Breast CancerXiaoming Xie, M.D. and Ph.D.

Department of Breast OncologySun Yat-Sen University Cancer Center

谢小明

中山大学肿瘤防治中心 乳腺科

Email:xxie1234@yahoo.com

Tel: 61639540 (O) ， 13826109540 (Cell)

Jemal ， A., et al. CA Cancer J Clin 2008; 58:71-96

Breast cancer is the most common cancer and the second leading cause of cancer-related death for women in USA

Breast cancer is more frequently diagnosed in affluent countries and the death rate is higher in developing

countries

Recent Decrease in UK and USA Breast Cancer Mortality at Ages 50 69 Years

Modified from Peto et al. Lancet 355:1822, 2000

Adj CTX

Adj HT

Screening

USA: Survival with breast cancer

• Survival rates are increasing1

74.9

87.7

65

70

75

80

85

90

1975– 1979 1995– 2000

5-y

ear

rela

tive

surv

ival

rat

es (

%)

1Ries, et al. SEER Cancer Statistics Review, 1975–2001. Available at: http://seer.cancer.gov/csr/1975_2001; 2004

Five Year Relative Survival Rates for Breast Cancer: 1973 - 2005

85

98

53

80

10

26

01020

3040

5060

7080

90100

Localized Regional Distant

19732005

Cancer survivors increased from 3 M to 9 M in the same period

CA, Jan 1973 and Jan 2005

Functional Anatomy

Blood Supply

(1) perforating branches of the internal mammary artery;

(2) lateral branches of the posterior intercostal arteries(3,4,5);

(3) branches from the axillary artery, including the highest thoracic, lateral thoracic, and pectoral branches of the thoracoacromial artery

The veins of the breast and chest wall

The three principal groups of veins (1) perforating branches of the

internal thoracic vein; (2) perforating branches of the

posterior intercostal veins; (3) tributaries of the axillary vein.

The vertebral venous plexus of Batson, which invests the vertebrae and extends from the base of the skull to the sacrum, may provide a route for breast cancer metastases to the vertebrae, skull, pelvic bones, and central nervous system. Lymph vessels generally parallel the course of blood vessels.

Neural anatomy of the breast

• Lateral cutaneous branches of the third through sixth intercostal nerves provide sensory innervation

• Lateral pectoral n.

• Medial pectoral n.

• Long Thoracic n.: supply the serratus anterior muscle. “winging of the scapula and loss of shoulder power”

• Thoracodorsal n. （ approach subscapular artery ） : supply latissimus dorsi muscle.

The lymphatic drainage of the breast

75%20-25%

The lymph node groups

1. level I LN(14-19). located lateral to or below the lower border of the pectoralis minor muscle: the axillary vein （ 4-6): external mammary （ 5-6), scapular groups （ 5-7 ）

2. Level II LN (5-8): located superficial or deep to the pectoralis minor muscle the central(3-4), interpectoral groups (Rotter’s ） (1-4)

3. Level III LN : located medial to or above the upper border of the pectoralis minor muscle: the subclavicular group （ 6-12)

Risk factors - unchangeable

1. Being a woman

2. Age

3. Genetic factors - mutations in BRCA1 or BRCA2; 50-60% of women inheriting a BRCA1 mutation from either parent will have breast cancer by age 70

4. Family history of breast cancer (not related to BRCA mutations)

5. Personal history of hyperplastic breast disease

Chance of developing breastcancer

20 30 40 50 60 70 80 900.00

0.05

0.10

0.15

Risk of ever developingcancer = 0.125 (1 in 8)

Age

rela

tive

ris

k

Risk factors - unchangeable

1. Being a woman

2. Age

3. Genetic factors - mutations in BRCA1 or BRCA2; 50-60% of women inheriting a BRCA1 mutation from either parent will have breast cancer by age 70

4. Family history of breast cancer (not related to BRCA mutations)

5. Personal history of hyperplastic breast disease

Risk factors - unchangeable/contd.

6. Personal history of breast cancer

7. Race: incidence is higher in Caucasian compared with African-American, Hispanic or Asian women.

8. Radiation treatment: chest irradiation as a child/young woman can significantly increase risk of developing breast cancer.

9. Dense breast tissue.

10. Menstrual history: early menarche (<12 yr) or late menopause (>50yr) has some association with increased risk. Also nulliparous, or first childbirth at >30 yrs.

