Breast Cancer
Cathy Percival, RN, FALU, FLMI
VP, Medical Director
AIG Life and Retirement
Cell Differentiation
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Process by which a less
specialized cell becomes a
more specific, functional cell
Involves the activation or
inactivation of certain genes
in response to the cell’s
interactions w/ neighboring
cells
Cell Proliferation & Apoptosis

Cell proliferation is a physiological process that occurs in almost all
tissues
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Genes control the process of cell division
Normal growth requires a balance between the activity of genes that
promote proliferation and those that suppress it
Apoptosis
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Genetically directed process of cell self-destruction
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Programmed cell death
Activated either by the presence of a stimulus or removal of a
suppressing agent
Eliminates DNA-damaged or superfluous cells
Normally the balance between proliferation and cell death is tightly
regulated to ensure the integrity of organs and tissues
Carcinogenesis
Cancer

A class of diseases or disorders characterized by uncontrolled proliferation
of cells and the ability of these cells to invade other tissues

Invasive cancers arise through a series of molecular alterations at the cell level

Damage to DNA results in unregulated growth, causing mutations to genes
that encode for proteins controlling cell division

Many mutation events may be required to transform a normal cell into a
malignant cell
Causes of Mutations

These mutations can be caused by:
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Carcinogens
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Exposure to radioactive materials
Genetics
Repeated exposure to cell injury
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Physical or chemical agents
Inflammation
Certain viruses
Exposure to environmental factors
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Tobacco smoke—35% of all cancer deaths
Alcohol
Carcinogens
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Substances and exposures that can lead to cancer
Directly alter DNA of gene or cause increased rate of cell
division that could result in changes to DNA
Varying levels of cancer-causing potential

Classification systems based on potential of substance to cause
cancer
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International Agency for Research on Cancer (IARC/WHO)
National Toxicology Program
Environmental Protection Agency
Malignant Tumors
Characteristics
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Evade apoptosis
Ability to promote blood vessel
growth
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Unlimited growth potential
Self-sufficiency of growth factors
Insensitivity to anti-growth factors
Increased cell division rate
Altered ability to differentiate
Ability to invade neighboring tissues
Ability for metastasis to distant sites
Microscopic findings
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Large number of dividing cells
Variation in nuclear size and shape
Variation in cell size and shape
Loss of specialized cell features
Loss of normal tissue organization
Poorly defined tumor boundary
Breast Cancer Facts
Leading cause of cancer in women
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124.6 cases/100,000
220,097 diagnosed/40,931 deaths in 2011 (CDC)
Increased incidence due to:
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Early detection—increased screening
Change in reproductive patterns
Dietary changes
Decreased activity
Mortality has improved slightly due to:
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Early detection
Improved treatment modalities
Male breast cancer
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Accounts for 1% of all breast cancers
2,078 diagnosed/443 deaths in 2011 (CDC)
SEER Data
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2014 Estimates
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1 in 8 women will be diagnosed w/ breast cancer during their lifetime
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232,670 women diagnosed (226,870 in 2012)
40,000 deaths (39,510 in 2012)
12.38% of women
On January 1, 2011, there were almost 2.9 million women in the US living w/ breast
cancer (2.7 million in 2009)
Leading Causes of Cancer Deaths
Among Females in 2009
(American Cancer Society)
Percent of Cases & 5-Year
Relative Survival by Stage
2%
Percent of Cases
61%
120.00%
100.00%
80.00%
98.5%
84.6%
60.00%
40.00%
20.00%
5-Year Survival
49.8%
25.0%
0.00%
ca
liz
ed
R
eg
io
na
l
D
is
ta
nt
U
ns
ta
ge
d
32%
Localized
Regional
Distant
Unstaged
Lo
5%
Localized
Regional
Distant
Unstaged
Breast Cancer Risk Factors
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Advanced Age
Family History
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FH of ovarian cancer in women
<50 yrs
One first-degree relative, or 2 or
more relatives w/ breast cancer
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Personal history
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+BRCA1/BRCA2 mutation
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4-5x increased risk of new
primary breast cancer
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Breast bx w/ atypical hyperplasia
Breast bx w/ LCIS or DCIS
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Use of HRT
Current or recent use of oral
contraceptives
Lifestyle factors
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55-65% lifetime risk
Accounts for 5-10% of all breast
cancers
Early age at menarche (<12 yrs)
Late age at menopause
Late age of first pregnancy
Prolonged estrogen
exposure
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Prior hx of breast cancer
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Reproductive history
Adult weight gain
Sedentary lifestyle
Alcohol consumption
Environmental factors
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Radiation to the breast
Mantle radiation to treat
Hodgkin’s disease
Breast Anatomy
Breasts

