2014, the Canadian National Breast Screening Study concluded a 25-year follow-up analysis. The

cumulative mortality from breast cancer was similar between women randomized to the mammography

arm or to the control arm. For women aged 40 to 49 years, they were randomly assigned to

mammography or usual care, and for women aged 50 to 59 years, they were randomly assigned to

mammography plus CBE or to CBE alone. As such, the study concluded that annual mammography in

women aged 40 to 59 years does not reduce mortality from breast cancer beyond that of physical

examination or usual care in the era of modern adjuvant therapy. In addition, they reported that 22%

(106/484) of screen-detected invasive breast cancers were overdiagnosed.125 The primary risk of

screening mammography is false-positive test results, which can result in patient anxiety, overdiagnosis,

increased medical costs, and unnecessary biopsies.

Algorithm 74-4. Management of the patient with an abnormal screening mammogram. When pathology is benign, concordance or

discordance with imaging findings dictates whether surgical excisional biopsy is indicated.

4 All expert groups in North America agree that screening mammography should be performed in

women 50 years of age and older. However, differences exist about whether screening should be

performed between 40 and 49 years of age. The American Cancer Society, the American College of

Radiology, the American Medical Association, the National Cancer Institute, the American College of

Obstetricians and Gynecologists, and the NCCN all support starting routine screening mammography at

the age of 40 years. Other groups including the USPSTF, the American College of Physicians, and the

CTFPHC recommend initiating screening at the age of 50 years. Although most groups agree with

continuing screening until the age of 74 years, some recommend stopping screening after the age of 74

years (USPSTF and the CTFPHC). Others feel that this decision should be individualized (the American

College of Obstetricians and Gynecologists and the American College of Radiology). The frequency of

mammography (annually or biennially) has also been debated among the various expert groups;

however, most groups in North America advocate for annual screening. Until further studies are

performed, we continue to recommend annual screening mammography starting at the age of 40 years.

Routine mammography consists of two views (craniocaudal (CC) and mediolateral oblique (MLO)) of

each breast. Breast positioning is instrumental to mammography, with the CC view obtained by lifting

the breast and positioning it on the plate with compression applied from above, whereas the MLO view

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is obtained with the breast being compressed from the side. These images are then evaluated and

classified according to the American College of Radiology breast imaging reporting and data system (BIRADS)126 (Algorithm 74-4) (Table 74-6). Screening mammography with a completely negative

examination is classified as BI-RADS 1. Screening mammography with benign findings such as a cyst or

a fibroadenoma is classified as BI-RADS 2. If any indeterminate or concerning findings exist on

screening mammography requiring additional diagnostic imaging, then a BI-RADS 0 is assigned.

Probable benign findings are classified as BI-RADS 3 with a typical recommendation of repeat imaging

in 6 months. Suspicious abnormalities are classified as BI-RADS 4 or 5 with recommendation for biopsy.

Screening mammography is a relatively sensitive but nonspecific test, and only 20% to 30% of

abnormalities found ultimately prove to be malignant (Fig. 74-15). Methods to increase the specificity

of mammography include computer- aided detection (CAD) and more recently breast tomosynthesis.

CAD is a computer-based technology that recognizes mammographic patterns and assists breast imaging

specialists in identifying areas of concern. Its use has been approved by the FDA since 1998.127 More

recently, the FDA approved breast tomosynthesis, also known as 3-D mammography, for routine clinical

use as an adjunct to digital mammography with early findings suggesting a decrease in recall rate and

an increase in cancer detection rate.128

CLASSIFICATION

Table 74-6 BI-RADS Classification of Mammographic Abnormalities

Screening MRI

Screening MRI is more sensitive but less specific than mammography. It is commonly used by providers

as an adjunct to mammography to screen women at high risk for breast cancer; however, the effect of

MRI screening on survival in high-risk groups has not been supported by any prospective randomized

trial. The American Cancer Society does recommend offering annual MRI in addition to mammography

to women within certain high-risk groups, such as those with BRCA mutations, first degree relatives of

known BRCA mutation carriers, and those with a lifetime risk of breast cancer that is estimated to be 20

percent or higher based on risk prediction models (see the section on Management of Patients at High

Risk for Breast Cancer). The NCCN has similar recommendations and also includes patients who

received radiation treatment to the chest between ages 10 and 30 and those who have TP53 (Li–

Fraumeni syndrome) or PTEN genetic (Cowden syndrome) mutations. The National Institute of Health

and Care Excellence (UK) has similar recommendations, advocating for MRI in high-risk patients.

