1 the breast sara sukumar pathobiology, september 6, 2013

1

The BREAST

Sara SukumarPathobiology,

September 6, 2013

Breast Cancer

• 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

Breast cancer is second only to lung cancer as a cause of cancer deaths in American women

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

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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

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Stucture of the Breast

• Breast has no muscle tissue

• There are muscles underneath the breasts separating them from the ribs

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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

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Ducts

• Lobes, Lobules and bulbs, are linked by a network of thin tubes (ducts)

• Ducts carry milk from bulbs toward dark area of skin in the center of the breast (areola)

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Ducts join together into larger ducts ending at the nipple, where milk is delivered

Duct

Areola

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

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

Intralobular stroma

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.

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Lymphatic System• 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

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A network of vessels

Lymph ductLymph node

Three Types of Vessels

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Bacteria

NourishmentBlood

VesselsCell life

2

Waste products

LymphNodes

LymphVessels

3

MilkLobules Ducts Nipple

1

Signs and Symptoms

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Most common: lump or thickening in breast. Often painless

Change in color or appearance of areola

Redness or pitting of skin over the breast, like the skin of an orange

Discharge or bleeding

Change in size or contours of breast

Noncancerous Conditions (1)

• Fibrocystic changes: Lumpiness, thickening and swelling, often associated with a woman’s 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 lump04/18/23 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)

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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

04/18/23 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

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Enlargement

A normal duct cells

B basement membrane (duct wall)

C lumen (center of duct)

Illustration © Mary K. Bryson

Ductal Carcinoma in situ (DCIS)

22Illustration © Mary K. Bryson

Ductal cancer cells

Normal ductal cell

Invasive Ductal Carcinoma (IDC – 80% of breast cancer)

• 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


Ductal cancer cells breaking through the wall

Range of Ductal

Carcinoma in situ (DCIS)

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Invasive Lobular Carcinoma (ILC)


Lobular cancer cells breaking through the wall

Cancer Can also Invade Lymph or Blood Vessels-Metastatic breast

cancer


Cancer cells invade lymph duct

Cancer cells invade blood vessel

Factors determining risk of developing

Breast Cancer

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GENDER - All women are

at risk

Age

Family/PersonalHistory

ReproductiveHistory

MenstrualHistoryRace

Genetic Factors

Breast Cancer Risk Factorsunalterable factors

Radiation

Treatment withDES

All women are

at risk

Obesity

Breastfeeding

Not having children

Birth ControlPills

AlcoholHormone

ReplacementTherapy

Exercise

All women are

at risk

Obesity

Breastfeeding

Not having children

Birth ControlPills

AlcoholHormone

ReplacementTherapy

Breast Cancer Risk Factorsthat can be controlled

Exercise

Potential Applications forBreast 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

SporadicSporadic

Family clustersFamily clusters

HereditaryHereditary

Ovarian CancerOvarian CancerBreast CancerBreast Cancer

5%–10%5%–10% 5%–10%5%–10%

15%-20%15%-20%

Causes of Hereditary Susceptibility to Breast

Cancer

GeneGene

BRCA1BRCA1

BRCA2BRCA2

TP53TP53

PTENPTEN

Undiscovered genesUndiscovered genes

Contribution to Hereditary Breast

Cancer

20%–40%

10%–30%

<1%

<1%

30%–70%

5 to 10% of breast cancers can be attributed to inherited factors

* Li-Fraumeni Syndrome, abnormal TP53

gene on chromosome 17p, associated with

premenopausal breast cancer, childhood

sarcomas, brain tumors, leukemia, and

adrenocortical adenomas

*Cowden’s 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

Possible increased risk of other cancers (e.g. prostate, colon)

Breast cancer 50%-85%(often early age at onset, less than 40 years)

