy with conjugated equine estrogens plus medroxyprogesterone acetate (MPA) in the WHI trial primarily promoted the growth of pre-existing, occult lesions and minimally initiated de novo tumors. The paradoxical reduction of breast cancer incidence in women receiving estrogen alone is consistent with a model that this hormone causes apoptosis in women deprived of estrogen long term as a result of the cessation of estrogen production after the menopause. Understanding of the kinetics of occult tumors suggests that breast cancer “prevention” with anti-estrogens or aromatase inhibitors represents early treatment rather than a reduction in de novo tumor formation.

Our in vivo data suggest that the combination of a SERM, bazedoxifene (BZA), with conjugated equine estrogen (CEE) acts to block maturation of the mammary gland in oophorectomized, immature mice. This hormonal combination is defined by the generic term, tissue selective estrogen complex or TSEC. Xenograft studies with the BZA/CEE combination show that it blocks the growth of occult, hormone dependent tumors in nude mice. These pre-clinical data suggest that the BZA/CEE TSEC combination may prevent the growth of occult breast tumors in women. Based on the beneficial effects of this TSEC combination on symptoms and fracture prevention in menopausal women, the combination of BZA/CEE might be used as a means both to treat menopausal symptoms and to prevent breast cancer.

This article is part of a Special Issue entitled ‘CSR 2013’.

Introduction

An estimated 7% of 40–80 year old women are found to have undiagnosed breast cancer at autopsy [1], [2], [3], [4], [5], [6], [7], [8]. We have developed both a biologically based and a computer-derived model to assess the growth of these occult tumors during the period in which they are too small to be detected by mammography. The biologic properties of the undiagnosed tumors provide insight into interpretation of the Women's Health Initiative (WHI) studies, breast cancer prevention trials, and risk prediction methods [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23]. From these models, we conclude that the majority of the observed breast cancer effects of menopausal hormone therapy are exerted on pre-existing occult tumors commonly present in the population of otherwise healthy post-menopausal women. Additionally, use of anti-estrogens or aromatase inhibitors for breast cancer prevention actually represents early treatment of occult lesions.

The substantial prevalence of occult breast tumors in women has important implications. Recent data have indicated that most symptomatic women just entering menopause experience more benefit than risk from menopausal hormone therapy [2]. Current recommendations suggest use of hormone therapy in these women provided that they are not at enhanced risk for heart disease or breast cancer. However, a strategy that would both relieve symptoms and prevent breast cancer would add another dimension to this approach. Accumulating clinical data suggest that the combination of an estrogen with a SERM might relieve symptoms and at the same time provide early treatment for occult breast cancers. The SERM/estrogen combination has been termed a TSEC or tissue selective estrogen complex. This review will provide an overview of the biologic data indicating the importance of occult breast tumors and detail the studies suggesting that a TSEC might serve as early treatment of occult lesions. In this manuscript, we will cite our own data predominantly but also refer to studies that confirm and extend the concepts underlying the kinetics of occult tumor growth.