Breast Cancer Overview: Risk Factors, Screening, Genetic Testing, and Prevention

Breast Cancer Overview: Risk Factors, Screening, Genetic Testing, and Prevention


Breast cancer is the most common malignancy in women, accounting for 27% of all female cancers; it accounts for < 1% of all cancer cases in men. Breast cancer also is responsible for 15% of cancer deaths in women, making it the number-two cause of cancer death. An estimated 226,870 new breast cancer cases were diagnosed in women and 2,190 new cases were diagnosed in men in the United States in 2012, and 39,510 women and 410 men died of this cancer. As of 2012, there were approximately 2.9 million breast cancer survivors in the United States.

FDA Approvals

In September 2012, the US Food and Drug Administration (FDA) approved an ultrasound device shown to be capable of detecting small masses in dense breasts. The device, the somo-v Automated Breast Ultrasound System (ABUS), is indicated for use in combination with mammography for breast cancer screening. (While 40% to 60% of women in the United States have dense breasts, and women with dense breasts are four to six times more likely to be diagnosed with breast cancer, standard mammography fails to detect breast cancer in about one-third of these cases.) For the study that led to its approval, 200 asymptomatic women with dense breasts, from a prospective multicenter registry, were screened with both mammography and somo-v ABUS technology. Use of the ultrasound device improved cancer detection with an area under the curve (AUC) of 0.75 compared with an AUC of 0.60 for mammography alone, a 24% increase over mammography alone (P < .001).



Breast cancer is relatively uncommon in men; the female-to-male ratio is approximately 100:1. The incidence of breast cancer in men has remained relatively stable over the past decades, except in Africa, where, for unclear reasons, the incidence is rising. BRCA2 mutations are associated with an increased risk of breast cancer in men. The most common presentations of breast cancer in men are asymmetric gynecomastia or a palpable mass. All palpable masses in men should be carefully examined. Based on the physical examination findings, mammography and breast ultrasonography should be considered. Fine-needle aspiration (FNA) or core biopsy can be used to distinguish between gynecomastia and breast cancer. Core biopsy may be performed if the FNA is nondiagnostic.


The risk of developing breast cancer increases with age. The disease is less common in women younger than 40 years of age; only about 0.8% of breast cancers occur in women < 30 years old, and approximately 6.5% develop in women between 30 and 40 years old.


Caucasian women have a higher overall rate of breast cancer than do African-American women; however, this difference is not apparent until age 50 and is marked only after menopause. There is a higher incidence in young African-American women when compared to young Caucasian women. In the United States, the incidence of breast cancer in Asian and Hispanic women is approximately half that in white women. Breast cancer risk is extremely low in Native-American women.


There is at least a fivefold variation in the incidence of breast cancer reported in different countries, although this difference appears to be narrowing. The incidence of breast cancer is significantly lower in Japan, Thailand, Nigeria, and India than in Denmark, the Netherlands, New Zealand, Switzerland, the United Kingdom, and the United States. Women living in North America have the highest rate of breast cancer in the world. It has been suggested that these trends in breast cancer incidence somehow may be related to dietary influences, particularly dietary fat consumption (see section on "Etiology and risk factors").

Socioeconomic Status

The incidence of breast cancer is higher in women of higher socioeconomic background. This relationship is most likely related to lifestyle differences, such as age at first birth and dietary fat intake.

TABLE 1Survival of women with breast cancer, according to stage, without chemotherapy


Survival rates for patients with nonmetastatic breast cancer have improved in recent years (Table 1). These improvements may be secondary to advances in screening, systemic therapy, and locoregional radiation therapy. The contribution of screening mammography to breast cancer–specific survival is variable, favoring a reduction in breast cancer mortality of up to 25% in some series. Its impact on overall survival is less certain.

Etiology and Risk Factors

The development of breast cancer has been associated with numerous risk factors, including genetic, environmental, hormonal, and nutritional influences. Despite all of the available data on breast cancer risk factors, 75% of women with this cancer have no readily identifiable risk factors.

Genetic Factors

Hereditary forms of breast cancer constitute only 5% to 10% of breast cancer cases overall. However, the magnitude of the probability that a woman will develop cancer if she inherits a highly penetrant cancer gene mutation justifies the intense interest in predictive testing. Commercial testing is available for several genes (BRCA1, BRCA2, tumor protein p53 gene [TP53]) associated with a high risk of breast cancer development.

Elevated risk of breast cancer is also associated with mutations in the PTEN gene in Cowden Syndrome (described later in this chapter). In addition, a modest increased risk (relative risk of 3.9 to 6.4) may be seen in women who are heterozygous for a mutation in the ataxia-telangiectasia mutated gene (ATM gene), which is associated with the recessive disease ataxia-telangiectasia in the homozygous state. A moderately increased risk of breast cancer (2-fold for women and 10-fold for men) has also been associated with a variant (1100 delC) in the cell-cycle checkpoint kinase gene, CHEK2.

