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Case 93-4 (Questions 1–5)

BREAST CANCER

Incidence, Prevalence, and

Epidemiology

Breast cancer is the most common malignancy in American

women and is second to lung cancer in mortality rates. It

arises from the tissues of the breast, usually the ducts (tubes

that carry milk to the nipple) and lobules (glands that make

milk). In 2010, it was estimated that 209,060 women would be

diagnosed with breast cancer and approximately 40,230 were

expected to die from their disease.1 Approximately 1,970 cases

were estimated to be diagnosed in men, indicating it is not a

disease solely of women.1 The incidence rates of breast cancer

have continued to decline from 1999 through 2004 due to the

decreased use of hormone-replacement therapy. This decline

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2198Section 17 Neoplastic Disorders

follows the results of the Women’s Health Initiative study, which

demonstrated increased risk of breast cancer in those receiving hormone-replacement therapy.2 One in eight women are

expected to develop the disease over the course of their lifetime.

However, this frequently quoted statistic may overestimate the

risk of breast cancer because it is derived from women who live

to be 110 years of age.

If breast cancer is diagnosed early, it is curable. The likelihood

of diagnosing breast cancer is increased by the use of standardized screening methods. Currently, many different guidelines are

available for breast cancer screening including recommendations

from the American Cancer Society, National Comprehensive

Cancer Network, and the US Preventative Services Task Force.

All recommend combination modalities of screening because no

one test is considered conclusive.

Breast cancer can be prevented in patients who are considered

at high risk of developing breast cancer. Both surgical and pharmacologic options are available. Prophylactic mastectomies can

be successfully completed; however, they do not provide a 100%

guarantee of the prevention of breast cancer.3 Pharmacologic

therapies have been approved for the prevention of breast cancer

including tamoxifen and raloxifene.4,5 Two large studies in highrisk women demonstrated decreased incidences in breast cancer

in those women who received tamoxifen or raloxifene for 5 years.

Pathophysiology

The breast itself is composed of many different structures including fat, muscle, ducts, and lobules (Figure 93-1). Lobules arise

from glandular tissue that forms into a spoke-like formation

Clavicle

Ribs

Pectoralis major

muscle

Lobules

Duct

Suspensory ligaments

Fat

FIGURE 93-1 Anatomy of the breast. (Asset

provided by Anatomical Chart Co.)

2199Breast Cancer Chapter 93

to constitute a lobule of two layers of epithelial cells. The

ducts connect the milk-secreting lobules to the nipple.6 A breast

cancer is defined by where the tumor cells originate. The two

most common histologic types of breast cancer are ductal and

lobular carcinoma. Ductal tumors may either be classified as

invasive ductal carcinoma if it has invaded through the basement

membrane of the duct, or ductal carcinoma in situ (DCIS), if it

has not. Likewise, lobular tumors may be classified similarly (i.e.,

invasive lobular carcinoma or lobular carcinoma in situ [LCIS]).

Other types of breast cancers include inflammatory (which will

be discussed later in the chapter) and rare histologies such as

tubular or medullary carcinomas or sarcomas.

Overview of Treatment and Diagnosis

The treatment of breast cancer includes multiple modalities.

Surgery, radiation therapy, hormonal therapy, chemotherapy,

and biologic therapy can all be used in many different combinations based on a patient’s specific disease. If therapy is given

before surgery it is called neoadjuvant therapy and if treatment is

administered after surgery it is termed adjuvant therapy. Therapy

is determined based on the stage of disease. Staging is completed

by evaluating the size of the tumor (either on clinical examination or from the surgical specimen), the extent of positive

lymph nodes (evaluated on physical examination and with surgical removal through an axillary lymph node dissection), and

the extent of disease (which is evaluated with radiologic examinations including computed tomography [CT] scan of the chest,

abdomen, and pelvis and a bone scan to identify any metastatic

disease).

Early-stage disease is highly curable whereas metastatic disease is not. The 5-year survival for localized, early-stage disease is

approximately 98%. Most patients will present with early-stage

disease. Many present with a painless lump found upon breast

examination (either by themselves or by a clinician) or with a

lump found on routine mammogram. In patients with stage II or

III disease, the 5-year survival is approximately 83%, and for those

with stage IV disease, the 5-year survival is approximately 26%.

Patients who present with metastatic disease typically present

with symptoms of their disease based on the metastatic site (such

as bone pain with bone metastases or shortness of breath with

lung metastases). In patients with metastatic disease, the goal is

palliation of symptoms and improvement in quality of life.