Risk factors associated with lifestyle

1. Oral contraceptives - remains controversial

2. Hormone replacement therapy - >5 years of therapy with combined estrogen and progesterone may increase risk

3. Not breast feeding

4. Obesity, lack of physical activity

5. Alcohol - 2-5 drinks/day can increase risk x 1.5 over non-drinkers.

Factors with uncertain, controversial or unproven effects on risk of developing breast

cancer

1. High fat diet 2. Induced abortions3. Breast implants4. Environmental chemical exposure (e.g. pesticides)5. Tobacco smoke6. Night shift work7. Human mammary tumor virus ?

Hereditary Breast Cancer

• Hereditary breast-ovarian cancer (HBOC) syndrome ：Mutation in BRCA1, BRCA2 genes

• Ataxia telangiectasia (A-T) : Mutation in ATM gene

• Li-Fraumeni syndrome: Mutation in p53 gene (? CHEK2 gene).

• Cowden syndrome: Mutation in PTEN gene

• Peutz-Jeghers syndrome: Mutation in STK11 gene

Breast cancer risk assessment tool (BCRAT)

• BCRAT- based on Gail model, using woman’s personal medical history (previous breast biopsies, ATH), reproductive history, whether first degree relatives had breast cancer, to estimate risk of invasive breast cancer over specific periods of time (www.cancer.gov/bcrisktool)

• CARE model gives more accurate estimates of breast cancer risk for African-American women. Gail et al, JNCI 99: 1782-1792, 2007.

Histopathology of Breast Cancer

Carcinoma In Situ

• Ductal carcinoma in situ (DCIS) ,cribriform type

• Ductal carcinoma in situ (DCIS) , cemedo type

• Lobular carcinoma in situ (LCIS)

Invasive Breast Carcinoma• Paget's disease of the nipple

• Invasive ductal carcinoma.A. Adenocarcinoma with productive fibrosis (scirrhous, simplex, NST) 80%B. Medullary carcinoma 4%C. Mucinous (colloid) carcinoma 2%D. Papillary carcinoma 2%E. Tubular carcinoma (and ICC) 2%

• 3 ） Invasive lobular carcinoma 10%

• 4 ） Rare cancers (adenoid cystic, squamous cell, apocrine)

Invasive ductal carcinoma

• Infiltrating lobular carcinoma

• Blood vessel invasion

• Lymphatic invasion

Microinvasive breast cancer

• The extension of cancer cells beyond the basement membrane into the adjacent tissues with no focus greater than 0.1 cm in its greatest dimension.

• Stage: T1mic.• Can be seen in association with DCIS and LCIS• First stage in the development of invasion.

Diagnosing breast cancer

Triple assessment

Clinical Imaging Pathology

Age

Examination

Ultrasound

Mammography

MRI

Fine needle aspiration cytology

Core-cut biopsy

Clinical Presentation

• New lumps or a thickening in the breast or under the arm

• Nipple tenderness, discharge, or physical changes

• Skin irritation or changes (puckers, dimples, scaliness, or new creases)

Symptoms that may indicate breast cancer• Lumps in the breast: single, hard and painless, irregular in shape

• Lumps in the armpit

• Breast pain: seldom (most the menstrual cycle, cyclic mastalgia)

• Bleeding or discharge from the nipple (5%)

• Involution or inversion of the nipple

• Swelling of the arm (lymphedema)

• Dimpling, ulceration of skin

• Changes in size or shape of the breast

• Symptoms of secondary tumors

• A breast lump is most often the clinical problem that causes women to seek treatment and remain the most common presentation of breast carcinoma. 65% of breast cancer cases.

• Other less frequent presenting signs and symptoms of breast cancer include (1) breast enlargement or asymmetry; (2) nipple changes, retraction, or discharge; (3) ulceration or erythema of the skin of the breast; (4) an axillary mass; and (5) musculoskeletal discomfort.

• However, some of women presenting with breast complaints have no physical signs of breast pathology. Breast pain usually is associated with benign disease.

Lump

Dimpling: skin retraction, tumors deep within the substance of the breast that involves the Cooper’s ligaments)

Peau d’orange: edema of the breast.

Usually obstruction of the dermal lymphatics with tumor, extensive axillary LN involvement related met tumor, primary disease of the axillary nodes, axillary dissection. (also after irradiation of the breast).

