The BREAST

Sara Sukumar
Pathobiology,
September 6, 2013

1
 Breast Cancer
Breast cancer is second only to lung cancer as
a cause of cancer deaths in American women
One out of every eight women
will be diagnosed with breast
cancer in 2011
Fortunately, radical mastectomy
(surgical removal) is rarely
needed today with better
treatment options

2
Trends since 1950 in
age-standardized
death rates
comparing breast and
selected other types
of cancer, among
women in the USA

EBCTCG, Lancet, 2010

 BREAST CANCER IN THE WORLD

1.15 million new cases

Incidence increasing in most

countries

470 000 deaths

Half of the global burden in low-

and medium-resourced countries
 Outline- Part 1

Development of the Breast

Female Breast Anatomy
Breast Cancer
Risk Factors- Sporadic and
Hereditary Breast Cancer
Biology of Breast Cancer

5
 Outline- Part 2

How breast cancer is:

Detected
Diagnosed
Treated

6
Development of the Breast Ductal Tree
Occurs mainly after birth
Female Breast Anatomy

The bulk of the breast

tissue is adipose tissue
interspersed with
connective tissue
Breast ducts comprise
only about 10% of the
breast mass

lobes
ducts
lymph nodes

8
Stucture of the Breast

Breast has no
muscle tissue
There are muscles
underneath the
breasts separating
them from the ribs

9
Breast Gland

Each breast has 8 to 10

sections (lobes) arranged
like the petals of daisy

Inside each lobe are many

smaller structures called
lobules
At the end of each lobule
are tiny sacs (bulbs) that
can produce milk
10
 Ducts

Lobes, Lobules and bulbs,

are linked by a network of
thin tubes (ducts)
Duct
Ducts carry milk from
bulbs toward dark area of
skin in the center of the
Areola
breast (areola)

Ducts join together into larger ducts ending at

the nipple, where milk is delivered
11
 Breast development-Adult
4A: Premenopausal adult breast
section (H and E) showing a
terminal duct (td) entering a
TDLU. ils: intralobular stroma; iels:
interepithelial lobular stroma
4B: High power of A.
4C: Intralobar stroma reactive
Intralobular stroma antibody
4D: Increase in number of lobules
with loss of fat, still separated by
intralobular connective tissue
4E: Lactating mammary gland
composed of dilated acini
containing milk
4F: Following weaning, involution
occurs. The two layered
epithelium of the resting breast is
reformed in cycles of pregnancy
and lactation
4G, H: Virginal hypertrophy
Breast development- Involution, and
benign breast conditions
Postmenopausal breast- both lobules and
ducts are reduced in number. Intralobular
stroma is replaced with collagen
5A: Few acini and ducts remain,
embedded in thin strands of collagen,
widely dispersed in the fat. Connective
tissue regresses, replaced by fat

Benign breast conditions-

5B:Cysts containing secretions
5C: Apocrine metaplasia-lining epithelium
takes on features of apocrine glands of the
axilla. Granular cytoplasm, large nuclei,
nucleoli.
5D:Sclerosing adenosis-lobular
proliferation with acini are infiltrative at the
margins
5F: Epithelial hyperplasia-expansion of
lobules
 Blood Vessels

Oxygen, nutrients, and other

life-sustaining nourishment
are delivered to breast tissue
by the blood in the arteries
and capillaries.

14
 Lymphatic System
Lymph ducts: Drain fluid
that carries white blood
cells (that fight disease)
Lymph node Lymph duct from the breast tissues
into lymph nodes under
the armpit and behind
the breastbone
Lymph nodes: Filter
harmful bacteria and
play a key role in
fighting off infection
A network of vessels

15
 Three Types of Vessels

1
Lobules Ducts Nipple Milk
3
Lymph Lymph
Waste
Nodes Vessels produc
ts

Bacteria
2
r is hment
Blood No u
Cell life
Vessels

16
 Signs and Symptoms

Most
common:
lump or
thickening in
breast.
Often
painless

Dischar Redness or
ge or pitting of skin
bleedin over the
g breast, like the
skin of an
Change in
size or Change inorange
contours of color or
breast appearance 17
 Noncancerous Conditions (1)
Fibrocystic changes: Lumpiness, thickening and
swelling, often associated with a womans period
Cysts: Fluid-filled lumps can range from very tiny
to about the size of an egg
Fibroadenomas: A solid, round, rubbery lump that
moves under skin when touched, occuring most in
young women
Infections: The breast will likely be red, warm,
tender and lumpy
Trauma: a blow to the breast or a bruise can cause
a lump
06/04/17 18
 Noncancerous Conditions (2)