Milk-producing glands situated
on front of chest wall

Each breast contains 15-20
lobes arranged in a circular
fashion
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Each lobe is comprised of many
lobules, at the end of which are
glands where milk is produced
in response to hormones
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6-10 major ducts exit the nipple
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Most breast cancers are
adenocarcinomas—epithelial
tumors that develop from cells
lining the ducts or lobules
Breast Abnormalities
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Hyperplasia
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Overproduction of normal
appearing cells
Atypical hyperplasia
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Cells begin to take on
abnormal appearance
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In-situ cancer
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Invasive cancer
Types of Breast Cancer
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Ductal carcinoma in-situ (DCIS)
Lobular carcinoma in-situ (LCIS)
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Infiltrating (invasive) ductal carcinoma
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Incidence has doubled over last 25 yrs
Most common—75% of all breast cancers
Infiltrating lobular carcinoma (<15%)
Medullary carcinoma (5%)
Mucinous (colloid) carcinoma (<5%)
Tubular carcinoma (1-2%)
Papillary carcinoma (1-2%)
Metaplastic breast cancer (<1%)
Mammary Paget disease (1-4%)
Inflammatory breast cancer
Ductal Carcinoma
In Situ (DCIS)
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64,000 cases diagnosed each year
Cells show malignant changes but have
not invaded through the basement
membrane
Accounts for >85% of in situ lesions
Classic finding of clustered
microcalcifications on mammogram
Precurser lesion
½ of DCIS lesions that do occur do
so as invasive cancers
Risk factors for recurrence:
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Higher nuclear grade
Comedonecrosis
Younger age at onset
Larger size
Presence of palpable nodule
Multiple in situ lesions
DCIS Histologic Grading
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Grade I—Low grade
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Grade II—Moderate grade
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Cells appear very similar to normal cells or atypical
ductal hyperplasia cells
Cells appear less like normal cells
Cells grow at faster rate
Grade III—High grade
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More rapid growth
Higher risk of invasive cancer
Comedo necrosis
Patterns of Low-Moderate DCIS
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Papillary DCIS
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Cribiform DCIS
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Cancer cells are arranged in a finger-like
pattern within the ducts
Micropapillary—term used when cells are
very small
Appearance of gaps between cancer cells
in the affected breast ducts
Solid DCIS
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Cancer cells completely fill the affected
breast ducts
Comedo Pattern DCIS
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Comedonecrosis
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Areas of dead (necrotic) cancer cells that build up
inside the tumor