Changes in the skin of the breast (DPUSE)

Ulceration: in advanced case, the tumor may involve the skin, leading to it.

Satellite change: tumor cells enter the lymphatic vessels and form masses around the primary site.

Erythema ： inflammatory breast cancer, usually involves the entire breast and is distinguished from the inflammation due to infection by the absence of breast tenderness and fever.

Nipple retraction ： tumor involves the tissue beneath the nipple.

Bleeding:

Eczematous change: Paget's

Changes in the character of the skin.

The nipple change

Lymph nodes

Breast self-examination

• Encourage • Adverse effect: a lifetime of uncertainty and

anxiety for the patient (of proven harm!)• Controversy

Mammography

• Annual screening mammography beginning at age 40 years is recommended in the United States

• Mammography is shown to reduce mortality from breast cancer by as much as 44%

• American Cancer Society (ACS) 1997

Aged > 40 Annual mammogram

Screening Mammography (cont.)

Invasive cancer (4 mm) Malignant microcalcifications

Ultrasonography

• Ultrasonography is an important method of resolving equivocal mammography findings, defining cystic masses, and demonstrating the echogenic qualities of specific solid abnormalities.

• Breast cysts are well circumscribed, with smooth margins and an echo-free center

• Benign breast masses usually show smooth contours, round or oval shapes, weak internal echoes, and well-defined anterior and posterior margins

• Breast cancer characteristically has irregular walls

．

乳腺癌沿 Cooper’s韧带浸润》 50% ， C3级

肿瘤穿破浅筋膜浅层和韧带已达皮下， C4级。

MRI

• High sensitivity (94 – 100%)• Low specificity (37 – 97%)• Better “screening” tool than mammography in

high-risk populations• Expensive, invasive and more time consuming

Breast Biopsy 1. Fine-needle aspiration (FNA) biopsy

Sensitivity: 65 ～ 98%

Specificity: 34 ～ 100%

False-positive Rate: 0.17%

2. Core-needle biopsy 2. Core-needle biopsy

Automated biopsy gun (14-guage, 5 core samples for mass and 5-10 for Automated biopsy gun (14-guage, 5 core samples for mass and 5-10 for microcalcification)microcalcification)

Directional vacuum-assisted biopsy (Mammotome, EnCore)

Stereotactic Core Biopsy

Nonpalpable Lesion

Sensitivity: 92 ～ 100%

Nonpalpable Lesion

Imaging-guide Needle Localization

3. Incisional or Excisional Biopsy

Biomarkers and Circulatory tumor cells

• Carcinoembryonic antigen (CEA): positive rate 20%-70%.

• The MUC -1 gene product (CA15-3: positive 33-60%; CA27.29).(Ch 1q21-24).

• The HER-2/neuextrocellular domain (Ch 17q11-12). 20-30% overexpression.

• New serum tumor markers (uPA ， urokinase plasminogen activator; PAI-1, plasminogen activator inhibitor-1).

• Circulatory tumor cells (CTC), 5 or more CTC cells in the blood of patients with MBC.

Comparative frequency of fibrocystic changes, fibroadenomas, and carcinomas by age groups

Staging

• TNM• Histologic type (DCIS. LDIS, IBC)• Hormone receptors (ER,PR)• Oncogenes (Her-2)• Staging procedures

TNM staging

• TNM 'Staging' takes into account the size of the tumour (T); whether the lymph nodes (N) are affected and;

whether the tumor has matastasized (M) anywhere else. 

• The TNM system for staging is a frequently used staging system used all over the world. 

• More likely to use this staging system because it describes stage more accurately than others.

• Treat breast cancer according to the staging and grade.

The T0 and Tis Stage

Tx: primary tumor cannot be assessed

T0 ： No evidence of primary tumor

Tis: Carcinoma in situ

Tis (DCIS), Ductal carcinoma in situ

Tis (LCIS), lobular carcinoma in situ

Tis (Paget’s), paget’s disease of the nipple with

no tumor.

Modified from American Joint Committee on Cancer: AJCC Cancer Staging Manual, 6th ed. New York: Springer, 2002, pp 227–228.