Microcalcifications: Tiny deposits of calcium

can appear anywhere in a breast and often
show up on a mammogram
Most women have one or more areas of
microcalcifications of various sizes
Majority of calcium deposits are harmless
A small percentage may be precancerous or cancer
(biopsy is sometimes recommended)

19
 Causes

Some of the cells begin growing abnormally

These cells divide more rapidly than healthy
cells do and may spread through the breast,
to the lymph or to other parts of the body
(metastasize)
The most common type of breast cancer
begins in the milk-production ducts, but
cancer may also occur in the lobules or in
other breast tissue

06/04/17 20
 Normal Breast

Breast profile
A ducts
B lobules
C dilated section of duct to hold milk
D nipple
E fat
F pectoralis major muscle
G chest wall/rib cage

Enlargement
A normal duct cells
B basement membrane (duct wall)
C lumen (center of duct)

Illustration Mary K. Bryson 21

 Ductal Carcinoma in situ (DCIS)

Ducta
l
cance
r cells

Norm
al
ducta
l cell 22
Illustration Mary K. Bryson
 Invasive Ductal Carcinoma (IDC
80% of breast cancer)

Ductal
cancer cells
breaking
through the
wall

The cancer has spread to the

surrounding tissues
Carcinoma refers to any cancer
that begins in the skin or other
tissues that cover internal
organs 23
Illustration Mary K. Bryson
 Range of
Ductal
Carcinoma in
situ (DCIS)

24
Invasive Lobular Carcinoma (ILC)

Lobular
cancer cells
breaking
through the
Illustration Mary K. Bryson wall 25
Cancer Can also Invade Lymph or Blood
Vessels-Metastatic breast cancer

Cancer
cells
invade
lymph
duct

Cancer
cells
invade
blood
vessel
Illustration Mary K. Bryson 26
Factors determining risk
of developing Breast
Cancer

27
 Breast Cancer Risk Factors
unalterable factors
Age
GENDER - All
Reproductive
women are
History
Family/Personal at risk
History

Menstrual
Race History
Radiation
Treatment with Genetic
DES Factors
Breast Cancer Risk Factors
that can be controlled
Obesity
All Not having
Exercise women are children
at risk

Breastfeeding
Birth Control
Hormone Pills
Alcohol Replacement
Therapy
 Potential Applications for
Breast Cancer Biology

Predict risk of cancer development

Estimate prognosis for established
cancer
Predict response to therapy
Identify therapeutic targets
Identify early detection markers
 Family history as a risk factor-
Hereditary Breast and Ovarian Cancer

15%-20%

5%10% 5%10%

Breast Cancer Ovarian Cancer

Sporadic
Family clusters
Hereditary
 Causes of Hereditary
Susceptibility to Breast Cancer
5 to 10% of breast cancers can be attributed to inherited factors
Contribution to
Hereditary Breast
Gene Cancer
BRCA1 20%40%
BRCA2 10%30%
TP53 <1%
PTEN <1%
Undiscovered genes 30%70%
* Li-Fraumeni Syndrome, abnormal TP53 gene on
chromosome 17p, associated with premenopausal
breast cancer, childhood sarcomas, brain tumors,
leukemia, and adrenocortical adenomas

*Cowdens Syndrome, abnormal PTEN tumor

suppressor gene on chromosome 10 associated
with premenopausal breast cancers,
gastrointestinal malignancies, and benign and
malignant
 Features That Indicate Increased
Likelihood of Having BRCA Mutations

Multiple cases of early onset breast cancer

Ovarian cancer (with family history of
breast or ovarian cancer)
Breast and ovarian cancer in the same
woman
Bilateral breast cancer
Ashkenazi Jewish heritage
Male breast cancer
BRCA1-Associated Cancers:
Lifetime Risk

Breast cancer 50%-85%

(often early age at onset, less than 40
years)
Second primary breast cancer 40%-60%
Ovarian cancer 15%-45%

Possible increased risk of other

cancers (e.g. prostate, colon)
BRCA2-Associated Cancers:
Lifetime Risk

breast cancer
(50%-85%)
male breast cancer
(6%)
ovarian cancer
(10%-20%)

Increased risk of prostate,

laryngeal, and pancreatic
cancers (magnitude unknown)
 Comparing Breast Cancer Risk Estimates in
BRCA Mutation Carriers

BRCA1+ carriers
(BCLC)