SCREENING

CASE 93-1

QUESTION 1: M.P. is a 42-year-old woman with no personal

history of breast cancer. She has a cousin who was diagnosed with breast cancer at the age of 65 years. M.P. is in her

doctor’s office today to discuss routine breast cancer screening. Based on M.P.’s personal and family history, would M.P.

be considered an average risk or high-risk patient and what

modalities of screening are recommended for average and

high-risk patients?

For the average-risk patient, screening involves a clinical breast

examination, mammography, and a breast self-examination (if

the woman chooses to do so). Although the risk of breast cancer

is low in one’s 20s, these breast examinations allow a woman to

become more familiar with her body and better able to discern

changes at older ages. In the current American Cancer Society

(ACS) guidelines, it states that women may choose to do breast

self-examinations regularly, occasionally, or not at all.7 Clinical

breast examinations are recommended to begin between the ages

of 20 to 39 years at least every 3 years and then annually starting

at the age of 40 during the woman’s regular health examination.

Screening mammography has been the gold standard for

breast cancer for many decades. Based on the ACS guidelines,

screening should be initiated at the age of 40 years and annually

thereafter. Recently, there has been controversy regarding the

utility of mammography and when screening should begin (40

or 50 years of age). This controversy stemmed from recommendations by the US Preventative Services Task Force (USPSTF).8

Their recommendation was based on a cumulative review of all

mammography trials for breast cancer screening. When evaluating breast cancer mortality, the relative risk reduction increases

in women ages 40 to 49 years who were screened with mammography, but the greatest relative risk reduction was in women

ages 60 to 69 years. Based on these data, the USPSTF concluded

that for women in the younger age group, the benefits did not

outweigh the harms of increased anxiety, radiation exposure, and

inconvenience due to false positives. The task force further recommended that women aged 50 to 74 years only needed biennial

screening rather than annual screenings. Although the relative

risk reduction is lower in younger women, the ACS as well as all

of the other organizations who publish breast cancer screening

guidelines did not change their recommendation of annual mammography starting at the age of 40 years. One positive outcome

from these controversial recommendations was the heightened

awareness to the general public of the breast cancer screening

guidelines.

M.P. has no first-degree relatives with breast cancer, or other

family members affected by early breast cancer. M.P. is an

average-risk patient and she should start standard screening

modalities and intervals of testing with annual mammograms

and clinical breast examinations. She may also decide to do breast

self-examinations.

Individuals considered high risk (a) have a known BRCA gene

mutation, (b) are untested for the BRCA gene mutation but

have a first-degree relative with a BRCA mutation, (c) have a

lifetime risk of experiencing breast cancer of approximately 20%

to 25% or more based on risk estimation models, or (d) have

a strong family history of breast cancer.7 Screening with breast

magnetic resonance imaging (MRI) is recommended in high-risk

individuals. Annual mammography and breast MRIs should be

initiated starting at the age of 30 years. An MRI allows a radiologist to see a contrasted view of the breast and is more sensitive

to detecting breast cancer. In addition, breast tissue in younger

patients can be denser due to higher levels of estrogen, making

mammography less sensitive.9 M.P. does not have an immediate

family history of breast cancer, so no additional screening should

be done in her case.

PREVENTION

CASE 93-1, QUESTION 2: M.P. works at her local hospital as

a nurse and is volunteering this year at their breast cancer

awareness seminar that is offered by her hospital. She was

asked to prepare a talk for the event about breast cancer

awareness. She wants to discuss breast cancer prevention.

What are the common modalities of breast cancer prevention that M.P. should address and what chemopreventative

agents should she include?

Prevention is key with any cancer. Women who are considered

high risk for breast cancer may decide to undergo prophylactic

mastectomy with reconstruction as an alternative to living with

the prospect that they may develop breast cancer in their life. This

modality of prevention is very successful, but does not completely

eliminate the risk for developing breast cancer.3

2200Section 17 Neoplastic Disorders

Chemoprevention is also another option. Two agents

approved for prevention are tamoxifen and raloxifene. The Breast

Cancer Prevention Trial (or P1 trial) was conducted in more than

13,000 high-risk women (women were randomly assigned into

three groups: those older than 60 years, women between 35 and

59 years of age with an increased risk of breast cancer based on

a score of at least 1.66 as determined by the Gail risk model,

or women older than 35 years with a history of LCIS, a risk

factor for developing invasive breast cancer).4 Women received

tamoxifen 20 mg daily or placebo for 5 years of therapy. Tamoxifen significantly decreased the risk of developing breast cancer

