Pharmacological intervention in the prevention of breast cancer

Abstract

Breast cancer accounts for the most common malignancy in women worldwide, accounting for 27% of cancer cases in women (1) and second overall when both sexes considered together. It is responsible for 15% of cancer deaths in the US, the second commonest cause of cancer deaths in women, following lung cancer (causes 26% of cancer deaths) (1). Approximately 1in 8 women in the US will develop breast cancer over her lifetime (12.56% lifetime breast cancer risk), where the lifetime probability of developing a cancer at any site is 1in3 (2). The breast cancer risk increases exponentially with increasing age. Epidemiological studies suggest that risk factors for breast cancer include: age (higher risk with advancing age (4, 5), gender (being a female), family history, benign breast disease, reproductive factors – age at menarche (higher risk for breast cancer if menarche occurred at age≤11) (4,6,7) age at menopause (the risk is higher if menopause occurred at ≥54years) (4,6) parity (nulliparity is associated with increased risk of breast cancer) (7,8) age at first baby (if ≥30 years, there is relative increased risk of breast cancer) (4,7,9) breastfeeding (women who breastfeed have lower relative risk for breast cancer compared with those who do not) (10), endogenous/exogenous hormones, diet, adiposity (14), physical activity, alcohol and radiation. Correlation between hormone level and breast cancer risk has been studied (11) and a direct association between breast cancer risk and level of both estrogens and androgens was found, but not with progesterone level. This association was mostly exhibited in estrogen receptor [ER]-positive and progesterone receptor [PR]-positive [ER+/PR+] breast tumours. When comparing the highest and lowest fourths of plasma hormone concentration in this subgroup, it was concluded that there is increased risk of breast cancer with increased levels of estradiol, testosterone, androstenedione and dehydoepiandrosterone sulfate. The Women’s Health Initiative (WHI) studies yielded somewhat different results. The major finding from the Estrogen-Alone (E-Alone) trial which included 10,739 postmenopausal women with prior hysterectomy suggested that women taking conjugated equine estrogen pills had 23% lower breast cancer risk compared to those assigned to take the placebo (average follow-up 6.8years). These findings were however not statistically significant (12). In contrast, findings from the WHI hormone trial of combined estrogen plus progestin (E+P) show that healthy postmenopausal women with a uterus who used combined estrogen and progestin had a significant increase in total and invasive breast cancers compared to placebo. This increased breast cancer risk emerged by around 5 years follow-up 13. Adiposity is proposed to affect circulating hormones and thus may itself be a modifiable risk factor for breast cancer. When correlating the weight change from 18years of age to menopause age with breast cancer risk in postmenopausal women (14), there was an association between weight gain, especially since the menopause, with increased risk for breast cancer. Relation was seen most clearly among women who never have used postmenopausal hormones. On the other hand, women who lost weight after menopause were at a decreased risk of breast cancer. Trends are more towards cancer prevention research, to try finding ways to lower the risk of the respective disease. Predicted breast cancer risk is calculated using the Gail Model which is a multivariable logistic regression model. Variables included are age, race, number of first degree relatives with breast cancer, nulliparity or age at first live birth, number of benign breast biopsies, pathologic diagnosis of atypical hyperplasia, and age at menarche (15). “Prevention is better than healing because it saves the labor of being sick” Thomas Adams 17th Century Physcian.