BREAST CANCER

Başak Oyan-Uluç, MDYeditepe University Hospital

Department of Medical Oncology

Epidemiology

• Breast cancer is the most common lethal neoplasm in women.

• The incidence varies among different populations.

• 1 out of 8 women will have BC in her life-time.

• The incidence of male breast cancer is about 1 % of all breast cancer cases occur in men.

2007 Estimated US Breast Cancer incidence and mortality*

*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.Source: American Cancer Society, 2007.

Women678,060

•26% Breast

•15% Lung & bronchus

•11% Colon & rectum

•6% Uterine corpus

• 4% Non-Hodgkin lymphoma

•4% Melanoma of skin

• 4% Thyroid

• 3% Ovary

• 3% Kidney

•3% Leukemia

•21% All Other Sites

Women270,100

•26% Lung & bronchus

•15% Breast

•10% Colon & rectum

• 6% Pancreas

• 6% Ovary

• 4% Leukemia

• 3% Non-Hodgkin lymphoma

• 3% Uterine corpus

• 2% Brain/ONS

• 2% Liver & intrahepaticbile duct

•23% All other sites

INCIDENCE MORTALITY

Lifetime Probability of Developing Cancer, by Site, Women, US, 2001-2003*

Site Risk

All sites† 1 in 3

Breast 1 in 8

Lung & bronchus 1 in 16

Colon & rectum 1 in 19

Uterine corpus 1 in 40

Non-Hodgkin lymphoma 1 in 55

Ovary 1 in 69

Melanoma 1 in 73

Pancreas 1 in 79

Urinary bladder‡ 1 in 87

Uterine cervix 1 in 138

Source: DevCan: Probability of Developing or Dying of Cancer Software, Version 6.1.1 Statistical Research and Applications Branch, NCI, 2006. http://srab.cancer.gov/devcan

* For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2001 to 2003.

† All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder.

‡ Includes invasive and in situ cancer cases

Incidence varies among different populationsAge-specific incidence (per 100,000)

Adapted from New Horizons in Cancer Management, SRI International, 1990.

Inc

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ate

sIn

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Ra

tes

20 25 30 35 40 45 50 55 60 65 70 75 80 85+24 29 34 39 44 49 54 59 64 69 74 79 84

420400

300

200

100

0

AgeAge

UnitedStates

Englandand Wales

Italy

France

Japan

5-year Relative Survival

*5-year relative survival rates based on follow up of patients through 2003. †Recent changes in classification of ovarian cancer have affected 1996-2002 survival rates.Source: Surveillance, Epidemiology, and End Results Program, 1975-2003, Division of Cancer Control andPopulation Sciences, National Cancer Institute, 2006.

 

 

 

Site 1975-1977 1984-1986 1996-2002• All sites 50 53 66• Breast (female) 75 79 89• Colon 51 59 65• Leukemia 35 42 49• Lung and bronchus 13 13 16• Melanoma 82 86 92• Non-Hodgkin lymphoma 48 53 63• Ovary 37 40 45• Pancreas 2 3 5• Prostate 69 76 100• Rectum 49 57 66• Urinary bladder 73 78 82

†

Etiology

• Hormones• Endogenous exposure: major risk• Exogenous exposure: e.g. hormone replacement therapy

• Genetics• Majority of BC are diagnosed in women with no risk

factors• 10-20% have a family history• Only 5-10%: attributed to a known gene defect

• Other• Age • Radiation• Breast disease • Alcohol• Parity and lactation • Physical activity

Hormones

• Endogenous exposure– Early menarche: <12 years – Late menapouse: >55 years – Delayed childbirth: >30 years – Postmnopausal obesity

• Exogenous exposure– Hormone replacement therapy

• Increased risk if used >5 years • Risk increase more with combined estrogen-progesterone replacement

– Oral contraceptive • Not increase risk

• Surgical or medical castration <37 years: decrease risk

Age

• Age: risk increases steadily after age 50

Age Risk25 19.600855 1/3375 1/1180 1/10All 1/8

Benign breast cancer

• Benign breast disease– Fibrocystic disease: not increase risk– Hyperplasia with atypia– Papilloma increased risk– Sclerosing adenosis– Lobular carcinoma in situ

Other risk factors

• Lactation: Decrease risk

• Nulliparity

• Diet and lifestyle – Obesity esp. postmenapousal, – Excessive alcohol consumption: >1 drink/day

• Physical activity

• Radiation before age 40• Up to a 30% increased risk• 20 years after exposure

How Much Breast and Ovarian Cancer is Hereditary?