(p <0.00001). In addition, this study illustrated toxicities associated with tamoxifen therapy especially in women older than

50 years of age. In those patients, a higher risk of deep vein

thrombosis, stroke, pulmonary embolism, and endometrial cancers were identified.4

Raloxifene, a selective estrogen receptor modulator (SERM),

is approved for chemoprevention in breast cancer. This originated from observations made in osteoporosis studies with raloxifene where patients who had received raloxifene therapy had a

decreased risk of breast cancer. With this information, a large

randomized chemoprevention trial of more than 19,000 postmenopausal women was conducted evaluating the use of raloxifene 60 mg daily compared to tamoxifen 20 mg daily for 5 years.5

There was no difference in the number of invasive breast cancers diagnosed in the two treatment arms (relative risk, 1.02;

95% confidence interval, 0.82–1.28). Interestingly, more noninvasive breast cancers were identified in the raloxifene group (80

cases) compared with tamoxifen (57 cases); however, the clinical

significance of this difference is unknown. The tamoxifen arm

reported more hot flashes and uterine cancer and the raloxifene

arm demonstrated fewer thromboembolic events, cataracts, but

more musculoskeletal problems and weight gain. Raloxifene was

considered as effective as tamoxifen with less toxicity such as

thromboembolic events and uterine cancer. Based on the results

of this trial, raloxifene received an indication for chemoprevention in high-risk women. M.P. should include information on

both tamoxifen and raloxifene in her talk.

RISK FACTORS

CASE 93-2

QUESTION 1: B.W., a 59-year-old woman, is found to have a

2.2-cm mass in the upper, outer quadrant of her left breast

during a routine screening mammogram. The rest of her

physical examination is unremarkable, and she has no complaints. All laboratory values, including the complete blood

count and liver function tests are within normal limits. A

chest x-ray is negative. B.W. reports that she had her first

menstrual cycle at the age of 10 years and has had regular

periods since that time. She is married but has never been

pregnant. What are B.W.’s risk factors for developing breast

cancer?

Many different risk factors have been identified and are associated with the development of breast cancer. However, in greater

than 50% of patients, there are no identifiable risk factors except

increased age and female sex10 (Table 93-1). One’s risk increases

with each decade of life and the median age of diagnosis is

between 60 and 65 years of age. If the patient has had a previous history of breast cancer or atypical hyperplasia from previous

breast biopsies, this increases her risk of developing breast cancer.

Breast cancer is a hormonally mediated disease and many risk

factors are associated with hormonal influences. Early menarche (generally defined as younger than 12 years of age) and late

menopause (generally defined as older than 55 years of age)

TABLE 93-1

Risk Factors for Developing Breast Cancer

Known Risk Factors

Gender: Female > male

Personal history of breast cancer

Family history of breast cancer (first-degree relatives)

Benign breast “cancer” (i.e., atypical hyperplasia)

Early menarche (<12 years of age), late menopause (>55 years of age)

Late first pregnancy (≥ 30 years) or no pregnancy

Advancing age

Long-term use of hormone-replacement therapy (estrogen)

Previous chest wall irradiation

Possible Risk Factors

Alcohol

Obesity

High-fat diet

Source: Carlson RW et al. Invasive breast cancer. J Natl Compr Canc Netw.

2011;9:136; Chlebowski RT et al. Influence of estrogen plus progestin on breast

cancer and mammography in healthy postmenopausal women: the women’s

health initiative randomized trial. JAMA. 2003;289:3243.

exposes a woman to more estrogen throughout her lifetime,

increasing her risk. Based on the results of the Women’s Health

Initiative, the use of hormone-replacement therapy was shown

to increase one’s risk of breast cancer.11 Nulliparity, or having

children after the age of 30 years, has been associated with an

increased risk. Oral contraceptives have long been thought to

increase the risk of breast cancer; however, investigators have

refuted this claim based on more recent data.12 Earlier forms

of oral contraceptives contained much higher doses of estrogen

compared with products today. The dose of estrogens in those

products was thought to increase a woman’s risk of developing breast cancer. However, a meta-analysis demonstrated no

difference in risk no matter the dose of estrogen in the oral

contraceptives.12 Hereditary breast cancers (one or more firstdegree relatives with the disease) only account for approximately

10% of breast cancer cases; however, these individuals have the

highest risk of developing breast cancer.13

B.W. has risk factors that increased her risk of developing

breast cancer. B.W. started menses early at the age of 10 years

and therefore has been exposed longer to estrogen and she does

not have any children. She is also 59 years of age and the risk of

breast cancer increases with each decade of life. Therefore, all of

these are considered risk factors for B.W.