Breast BRCA1+
cancer carriers
risk (%) (Ashkenazi
Jews)

General population

Easton DF et al. Am J Hum Genet 56:265, 1995 Age

Struewing JP et al. N Engl J Med 336:1401, 1997
Established Prognostic Markers for
Breast Cancer

Axillary lymph nodes

Tumor size
Histological grade
Histological tumor type
Steroid receptor status
Age
NIH Consensus Conference 2000
 Potential Applications for
Breast Cancer Biology

Predict risk of cancer development

Estimate prognosis for established
cancer
Predict response to therapy
Identify therapeutic targets
Identify early detection markers
 Molecular Portrait of Breast Cancers
Basal- HER- Normal Lumina
lB Lumina
like 2 lA

Sorlie T et al, PNAS 2001

 Subtypes and Prognosis

Sorlie T et al, PNAS 2001

 Potential Applications for
Breast Cancer Biology

Predict risk of cancer development

Estimate prognosis for established
cancer
Predict response to therapy
Identify therapeutic targets
Identify early detection markers
 Common molecular alterations in
breast cancer

Mutations- Very rare compared to colon ca.

PI3KCA single point mutations, insertions, frame shifts-
25-30%
p53- Around 15-25%; 50% inclusive of intronic
mutations
Other genes with less than 5% incidence of mutations
Overexpression of oncogenes- by amplification or
transcriptional deregulation ex. Myc, HOXs, syk, TKs
Loss of expression of tumor suppressor genes- by
deletion, or methylation of promoter sequences
microRNAs and long noncoding RNAs- emerging players
The Estrogen Receptors

2 cys-rich zinc fingers

Recognize EREs, and stabilize Variable

Tx activation Hinge region

domain
Activation of Estrogen
Receptor

JM Hall et al, JBC

 Her-2 overexpression in breast
cancer- 1985-1998

About 20-30% of breast cancers overexpress HER-

2 protein (usually because of gene amplification)
Monotherapy with anti-HER-2 monoclonal antibody
(trastuzumab or Herceptin) has a 30% response
rate in HER-2-positive metastatic breast cancer
Combination of trastuzumab plus chemotherapy
improves time to progression and overall survival in
advanced HER-2 positive breast cancer
Trastuzumab plus anthracycline results in a 20%
incidence of cardiotoxicity
 Potential Applications for
Breast Cancer Biology

Predict risk of cancer development

Estimate prognosis for established
cancer
Predict response to therapy
Identify therapeutic targets
Identify early detection markers
 The EGFR (ErbB) family and ligands
EGF
TGF
Amphiregulin NRG2
-cellulin NRG3
HB-EGF Heregulins
Epiregulin Heregulins -cellulin

100 44 36 48 Cysteine-rich
domains

Tyrosine kinase 100 82 59 79

domain
100 33 24 28 C-terminus

ErbB-1 ErbB-2 ErbB-3 ErbB-4

Her1 Her2 Her3 Her4
EGFR neu
www.astrazeneca.com
 The dual ErbB-1 (EGFR) and ErbB-2 tyrosine
kinase inhibitor lapatinib kills MDA-MB-361 and
MCF7 human breast cancer cells better than
trastuzumab.

Slamon, D. J. Oncologist 2004;9(Suppl 3):1-3

Copyright 2004 AlphaMed Press

 Applications of Expression Microarrays
in Predicting Response to Therapy

Different profile of sporadic vs hereditary breast

cancer (Heldenfalk, NEJM 2001)

Identify subset of young women with poor prognosis early

breast cancer (vant Veer, Nature 2002)

Subset outcomes for women with node-negative

ER-positive breast cancer treated with
tamoxifen (Paik, NEJM 2004, SABCS 2004)
So What Good is All this Molecular Analysis??

Now available--$3400
Should we use it?
For whom?
How?
 Candidate Gene Selection
From ~40,000 genes

M ata
ic *
D
ro
ar
ra

ta mic
C iter

s
se
an a

y
L

Da eno
ba
ce tur
r e

ar

G
ul
l ec gy
o
M iolo
B
250
cancer-related
candidate genes
*Sources include:
1) Van 't Veer et al, Nature 415:530, 2002
2) Sorlie et al, Proc. Natl. Acad. Sci. USA 98:10869
3) Ramaswamy et al, Nature Genetics 33:4, 2003
4) Gruvberger
Paik etet
al,al, Cancer
SABCS 2003 Res. 61:5979, 2001
 Three Breast Cancer Studies Used to Select 16
Cancer and 5 Reference Genes