Providers who choose to screen with MRI and mammography often do so in a staggered fashion such

that the patient is undergoing imaging every 6 months.

MANAGEMENT OF PATIENTS AT HIGH RISK FOR BREAST CANCER

Risk Factors

Breast cancer is the most common cancer in women in the United States. Approximately 200,000

women and 2,000 men are diagnosed with invasive breast cancer each year.129 Breast cancer is the most

common cancer in women of every major ethnic group, and the highest rate is among Caucasian

women, with 122 newly diagnosed breast cancer cases per 100,000 women each year.130 Understanding

the risk factors for breast cancer is important, as some of these risks can be modified to decrease a

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patient’s risk through lifestyle/behavioral changes and/or the use of chemoprevention.

Figure 74-15. Workup of abnormal screening mammogram. A: Craniocaudal view showing an increased density with a slightly

spiculated appearance (arrow). B: Spot magnification view of the density demonstrating normal breast tissue.

Increasing Age

As a woman ages, her risk for breast cancer increases: birth to age 49 years, 1.9% probability of

developing invasive breast cancer (1 in 53); age 50 to 59 years, 2.3% (1 in 43); age 60 to 69 years,

3.5% (1 in 29); and age 70 years and older, 6.7% (1 in 15). From birth to death, the probability of

developing invasive breast cancer is 12.3% or 1 in 8.129

Estrogen Exposure

A woman’s lifetime exposure to estrogens appears to correlate with her risk for breast cancer.131

Exposure to estrogens can be approximated by age of first menarche, age of menopause, and age of first

live birth, with nulliparous women who have an early menarche and a late menopause having the

highest risk. Premenopausal women who undergo bilateral oophorectomy are at decreased risk. Given

that high endogenous levels of estrogen is known to increase the risk of breast cancer in both

premenopausal and postmenopausal women, the use of exogenous hormones and their associated risk

for breast cancer has been studied and debated. The use of hormonal contraceptives does not appear to

significantly increase the risk of breast cancer.132 However, the use of hormone replacement therapy in

postmenopausal women has been associated with an increased risk of breast cancer as reported in the

Women’s Health Initiative Estrogen Alone and Estrogen-Plus-Progestin Studies, which were stopped

early secondary to this and other concerns.133 In the Estrogen-Plus-Progestin study, the HRT used was a

combined estrogen–progestin therapy (EPT) that was given to postmenopausal women with an intact

uterus. The risk of breast cancer is relatively low, as EPT would result in an additional eight cases of

breast cancer if 10,000 women took EPT for a year. More recently, it was determined that the rate of

death from breast cancer among those taking EPT was 2.6 per 10,000 women per year, compared with

1.3 per 10,000 women per year among those taking placebo.134 Short-term use for less than 3 years

does not appear to significantly increase the risk of breast cancer and after the cessation of EPT use for

3 years, a woman’s risk returns to baseline.

Given that lactation interrupts ovulation and modifies pituitary and ovarian hormone secretion, it has

been postulated that breast-feeding can reduce breast cancer risk. This finding remains inconclusive.

Limited data suggest that longer duration of lactation in premenopausal women may reduce risk.135 A

pooled analysis consisting of more than 50,000 women with breast cancer and 96,000 controls

concluded that for every 12 months of breast-feeding, there was an associated 4.3% reduction in the RR

of breast cancer.136

Environmental and Lifestyle Factors

Women who were subjected to ionizing radiation of the chest, such as for treatment of Hodgkin

lymphoma or through exposure from nuclear plant accidents or the atomic bomb, have an increased risk

of breast cancer. The prepuberty stage (age 10 to 14 years) appears to be the most vulnerable time for

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exposure, with little associated risk when exposure occurs after age of 45 years.137–139 Alcohol use is

associated with an increased risk of breast cancer and correlates with the amount of consumption, with

differences noted with alcohol intake as low as three drinks per week versus those who abstain from

alcohol. A meta-analysis of 110 studies shows a small but significant association (RR, 1.05; 95% CI, 1.02

to 1.08).140,141 The relationship between cigarette use and breast cancer risk remains controversial

because of unresolved issues of confounding and dose response; however, a recent meta-analysis found

that smoking before menarche and before the first birth was associated with an increased risk for breast

cancer.142 Furthermore, in women diagnosed with breast cancer, lifetime cigarette smoking (≥20 packyears) was associated with an increased risk of recurrence and all-cause mortality.143 The role of dietary

factors such as fat intake, red meat and processed meat, phytoestrogens, calcium/vitamin D, and

antioxidants in modifying breast cancer risk remains inconclusive. Regular physical exercise and a diet

composed mainly of fruits and vegetables likely provide protection against breast cancer.