INHERITED BREAST CANCER MUTATIONS

CASE 93-3

QUESTION 1: C.D., a 37-year-old woman, is found to have a

2.2-cm mass in the outer quadrant of her right breast during

a mammogram. All of her laboratory values were normal and

her chest x-ray was negative. Her family history is significant

in that her mother died of breast cancer at the age of 42

years and her 44-year-old sister had a breast tumor removed

5 years ago. With C.D.’s family history, what genetic testing

could be performed for her or for anyone else in her family? If C.D. did not have a family history of breast cancer,

what other tests could be conducted to estimate her risk of

developing breast cancer?

C.D. has two first-degree relatives with early-age breast cancer. This would indicate an inherited genetic mutation. Genetic

testing for the presence of BRCA1 and BRCA2 mutations should

be discussed with C.D. A person with a BRCA1 mutation has a

2201Breast Cancer Chapter 93

40% to 85% lifetime risk of developing breast cancer and a 25%

to 65% risk of ovarian cancer. BRCA2 mutation carriers have the

same risk of breast cancer but lower risk for ovarian cancer (15%–

20%).14 One population with a high incidence of BRCA mutations

are those of Ashkenazi Jewish descent, where 1 in 50 individuals

are BRCA carriers.15 C.D. should meet with a genetic counselor

to discuss risks and benefits of genetic testing for her and her

family members.

An average risk patient (high-risk patients were previously

described in the Screening section) can assess their risk of developing breast cancer by using validated risk tools. One such instrument is the Gail model, which takes into account numerous factors such as age at menarche, age of first live birth, presence

of atypical hyperplasia, and number or previous breast biopsies.

This model is available on-line (www.cancer.gov/bcrisktool/).

Other models that have been validated include BRCAPRO and

the Breast Cancer Risk Assessment Tool.16,17 BRCAPRO is a statistical program that uses information from both affected and

unaffected relatives to predict the likelihood if a person would

have an inherited mutation in BRCA1 or BRCA2.14 This tool would

be used in an individual with a high risk of developing breast

cancer. There are numerous resources for patients and family

members to help understand their risk of developing breast cancer. Concerned individuals should have a conversation with their

physician regarding their risk of breast cancer and the utility of

these risk assessment tools based on their personal and family

history.

Clinical Presentation

CASE 93-3, QUESTION 2: What are the typical signs and

symptoms of breast cancer and does C.D. have any?

Typical presentation involves the identification of a painless

lump on clinical examination by a health care professional, by

the patient, or visualization of a painless lump on mammography. Other symptoms are nipple discharge or retraction, or

skin changes of the breast.18 Less than 10% of patients will

present with metastatic disease. Symptoms on presentation can

reflect their metastatic disease (i.e., back pain: bone metastases; headaches/nausea/vomiting: brain metastases; dyspnea:

lung metastases; or abdominal pain: liver metastases).18 C.D. had

a painless lump identified on mammogram as her presenting sign.

Diagnosis

CASE 93-3, QUESTION 3: After the identification of C.D.’s

breast mass on mammogram, what diagnostic procedures

should be done to determine C.D.’s type and stage of breast

cancer?

Workup for breast cancer includes radiographic examinations, patient history, and a physical examination. If a mass is

palpated, a mammogram is completed to identify the abnormality. A breast ultrasound can also be added after the mammogram

to differentiate fluid-filled cysts (which are usually benign) versus discreet masses. Once identified, a biopsy would then be

performed to diagnose the disease. This is achieved with a core

biopsy—the standard method used to obtain a tissue sample.

This procedure uses a large bore needle for tissue collection and

can distinguish invasive versus noninvasive disease. Other methods are available for tissue diagnosis such as fine-needle aspiration and excisional biopsy, but the core biopsy is considered the

standard approach.18

For a short video on the differences in biopsy

methods, courtesy of CancerQuest (http://

www.cancerquest.org), go to http://thepoint.

lww.com/AT10e.