Causes of Hereditary Susceptibility

BRCA1-Associated Cancers: Lifetime Risk

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

BRCA-1

• On chromo. 17

• Tumor supressor gene

BRCA 2-Associated Cancers: Lifetime Risk

Increased risk of prostate, laryngeal, melanoma and pancreatic cancers (magnitude unknown)

BRCA-2

• On chromo. 13

• Tumor supressor gene

Other Gene Defects in Breast Cancer

• P53 gene (tumor supressor gene)– On chromosome 17– Associated with Li-Fraumeni syndrome– Increased risk of breast and rare tmors (sarcoma, brain tm,

leukemia, tumors of adreanl glands)– Lifetime risk for breast cancer: 50%

• PTEN (tumor supressor gene)– Associated with Cowden’s syndrome (multiple benign

hamartomes and malignant tumors)– Premenopausal breast cancers, gastrointestinal

malignancies, and benign and malignant thyroid disease

Indications for genetic testing of BRCA-1 and BRCA-2

• Multiple cases of early onset breast cancer in family history

• Breast and ovarian cancer in the same woman

• Bilateral breast cancer

• Male breast cancer

• Ashkenazi Jewish decent with breast cancer

Pathology• Non-invasive carcinoma in situ

– Ductal carcinoma in situ (DCIS)– Lobular carcinoma in situ (LCIS)

• Invasive carcinoma– Invasive ductal carcinoma (70-80%)– Invasive lobular carcinoma (10%)– Special types with a good prognosis:

• Medullary, mucinous, papillary and tubular carcinomas• Adenocystic carcinoma

• Uncommon tumors– Inflammatory carcinoma (1%)– Paget’s disease

Dollinger M, et al. Everyone’s Guide to Cancer Therapy. 1997;356-384.

Normal breastduct

DCIS (Ductal Carcinoma in Situ)

Invasive Cancer

Metastasis to lymph nodes

Invasive Cancer

Invasive ductal carcinoma:

Tends to be unilateral

Invasive lobular carcinoma:

Increased risk of bilateral breast cancer

Inflammatory carcinoma:

Poorest prognosis

Breast dermal lymphatics are infiltrated with tumor

Inflammatory breast cancer

• Rare, fast-growing type of cancer• Often causes no distinct lump• Breast skin may become thick, red, and may look pitted -- like an orange

peel. • May also feel warm or tender and have small bumps that look like a rash.

Paget’s disease of breast

• Unilateral eczema appearance of the nipple

• Always associated with DCIS in women

LocationMost are located in upper outer quadrant

RIGHT

Upper inner

Nipple

Central portion

Lower inner

Upper outer

Axillary tail

Lower outer

Spread to lymph nodes

Supraclavicular

Subclavicular

Distal (upper)

axillary

Central (middle)

axillary

Proximal (lower)

axillary

Mediastinal

Internal mammary

Interpectoral

(Rotter’s)

Sites of distant metastases

SkinSkin

LiverLiver

BoneBone

PleuraPleura

LungLung

Lymph nodesLymph nodesBrainBrain

Natural history

• Highly variable in different patients

• Relatively slow growth rate

• Median survival without treatment: 2.8 yrs

• Generally present several years by time of diagnosis

• Long preclinical period enables early detection

Henderson IC. American Cancer Society Textbook of Clinical Oncology. 1995;198-219.

Screening and Early Detection

Breast self-examination Clinical breast Mammography—the examination only modality shown

to decrease mortality

American Cancer SocietyScreening Recommendations

Annual mammograms starting at age 40

− 24% reduction in mortality rate

Clinical breast exams– every 3 years for women age 20-39

– every year starting at age 40

Self-breast exams monthly, starting at age 20

Goals of mammography screening

• Earlier diagnosis in asymptomatic individuals• Reduction of mortality due to detection at earlier

stage

AgeAge Mortality Reduction (%)Mortality Reduction (%)

40-49 17% 15 years post-screening

50-69 25%-30% 10-12 years post-screening

70+ Insufficient data

PDQ: Screening for breast cancer for health professionals: http://Cancernetnci.nih.gov/. Accessed November 28, 1999.

Mamography

• Microcalcifications Spicular mass lesion

Screening in High-risk patients

Annual mammogram, beginning 5 years before age of youngest affected relative at time of diagnosis

– High familial risk

– BRCA 1/2-positive

Tripathy D, Henderson IC. Current Cancer Therapeutics. 3rd ed. 1999;123-129.

