Global Impact of Breast Cancer

Among developed countries, the United States has the highest annual incidence rates of breast cancer exceeding 100 cases per 100,000. The lifetime risk of breast cancer for American women is approximately 1 in 8 compared to a lifetime risk of only 1 in 66 for Chinese women. Breast cancer mortality rates show a narrower range than incidence rates ranging from 5.5 deaths per 100,000 Chinese women to 27.8 deaths per 100,000 Danish women. The incidence and mortality rates of breast cancer tend to be higher for women in developed countries compared to those in underdeveloped countries.

Breast Cancer Detection, Staging, and Survival

Mammography is a radiographic imaging process using low-dose X-rays to assist in the detection and diagnosis of breast cancer. The goal of mammography as a screening tool is to detect breast tumors early in their growth and development so they can be completely excised by qualified breast surgeons. Screening mammography together with effective biopsy ( Fine Needle Aspiration Biopsy), accurate pathologic evaluation, and surgical excision of breast tumors has been shown to reduce the mortality from breast cancer by approximately 30% in women over the age of 50 years. Because of the difficulty in discriminating normal active mammary glands from abnormal neoplastic growths in women during their reproductive years, there is controversy about the value of screening for breast cancer by mammography in premenopausal women (before age 50). Currently, the American National Cancer Institute recommends that women initiate biannual screening for breast cancer by mammography at age 40–49, whereas after age 50, screening is recommended on an annual basis ( Mammographic Breast Density and Cancer Risk). Other imaging techniques such as ultrasound,  Magnetic Resonance Imaging (MRI) and  Positron Emission Tomography (PET) are now being widely used by physicians to assist in the evaluation and diagnosis of breast tumors. Breast-self-examination (BSE) and physician examination are also considered essential components of regular breast care.

Pathology

Tumor staging ( Staging of Tumors) refers to the microscopic evaluation of tissue by a pathologist to assess size, exact anatomic location, growth, and spread of a cancerous lesion. While imaging procedures are important for the identification of suspicious lesions, the ultimate diagnosis of breast cancer (or any other malignant neoplasm) must be confirmed by microscopic examination of cancerous tissue (obtained by  biopsy) by a qualified pathologist.

Mechanisms of Breast Carcinogenesis

Breast carcinogenesis is most probably due to stimulation of  epithelial cells that line the breast ducts by estrogens ( Estrogenic Hormones). The major evidence for this is that breast cancer primarily occurs in women, although occasionally breast tumors do develop in men, particularly in association with Klinefelter syndrome, where there is an extra X chromosome in the karyotype (XXY) or by ingestion of synthetic estrogens such as diethylstibesterol in the treatment of prostate cancer ( Prostate Cancer Clinical Oncology).

Several theories have been proposed to explain breast carcinogenesis. Perhaps the best known of these relates breast cancer risk to the sustained stimulus of estrogen over many years. The “estrogen-stimulus” theory of breast cancer postulates that the risk is enhanced with a sustained continuum of estrogen cycles unbroken by pregnancy or other mechanisms of estrogen ablation such as ovariectomy. Both endogenous and exogenous factors may potentially increase estrogen stimulus of the mammary gland in association with breast cancer development.

Risk Factors

Several “risk factors” have been identified that increase a woman’s chance of developing breast cancer. Nevertheless, cause and effect cannot be established in most individual cases. The classical risk factors of breast cancer include familial and genetic predisposition, early menses, delayed reproductive history, nulliparity, late menopause, and the natural process of aging.

Estrogen Replacement Therapy

Approximately 75% of breast cancers are diagnosed in women after they undergo menopause. A number of investigations have examined the association between  estrogen replacement therapy (ERT) and postmenopausal breast cancer risk. There is a general consensus that ERT (with or without  progesterone) elevates the risk of postmenopausal breast cancer by two to threefold. Several studies show consistency in observing an interaction between body mass and ERT in elevating the risk of breast cancer in postmenopausal women. Specifically, lean women who receive ERT after menopause have been found to be at significantly higher risk for the development of breast cancer. One possible explanation for this is the relatively higher concentration of ERT in women of smaller body mass.

Diet

From an etiologic standpoint, rates of breast cancer are changing in populations that historically have been at low risk, whereas the rates have remained relatively constant in populations at higher risk. For example, breast cancer mortality rates among Japanese, Indian, and Chinese women have increased approximately threefold in the past two decades, whereas the United States, the United Kingdom, and European (French) rates have remained constant or slightly declined (Fig. 1).

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Concurrently, the Japanese, Indian, and Chinese  diets have also changed dramatically with higher intakes of fat and calories. However, other risk factors may also be involved since birth rates are declining, age at first pregnancy is being delayed, and nulliparity is increasing in these populations.

Various hypotheses postulate that dietary factors are related to the  initiation and promotion of breast cancer. One such hypothesis states that breast cancer development is due to intake of certain types of essential fatty acids that increase  inflammation and estrogen biosynthesis and thus promote breast cancer development. However, there is controversy among epidemiologists regarding the role of dietary fat or other dietary factors in the development of breast cancer ( Cancer Causes and Control).

The highest risk target organ for development of breast cancer is the contralateral (opposite) breast of a woman who has already manifested unilateral disease ( Contralateral Breast Cancer). In addition, the familial breast cancer patient has a markedly enhanced risk for development of malignancy in the contralateral breast (about 50% over 20 years, post- mastectomy).

Many studies in biochemical epidemiology have been performed with the objective of identifying a biochemical marker of breast cancer risk. The various subtypes of estrogens (estradiol, estrone, and estriol) and their ratios,  androgens and other steroids, polypeptide hormones such as prolactin, and various indices of these parameters have been tried; however, no single parameter or index of parameters has been developed which accurately predicts an individual’s risk of for developing cancer of the breast.

Prevention

Breast cancer specimens ascertained by biopsy or surgical procedures (mastectomy) are routinely subjected to laboratory analysis of estrogen receptors (ER) and progesterone receptors (PR). Breast tumors that are positive for ER/PR may respond to hormone therapy by administration of antiestrogenic compounds such as  Tamoxifen. Tamoxifen is now being offered to women treated for early stage breast cancer for  chemoprevention against the development of second primary cancer in the contralateral breast.

Large independent clinical trials have been performed to examine the preventive activity of Tamoxifen. While a US trial showed beneficial effects, the results of two European trials were negative. Despite this apparent discrepancy of results, the US FDA has approved Tamoxifen for use as a preventive agent in high risk women. This action tends to disregard adverse side effects of the drug, including increased risks of endometrial cancer, ER negative breast cancer,  colon cancer, and pulmonary embolus.

Many epidemiologic studies have noted a significant preventive effect of  nonsteroidal anti-inflammatory drugs (NSAIDs) against breast cancer. These investigations suggest that the risk of breast cancer is reduced by 20–30% with regular use of common over the counter NSAIDs such as  aspirin and ibuprofen. Studies in  molecular epidemiology and in animals suggest that this effect is manifest due to blockade of cyclooxygenase isozymes of the inflammatory cascade, particularly the inducible isoform,  Cyclooxygenase-2.