Multifactorial Disease

It is a multifactorial disease that involves both environmental and genetic factors.

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BREAST CANCER
Breast cancer is perhaps the single most important medical concern women face
today. Although there has been an overall decrease in breast caner rates in the
United States in recent decades, in 2007 there were greater than 180,000 new cases
of invasive breast cancer and 40,910 breast cancer-related deaths. This is equivalent
to a breast cancer diagnosis every 2 minutes.2 Breast cancer is the leading cause of
cancer in women, accounting for one-third of all cancer cases.3 All women are
affected by breast cancer—whether by literal diagnosis or a lifetime of worry about
whether they will experience this disease.2 It has been estimated that 50% of all
women in the United States at some point in their lives will ask their physicians
about a concerning lump or other worrisome breast finding with the anxiety that they
have breast cancer. Many have known a friend, relative, or colleague who has gone
through a possible or actual breast cancer diagnosis.
Breast cancer, from etiology to treatment, is a vast and complex topic with an
enormous literature. There is controversy over screening methods, treatments, and
the role of complementary and alternative therapies in the care of women with breast
cancer. There are still many unknowns in cancer diagnosis, prevention, and
treatment. It would be impossible to elucidate the entire topic of breast cancer, or
even that of breast cancer and CAM, within the confines of a single chapter. It is
hoped that this chapter will help the reader begin to understand the magnitude of
breast cancer as a disease that effects all women, whether as a direct clinical reality
or a lifelong concern, to understand nonmodifiable and modifiable breast cancer risk
factors, to gain perspective on the complexity of issues women must sort through
regarding screening and, if diagnosed, choices regarding their treatment, including
whether and how to use CAM therapies. This chapter does not provide guidelines for
the botanical treatment of breast cancer, although does direct readers to additional
resources on evidence for botanicals commonly used in cancer treatment protocol.

Abstract
Breast cancer is the most common type of invasive cancer and the second cause of
cancer-related death in women. In addition to clinical information, benign findings
and pitfalls in fludeoxyglucose (FDG) PET/CT reading, and teaching cases, this
chapter reviews evidence-based recommendations regarding PET/CT examination in
breast cancer and compares them with statements in major clinical guidelines.
According to evidence-based data, FDG PET/CT can potentially replace conventional
imaging modalities in staging of locally advanced breast cancer and is recommended
for the evaluation of response to chemotherapy or radiation therapy. Interestingly,
FDG uptake is higher in patients with triple-negative or HER2-positive malignant
lesions and inversely correlates with prognosis.
Definition
Breast cancer is an uncontrolled growth of epithelial cells originating in the ducts or
breast lobules Carbone et al (1993). The disorder includes early, noninvasive breast
cancer, such as ductal carcinoma in situ (DCIS) or lobular carcinoma in situ (LCIS),
breast cancer that has invaded the surrounding breast stroma (primary invasive
breast cancer); and breast cancer that has spread to the draining lymph nodes or to
distant organs (advanced or metastatic breast cancer). The disease is differentiated
from benign breast pathologies, such as fibroadenoma, fibrocystic disease, or
benign hyperplasia.

Breast cancer is a multifactorial disease. Its etiology is poorly

understood, although genes and hormones appear to be key
players. Breast cancer develops initially as a genetic
transformation that leads to a series of molecular changes in
the epithelial cells lining the ducts or lobules of the breast.
Etiology
Identifying factors associated with an increased incidence of breast cancer development is
important in general health screening for women.[4][5] Risk factors for breast cancer can be
divided into 7 broad categories:
1. Age: The age-adjusted incidence of breast cancer continues to increase with the
advancing age of the female population.
2. Gender: Most breast cancers occur in women.
3. Personal history of breast cancer: A history of cancer in one breast increases the
likelihood of a second primary cancer in the contralateral breast.
4. Histologic risk factors: Histologic abnormalities diagnosed by breast biopsy constitute
an important category of breast cancer risk factors. These abnormalities include
lobular carcinoma in situ (LCIS) and proliferative changes with atypia.
5. The family history of breast cancer and genetic risk factors: First-degree relatives of
patients with breast cancer have a 2-fold to 3-fold excess risk for developing the
disease. Five percent to 10% of all breast cancer cases are due to genetic factors, but
they may account for 25% of cases in women younger than 30
years. BRCA1 and BRCA2 are the 2 most important genes responsible for increased
breast cancer susceptibility.
6. Reproductive risk factors: Reproductive milestones that increase a woman’s lifetime
estrogen exposure are thought to increase her breast cancer risk. These include the
onset of menarche before 12 years of age, first live childbirth after age 30 years,
nulliparity, and menopause after age 55 years.
7. Exogenous hormone use: Therapeutic or supplemental estrogen and progesterone are
taken for various conditions, with the two most common scenarios being
contraception in premenopausal women and hormone replacement therapy in
postmenopausal women.

