Elsevier

Maturitas

Volume 51, Issue 1, 16 May 2005, Pages 83-97
Maturitas

Breast cancer risk in the WHI study: The problem of obesity

https://doi.org/10.1016/j.maturitas.2005.02.018Get rights and content

Abstract

In the climacteric, about 40% of the women have occult breast tumors the growth of which may be stimulated by hormones. Many genetic, reproductive and lifestyle factors may influence the incidence of breast cancer. Epidemiological data suggest that the increase in the relative risk (RR) of breast cancer induced by hormone replacement therapy (HRT) is comparable with that associated with early menarche, late menopause, late first birth, alcohol consumption, etc. One of the most important risk factors is obesity which exceeds the effect of HRT by far, and in overweight postmenopausal women the elevated risk of breast cancer is not further increased by HRT. As in the WHI study the majority of women was overweight or obese, this trial was unsuitable for the investigation of breast cancer risk. In the women treated with an estrogen/progestin combination, the RR of breast cancer rose only in those women who have been treated with hormones prior to the study, suggesting a selection bias. In the women not pretreated with hormones, it was not elevated. In the estrogen-only arm of the WHI study, there was no increase but a steady decrease in the RR of breast cancer during 6.8 years of estrogen therapy. This result was unexpected, as estrogens are known to facilitate the development and growth of breast tumors, and the effect is enhanced by the addition of progestins.

Obese women are at high risk to develop a metabolic syndrome including insulin resistance and hyperinsulinemia. In postmenopausal women, elevated insulin levels are not only associated with an increased risk for cardiovascular disease, but also for breast cancer. This might explain the effects observed in both arms of the WHI study: HRT with relative low doses of estrogens may improve insulin resistance and, hence, reduce the elevated breast cancer risk in obese patients, whereas this beneficial estrogen effect may be antagonized by progestins. The principal options for the reduction of breast cancer risk in postmenopausal women are the prevention of overweight and obesity to avoid the development of hyperinsulinemia, the medical treatment of insulin resistance, the use of low doses of estrogens and the reduction of exposure to progestins. The latter might include long-cycles with the sequential use of appropriate progestins every 3 months for 14 days. There are large inter-individual variations in the proliferative response to estrogens of the endometrium. Control by vaginalsonography and progestin challenge tests may help to identify those women who may be candidates for low-dose estrogen-only therapy.

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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