Full radiologic testing should also be completed including

a CT scan of the chest, abdomen, and pelvis, and bone scan

to assess for metastatic disease. The most common places for

breast cancer to metastasize are the bone, lung, liver, lymph

nodes, and brain.19 Evaluation for brain metastases will usually

be performed if the patient is experiencing signs and symptoms

such as blurry or double vision, uncontrolled nausea/vomiting,

headaches, and unsteady gait. These tests are used to determine

the extent and stage of the disease and ultimately help determine

the prognosis and treatment of the patient. C.D. will need to

undergo a biopsy and full staging with a CT scan of the chest,

abdomen, and pelvis and a bone scan.

Types of Breast Cancer and Staging

CASE 93-3, QUESTION 4: C.D. had a core biopsy performed

which revealed invasive ductal carcinoma. Other staging

tests included a CT scan of the chest, abdomen, and pelvis

and a bone scan. All tests were negative. Physical examination revealed ipsilateral lymph node involvement. Mammogram revealed a 2.2-cm mass in the left breast. What are

the common types of breast cancer and what stage is C.D.’s

breast cancer?

The histology of breast cancer is typically divided into two

categories: invasive and noninvasive (in situ) disease. Invasive

ductal carcinoma is the most common type found (∼75% of

cases) and invasive lobular carcinoma is second (∼5%–10%). The

noninvasive tumors are less common (DCIS and LCIS).18 Other

less common histologies include medullary, mucinous, tubular,

and papillary. One of the most aggressive forms of breast cancer

is inflammatory breast cancer, which is distinctly different from

the other types of breast cancer mentioned. Breast cancer can

take years to develop into a mass that is identifiable on physical

examination or mammogram. In contrast, the onset of inflammatory breast cancer is sudden and can develop in weeks. Presentation includes a breast that looks “inflamed,” red, and has

the look of an orange peel (peau d’orange). The diagnosis may be

delayed because the skin has the appearance of cellulitis. Antibiotics are typically prescribed first; however, the symptoms do not

improve with treatment.20

Staging is conducted to evaluate the extent of disease. This

is completed to understand a patient’s prognosis and to help to

determine the best treatment course. Staging of breast cancer

is determined using the TNM (T, tumor size; N, nodal status;

M, any site of metastatic disease) classification. This information

is determined by both clinical and pathologic examination. In

2002, the breast cancer staging system was updated by the American Joint Commission on Cancer.21 Stage I disease involves small

tumors (<2 cm) with no lymph node involvement and is highly

curable (∼98% 5-year survival). Stage II includes small tumors

with lymph node involvement or larger tumors (>2 cm and ≤5

cm) with no lymph node involvement. Stage III tumors are larger

(>5 cm) with lymph node involvement with a 5-year survival of

approximately 80%. Stage IV disease has metastasized to other

distant organs and has the poorest prognosis with a 5-year survival of approximately 26% (Table 93-2).18,21 Most patients will

present with stage I or II disease due to routine screening. Based

on C.D.’s clinical staging, she is considered to have stage II disease

2202Section 17 Neoplastic Disorders

TABLE 93-2

American Joint Committee on Cancer Staging for

Breast Cancer

Stage T N M

0 Tis N0 M0

I T1 N0 M0

II T0–T3 N0–N1 M0

IIIA T0–T3 N1–N2 M0

IIIB T4 N0–N2 M0

IIIC Any T N3 M0

IV Any T Any N M1

M, metastatic disease; N, presence of lymph nodes; N0, no lymph node

involvement; N1, movable ipsilateral lymph nodes; N2, ipsilateral axillary lymph

nodes (fixed or matted); or clinical ipsilateral internal mammary nodes with no

axillary lymph node involvement; N3, ipsilateral infraclavicular lymph nodes,

clinical ipsilateral internal mammary lymph nodes, clinical axillary lymph nodes,

or ipsilateral supraclavicular lymph nodes with or without axillary or internal

mammary lymph node involvement; T, tumor size; Tis, carcinoma in situ; T1,

≤2 cm; T2, >2 to 5 cm; T3, >5 cm; T4, any size with skin invasion or direct

invasion to the chest wall.

Source: Singletary SE et al. Revision of the American Joint Committee on

Cancer Staging System for Breast Cancer. J Clin Oncol. 2002;20:3628.

based on the size of her disease and the involvement of ipsilateral

lymph nodes.

Prognostic Factors

CASE 93-3, QUESTION 5: Further pathologic analysis of

C.D.’s breast tumor reveals estrogen receptor (ER)-positive