Epidemiology
Invasive breast cancer affects 1 in 8 women in the United States (12.4%) during their
lifetime.[6][7][8] In the United States, about 266,120 women will have invasive breast
carcinoma in 2018, and 63,960 will have in situ breast cancer. In 2018, approximately 2550
men will have invasive breast cancer. Approximately 1 in 1000 men will have breast cancer
during their lifetime. In the year 2000, the incidence of breast cancer in the United
States began decreasing. This decrease may be due to the reduced use of hormone
replacement therapy (HRT) by women. A connection was suggested between HRT and
increased breast cancer risk. About 40,920 US women may die in 2018 from breast cancer.
Larger decreases occur in women younger than 50 years old. In 2008, there were an
estimated 1.38 million new cases of invasive breast cancer worldwide. The 2008 incidence of
female breast cancer ranged from 19.3 cases per 100,000 in Eastern Africa to 89.9 cases per
100,000 in Western Europe. With early detection and significant advances in treatment, death
rates from breast cancer have been decreasing over the past 25 years in North America and
parts of Europe. In many African and Asian countries (e.g., Uganda, South Korea, and India),
however, breast cancer death rates are rising. The incidence rate of breast cancer increases
with age, from 1.5 cases per 100,000 in women 20 to 24 years of age to a peak of 421.3 cases
per 100,000 in women 75 to 79 years of age; 95% of new cases occur in women aged 40
years or older. The median age of women at the time of breast cancer diagnosis is 61
years. According to the American Cancer Society (ACS), breast cancer rates among women
from various racial and ethnic groups are as follows:
 Non-Hispanic white: 128.1 in 100,000
 African American: 124.3 in 100,000
 Hispanic/Latina: 91.0 in 100,000
 American Indian/Alaska Native: 91.9 in 100,000
 Asian American/Pacific Islander: 88.3 in 100,000
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Pathophysiology
Breast cancer develops due to DNA damage and genetic mutations that can be influenced by
exposure to estrogen. Sometimes there will be an inheritance of DNA defects or pro-
cancerous genes like BRCA1 and BRCA2. Thus the family history of ovarian or breast cancer
increases the risk for breast cancer development. In a normal individual, the immune system
attacks cells with abnormal DNA or abnormal growth. This fails in those with breast cancer
disease leading to tumor growth and spread.
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Histopathology
Breast cancer can be invasive or non-invasive according to its relation to the basement
membrane. Noninvasive neoplasms of the breast are broadly divided into two major types,
lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS).
LCIS is regarded as a risk factor for the development of breast cancer. LCIS is recognized by
its conformity to the outline of the normal lobule, with expanded and filled acini. DCIS is
more morphologically heterogeneous than LCIS, and pathologists recognize four broad types
of DCIS: papillary, cribriform, solid, and comedo.
DCIS is recognized as discrete spaces filled with malignant cells, usually with a recognizable
basal cell layer composed of presumably normal myoepithelial cells. The papillary and
cribriform types of DCIS are generally lower grade lesions and may take longer to transform
into invasive cancer.
The solid and comedo types of DCIS are generally higher-grade lesions. DCIS, if not treated,
usually transforms into invasive cancer. Invasive breast cancers are recognized by their lack
of overall architecture, infiltration of cells haphazardly into a variable amount of stroma, or
formation of sheets of continuous and monotonous cells without respect for the form and
function of a glandular organ. Pathologists broadly divide invasive breast cancer into ductal
and lobular histologic types.
Invasive ductal cancer tends to grow as a cohesive mass; it appears as discrete abnormalities
on mammograms and is often palpable as a discrete lump in the breast smaller than lobular
cancers. Invasive lobular cancer tends to permeate the breast in a single-file nature, which
explains why it remains clinically occult and often escapes detection on mammography or
physical examination until the disease is extensive. Invasive ductal cancer, also known as
infiltrating ductal carcinoma, is the most common form of breast cancer; it accounts for 50%
to 70% of invasive breast cancers.
Invasive lobular carcinoma accounts for 10% of breast cancers, and mixed ductal and lobular
cancers have been increasingly recognized and described in pathology reports. When invasive
ductal carcinomas take on differentiated features, they are named according to the features
that they display. If the infiltrating cells form small glands lined by a single row of the bland
epithelium, they are called infiltrating tubular carcinoma. The infiltrating cells may secrete
copious amounts of mucin and appear to float in this material. These lesions are called
mucinous or colloid tumors.
Tubular and mucinous tumors are usually low-grade (grade I) lesions; these tumors account
for approximately 2% to 3% of invasive breast carcinomas. Medullary cancer is characterized
by bizarre invasive cells with high-grade nuclear features, many mitoses, and lack of an in
situ component. The malignancy forms sheets of cells in an almost syncytial fashion,
surrounded by an infiltrate of small mononuclear lymphocytes. The borders of the tumor push
into the surrounding breast rather than infiltrate or permeate the stroma. In its pure form,
medullary cancer accounts for only approximately 5% of breast cancers.
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Histopathology
Breast cancer can be invasive or non-invasive according to its relation to the basement
membrane. Noninvasive neoplasms of the breast are broadly divided into two major types,
lobular carcinoma in situ (LCIS) and ductal carcinoma in situ (DCIS).
LCIS is regarded as a risk factor for the development of breast cancer. LCIS is recognized by
its conformity to the outline of the normal lobule, with expanded and filled acini. DCIS is
more morphologically heterogeneous than LCIS, and pathologists recognize four broad types
of DCIS: papillary, cribriform, solid, and comedo.
DCIS is recognized as discrete spaces filled with malignant cells, usually with a recognizable
basal cell layer composed of presumably normal myoepithelial cells. The papillary and
cribriform types of DCIS are generally lower grade lesions and may take longer to transform
into invasive cancer.
The solid and comedo types of DCIS are generally higher-grade lesions. DCIS, if not treated,
usually transforms into invasive cancer. Invasive breast cancers are recognized by their lack
of overall architecture, infiltration of cells haphazardly into a variable amount of stroma, or
formation of sheets of continuous and monotonous cells without respect for the form and
function of a glandular organ. Pathologists broadly divide invasive breast cancer into ductal
and lobular histologic types.
Invasive ductal cancer tends to grow as a cohesive mass; it appears as discrete abnormalities
on mammograms and is often palpable as a discrete lump in the breast smaller than lobular
cancers. Invasive lobular cancer tends to permeate the breast in a single-file nature, which
explains why it remains clinically occult and often escapes detection on mammography or
physical examination until the disease is extensive. Invasive ductal cancer, also known as
infiltrating ductal carcinoma, is the most common form of breast cancer; it accounts for 50%
to 70% of invasive breast cancers.
Invasive lobular carcinoma accounts for 10% of breast cancers, and mixed ductal and lobular
cancers have been increasingly recognized and described in pathology reports. When invasive
ductal carcinomas take on differentiated features, they are named according to the features
that they display. If the infiltrating cells form small glands lined by a single row of the bland
epithelium, they are called infiltrating tubular carcinoma. The infiltrating cells may secrete
copious amounts of mucin and appear to float in this material. These lesions are called
mucinous or colloid tumors.
Tubular and mucinous tumors are usually low-grade (grade I) lesions; these tumors account
for approximately 2% to 3% of invasive breast carcinomas. Medullary cancer is characterized
by bizarre invasive cells with high-grade nuclear features, many mitoses, and lack of an in
situ component. The malignancy forms sheets of cells in an almost syncytial fashion,
surrounded by an infiltrate of small mononuclear lymphocytes. The borders of the tumor push
into the surrounding breast rather than infiltrate or permeate the stroma. In its pure form,
medullary cancer accounts for only approximately 5% of breast cancers.[9][10][11]