BRCA1 gene

The BRCA1 gene is located on chromosome 17. This gene is extremely large and complex, and there are more than 1,000 different possible mutations. BRCA1 mutations are inherited in an autosomal-dominant fashion and are associated with an increased risk of breast, ovarian, and, to a lesser degree, prostate cancers. A BRCA1 mutation carrier has a 56% to 85% lifetime risk of developing breast cancer and a 15% to 45% lifetime risk of developing ovarian cancer.

BRCA2 gene

The BRCA2 gene is located on chromosome 13. BRCA2 is approximately twice as large as BRCA1 and is similarly complex. Alterations in BRCA2 have been associated with an increased incidence of breast cancer in both women (similar to BRCA1) and men (6% lifetime risk). BRCA2 mutations are also associated with an increased risk of ovarian cancer, pancreatic cancer, prostate cancer, and melanoma. Together, mutations of BRCA1 and BRCA2 have been linked to most hereditary breast and ovarian cancer families and approximately half of hereditary breast cancer families.

The incidence of BRCA gene mutations in the general breast cancer population is unknown, since most of the data have come from studies of high-risk populations. In one population-based study of women with breast cancer, 9.4% of women < 35 years of age at the time of diagnosis and 12% of women < 45 years old who also had a first-degree relative with breast cancer had germline BRCA1 or BRCA2 mutations. However, a 40-year-old woman of Ashkenazi Jewish ancestry who has breast cancer has a 20% to 30% probability of bearing one of three founder BRCA gene mutations, based on data from high-risk clinics, testing vendors, and Israeli series. BRCA probability models are discussed below.

Li-Fraumeni syndrome

This rare syndrome is characterized by premenopausal breast cancer in combination with childhood sarcoma, brain tumors, leukemia, and adrenocortical carcinoma. Tumors frequently occur in childhood and early adulthood and often present as multiple primaries in the same individual. Germline mutations in the TP53 gene on chromosome 17p have been documented in persons with this syndrome. Inheritance is autosomal dominant, with a penetrance of at least 50% by age 50. Although the rarity of this syndrome, the diversity of tumor types, and the fact that the age of patients at risk spans from childhood to young adulthood makes coherent screening strategies beyond those for early-onset breast cancer risk difficult to find, a recent pilot study with 18-fluorodeoxyglucose positron emission tomography/CT scanning was promising. Gonzalez et al recently reported on the largest experience with clinical TP53 testing published thus far. In all, 91 of 525 patients had a deleterious mutation. The investigators derived user-friendly mutation-probability tables based upon presenting features of individuals and families, with the highest yield noted among children with choroid plexus tumors. Testing for TP53 mutations in BRCA-negative women diagnosed with breast cancer under 30 years old was cited in the 2009 National Comprehensive Cancer Network (NCCN) guidelines.

Cowden syndrome

This syndrome is inherited as an autosomal-dominant trait and is notable for a distinctive skin lesion (trichilemmoma) and mucocutaneous lesions. Patients with this uncommon syndrome have a high incidence of hyperplastic gastrointestinal polyps, early-onset uterine cancer, and thyroid disorders; lifetime estimates for breast cancer among women with this syndrome range from 25% to 50%. Germline mutations in the PTEN gene, located on chromosome 10q23, are responsible for this syndrome. The key issues for management include screening for breast, thyroid, and uterine cancers.

Family History

The overall relative risk of breast cancer in a woman with a positive family history in a first-degree relative (mother, daughter, or sister) is 1.7. Premenopausal onset of the disease in a first-degree relative is associated with a threefold increase in breast cancer risk, whereas postmenopausal diagnosis increases the relative risk by only 1.5. When the first-degree relative has bilateral disease, there is a fivefold increase in risk. The relative risk for a woman whose first-degree relative developed bilateral breast cancer prior to menopause is nearly 9.

Proliferative Breast Disease

The diagnosis of certain conditions on a breast biopsy is also associated with an increased risk for the subsequent development of invasive breast cancer. They include moderate or florid ductal hyperplasia and sclerosing adenosis, which pose only a slightly increased risk of breast cancer (1.5–2 times); atypical ductal or lobular hyperplasia, which moderately increases risk (4–5 times); and lobular carcinoma in situ (LCIS), which markedly increases risk (8–11 times; see more detailed discussion of LCIS in the "Stages 0 and I Breast Cancer" chapter). Patients who have a family history of breast cancer along with a personal history of atypical epithelial hyperplasia have an 8-fold increase in breast cancer risk when compared with patients with a positive family history alone and an 11-fold increase in breast cancer risk when compared with patients who do not have atypical hyperplasia and have a negative family history.

