The BREAST

Sara Sukumar
Pathobiology,
September 6, 2013

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

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 lowand 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

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

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

Areola

Ducts carry milk from

bulbs toward dark area of
skin in the center of the
breast (areola)

Ducts join together into larger ducts ending at

the nipple, where milk is delivered
11

Breast development-Adult

Intralobular stroma

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
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 conditions5B: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 node

Lymph duct

A network of vessels

Lymph ducts: Drain fluid

that carries white blood
cells (that fight disease)
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

15

Three Types of Vessels

1
Lobules

Lymph
Nodes
Bacteria

Ducts
3

Lymph
Vessels

Blood
Vessels

Nipple

Milk

Waste
produc
ts

hment
s
i
r
u
o
N

Cell life

16

Signs and Symptoms

Most
common:
lump or
thickening in
breast.
Often
painless

Dischar
ge or
bleedin
g
Change in
size or
contours of
breast

Redness or
pitting of skin
over the
breast, like the
skin of an
Change inorange
color or
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
02/06/16

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
02/06/16

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

basement membrane (duct wall)

C lumen (center of duct)

Illustration Mary K. Bryson

21

Ductal Carcinoma in situ (DCIS)

Ducta
l
cance
r cells

Illustration Mary K. Bryson

Norm
al
ducta
l cell

22

Invasive Ductal Carcinoma (IDC

80% of breast cancer)
Ductal
cancer cells
breaking
through the
wall

Illustration Mary K. Bryson

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

Range of
Ductal
Carcinoma in
situ (DCIS)

24

Invasive Lobular Carcinoma (ILC)

Illustration Mary K. Bryson

Lobular
cancer cells
breaking
through the
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
Family/Personal
History

GENDER - All
women are
at risk

Race
Treatment with
DES

Radiation

Reproductive
History
Menstrual
History
Genetic
Factors

Breast Cancer Risk Factors

that can be controlled
Obesity

All
women are
at risk

Exercise
Breastfeeding
Alcohol

Not having
children

Birth Control
Pills
Hormone
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%

Breast Cancer

5%10%

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

Gene

Contribution to
Hereditary Breast
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

ovarian cancer

(6%)

(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
cancer
risk (%)

BRCA1+
carriers
(Ashkenazi
Jews)
General population

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

Struewing JP et al. N Engl J Med 336:1401, 1997

Age

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

Basallike

HER2

Sorlie T et al, PNAS 2001

Normal

Lumina
lB

Lumina
lA

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 shifts25-30%
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 HER2 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
-cellulin
HB-EGF
Epiregulin

Tyrosine kinase
domain

Heregulins

NRG2
NRG3
Heregulins
-cellulin

100

44

36

48

100

82

59

79

100

33

24

28

ErbB-1
Her1
EGFR

ErbB-2
Her2
neu

ErbB-3
Her3

Cysteine-rich
domains

C-terminus

ErbB-4
Her4
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

y
ra
ar
ro
ic *
M ata
D

r e
ce tur
an a
C iter
L

G
Da eno
ta mic
ba
se
s

From ~40,000 genes

ar
l
u
ec gy
l
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
Paik etet
al,al,
SABCS
2003 Res. 61:5979, 2001
4) Gruvberger
Cancer

Three Breast Cancer Studies Used to Select 16

Cancer and 5 Reference Genes
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2

HER2
GRB7
HER2
GSTM1

INVASION
Stromelysin 3
Cathepsin L2

CD68

Best RT-PCR performance

and most robust predictors

BAG1

Paik et al NEJM 2004

ESTROGEN
ER
PGR
Bcl2
SCUBE2
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC

Three Breast Cancer Studies Used to

Develop Recurrence Score (RS) Algorithm

Recurrence
Category
Low risk
Intermediate risk
High risk

RS (0 100)
< 18
18 30
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

DRFS

0 .6

0 .4

0 .2

0 .0

P la c e b o
T a m (B 1
T a m (B 2
Tam + C
0

(B 1 4 )
4)
0)
h e m o (B 2 0 )
2

N
355
668
227
424
4

6
Y e a rs

Paik, SABCS, 2004

10

Intermediate recurrence score means:

Clear benefit from tamoxifen
Uncertain benefit from chemotherapy
1 .0

T CT
0 .8

DRFS

0 .6

0 .4

0 .2

0 .0

P la c e b o
T a m (B 1
T a m (B 2
Tam + C
0

(B 1 4 )
4)
0)
h e m o (B 2 0 )
2

N
355
668
227
424
4

6
Y e a rs

Paik, SABCS, 2004

10

High recurrence score means:

No benefit from tamoxifen
Clear benefit from chemotherapy
1 .0

CT
0 .8

P T
DRFS

0 .6

0 .4

0 .2

0 .0

P la c e b o
T a m (B 1
T a m (B 2
Tam + C
0

(B 1 4 )
4)
0)
h e m o (B 2 0 )
2

N
355
668
227
424
4

6
Y e a rs

Paik, SABCS, 2004

10

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)

Top-to-Bottom

67

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
02/06/16

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
02/06/16

72

Stage
Stage

Stages
of
Breast
Cancer

0 --carcinoma in situ
I tumor < 2 cm, no

nodes
Stage II tumor 2 to 5 cm, +/nodes
Stage III locally advanced

disease, fixed or matted lymph

nodes and variable tumor size
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
discussion
provider.

is
individualized,
with health care

BREAST CONSERVING THERAPY

(BCT)
Breast cancer
screening programs

Increase mass
awareness

BREAST
CONSERVING
SURGERY

Patients with earlier

stages presenting
to clinic

Better Quality
of life

Better psycho-social
Adjustment

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%

Node Negative Women

5 year gain
30.1%

Node Positive Women

EBCTCG meta-analysis. Lancet 2005; 366: 20872106

Chemotherapy Drugs
Adriamycin,
Taxol,

Epirubicin

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
Side

effects 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

time

daily by mouth for variable periods of

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.