History and Physical

Most early breast cancer patients are asymptomatic and discovered during screening
mammography. With increasing size, the patient may discover cancer as a lump that is felt
accidentally, mostly during combing or showering. Breast pain is an unusual symptom that
happens 5% of the time. The locally advanced disease may be presented with peau d'orange,
frank ulceration, or fixation to the chest wall. Inflammatory breast cancer, an advanced form
of breast cancer, frequently resembles breast abscess and presents with swelling, redness, and
other local signs of inflammation. Paget disease of the nipple usually presents with nipple
changes that must be differentiated from nipple eczema.
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Evaluation
Evaluation of Patients with breast cancer needs a triple assessment using clinical evaluation,
imaging, and tissue biopsy. Mammography is the most commonly used modality for the
diagnosis of breast cancer. Most of the asymptomatic cases are diagnosed during screening
mammography. Breast cancer always presents as calcifications, dense lump, with or without
architecture distortion. However, mammography is not sensitive in young women for whom
breast ultrasonography can be used. Ultrasonography is useful in assessing the consistency
and size of breast lumps. It has a great role in guided needle biopsy. Magnetic resonance
imaging has good sensitivity for describing abnormalities in soft tissues, including the breast.
It is indicated if there are occult lesions, or suspicion of multifocal or bilateral malignancy,
especially ILC, and in the assessment of response to neoadjuvant chemotherapy, or when
planning for breast conservation surgery and screening in the high-risk patient. Tissue biopsy
is an important step in the evaluation of a breast cancer patient. There are different ways
to take a tissue specimen, and these include fine-needle aspiration cytology, core biopsy
(Trucut), and incisional or excisional biopsy.[12][13][14]
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Treatment / Management
The 2 basic principles of treatment are to reduce the chance of local recurrence and the risk of
metastatic spread. Surgery with or without radiotherapy achieves local control of cancer.
When there is a risk for metastatic relapse, systemic therapy is indicated in the form of
hormonal therapy, chemotherapy, targeted therapy, or any combination of these. In locally
advanced disease, systemic therapy is used as a palliative therapy with a small or no role for
surgery.[15][16][17]
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Differential Diagnosis
 Breast abscess
 Fat necrosis
 Fibroadenoma
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Surgical Oncology
Surgery has a major role in the treatment of breast cancer. It is the basic way to use for local
control of the disease. Radical mastectomy of Halsted, which removed the breast with
axillary lymph node dissection and excision of both pectoralis muscles, is no longer
recommended due to the high rate of morbidity without a survival benefit. Now, the modified
radical mastectomy of Patey is more famous. It entails removing the whole breast tissue with
a large part of the skin and the axillary lymph nodes. The pectoralis major and minor muscles
are preserved. Breast-only removal without axillary dissection is referred to as simple
mastectomy. This procedure can be performed in small tumors with negative sentinel lymph
nodes. Breast-conserving surgery (BCS) is aimed at removing the tumor plus a rim of at least
1 cm of normal breast tissue (wide local excision). A quadrantectomy involves removing the
entire segment of the breast that contains the tumor. The last 2 procedures are usually
combined with axillary clearance through a separate incision. Axillary procedures may
include sentinel lymph node biopsy, sampling, partial (II), or complete (III) axillary lymph
node dissection. Lumpectomy is the removal of a benign mass without excision of the normal
breast tissue.
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Radiation Oncology
Radiation therapy has a significant role in local disease control. The risk of cancer recurrence
decreases by about 50% at 10 years, and the risk of breast cancer death reduces by almost
20% at 15 years when radiation therapy follows BCS. However, radiation is not necessary for
women 70 years of age and older with small, lymph node-negative, hormone receptor-
positive (HR+) cancers because it has not been shown to improve survival in patients who
take hormonal therapy for at least 5 years. Radiation therapy is beneficial in large tumors
(greater to 5 cm) or if the tumor invades skin or chest wall and if there are positive lymph
nodes. It can also be used as palliative therapy in advanced cases, such as a central nervous
