Breast cancer is the most Common cause of cancer mortality in women worldwide, and its incidence continues to increase1. The majority of breast cancer cases (90–95%) are sporadic (i.e. Non hereditary), with only a modest or absent family history of breast or ovarian cancer. Sporadic cancer is considered to be a polygenic or multifactorial disorder involving many genes that interact with nutrition and lifestyle factors2. In addition, oestrogen exposure is one of the most important risk factors as its metabolites can attack DNA and cause double stranded breaks. For this reason, the functional polymorphisms of genes involved in oestrogen metabolism should be identified for inclusion in a multi gene breast cancer risk reduction approach, as well as prior to the commencement of any hormone replacement therapy (HRT).
The dangers of hormone replacement therapy
Conventional HRT has been used for many years without any major health concerns, until the Women’s health initiative randomised controlled trial (which abruptly ended in July 2002) found that the overall health risk exceeded the benefit from the use of combined oestrogen and progestin for an average 5.2-year follow-up among healthy postmenopausal women3. The study found a 26% increase in breast cancer cases, as well as increases in cardiovascular disease, deep vein thrombosis and stroke. Similarly, the million Women study found that the use of HRT by women aged 50–60 years in the UK over the previous decade resulted in an estimated 20 000 extra breast cancer cases, 15 000 of which have been associated with oestrogen–progestin4. It was found that conjugated equine oestrogens (cee) and synthetic progestins in a conventional HRT regimen prescribed to every woman in the same dose, was mostly to blame (Figure 1).however, the French e3n cohort study showed an unequal risk for breast cancer associated with different HRT regimens (conventional versus bioidentical), giving a better idea as to the direction in which HRT treatment approaches should go5(Figure 2). From this study, it is possible to surmise that the smallest relative risk for breast cancer is after the use of combined oestrogen–progesterone, preferably not longer than 6 years, and in combination with weaker oestrogens (e.g. Estriol).
Understanding the role of oestrogen metabolites
There is a complex causal relationship between hormone-sensitive sporadic breast cancer and oestrogen, unlike the dose-related relationship between oestrogen and endometrial cancer. Understanding the role of oestrogen in the pathophysiology of breast cancer will ultimately lead to an understanding of why conventional HRT (where ‘one size fits all’) should be replaced with personalised bioidentical HRT (BHRT) supported by a close monitoring of individual oestrogen metabolites and their ratios, tailored nutrition, and lifestyle changes. The human body perceives its own oestrogen as a toxin. The metabolism of oestrogen primarily takes place in the liver through phase i (hydroxylation) and phase ii (methylation, glucuronidation and sulfation) pathways, with a final excretion in the urine and faeces. Oestrogen and its metabolites show a great variation in biological activity, oestrogen receptor affinity, and carcinogenicity; therefore, the ultimate biologic effect depends on how oestrogen is metabolised. This will depend on the specific polymorphism (single nucleotide polymorphism; snps) of the genes involved in oestrogen detoxification in each individual, their interaction with nutrition, and the environment, and the total body oestrogen burden. It is unique to every patient.