PROLIFERATION ESTROGEN
Ki-67 HER2 ER
STK15 GRB7 PGR
Survivin HER2 Bcl2
Cyclin B1 SCUBE2
MYBL2
GSTM1
REFERENCE
INVASION CD68 Beta-actin
Stromelysin 3 GAPDH
Cathepsin L2 RPLPO
BAG1
GUS
Best RT-PCR performance
and most robust predictors TFRC
Paik et al NEJM 2004
 Three Breast Cancer Studies Used to
Develop Recurrence Score (RS) Algorithm

Recurrence
Category RS (0 100)
Low risk < 18
Intermediate risk 18 30
High risk 31
Paik et al, SABCS 2003
 Low recurrence score means:
Clear benefit from tamoxifen
No benefit from chemotherapy

1 .0
T CT
P
0 .8

0 .6
DRFS

0 .4

N
0 .2 P la c e b o (B 1 4 ) 355
T a m (B 1 4) 668
T a m (B 2 0) 227
Tam + C h e m o (B 2 0 ) 424
0 .0
0 2 4 6 8 10
Y e a rs

Paik, SABCS, 2004

Intermediate recurrence score means:
Clear benefit from tamoxifen
Uncertain benefit from chemotherapy

1 .0

T CT
0 .8

0 .6
P
DRFS

0 .4

N
0 .2 P la c e b o (B 1 4 ) 355
T a m (B 1 4) 668
T a m (B 2 0) 227
Tam + C h e m o (B 2 0 ) 424
0 .0
0 2 4 6 8 10
Y e a rs
Paik, SABCS, 2004
High recurrence score means:
No benefit from tamoxifen
Clear benefit from chemotherapy

1 .0

CT
0 .8

P T
0 .6
DRFS

0 .4

N
0 .2 P la c e b o (B 1 4 ) 355
T a m (B 1 4) 668
T a m (B 2 0) 227
Tam + C h e m o (B 2 0 ) 424
0 .0
0 2 4 6 8 10
Y e a rs

Paik, SABCS, 2004

 Potential Applications for
Breast Cancer Biology

Predict risk of cancer development

Estimate prognosis for established
cancer
Predict response to therapy
Identify therapeutic targets
 Outline- Part 2

How is breast cancer:

Detected
Diagnosed
Treated

59
 Mammography

Use a low-dose x-ray system to examine breasts

Digital mammography replaces x-ray film by
solid-state detectors that convert x-rays into
electrical signals. These signals are used to
produce images that can be displayed on a
computer screen (similar to digital cameras)
Mammography can show changes in the breast up
to two years before a physician can feel them

60
Mammography Equipment

61
 Computer-Aided Diagnosis

Mammography allows for efficient diagnosis

of breast cancers at an earlier stage
Radiologists misdiagnose 10-30% of the
malignant cases
Of the cases sent for surgical biopsy,
only 10-20% are actually malignant
CAD systems can assist radiologists to
reduce the above problems National Cancer Institute

62
 What Mammograms Show
Two of the most important mammographic
indicators of breat cancers
Masses
Microcalcifications: Tiny flecks of calcium like
grains of salt in the soft tissue of the breast that
can sometimes indicate an early cancer.

63
 Detection of Malignant Masses
Malignant masses have a more spiculated
appearance

malignant benign 64
Mammogram Difficult Case*

Heterogeneously dense breast

Cancer can be difficult to
detect with this type of
breast tissue
The fibroglandular tissue
(white areas) may hide the
tumor
The breasts of younger
women contain more glands
and ligaments resulting in
dense breast tissue
65
Mammogram Easier Case*

With age, breast tissue

becomes fattier and has
fewer glands
Cancer is relatively easy
to detect in this type of
breast tissue

66
 Different Views
Side-to-Side
MRI - Cancer can have a unique
appearance many small irregular
white areas that turned out to be
cancer (used for diagnosis)

67
Top-to-Bottom
Calcification Features

The morphology of individual

calcification, e.g., shape, area,
and brightness
The heterogeneity of
individual features
characterized by the mean,
the standard deviation, and
the maximum value for each
feature.
Cluster features such as total
area, compactness
68
 Database Approach to
Computer-Aided Diagnosis

Content-based image retrieval techniques can provide

radiologists visual aids to increase confidence in
their diagnosis

The database consists of a large

number of images with verified
pathology results
Diagnosis is done by submitting the
suspected mass region as a query to
retrieve similar cases from the
database