system (CNS) or bone metastasis. It can be delivered as external beam radiation,
brachytherapy, or a combination of both.[18][19]
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Medical Oncology
Chemotherapy, hormone therapy, and targeted therapy are the systemic therapies used in
breast cancer management. A 25 percent reduction in the risk of relapse over a 10 to 15-year
period using a first-generation chemotherapy regimen such as cyclophosphamide,
methotrexate, and 5-fluorouracil (CMF) in a 6-month cycle. Anthracyclines (doxorubicin or
epirubicin) and the newer agents such as the taxanes are modern regimens used for breast
cancer. Three to 6-month period is used for adjuvant and neoadjuvant chemotherapy.
Adjuvant treatment of early-stage HR+ breast cancer with tamoxifen for at least 5 years has
been shown to reduce the recurrence rate by about half throughout the first 10 years and
reduces breast cancer mortality by about 30% throughout the first 15 years.
More recently, studies have shown that extended use of adjuvant tamoxifen (10 years versus
5 years) further reduces the risk of breast cancer recurrence and mortality, so clinical practice
guidelines now recommend consideration of adjuvant tamoxifen therapy for 10 years. The
mainstay of treatment for most premenopausal women with HR+ tumors is tamoxifen. Some
women may also benefit from surgical removal (oophorectomy) or chemical suppression of
the ovaries, which are the main source of estrogen before menopause. Treatment guidelines
recommend aromatase inhibitors (AIs) such as anastrozole should usually be included in the
treatment of postmenopausal women with HR+ breast cancer. Targeted therapy is usually
indicated in about 17% of breast cancers that overproduce the growth-promoting protein
HER2/neu. Trastuzumab, the first approved drug, is a monoclonal antibody that directly
targets the HER2 protein. It reduces the risk of recurrence and death by 52% and 33%,
respectively, if combined with chemotherapy in HER2+ early breast cancer if compared to
chemotherapy alone.[20][21]
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Staging
Breast cancer staging is determined clinically by physical examination and imaging studies
before treatment, and breast cancer stage is determined pathologically by pathologic
examination of the primary tumor and regional lymph nodes after definitive surgical
treatment. Staging is performed to group patients into risk categories that define prognosis
and guide treatment recommendations for patients with a similar prognosis. Breast cancer is
classified with the TNM classification system, which groups patients into 4 stage groupings
based on the primary tumor size (T), the regional lymph nodes status (N), and if there is any
distant metastasis (M). The most widely used system is that of the American Joint Committee
on Cancer:
Primary Tumor (T)
Tis: Carcinoma in-situ, Paget‘s with no tumor
T1: Less than 2 cmT1a: 0.1 to 0.5 cmT1b: 0.5 to 1.0 cmT1c: 1.0 to 2.0 cm
T2: 2 to 5 cm
T3: Larger than 5 cm
T4T4a: Chest wall involvementT4b: Skin involvementT4c: Both 4a and 4bT4d:
Inflammatory ca
Regional Lymph Nodes (N)
N1: Mobile ipsilateral axillary nodes
N2: Fixed/matted ipsilateral axillary nodes
N3N3a – Ipsilat infraclavicular nodesN3b – Ipsilat int mammary
nodesN3c – Ipsilateral supraclavicular nodes
Distant Metastases (M)
M1: Distant metastases
Stage 0 Tis
Stage IT1N0
Stage IIT2N0, T3N0 T0N1, T1N1, T2N1
Stage III
*skin, rib inv., matted LNs T3 N1 T0N2, T1N2, T2N2, T3N2 Any T, N3 T4, any N Locally
advanced BC
Stage IV
M1 Adv. BC
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Prognosis
The prognosis of early breast cancer is quietly good. Stage 0 and stage I both have a 100% 5-
year survival rate. The 5-year survival rate of stage II and stage III breast cancer is about 93%
and 72%, respectively. When the disease spreads systemically, its prognosis worsens
dramatically. Only 22% of stage IV breast cancer patients will survive their next 5 years.
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Complications
Complications can arise from the treatment, whether chemotherapy, radiation, hormonal
therapy, or surgery.
Surgical complications include:
 Infection
 Pain
 Bleeding
 Cosmetic issues
 Permanent scarring
  Alteration or loss of sensation in the chest area and reconstructed breasts
Chemotherapy complications include:
 Nausea/vomiting and diarrhea
 Hair loss
 Memory loss ("chemo brain")
 Vaginal dryness
 Menopausal symptoms/fertility issues
 Neuropathy
Complications accompanying hormonal therapy include:
 Hot flashes
 Vaginal discharge dryness
 Fatigue
 Nausea
 Impotence in males with breast cancer
Radiation can result in the following complications:
 Pain and skin changes
 Fatigue
 Nausea
 Hair loss
 Heart and lung issues (long-term)
 Neuropathy
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Deterrence and Patient Education

