Breast cancer risk in the WHI study: The problem of obesity
Introduction
Breast cancer is the most frequent malignant disease in Western countries and seems to be dependent on lifestyle and nutrition. The development of breast cancer is usually regarded as a multifactorial process which means that the etiology is unknown. There are many theories that are based on experimental investigation and relatively inconsistent epidemiological data. There is, however, no doubt that reproductive factors play an important role. Concerning the impact of sex steroids, the cumulative exposure to endogenous and exogenous estrogens and progestins seems to determine the life-time risk of breast cancer.
Section snippets
Risk factors for the development of breast cancer
Certain risk factors for the development of breast cancer like age and gene mutation (e.g., BRCA1 and BRCA2) must be accepted as an unchangeable predisposition. Many other risk factors, e.g., obesity or hormone replacement therapy (HRT) can, however, be avoided or changed. Early menarche and late menopause indicate a prolonged exposition to estrogens and progesterone that increase the risk of breast cancer, whereas long-term lactation decreases the risk (Table 1) [1], [2]. The latter may be due
Observational studies
Many observational studies on the influence of HRT on breast cancer risk revealed contradictory results, and every new case-control study or cohort study will enlarge this long row of inconsistent outcomes. The collaborative reanalysis from 1997 was an attempt to bring together and re-examine the individual data of all relevant studies published so far. It revealed that each year of delayed menopause increases the risk by 2.8% which was in the range of 2.3% for each year of HRT [4]. The
Effect of sex steroids on the proliferation of normal and malignant breast tissue
Although estrogens may be involved in the initiation of breast cancer, a carcinogenic/mutagenic role of sex steroids is rather improbable. The available experimental, clinical and epidemiological data suggest that the development of breast cancer is closely related to an accelerated hormone-induced growth of preexisting occult tumors. In an autopsy study, small occult breast cancers were found in 39% of women aged 40–50 years [39]. Epidemiological studies revealed that the impact of estrogens
Relation between breast cancer risk and body mass index
Obesity is associated not only with an elevated risk of developing coronary heart disease, but also with an increase in risk of various cancers [51], [52]. Moreover, there is a highly significant association between the risk of breast cancer and BMI, % body fat and weight gain in postmenopausal women (Table 3) [52], [53], [54], [55].
Epidemiological data suggest that a high BMI may attenuate the effect of estrogens on breast cancer risk. The collaborative reanalysis from 1997 found an
Characteristics of the women participating in the WHI study
Concerning the assessment of breast cancer risk, the high age of the women enrolled in the WHI study could be regarded as an advantage, because the incidence of invasive breast cancer rises with increasing age. The annual number of breast cancer diagnoses increases from 18/1000 women at age 50 years up to 45/1000 women at age 63 years and to 63/1000 women at age 70 [4]. In both arms of the WHI study the mean age was about 63 years on average and two third of the women were older than 60 years
Nutrition and body weight
Western lifestyle is associated with overweight, abdominal obesity, insulin resistance and low physical activity. Higher age, estrogen deficiency and obesity increase the prevalence of insulin resistance, and dietary habits may play a critical role. Even in non-obese postmenopausal women the prevalence of fasting hyperinsulinemia is high [60]. The risk of breast cancer in Western countries is five-fold that in Japan, but migration of Japanese women to the USA results in adaptation of risk [59].
Conclusion
HRT may stimulate growth of occult breast tumors in postmenopausal women. This concerns primarily hormone receptor-positive cancers, and the effect of estrogens is enhanced by progestins. Observational and randomised studies suggest that HRT with estrogen/progestin combinations increases the relative risk of breast cancer in postmenopausal women more than estrogens alone. Besides many other risk factors, overweight and obesity is associated with an elevated risk of breast cancer in
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