Due to the rapid growth of malignant cells, some cells
don’t receive adequate nourishment and die off
DCIS—2 Subtypes
DCIS Characteristic
Nuclear Grade
Estrogen Receptor
HER2 Overexpression
Distribution
Necrosis
Local Recurrence
Prognosis
Comedo
High
Negative
Present
Continuous
Present
High
Worse
Noncomedo
Low
Positive
Absent
Multifocal
Absent
Low
Better
Lobular Carcinoma In Situ (LCIS)
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Considered a biomarker of increased
breast cancer risk
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10-20% of women w/ LCIS will
develop invasive breast cancer
w/in 15 years
Increases lifetime risk of invasive
cancer to 12x that of normal women
May diffusely involve both breasts
Does not show up on mammogram,
but is incidentally found during
breast biopsy done for another
reason
Incidence has doubled over the last
25 yrs
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2.8/100,000 women
Peak incidence in women aged 40-50
Invasive Breast Cancers
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Invasive Ductal Carcinoma
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Also called infiltrating ductal carcinoma
Malignant cells invade, or spread, from milk ducts to surrounding breast tissue
Most common adenocarcinoma of the breast
Metastasizes via lymphatic system
Risk increases w/ age
Invasive Lobular Carcinoma
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Begins in lobules of breast and
invades into surrounding breast
tissue
Accounts for <15% of invasive breast
cancers
Tends to be multicentric
Increased risk of bilateral disease
Less Common Breast Cancers
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Medullary carcinoma
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Mucinous (colloid) carcinoma
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Tumor is made up of abnormal cells that
“float” in pools of mucin
Affects post-menopausal women ages
60’s-early 70’s
Less aggressive—good prognosis
Tubular carcinoma
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Soft, fleshy mass that resembles medulla
in the brain
Affects women in late 40’s-early 50’s
More common in women w/ BRCA1
mutation
High-grade in appearance and low-grade
in behavior
Usually small and composed of tubular
structures—low grade w/ good prognosis
Being diagnosed more frequently
Papillary carcinoma
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Moderate grade cancer w/ finger-like
projections
DCIS often also present
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Metaplastic breast cancer
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Mammary Paget disease
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Replacement of one differentiated
cell type w/ another differentiated
cell type
Histologic presence of two or more
cellular types
High-grade, aggressive malignancy
Malignant epithelial cells derived
from underlying ductal
adenocarcinom
Invades into the skin of the nipple
and areolar areas
Inflammatory breast cancer
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Advanced, aggressive cancer
Presents w/ breast pain and skin
changes
Often mistaken for other breast
conditions
Invades skin and lymph system
Diagnosis
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Signs/symptoms
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Imaging studies
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Most breast cancers are asymptomatic
Palpable lump or nodule found
on self-exam or by MD
Skin or nipple changes
Bloody nipple discharge
Lymph node enlargement
Mammogram
Ultrasound
MRI
Nuclear imaging
Biopsy
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Needle biopsy
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FNA, Core
Excisional biopsy
Histologic Features
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Important in determining course of treatment
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Size
Status of surgical margin
Presence or absence of estrogen receptor (ER) and
progesterone receptor (PR)
Nuclear and histologic grade
Proliferation
Vascular invasion
Tumor necrosis
Quantity of intraductal component
HER2 status
Prognostic Indicators
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Tumor size
Axillary lymph node status
Lymphatic/vascular invasion
Patient age
Histologic grade
Histologic subtypes
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Tubular
Mucinous (colloid)
Papillary
Response to neoadjuvant therapy
ER/PR status
HER2 gene amplification and/or overexpression
Markers of proliferation
Histologic Grade
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Represents aggressive potential of the tumor
Scoring based on 3 factors:
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Differentiation
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Nuclear features
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% of carcinoma composed of tubular structures
1: >75%
2: 10-75%
3: <10%
Pleomorphism—presence of multiple variations in appearance of malignant cells
1: Small, uniform cells
2: Moderate increase in size and variation
3: Marked variation
Mitotic count
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Speed of tumor cell division
1: <7 mitoses/hpf
2: 8-14 mitoses/hpf
3: >15 mitoses/hpf
Histologic Grade
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Overall Grade
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Grade 1: score of 3-5
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Well-differentiated tumors
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Grade 2: score of 6-7
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More favorable prognosis