Patients usually require counseling to deal with the condition and treatment. They should be
put in touch with psychological counseling, and there are also support groups available.
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Pearls and Other Issues

Breast cancer patients are advised to be followed up for life to detect early recurrence and
spread. Yearly or biannual follow-up mammography is recommended for the treated and the
other breast. The patient must be informed that they must visit a breast clinic if they have any
suspicious manifestations. Currently, there is no role for repeated measurements of tumor
markers or doing follow-up imaging other than mammography.
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Enhancing Healthcare Team Outcomes

After the treatment of breast cancer, long-term follow-up is necessary. There is a risk of local
and distant relapse, and hence an interprofessional team approach is necessary. The women
need regular mammograms and a pelvic exam. Also, women with risk factors for
osteoporosis need a bone density exam and monitoring for tumor markers for metastatic
disease. For those who are about to undergo radiation therapy, a baseline echo and cardiac
evaluation are necessary. Even though many types of integrative therapies have been
developed to help women with breast cancer, evidence for the majority of these treatments is
weak or lacking.[22]
Outcomes
Over the past four decades, the survival rates of most breast cancer patients have improved.
Of note is that the presence of breast cancer has gradually slowed down over the past decade,
which may be due to earlier detection and improved treatments. The prognosis for patients
with breast cancer is highly dependent on the status of axillary lymph nodes. The higher the
number of positive lymph nodes, the worse the outcome. In general, hormone-responsive
tumors tend to have a better outcome. In breast cancer survivors, adverse cardiac events are
common; this is partly due to the cardiotoxic drugs to treat cancer and the presence
of traditional risk factors for heart disease. The onus is on the healthcare provider to reduce
the modifiable risk factors and lower the risk of adverse cardiac events.[1][23] [Level 5)
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Review Questions
2)

Abstract
Each year, more than 250,000 women in the United States are diagnosed with invasive breast
cancer. Although overall mortality for breast cancer patients has declined, it is still the second
most common cause of cancer death in women. This article provides an overview of
nonmetastatic breast cancer in women, including general features, diagnostic considerations,
and treatments for the most common breast cancer subtypes.
 Figure

Box 1

Clinicians who work in settings other than oncology should have an understanding of breast
cancer to help care for women who are at risk, undergoing a workup for an abnormal
mammogram and/or a palpable breast mass, or being treated for breast cancer. Breast cancer
incidence is increasing in almost all ethnicities in the United States, and estrogen-positive
breast cancer incidence is increasing across all ethnicities.1 This cancer is the leading
nondermatologic malignancy and the second most common cause of cancer death among
women in the United States.1 Although overall death rates from breast cancer have continued
to decrease since 1989, the death rate among non-Hispanic black women remains
disproportionately high.1,2
Up to 80% of invasive breast cancers are infiltrating ductal carcinomas (IDC). Invasive
lobular carcinoma is the second most common type. Of the noninvasive in situ carcinomas,
more than 80% are ductal and about 10% are lobular.2
PATHOPHYSIOLOGY, RISK FACTORS, AND HISTOLOGY
The pathophysiology of breast cancer is multidimensional and still poorly understood, but
certain risk factors are known. Advancing age and female sex are the most common risk
factors. Genetic mutations, specifically BRCA 1 and 2, account for about 10% of breast
cancers.2 Other known risk factors include a history of ductal carcinoma in situ, high body
mass index (BMI), first birth at age greater than 30 years or nulliparity, early menarche
(before age 13 years), family history of breast or ovarian cancer, late menopause, and
postmenopausal hormone therapy use. Among women who use postmenopausal hormone
therapy, white women and women with a normal BMI and dense breasts are at greatest
risk.3 Women with a history of previous chest radiation also are at an increased risk.