Second primary breast cancer 40%-60%

Ovarian cancer 15%-45%

BRCA2-Associated Cancers: Lifetime Risk

Increased risk of prostate, laryngeal, and pancreatic

cancers (magnitude unknown)

breast cancer (50%-85%)

ovarian cancer (10%-20%)

male breast cancer (6%)

Comparing Breast Cancer Risk Comparing Breast Cancer Risk Estimates in BRCA Mutation CarriersEstimates in BRCA Mutation Carriers

Breast Breast cancer cancer

risk risk (%)(%)

General populationGeneral population

BRCA1BRCA1+ + carrierscarriers(BCLC)(BCLC)

BRCA1BRCA1+ + carrierscarriers(Ashkenazi (Ashkenazi Jews)Jews)

AgeAgeEaston DF et al. Easton DF et al. Am J Hum GenetAm J Hum Genet 56:265, 1995 56:265, 1995Struewing JP et al. Struewing JP et al. N Engl J MedN Engl J Med 336:1401, 1997 336:1401, 1997

0

20

40

60

80

100

40 50 60 70 80

Established Prognostic Markers for Breast Cancer

•Axillary lymph nodes•Tumor size•Histological grade•Histological tumor type•Steroid receptor status•Age• NIH Consensus Conference 2000

Molecular Portrait of Breast CancersHER-

2Basal-

likeLumina

l A

Luminal B

“Normal”

Sorlie T et al, PNAS 2001

Subtypes and Prognosis

Sorlie T et al, PNAS 2001

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

Tx activation domain

2 cys-rich zinc fingersRecognize EREs, and stabilize

Hinge region

Variable

Activation of Estrogen Receptor

JM Hall et al, JBC 2001.

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


• Predict risk of cancer development• Estimate prognosis for established cancer• Predict response to therapy• Identify therapeutic targets• Identify early detection markers

EGFTGF

Amphiregulin-cellulinHB-EGF

Epiregulin Heregulins

NRG2NRG3

Heregulins-cellulin

Cysteine-richdomains

Tyrosine kinasedomain

ErbB-1Her1

EGFR

ErbB-2Her2neu

ErbB-3Her3

ErbB-4Her4

C-terminus

100

100

100

44

82

33

36

59

24

48

79

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The EGFR (ErbB) family and ligands

www.astrazeneca.com

Copyright ©2004 AlphaMed Press

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

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.

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 (van’t Veer, Nature 2002)

• Subset outcomes for women with node-negativeER-positive breast cancer treated with tamoxifen (Paik, NEJM 2004, SABCS 2004)

Now available--$3400Should we use it?

For whom?How?

So What Good is All this Molecular Analysis??

Candidate Gene SelectionFrom ~40,000 genes

Cancer

Literature

Microarray

Data*G

enom

ic

Dat

abas

es

250 cancer-related

candidate genes

Molecu

lar

Biology

*Sources include:1) Van 't Veer et al, Nature 415:530, 20022) Sorlie et al, Proc. Natl. Acad. Sci. USA 98:10869, 20013) Ramaswamy et al, Nature Genetics 33:4, 2003 4) Gruvberger et al, Cancer Res. 61:5979, 2001Paik et al, SABCS 2003

Three Breast Cancer Studies Used to Select 16 Cancer and 5 Reference Genes

PROLIFERATIONKi-67STK15

SurvivinCyclin B1MYBL2

ESTROGENER

PGRBcl2

SCUBE2

INVASIONStromelysin 3Cathepsin L2

HER2GRB7HER2

GSTM1REFERENCEBeta-actin

GAPDHRPLPOGUSTFRC

Best RT-PCR performance and most robust predictors

CD68

BAG1

Paik et al NEJM 2004

Three Breast Cancer Studies Used to Develop Recurrence Score (RS) Algorithm

Paik et al, SABCS 2003

RS = + 0.47 x HER2 Group Score - 0.34 x ER Group Score + 1.04 x Proliferation Group Score + 0.10 x Invasion Group Score + 0.05 x CD68 - 0.08 x GSTM1 - 0.07 x BAG1