T1 Stage

• T1mic: <0.1 cm• T1a:>0.1- ≤ 0.5 cm• T1b: >0.5- ≤ 1.0 cm• T1c: >1.0- ≤ 2.0 cm

T2 Stage

• T2:>2.0-≤0.5

T3 Stage

• T3: >5.0 cm

T4 Stage

Tumor of any size with direct extension to (a) chest wall or (b) skin, only as described below

• T4a: The tumor is fixed to the chest wall• T4b: The tumor is fixed to the skin• T4c: T4a+T4b• T4d: inflammatory carcinoma (red, swollen,and painful

to the touch)

Risk of Recurrence and Survival by Tumor Size for Patients with Node-Negative Disease

Tumor Size

(cm)

10-Yr. Recurrence Rate

(%)

5-Yr. Survival Rate (%)

≤1.0 10 98

1.1-2.0 15 92

2.1-3.0 25 90

3.1-4.0 40 86

> 4.0 55 82

The N stage (clinical regional LN ）• Nx ： Regional lymph nodes cannot be assessed (e.g., previously

removed) .

• N0: No cancer cells found in any LN.

• N1: Metastasis to movable ipsilateral axillary LN.

• N2: N2a:Met in ipsilateral axillary LN fixed or matted or to other structures, N2b:Met only in clinically apparenta ipsilateral internal mammary LN and

in the absence of clinically evident axillary LN met.

• N3: N3a:Met in ipsilateral infraclavicular LN.

N3b: Met in ipsilateral internal mammary LN and axillary LN. N3c: Metastasis in ipsilateral supraclavicular LN.

0 12 24 36 48 60 72 84 96 108 120

Months

1.0

0.8

0.6

0.4

0.2

0.0

Pro

port

ion

Rel

apse

Fre

e

Nodal Status

01-34-910+

Chang JC, Hilsenbeck SG in Dis of the Br 3rd Ed, p 673-696, 2004

Relapse Free Survival and Number of Involved Lymph Nodes

Lymph Node Metastasis and SurvivalOverall Survival Disease-Free Survival

The N stage (pathologic regional LN ）• pNx ： Regional LN cannot be assessed (e.g., previously removed) • pN0: No regional LN met histologically. pN0(i-),IHC; pN0(i+), IHC ， no IHC cluster greater than 0.2 mm. pN0(mol-),RT-PCR; pN0(mol+), RT-PCR.

• pN1: Met in 1 to 3 axillary LN, and/or in internal mammary LN with microscopic disease detected by SLN dissection, not clinically apparent.

pN1mi: Micrometastasis (greater than 0.2 mm, none greater than 2.0 mm) pNia: met in 1-3 axillary LN.

pN1b: met in internal mammary LN with microscopic disease detected by SLN dissection pN1c: pNia+pN1b.

• pN2: Met in 4 to 9 axillary LN, or in clinically apparenta internal mammary LN in the absence of axillary lymph node metastasispN2a: Met in ipsilateral axillary LN fixed or matted to other structures,

pN2b:Met only in clinically apparenta ipsilateral internal mammary LN and in the absence of clinically evident axillary LN met.

• pN3: Met in 10 or more axillary LN (pN3a), or in infraclavicular LN (pN3a), or in clinically apparenta ipsilateral internal mammary LN in the presence of 1 or more positive axillary LN; or in more than 3 axillary LN with clinically negative microscopic met in internal mammary LN (pN3b); or in ipsilateral supraclavicular LN (pN3c).

The M stage (distant metastasis)

• Mx: Distant metastasis cannot be assessed • M0: No distant metastasis • M1 ： Distant metastasis.

Stage and Grade• The stage of breast cancer means how far it has

grown and whether it has spread. 

• The grade means what the cancer cells look like under the microscope.  Breast cancers can be

grade 1 (Low grade or slow growing)    

grade 2  ( Intermediate grade )  

grade 3 (High grade or fast growing)

What the number staging system

Stage 0. Tis, N0, M0.

Stage I. T1 ， N0, M0. When the cancer has spread beyond a milk duct or lobe, but not

outside the breast. The tumor size for this stage is equal to or less than 2 cm.

• The tumour is no more than 2 cm across (T1)    • The LN in the armpit are not affected    • The cancer has not spread

Stage II • This is divided into two groups

Stage IIA : T0,N1,M0; T1,N1,M0; T2,N0,M0; T1,N1,M0 : The tumour is less than 2 cm, the LN under the arm contain cancer but are not stuck to each other and the cancer has not spread.