Box 2

The four breast cancer subtypes (Table 1) are associated with specific histologies and
prognoses. Breast cancer also is classified by its anatomical origin, either lobular or ductal,
and its hormone receptivity and human epidermal growth factor receptor 2 (HER-2)
expression.

TABLE 1.:

Breast cancer subtypes

Hormone receptivity refers to the presence or absence of estrogen and progesterone receptor
expression in the malignancy. Hormone receptor positive breast cancer, particularly when
nonmetastatic, is amenable to hormone-blocking therapy. HER-2 positive malignancies are
generally responsive to HER-2 directed monoclonal antibodies. Hormone receptor positive,
HER-2 negative is the most common expression status of breast cancer.
Triple-negative breast cancer refers to malignancies that do not express hormone receptivity
or HER-2. About 12% of women with breast cancer will have triple-negative disease.4 Triple-
negative disease is more common among non-Hispanic black women, independent of age, but
tends to be diagnosed at earlier ages than other subtypes.4 Women with triple-negative disease
are also more likely to be diagnosed at a later stage (stage III or IV). In addition, triple-
negative basal subtype breast cancers tend to be of higher grade and thus more aggressive
malignancies than hormone receptor positive HER-2 negative disease.
The proliferation biomarker Ki-67 was recently used to help stratify risk of recurrence in
breast cancer. It is no longer recommended, but other immunohistologic biomarkers are being
discovered and may help to further stratify recurrence risk.
BREAST CANCER SUBTYPES
Ductal carcinoma in situ (DCIS) is a heterogeneous category of noninvasive, noninfiltrating
malignancies that are localized inside the mammary ducts. (Sometimes IDC also will have
mammographic or histologic evidence of DCIS.2) DCIS is further subclassified depending
upon its morphology, location, and cytological characteristics. Lobular carcinoma in situ is
less common than DCIS but tends to occur bilaterally. Both DCIS and LCIS are usually
hormone receptor positive and HER-2 negative.
IDC is the most common type of breast cancer. About 70% of women with IDC will be
hormone receptor positive and HER-2 negative.4
Infiltrating lobular carcinomas (ILCs) are more common among postmenopausal women and
have an increased risk of bilateral incidence. They are almost always estrogen and
progesterone receptor positive.2
Medullary breast cancer is more common in younger women who carry a BRCA 1
mutation.5 Inflammatory breast cancer is less common but more aggressive, and carries a
worse prognosis than other breast cancers. Mammary Paget disease is an adenocarcinoma
affecting the nipple and areola. Tubular, papillary, and mucinous breast cancers
and Phylloides tumors are less common cancers.5
CLINICAL ASSESSMENT AND DIFFERENTIAL
A palpable breast mass is evident in about 30% of women with breast cancer.2,6 Visible signs
associated with breast cancer include dimpling, an orange-peel appearance (peau d'orange),
erythema, edema, blistering, excoriations, sanguineous nipple discharge, and nipple
retraction. Skin changes such as peau d'orange and blistering are strongly associated with
inflammatory breast cancer and Paget disease of the breast. Sanguineous nipple discharge is
associated with papillary breast neoplasia. Ulcerations can be seen in advanced disease.
Remember to rule out malignancy in patients being treated for mastitis or a breast abscess
that is not improving clinically.
The differential diagnosis of a palpable breast mass in a woman includes benign conditions
such as fibroadenoma, breast cyst, intraductal papilloma, and fibrocystic changes. Once a
mass has been palpated, the next steps are to refer the patient for a diagnostic mammogram
and ultrasound.
DIAGNOSIS
Mammography and ultrasonography are used as initial imaging modalities. MRI may be used
in specific circumstances, such as in patients with dense breasts, those with a history of breast
cancer, those who are being evaluated for contralateral disease, and those at high risk for
breast cancer.7 MRI also can be used in the presurgical planning of biopsy-proven breast
cancer or in the evaluation of patients with dense breasts, contralateral disease, or a history of
breast surgery or radiation. MRI can more accurately identify skin changes common in
inflammatory breast cancer, such as skin invasion.
Common imaging findings in invasive, infiltrating breast cancer include an irregularly shaped
mass, spiculation, pleomorphic microcalcifications, anatomical distortion, axillary
lymphadenopathy, and posterior acoustic shadowing. The American College of Radiology
uses the Breast Imaging and Reporting Data System (BI-RADS) to categorize radiographic
findings.8
Disease is confirmed by tissue biopsy; samples can be obtained through percutaneous
ultrasound-guided core needle biopsy, excisional biopsy, stereotactic biopsy, or MRI-guided
biopsy. The preferred method for most patients is ultrasound-guided large-bore core needle
biopsy with or without a vacuum-assisted device.
Tissue biopsy results will contain information about:
 Tumor grade, which is based on cell differentiation. Low-grade tumors (grade 1) are
well differentiated, and high-grade (grade 4) tumors are undifferentiated.
 Immunohistology, based on the tumor's hormone receptivity and HER-2 expression.
  Oncotype DX Breast Recurrence Score, which provides an estimate of the potential
utility of neoadjuvant chemotherapy and risk of recurrence in patients with early-stage
breast cancer.
Breast cancer is staged using the TNM (tumor, nodes, metastasis) classification system. Most
women with a biopsy-proven malignancy should undergo genetic testing for BRCA 1 and 2
mutations (Table 2).9