Disease Site and Personal Cancer History

The left breast is involved slightly more frequently than the right, and the most common locations of the disease are the upper outer quadrant and retroareolar region. The risk of a second primary breast cancer is highest in BRCA1 and BRCA2 mutation carriers and in women whose first breast cancer was diagnosed at age < 50. The risk is approximately 0.5% per year after the first diagnosis in the setting of sporadic disease. The risk of contralateral breast cancer in women with a mutation of a breast cancer gene (BRCA) is approximately 3% to 5% per year or about 40% at 10 years after the initial diagnosis of breast cancer, with a cumulative lifetime risk of up to 64% in high-risk cohorts.

Tamoxifen reduces the risk of breast cancer and is an effective chemopreventive agent. Bilateral salpingo-oophorectomy (BSO) also reduces breast cancer risk, especially when this procedure is performed in women younger than age 50. The protective effect of BSO is pronounced among women who develop breast cancer premenopausally. Exemestane was recently shown to significantly reduce the risk of invasive breast cancer in high-risk postmenopausal women. It is another option for chemoprevention.

A personal history of breast cancer is a significant risk factor for the subsequent development of a second, new primary breast cancer. This risk has been estimated to be as high as 1% per year from the time of diagnosis of an initial sporadic breast cancer. Women with a history of endometrial, ovarian, or colon cancer also have a higher likelihood of developing breast cancer than do those with no history of these malignancies.

Menstrual and Reproductive Factors

Early onset of menarche (< 12 years old) has been associated with a modest increase in breast cancer risk (twofold or less). Women who undergo menopause before age 30 have a twofold reduction in breast cancer risk when compared with women who undergo menopause after age 55. A first full-term pregnancy before age 30 appears to have a protective effect against breast cancer, whereas a late first full-term pregnancy or nulliparity may be associated with a higher risk. There is also a suggestion that lactation protects against breast cancer development.

Radiation Exposure

An increased rate of breast cancer has been observed in survivors of the atomic bomb explosions in Japan, with a peak latency period of 15 to 20 years. It has also been noted that patients with Hodgkin lymphoma who are treated with mantle irradiation, particularly women who are younger than age 20 at the time of radiation therapy, have an increased incidence of breast cancer.

Exogenous Hormone Use

In regard to hormone replacement therapy (HRT) or postmenopausal hormone use, results from the Women's Health Initiative (WHI) showed that the overall risks of estrogen plus progestin outweigh the benefits. This large randomized clinical trial sponsored by the National Institutes of Health (NIH) included more than 16,000 healthy women. Results from the WHI trial were published in 2002, after an average 5.6 years of follow-up, and included a 26% increase in risk of invasive breast cancer among women taking estrogen plus progestin, as compared with women taking placebo. In addition, in women taking these hormones, there were increased risks of heart disease, stroke, and blood clots.

The NIH stopped the estrogen-alone arm of the WHI trial in March 2004. No increase in breast cancer risk was observed in the estrogen-alone arm during the study period (7 years of follow-up). The NIH concluded that estrogen alone does not appear to increase or decrease a woman's risk of heart disease, although it does appear to increase her risk of stroke and decrease her risk of hip fracture.

Following the publication of the WHI trial results, the use of HRT in the United States declined by almost 40% from 2002 to 2003. During approximately the same period, there was a 6.7% decline in the age-adjusted incidence of breast cancer. Furthermore, the decrease was evident only among women 50 years of age and older and primarily among those with estrogen receptor–positive breast cancers.


Moderate alcohol intake (two or more drinks per day) appears to modestly increase breast cancer risk.

High-Fat Diet

Diets that are high in fat have been associated with an increased risk for breast cancer. Women who have diets high in animal fat from high-fat dairy foods have an increased risk of developing breast cancer. Whether the increase in breast cancer risk is associated with the fat content or an unknown carcinogen in these foods is unclear. There is no association between the consumption of red meat and an increased risk of breast cancer.


Alterations in endogenous estrogen levels secondary to obesity may enhance breast cancer risk. Obesity appears to be a factor primarily in postmenopausal women.

In late 2007, the relative risks of cancer incidence and mortality from the Million Women Study were reported. The study analyzed data on 1.2 million women in the UK (age from 1996-2001, 50-64 years) who were followed for an average of 5.4 years for cancer incidence and 7 years for cancer mortality. In all, 45,037 incident cancers and 17,203 deaths from the disease occurred during follow-up. An increased incidence of breast cancer with increasing body mass index (BMI) was noted. For breast cancer, the effect of BMI on risk differed significantly according to menopausal status (relative risk in postmenopausal women = 1.40). Calculations were adjusted for BMI, age, geographic region, socioeconomic status, age at first birth, parity, smoking status, alcohol use, physical activity, years since menopause, and use of HRT.


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