Breast Cancer

Charles M. Haskell and Dennis A. Casciato

A. Incidence 1. Breast cancer is the most common lethal neoplasm in women. The American Cancer Society (ACS) has estimated that breast cancer will constitute 29% of all new malignant neoplasms and 16% of deaths from cancer in women. The annual incidence of breast cancer in the United States increases dramatically with age (5 per 100,000 population at 25 years of age, rising to 150 per 100,000 at 50 years of age and to more than 200 per 100,000 at 75 years of age). 2. The incidence of male breast cancer is about 2.5 per 100,000 population. Fewer than 1% of all breast cancer cases occur in men. B. Etiology Breast cancer is the result of mutations in one or more critical genes. Two genes in women on chromosome 17 have been implicated. The most important gene is called BRCA-1 (at 17q21); the other is the p53 gene (at 17p13). A third gene is the BRCA-2 gene on chromosome 13. A fourth gene implicated in the etiology of breast cancer is the androgen-receptor gene, found on the Y chromosome. Mutations of the latter gene have been associated with several cases of male breast cancer but not female breast cancer. The best established etiologic agent in breast cancer is exposure to radiation. A viral cause has also been postulated but never proved in humans. Complex experimental and epidemiologic evidence points strongly to the influence of hormones and diet in the pathogenesis of breast cancer. The variation of incidence of breast cancer in different populations is highly correlated with consumption of dietary fat, dietary sugar, or parity in 75% of cases affecting postmenopausal women and in about 50% of cases affecting premenopausal women. 1. Diet. Diets in Western countries typically have a high content of fat and sugar. The dietary contents of both fat and total calories independently are strongly correlated with the incidence of breast cancer. Women from Western countries have about six times the risk for breast cancer as do women from Asian or underdeveloped countries. The low breast cancer rate in Asian women may also relate to the higher oral intake of phytoestrogens in Asia than in the United States and Europe. The risk for breast cancer increases progressively with age except in countries with lowfat diets, where the risk is stabilized or decreased in older women. The risk changes accordingly when populations move from a low-risk country to a high-risk country and adopt the dietary habits of the new country. It is likely, however, that the effect of diet on breast cancer incidence occurs at an early age, such as in childhood or adolescence. No data in humans prove that changing from a high-fat diet to a low-fat diet later in life reduces the risk for breast cancer.

2. Hormones There is ample evidence implicating hormones in the cause of breast cancer, but the role of individual hormones is uncertain. High prolactin levels are clearly related to the development of breast cancer in animal models, but epidemiologic evidence is conflicting, and a causative relationship between prolactin and breast cancer has not been proved in humans. Estrogens, either alone or in combination with progestins in various oral contraceptive preparations, are also of concern. Short-term studies have shown no increased risk for breast cancer from oral contraceptives, whereas other studies suggest that long-term use may increase the risk for breast cancer in young women. 3. Links between diet and hormones Differences in estrogen and prolactin levels in female populations correlate with differences in dietary fat; that is, high-fat diets are associated with increased hormone secretion. Furthermore, obesity is associated with increased adrenal production of androstenedione, which is converted to estrogens in adipose tissue; this source of production and conversion continues after menopause. Finally, tumor-promoting steroid hormones are also fat soluble and likewise may be accumulated in breast tissue. 4. Hereditary breast cancer Familial aggregations of breast cancer occur in about 18% of cases, but only about 5% of cases can be considered truly familial based on extended pedigree analysis. Most of these are due to mutations in the BRCA-1 and BRCA-2 genes. The disease tends to occur at an earlier age and to be bilateral in patients with familial breast cancer. It can also be associated with carcinomas developing in other organs (especially the colon, ovary, or uterus) or with other rare cancers (sarcomas, brain, leukemia, adrenal glands) as part of the Li-Fraumeni syndrome associated with mutations in the p53 gene. Familial transmission can occur through either the maternal or paternal germ line as an autosomal dominant trait. In such families, the lifetime risk of women developing breast cancer is at least 50%. Features in the history of a patient that increase the liklihood of having BRCA mutations include the following: a.Multiple cases of early onset breat cancer in the family b.Ovarian cancer with family history of breast or ovarian cancer c.Breast and ovarian cancer in the same woman d.Bilateral breast cancer e.Ashkenazi Jewish heritage f.Male breast cancer C. Risk factors for breast cancer 1.High-risk factors (three-fold or more increase) a.Age (older than 40 years of age) b.Previous cancer in one breast, especially if it occurred before menopause c.Breast cancer in the family. Increased occurrence of breast cancer is seen in mothers, daughters, and sisters particularly, but also in aunts, cousins, and grandmothers. Mothers, daughters, and sisters of women who develop bilateral or unilateral breast cancer before menopause are at higher risk for developing breast cancer.

d.Hyperplasia with atypia. Most forms of benign breast disease do not predispose patients to the subsequent development of breast cancer. This is especially true of fibrocystic disease. Women with proliferative disease of the breast with atypical hyperplasia (atypia) are at increased risk for developing breast cancer (five-fold increase), however. The risk for atypia is greater in patients with a strong family history of breast cancer (11-fold increase). e.Parity. Women who are nulliparous or who were first pregnant after the age of 31 years are three to four times more likely to develop breast cancer than those who complete the first pregnancy before the age of 18 years. f.Lobular carcinoma in situ carries a 30% risk of invasive cancer. g.Risk factors in men. Klinefelters syndrome, gynecomastia, and family history of male breast cancer 2.Intermediate risk factors (1.2- to 1.5-fold increase) a.Menstruation history: 1.Early menarche 2.Late menopause b.Oral estrogens (see section I.B.2) in women c.History of cancer of the ovary, uterine fundus, or colon d.Diabetes mellitus e.Use of alcoholic beverages 3.Factors known to decrease risk a.Asian ancestry b.Term pregnancy before age 18 years of age c.Early menopause d.Surgical castration before the age of 37 years 4.Factors having no effect on risk (previously thought to be risk factors): multiparity, lactation, and breast feeding