TABLE 2.:

Criteria for BRCA 1 and 2 screening9

Cowden syndrome and Li-Fraumeni syndrome also are associated with an increased risk of
breast cancer. Patients with a family history of cancer of the breast, ovary, pancreas, prostate,
colon, thyroid, or endometrium should undergo more extensive genetic testing.10
MANAGEMENT
Treatment of breast cancer, including surgery, depends on the size of the lesion, hormone
receptivity and histologic markers, presence or absence of metastatic or contralateral disease,
patient age, and patient preference.
Surgical options include lumpectomy, mastectomy, and bilateral mastectomy. Breast-
conserving surgery (lumpectomy) is the preferred intervention for most patients with
unilateral disease, but many patients still opt for mastectomy.
Sentinel lymph node biopsy is preferred over wide lymph node dissections if the patient has
no radiographic or clinical evidence of axillary lymph node involvement. In patients with
evidence of lymph node involvement, expert consensus remains mixed as to whether axillary
node dissection has clinical benefit.11
Chemotherapeutic options depend on multiple variables, including hormone reception status,
HER-2 status, presence or absence of metastatic disease, and Oncotype DX recurrence score.
Locally advanced disease and triple-negative breast cancer usually are treated with
presurgical neoadjuvant chemotherapy. Chemotherapeutic agents include doxorubicin,
cyclophosphamide, and paclitaxel. Doxorubicin can cause significant nausea, vomiting,
diarrhea, and fatigue. Some women will experience a discoloration of their nails. A reddish
discoloration of urine, tears, and sweat also can occur. Heart failure has been documented in
women receiving doxorubicin, so carefully assess patients' cardiac function.
Cyclophosphamide can cause neutropenia, alopecia, and significant nausea and vomiting.
Paclitaxel can cause neutropenia, alopecia, arthralgias, myalgias, peripheral neuropathy, and
mucositis. A discussion of chemotherapeutic options for recurrent or metastatic breast cancer
is beyond the scope of this article.
Adjuvant chemotherapy is administered after surgery. Modalities include endocrine blockers,
anthracycline- and taxane-based chemotherapy, and monoclonal antibodies, depending upon
the histology, HER-2 status, and hormone receptor status of the malignancy.10
Aromatase inhibitors and selective estrogen receptor modulators (SERMs) can be used for
nonmetastatic estrogen and progesterone receptor positive breast cancer.12 HER-2 positive
breast cancer can be responsive to HER-2 blockers such as pertuzumab and trastuzumab.
Neoadjuvant and adjuvant anthracycline-based chemotherapy, in addition to HER-2 blocking
monoclonal antibodies, has shown clinical superiority.10 Monitor left ventricular ejection
fraction before and during treatment in patients who are treated with trastuzumab. Primary
resistance to trastuzumab is present in more than 30% of patients, and secondary resistance
occurs in more than 70% of patients.13
SERMs are used in premenopausal patients. Current recommendations for hormone-positive
breast cancer are to use a SERM for 5 years followed by an aromatase inhibitor for 5 years.
High-risk patients (those under age 35 years with positive nodes, high-grade, or large tumors)
who are hormone receptor positive and HER-2 negative may benefit from using the
aromatase inhibitor exemestane plus chemical ovarian suppression with a gonadotropic-
releasing hormone agonist, oophorectomy, or ovarian radiation.14 Tamoxifen is the most
commonly used SERM. Tamoxifen use has some association with endometrial hyperplasia
and carcinoma, so patients are advised to report any new abnormal uterine bleeding to their
gynecologist. Avoid coprescribing paroxetine, fluoxetine, bupropion, and duloxetine, because
these medications are strong inhibitors of CYP2D6 and may lower tamoxifen's effectiveness.
Escitalopram, citalopram, sertraline, and desvenlafaxine are moderate inhibitors of CYP2D6.
Venlafaxine seems to have a negligible effect on CYP2D6.15
Aromatase inhibitors are used in women with natural and surgically induced menopause. The
National Comprehensive Cancer Network provides guidance in diagnosing menopause in
patients with breast cancer. Consider a woman postmenopausal if she is:
 age 60 years or older
 has had an oophorectomy
 under age 60 years and has been amenorrheic for at least 12 months without any
exogenous medications that could alter ovarian function
 under age 60 years and taking a SERM, but has serum estradiol and/or follicle-
stimulating hormone levels that are consistent with menopause. 10