Paik et al, SABCS 2003

Recurrence Recurrence CategoryCategory RS (0 – 100)RS (0 – 100)

Low riskLow risk < 18< 18

Intermediate riskIntermediate risk 18 – 3018 – 30

High riskHigh risk ≥ ≥ 3131

Low recurrence score means:Clear benefit from tamoxifen

No benefit from chemotherapy

0 2 4 6 8 10

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS

P lacebo (B 14) Tam (B 14) Tam (B 20) Tam + C hemo (B 20)

N355668227424

P

T CT

Paik, SABCS, 2004

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

0 2 4 6 8 10

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS


N355668227424

P

T CT

Paik, SABCS, 2004

High recurrence score means: No benefit from tamoxifen Clear benefit from chemotherapy

0 2 4 6 8 10

Years

0.0

0.2

0.4

0.6

0.8

1.0

DR

FS


N355668227424

P T

CT

Paik, SABCS, 2004




• 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

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Mammography Equipment

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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

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National Cancer Institute

What Mammograms ShowTwo 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.

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Detection of Malignant Masses

Malignant masses have a more spiculated appearance

64malignant benign

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

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Different Views

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Top-to-Bottom

Side-to-Side

MRI - Cancer can have a uniqueappearance – many small irregularwhite areas that turned out to becancer (used for diagnosis)

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 toComputer-Aided 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

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Content-based image retrieval techniques can provide radiologists “visual aids” to increase confidence in their diagnosis

Outline- Part 2

• How is breast cancer:

• Detected

• Diagnosed

• Treated

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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 therapies—

radiation and/or chemotherapy,hormonal therapies

04/18/23 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 04/18/23 72

04/18/23 CBMS2006 73

Stages ofBreastCancer

Stage 0 --carcinoma in situ

Stage 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?

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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

How is breast cancer treated?

3. ADJUVANT THERAPY: Medical therapy to decrease the chance of tumor recurrence - to improve the chances for cureChemotherapy - many different therapiesHormonal 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.

BREASTCONSERVING

SURGERY

Breast cancer screening programs

Increase mass awareness

Patients with earlier stages presenting

to clinic

Better psycho-social Adjustment

BREAST CONSERVING THERAPYBREAST CONSERVING THERAPY(BCT)(BCT)

Better Quality of life

MRM Vs BCT

Randomized trials

Meta-analysis

Comparable local control, Overall survival

Better cosmetic outcome

BCT: EFFECT OF RADIOTHERAPY ON LOCAL BCT: EFFECT OF RADIOTHERAPY ON LOCAL RECURRENCERECURRENCE

EBCTCG meta-analysis. Lancet 2005; 366: 2087–2106

5 year gain 16.1%

5 year gain 30.1%

Node Negative Women Node Positive Women

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Chemotherapy Drugs

Adriamycin, Epirubicin

Cytoxan

Methotrexate, 5-fluorouracil

Taxol, Taxotere

Navelbine

Intravenous

Nausea, hair loss, low blood counts, cardiac toxicity,

bladder toxicity, nerve damage

Given for adjuvant or recurrent disease.

Tamoxifen*

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Can be given to pre or post menopausal women

Works by blocking estrogen receptors in breast cells, inhibiting their growth

Side effects include hot flashes, depression, increased risk of uterine cancer and blood clots

Taken daily by mouth for 5 years

Aromatase is the enzyme that converts androgens to estrogen

82

AIs are only given to postmenopausal women

“May” be more effective than Tamoxifen

Examples: Anastrozole/Arimidex, Letrozole/Femara, Exemestane/Aromasin

Side effects include hot flashes, depression, osteoporosis, joint pains

Taken daily by mouth for variable periods of time

Aromatase Inhibitors*

Trastuzumab/Herceptin

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

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.

1 the breast sara sukumar pathobiology, september 6, 2013

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