Family History

The number of first-degree relatives with breast cancer is strongly associated with a woman’s risk for

the future development of breast cancer. If one first-degree relative is affected, the risk of breast cancer

increases by approximately twofold, and if two first-degree relatives are affected, the risk of breast

cancer is increased by approximately threefold. The age at diagnosis of the first-degree relative is also

important, as a women’s risk is approximately threefold higher when the diagnosis occurs before age 30

but only 1.5-fold higher if the diagnosis is after age 60.144

When evaluating family history, it is important to note that the majority of breast cancers are caused

by sporadic mutations (mutations that occur in somatic cells that cannot be inherited). When studying

the family tree of women with sporadic breast cancer, these women typically have no family history of

breast cancer through two generations, including siblings, offspring, parents, and both maternal and

paternal aunts, uncles, and grandparents. Less than 10% of breast cancers are hereditary. In families

with hereditary breast cancer, the family tree is characterized by earlier onset of breast cancer, bilateral

breast cancer, a greater frequency of primary cancers such as breast and ovary, and an autosomal

dominant inheritance pattern (Fig. 74-16).145 For women who have first- or second-degree relatives

with breast cancer but do not meet the hereditary breast cancer definition noted above, these women

have familial breast cancer where it is likely that both genetic and environmental factors play a role in

their susceptibility.137

Most patients with hereditary breast cancer have mutations in the BRCA1 or BRCA2 genes, which are

localized to chromosome 17q21 and chromosome 13q12.3, respectively. Both serve as tumor suppressor

genes and function as gatekeepers in controlling gene transcription, regulating repair of DNA damage

(especially double strand breaks during cell replication), and may play a role in the maintenance of

genomic stability.146–148 Founder mutations exist in the Ashkenazi Jewish population with specific

mutations in BRCA1 (185delAG, 5382insC) and BRCA2 (617delT).149 Other BRCA-specific mutations

have been identified in Dutch, Scandinavian, French-Canadian, and Belgian populations.150,151

The lifetime risk of breast cancer in BRCA1 and BRCA2 mutation carriers is estimated to be as high as

85%, which is markedly elevated from a baseline risk of 12% in the general population (Table 74-7).

Ovarian cancer risk is higher in BRCA1 carriers with an estimated risk of 40% to 60% whereas BRCA2

carriers have a risk of 15%. Among male patients with breast cancer who have a BRCA mutation, onethird of mutations involve BRCA1 and two-thirds involve BRCA2. The risk of breast cancer in males is

1% to 5% with a BRCA1 mutation, and 5% to 10% with a BRCA2 mutation, versus a risk of 0.1% in the

general population.152–154 In addition, prostate and pancreatic cancer is more common in patients with

BRCA2 mutations.155,156

Several commercial tests exist for BRCA1 and BRCA2 testing. Prior to genetic testing, patients should

undergo genetic counseling where the complexities of testing are discussed along with potential

emotional and financial ramifications that can result from positive test results. Ideally, genetic testing

should start with a family member affected with breast or ovarian cancer or both. If that individual tests

negative, further testing on an unaffected relative is unlikely to be informative. Candidates for gene

testing include those with a known BRCA1 or BRCA2 gene mutation in the family, a personal history of

breast cancer at age 45 or younger, a personal history of breast cancer at age 50 or younger and a

family member (parent, sibling, child, grandparent, grandchild, uncle, aunt, nephew, niece or first

cousin) diagnosed with breast cancer at any age, a personal history of triple negative breast cancer

(TNBC) diagnosed at age 60 or younger, a personal history of ovarian cancer, a personal or family

history of male breast cancer, and Ashkenazi Jewish heritage and a personal or family history of breast

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