Does Menopausal Hormone Therapy Initiate New Breast Cancers or Promote the Growth of Existing Ones?

Abstract

Several observational studies over the past two decades have suggested that menopausal hormonal therapy (MHT) increases the risk of breast cancer [1]. The randomized Women’s Health Initiative (WHI) trial of estrogen plus progestin supported this conclusion by reporting an increased relative risk (RR) of 1.26 for breast cancer [2]. Little attention has focused on the mechanisms responsible and, specifically, on whether this finding represents an increased rate of diagnosis of occult cancers or the initiation of completely new ones. The answer to this question is critically important for interpretation of published data. How common are small, undiagnosed, occult breast cancers in the population of women who initially start on menopausal hormone therapy? Data on this question come primarily from autopsy studies conducted 20–30 years ago. Eight studies examined breast tissue at autopsy in 952 women dying from other causes and attempted to determine how many occult breast cancers were present [3,4]. The individual results varied but pooled data suggested that 5% of women have undiagnosed ductal carcinoma in situ at autopsy and another 1% have invasive breast cancer. The stringency of techniques utilized probably explains the variability in results. For example, some studies made serial sections throughout the breasts for histologic examination; others identified grossly visible lesions that were then sectioned and examined; and finally, radiographs were performed on excised breasts at autopsy with sections made from the areas with increased density. Pooling of results from these eight studies demonstrates a ‘reservoir’ of undiagnosed breast cancer in the population of women ranging from 50 to 80 years of age. Critical interpretation of these ‘old’ data from a 2008 perspective would suggest that this reservoir is probably smaller now because of the more sensitive mammographic techniques currently used and the frequency of their use. However, this may not necessarily be true since a recent study using MRI of the opposite breast in high-risk women with their first breast cancer, demonstrated a 3% prevalence of contralateral breast cancer that had not been diagnosed by prior mammography or breast examination [5]. Based on these various studies, we consider it likely that a substantial number of women, perhaps 3% as a conservative estimate, have undetected breast cancers when starting MHT at the present time. Further support for the hypothesis regarding the ‘reservoir of undiagnosed breast cancer’ comes from studies of tumor biology in women. It has been estimated that the doubling time of small breast tumors ranges from 50 to 100 days in younger women and up to 6 months in those over 70 years [6]. Breast cancers must start from a single cell and then grow to a billion cells before they reach a clinically detectable size (∼1 cm).