Moderately-differentiated tumors
Grade 3: score of 8-9
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Poorly-differentiated tumors
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More aggressive
Worse prognosis
Breast Cancer Staging
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American Joint Committee on Cancer (AJCC) staging
system
Groups patients into 4 stages according to TNM
system
 T (primary tumor size)
 N (lymph node status)
 M (distant metastasis)
Primary Tumor (T)
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Tx—Primary tumor cannot be assessed
T0—No evidence of primary tumor
Tis—In-situ
Tis—Paget disease of the nipple w/ no tumor
T1—Tumor <2cm
T1mic—Microinvasion <0.1cm
T1a—Tumor >0.1 but not >0.5cm
T1b—Tumor >0.5 but not >1cm
T1c—Tumor >1cm but not >2cm
T2—Tumor >2cm but not >5cm
T3—Tumor >5cm
T4—Tumor of any size, w/ direct extension to (a) the chest wall or (b) skin only, as
described below
T4a—Extension to chest wall, not including the pectorallis
T4b—Edema or ulceration of the skin of the breast or satellite skin nodules confined to the
same breast
T4c—Both T4a and T4b
T4d—Inflammatory disease
Regional Lymph Nodes (N)
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Nx—Regional lymph nodes cannot be assessed
N0—No regional lymph node metastasis
N1—Metastasis in movable ipsilateral axillary lymph node(s)
N2—Metastasis in ipsilateral axillary lymph node(s) fixed or matted, or in
clinically apparent ipsilateral internal mammary nodes in the absence of
clinically evident axillary lymph node metastasis
N2a—Metastasis in ipsilateral axillary lymph nodes fixed to one another or to
other structures
N2b—Metastasis only in clinically apparent ipsilateral
internal mammary nodes and in the absence of clinically
evident axillary lymph nodes
N3—Metastasis in ipsilateral infraclavicular or supraclavicular
lymph node(s) with or w/o axillary lymph node involvement,
or clinically apparent ipsilateral internal mammary
lymph node(s) and in the presence of axillary lymph node
N3a—Metastasis in ipsilateral infraclavicular lymph node(s)
N3b—Metastasis in ipsilateral internal mammary lymph node(s)
and axillary lymph node(s)
N3c—Metastasis in ipsilateral supraclavicular lymph node(s)
Distant Metastasis (M)
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Mx—Distant metastasis cannot
be assessed
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M0—No distant metastasis
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M1—Distant metastasis
Staging
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Stage of breast cancer at
time of diagnosis is the most
important prognostic
indicator
Breast Cancer Staging
5-year survival
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Stage
Stage
Stage
Stage
Stage
0:
1:
2:
3:
4:
99-100%
95-100%
86%
57%
20%
Takes into account:
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Tumor size
Degree of penetration
Invasion to lymph nodes
and adjacent organs
Presence of metastasis
Biomarkers
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Prognostic
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Predictive
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Independent measures of prognosis such that the presence
or absence of the biomarker is associated w/risk or
recurrence and mortality
Predict whether or not a patient will respond to a given
therapy
Important breast cancer biomarkers
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Estrogen receptors (ER)
Progesterone receptors (PR)
Human epidermal growth factor receptor (HER2)
Estrogen and Progesterone
Receptors (ER and PR)
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Proteins that allow cells to respond metabolically to estrogen and progesterone
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Estrogen receptors are over-expressed in about 70% of breast cancers
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Binding of estrogen to the ER stimulates proliferation of mammary cells, causing
increased cell division and DNA replication, leading to mutations
Estrogen metabolism produces genotoxic waste
Both of these processes cause disruption of cell cycle, apoptosis and DNA
repair
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Results in tumor formation
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ER/PR status reflects tumor responsiveness to endocrine treatment
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Weak prognostic but strong predictive biomarkers
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Receptor status has less effect on the probability of recurrence and more effect
on when, during the disease course, recurrence occurs
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Receptor negative individuals have higher early recurrence rates
Receptor positive individuals have higher later recurrence rates
HER2 Oncogene
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Promotes cellular proliferation
Overexpression of HER2 is associated w/ increased disease recurrence
and a poor prognosis
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Present in 18-20% of invasive breast cancers
HER2 status has been shown to be predictive for response to certain
chemotherapeutic agents and HER2-targeted therapies
Breast Cancer Treatment
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DCIS
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Goal of treatment is to prevent local recurrence
Lumpectomy w/ local radiation or mastectomy
LCIS
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Local tumor doesn’t progress
Goal is to prevent development of other invasive cancers