Women who take aromatase inhibitors experience accelerated bone loss, so regular
monitoring of bone density is recommended. Consider prescribing bisphosphonates in
postmenopausal women with hormone receptor positive breast cancer to help prevent further
bone loss from aromatase inhibitor therapy. Aromatase inhibitors can cause significant joint
pain. Patient education and support are necessary to help ensure adherence. Treatment of
aromatase-induced arthralgia includes NSAIDs and acetaminophen. Patients may find relief
from physical therapy, acupuncture, exercise, and other complementary therapies.
Triple-negative basal subtype breast cancer is managed with a combination of doxorubicin,
cyclophosphamide, and paclitaxel. Clinical trials with immunotherapies and other targeted
therapies are underway. Because triple-negative breast cancer does not have endocrine
receptivity, endocrine therapy is not indicated.
Radiation therapy is almost always used, either before surgery or more commonly after it.
Whole-breast and targeted nodal radiation have been considered the gold standard treatment.
Women typically receive radiation therapy five times a week for 4 to 7 weeks. A “boost” of
lower radiation may be considered in women at high risk of recurrence. Accelerated partial
breast irradiation may be considered in women over age 50 years who are node-negative,
hormone receptor positive, and BRCA-negative.10 Women who undergo breast-conserving
surgery receive postsurgical radiation of the breast and axilla. In women with positive lymph
nodes and tumors greater than 5 cm, radiation may be used on the axilla, supraclavicular
areas, and sternum.10
Presurgical radiation therapy often is used for tumors that have been staged at T2 or higher,
using specific criteria to guide radiation decisions. Recent data suggest that women age 65
years and older with hormone receptor positive, node-negative disease with a primary tumor
less than 3 cm may have the option of foregoing radiation.16
Patients undergoing radiation are advised to avoid the use of deodorants, antiperspirants, and
underwire bras. In addition, patients should avoid the use of topical creams, lotions, and
ointments before their treatments because thicker applications could affect the radiation dose
received.17 They should not use heavily perfumed lotions and creams on the breast, and use
only specific topical products (such as aloe vera and hydrocortisone) on skin burns that occur
during radiation therapy. Other adverse reactions common to patients undergoing radiation
include fatigue, pain, and breast discoloration. Women with large breasts are also at risk of
developing a candidal dermatitis under the breast. Prompt treatment with an appropriate
antifungal is essential.
BREAST CANCER SCREENING
The US Preventive Services Taskforce (USPSTF) recommends screening mammography in
women ages 50 to 74 years.18 Women ages 40 to 49 years should have a screening regimen
based on the best-available evidence, including the patient's risk factors, through shared
decision-making.18 Annual mammography is not recommended for average-risk women in
any age group, and the benefit of screening in women over age 75 years has not been
established.18 However, the American College of Obstetricians and Gynecologists (ACOG)
advocates for individualized shared decision-making about screening with each patient,
taking into consideration the patient's risk factors and values.19 Monthly breast self-
examinations are not explicitly recommended by any professional organization and clinical
breast examination recommendations vary by professional organization. ACOG and the
National Comprehensive Cancer Network recommend clinical breast examinations every 1 to
3 years, but the American Cancer Society and the USPSTF do not recommend clinical breast
examinations.19
CONCLUSION
Breast cancer is a multifactorial, heterogeneous disease that requires clinical acumen and a
multidisciplinary approach to diagnose and manage. Clinicians working in nononcology
settings are likely to encounter patients who are in the early stages of diagnosis and later
stages of treatment, thus an understanding of the current state of the evidence will help guide
the care of these patients.
REFERENCES
1. DeSantis CE, Ma J, Goding Sauer A, et al. Breast cancer statistics, 2017, racial disparity in mortality by
state. CA Cancer J Clin. 2017;67(6):439–448.

 Cited Here |

 PubMed | CrossRef
2. American Cancer Society. Breast Cancer Facts & Figures 2017-
2018. www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/breast-cancer-facts-
and-figures/breast-cancer-facts-and-figures-2017-2018.pdf. Accessed June 13, 2019.
 Cited Here
3. Hou N, Hong S, Wang W, et al. Hormone replacement therapy and breast cancer: heterogeneous risks
by race, weight, and breast density. J Natl Cancer Inst. 2013;105(18):1365–1372.

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