69
 Outline- Part 2

How is breast cancer:

Detected
Diagnosed
Treated

70
 Diagnosis and Treatment

. Patient feels a breast mass or has an

abnormal radiologic screening exam
. Surgical biopsy or aspiration
. Observation (LCIS), lumpectomy or
mastectomy
. Staging
. Delivery of adjuvant therapiesradiation
and/or chemotherapy,hormonal therapies

06/04/17 71
 Tumor characteristics
Invasive vs. Non-invasive .
Histologic Type-Ductal (85%) vs. Lobular .
Grade (estimate of the aggressiveness
under microscope) .
Size .
Margins .
Lymph Nodes .
Estrogen/ Progesterone Receptor (2/3
positive) .
Her-2/ neu
06/04/17 72
 Stage 0 --carcinoma in situ
Stage I tumor < 2 cm, no
nodes
Stage II tumor 2 to 5 cm, +/-
Stages nodes
of Stage III locally advanced
Breast disease, fixed or matted lymph
nodes and variable tumor size
Cancer Stage IV distant metastases
(bone, liver, lung, brain)
 What now?
Stage 0-III

Risk of recurrence is individual

What can we do to reduce the risk of
recurrence in the breast, and
systemically ?

Meet with Radiation Oncologist and

Medical Oncologist

74
 How is breast cancer treated?

3. ADJUVANT THERAPY: Medical therapy

to decrease the chance of tumor
recurrence - to improve the chances for
cure
Chemotherapy - many different therapies
Hormonal therapy - tamoxifen, aromatase
inhibitors
4. RADIATION THERAPY - to prevent
tumor recurrence in the remaining breast
tissue; required for breast preserving
therapy
 Adjuvant Therapy
Radiation Therapy (local)
Chemotherapy (systemic)
Hormonal agents (systemic)
Each therapy adds to reduction of
recurrent disease.
Therapy is individualized,
discussion with health care
provider.
 BREAST CONSERVING THERAPY
(BCT)

Breast cancer
screening programs

BREAST Better Quality

Increase mass
CONSERVING of life
awareness
SURGERY

Patients with earlier Better psycho-social

stages presenting Adjustment
to clinic
 MRM Vs BCT
Randomized trials
Meta-analysis

Comparable local control, Overall survival

Better cosmetic outcome
BCT: EFFECT OF RADIOTHERAPY ON LOCAL
RECURRENCE

5 year gain
16.1%
5 year gain
30.1%

Node Negative Women Node Positive Women

EBCTCG meta-analysis. Lancet 2005; 366: 20872106
 Chemotherapy Drugs
Adriamycin, Epirubicin
Taxol, Taxotere
Navelbine
Cytoxan

Methotrexate, 5-fluorouracil
Intravenous
Nausea, hair loss, low blood counts, cardiac toxicity,
bladder toxicity, nerve damage
Given for adjuvant or recurrent disease. 80
Tamoxifen
*
Works by blocking estrogen
receptors in breast cells, inhibiting
their growth
Can be given to pre or post menopausal
women

Sideeffects include hot flashes, depression,

increased risk of uterine cancer and blood
clots
Taken daily by mouth for 5 years
81
Aromatase Inhibitors*
Aromatase is the enzyme that converts
androgens to estrogen
AIs are only given to postmenopausal
women
Examples: Anastrozole/Arimidex,
Letrozole/Femara, Exemestane/Aromasin
May be more effective than Tamoxifen
Side effects include hot flashes,
depression, osteoporosis, joint pains
Taken daily by mouth for variable periods of
time 82
Trastuzumab/Herceptin

Given to patients whose cancer cells

overexpress Her-2-neu as measured
by IHC or FISH (25 to 30% of patients)

83
 Bisphosphonates
Bone strengtheners
Given for therapy-induced osteoporosis or for
cancer that has spread to bone

Zometa (Zoledronic acid)

Aredia (Pamidronate)
Each lowers calcium and has been shown to
reduce the risk of fracture in pts with cancers
metastatic to bone.
 Summary
The breast is a dynamic organ- undergoes cyclical proliferative
changes throughout life under the influence of hormones and
growth factors- so may be likely to be more altered by
environmental carcinogens

Key function for ER and PR in breast cells. The same hormones

that are important for breast growth during pregnancy are
also important for breast cancer.

ER function in signaling through other growth factor receptor

pathways becomes very important in cancer. Production of
estrogen through alternate sources keeps E supply ongoing in
postmenopausal women.