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Prophylactic mastectomy
Chemoprevention using
hormonal therapy
Use of aromatase inhibitor
drugs
Breast Cancer Treatment
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Invasive Breast Cancer
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Goals of treatment:
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Complete elimination of all malignant cells w/ negative margins
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Positive margins are associated w/ at least a 2-fold increase in
same side breast tumor recurrence
Prevention of lymph node invasion and metastasis
Surgical Treatment
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Lumpectomy or Mastectomy
Lymph node evaluation
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Axillary lymph node dissection (ALND)
Sentinal node biopsy
 Key lymph node draining the area of
the lesion
 Positive sentinal node biopsy usually
results in full lymph node dissection
Adjuvant Treatment
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Localized radiation
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Eradication of local subclinical residual disease
Reduction of local recurrence rates
Treatment of advanced/metastatic disease
Considered standard of care, even in lowest-risk disease w/ the most
favorable prognostic features
Systemic chemotherapy
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Treatment of recurrent or metastatic breast cancer
Treatment of micrometastatic disease
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Malignant cells that have escaped the breast and regional lymph nodes but
which have not yet had an identifiable metastasis
Used to reduce risk of future recurrence
Estimated to be responsible for 35-72% of the reduction in mortality
Radiation Therapy
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2 approaches
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External-beam radiotherapy (EBRT)
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Partial-breast irradiation (PBI)
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Whole-breast radiotherapy (WBRT) consists of EBRT delivered to the breast over 5-6 weeks
followed by a boost dose specifically direct to the area of the breast where the tumor was
removed
Delivers larger fraction sizes while maintaining a low risk of late
side effects
Interstitial brachytherapy
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Multiple catheters placed through the breast
Intracavitary brachytherapy
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Balloon catheter inserted into lumpectomy site
Complications
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Catheter placement followed by removal secondary to
inadequate skin spacing, infection, seroma, fibrosis,
chronic pain, disease recurrence, cosmetic issues
Side effects
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Fatigue, breast pain, swelling and skin desquamation
Late toxicity (lasting >6 months after tx)
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Breast edema, pain, fibrosis, skin hyperpigmentation
Rare side effects: rib fractures, pulmonary fibrosis, cardiac disease, secondary malignancies
Adjuvant Therapy
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Selective estrogen receptor modulators (SERMs)
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Block the effects of estrogen in the breast tissue
Reduce the development of tumors in the opposite breast by at least 1/3
3 drugs used:
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Tamoxifen (Nolvadex)
Raloxifene (Evista)
Toremifene (Fareston)
Aromatase inhibitor drugs
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Used in postmenopausal women
May be superior to SERMs in preventing disease in the opposite breast
Block the enzyme aromatase that converts androgens to estrogens in
adipose tissue, adrenal glands and some breast tumors
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Cuts off supply of hormone to the tumor
First line therapy for metastatic disease
These drugs include:
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Anastrozole (Arimidex)
Letrozole (Femara)
Exemestane (Aromasin)
Adjuvant Therapy
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HER2 targeted therapies:
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May be used alone or in combination w/ other chemotherapeutic
agents
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Herceptin (Trastuzumab)
Tykerb (Lapatinib)
Perjeta (Pertuzumab)
Kadcyla (Ado-trastuzumab emtansine)
Used to treat HER2+ breast cancers, advanced/metastatic breast
cancer, and recurrent disease
Adverse effects
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Cardiotoxicity
Inflammation of the liver
Diarrhea
Rash
Thrombocytopenia
Neutropenia
Mortality Risk
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Can extend out to many years after original diagnosis
Older studies show reduced relative survival for up to 40 years
after diagnosis due to:
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The breast cancer itself
Secondary malignancies
Cardiovascular disease as a complication of
adjuvant treatment
Recurrence patterns
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Most occur within the first several years
after diagnosis
However risk of recurrence can extend for
many years
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Mortality from the disease has been observed
20 years or more after diagnoses
Secondary malignancies
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This risk remains constant over time