T2,N0,M0: The tumour is less than 5 cm, there are no cancer cells in LN in the armpit and the cancer has not spread.

T0,N1,M0: Although no tumour is seen in the breast, the LN under the arm contain cancer cells but are not stuck together, and there is no sign of spread to other parts of the body.

Stage IIB: T2,N1,M0; T3,N0,M0T2,N1,M0 : The tumour is less than 5 cm and the LN under the arm contain cancer cells but are not stuck to each other, and the cancer has not spread or    T3,N0,M0 : The tumour is bigger than 5 cm across, there are no cancer cells in the lymph nodes in the armpit and the cancer has not spread

Stage IIIStage IIIA: T0,N2,M0; T1,N2,M0; T2,N2,M0;T3,N1,M0;T3,N2,M0.

Although no tumour is seen in the breast, the lymph nodes under the arm contain cancer cells and are stuck together, but there is no sign of cancer spread or    The tumour is 5 cm or less, the lymph nodes in the armpit contain cancer cells and are stuck to each other, but the cancer has not spread elsewhereor    The tumour is more than 5 cm, the lymph nodes in the armpit contain cancer cells and may be stuck together, but there is no further spread.

Stage IIIB: T4,N0,M0; T4,N1,M0; T4,N2,M0.The tumour is fixed to the skin or chest wall, the lymph nodes may or may not contain cancer cells, but there is no further spread.

Stage IIIC: Ant T, N3, M0. The tumour can be any size and has spread to lymph nodes in the armpit

and under the breast bone, or to nodes above or below the collarbone, but there is no further spread.

Stage IV• Stage IV. Ant T, any N, M1.

Metastatic cancer, which is cancer that has spread to other more distant organs of the body.

Frequent metastatic sites for breast cancer are the bones, lungs, liver or brain. Stage IV is also the classification given to inflammatory breast cancer or breast cancer that has spread to the lymph nodes in the neck near the collarbone.

• The tumour can be any size   

• The lymph nodes may or may not contain cancer cells   

• The cancer has spread or metastasised to other parts of the body such as the lungs, liver or bones

Survival rate and prognosis factors

Stage Survival rate at 8 year(%)

Stage 90Ⅰ

Stage 70Ⅱ

Stage 40Ⅲ

Stage 10Ⅳ

Early Breast Cancer TNM Staging System

T0 No evidence of primary tumor

Tis Ductal carcinoma in situ or lobular carcinoma in situ

T1 Tumor ≤2 cm

T2 Tumor >2 cm but ≤5 cm

Greene FL, et al. AJCC Cancer Staging Manual, 6th ed., 2002.

Early Breast Cancer TNM Staging System (cont.)

NX Regional lymph nodes cannot be assessed

N0 No involvement of regional lymph nodes

N1 Involvement of one to three axillary lymph nodes

MX Distant metastases cannot be assessed

M0 No distant metastases

Stage Classifications for Early Stage Disease

Stage 0 Tis N0 M0

Stage I T1 N0 M0

Stage IIA T0 N1 M0

T1 N1 M0

T2 N0 M0

Stage IIB T2 N1 M0

Singletary SE, et al. J Clin Oncol. 2002;20:3576-3577.

Locally Advanced Breast Cancer （ LABC ）

This means the cancer has not spread to another part of the body but may be:

• Bigger than 5 cm across    • Growing into the skin or muscle of the chest    • Present in the lymph nodes in the armpit, and these

lymph nodes are either stuck to each other, or other structures

NCCN 2010 Breast Cancer

Overall survival for women with breast cancer according to axillary lymph node status.

Risk of metastases according to breast cancer volume and diameter

Biomarkers of Breast cancer

Biomarkers and Circulatory tumor cells

• Carcinoembryonic antigen (CEA): positive rate 20%-70%.

• The MUC -1 gene product (CA15-3: positive 33-60%; CA27.29).(Ch 1q21-24).

• The HER-2/neuextrocellular domain (Ch 17q11-12). 20-30% overexpression.

• New serum tumor markers (uPA ， urokinase plasminogen activator; PAI-1, plasminogen activator inhibitor-1).

• Circulatory tumor cells (CTC), 5 or more CTC cells in the blood of patients with MBC.

>30%

Comparison of IHC （ 3+ ） and FISH for Her-2

×40 ×100

ID ： 177319

Invasive ductal carcinoma grade II. IHC ： +++

FISH ： +