Management of High Risk Patients

• Enhanced Screening– Starting as early as age 25, shorter screening intervals– Inclusive of screening breast MRI, USG

• Chemoprevention– Tamoxifen– Evista (Raloxifene)?

• Surgical risk reduction– Prophylactic mastectomy

• Reduces risk of breast cancer by >90%– Prophylactic bilateral salpingo-oophorectomy

• Reduces risk of ovarian cancer by 90%• Reduces risk of breast cancer by 65%

• Counseling other family members

Breast examination

Breast inspection

Skin dimpling

Breast palpation

Regional node assessment

Signs and symptoms at presentation

Mass or painMass or pain

in the axillain the axilla

Palpable massPalpable mass ThickeningThickening PainPain

Nipple dischargeNipple discharge Nipple retractionNipple retraction

Edema or erythemaEdema or erythema

of the skinof the skin

Presentation

The majority of carcinoma in situ, T1, or T2:– Painless or slightly tender breast mass or have an

– abnormal screening mammogram.

Patients with more advanced tumors:– breast tenderness, skin changes, bloody nipple discharge, or

occasionally change in the shape and size of the breast.

Rarely patients may present with axillary lymphadenopathy (occasionally painful)

Distant metastasis.

Evaluation of a Breast Mass

• Breast mass in women under 30– USG is preferred– If mass is solid or suspicious, then mammography

followed by biopsy– Cystic mass: Simple cyst observe

Complex cyst: Aspirate

• Breast mass in women over 30– Diagnostic mammography– If indeterminate features in mammography, then USG– Biopsy as needed

Diagnosis

• Radiological tests– Mammography

• Detects 85% of breast cancers

– USG– MRI

• In dense breasts

• A mass with normal USG and mammography

• Biopsy– Fine-needle aspiration biopsy– Core biopsy– Excisional biopsy

Mammography

Mammography

Ultrasonography

Staging procedures

• Complete blood count, liver function tests• Chest radiograph• Diagnostic bilateral mammography• Bone scan• Radiological evaluation of liver • Bone marrow aspiration if unexplained

cytopenia or a leukoerytroblastic blood smear

Liver metastasis

MRI scan

Staging

• 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)

Prognostic Factors

• Tumor subtype– Estrogen/progesterone receptors

• (Positive in 2/3 of tumors)

– HER2/neu overexpression

• Number of positive axillary nodes• Tumor size• Tumor grade• Lymphatic and vascular invasion• Age

Breast cancer classification

• DNA microarray-based gene expression profiling– 85 samples

• 78 carcinoma• 3 benign tumor• 4 normal breast tissue

Sorlie et al, Proc Natl Acad Sci 100:8418, 2003Sorlie et al, Proc Natl Acad Sci 100:8418, 2003

Breast cancer– Intrinsic subtypes

Diffreneces between subtypes

• Risk of recurrenceRisk of recurrence

• Sites of metastasesSites of metastases

• Response to treatmentResponse to treatment

• İncidence varies between different İncidence varies between different populationspopulations

Biyolojik sınıflamaImmünhistokimya (IHC)

Hormone receptor positive• Luminal A ER+ &/or PR+ HER2 (–), Ki67

low• Luminal B ER+ &/or PR+ Ki67 high or

HER2+

HER2+ ER–/PR– HER2+

Bazal (triple negatif) ER–/PR– HER2 (-) & CK5/6+

HER-2/neu overexpression

• Overexpressed in 25-30% of breast cancer patients

• Significant decrease in 5-year survival for patients who overexpress HER-2/neu

• Trastuzumab:

– Anti-Her2 Antibody

– Targets Her2

Slamon DJ. Chemotherapy Foundation Symposium. 1999;46. Abstract 39. Goldenberg MM. Clinical Therapeutics. 1999;21(2):309-318.

Treatment

• Surgery• Chemotherapy• Radiation Therapy• Hormonal Therapy• Targetted therapy

– Monoclonal antibodies (e.g. Trastuzumab)

Surgical management

• Breast conservation therapy

• Modified radical mastectomy

• Breast reconstruction

Treatment

• Stage I-III– Aim: Cure– Surgery is the mainstay treatment– Adjuvant therapy as indicated

• Stage IV– Aim: Palliation, prolongation of survival– Chemotherapy, hormonal therapy,

monoclonal antibodies

Principle of Adjuvant Treatment

Adjuvant Therapy

• Radiation Therapy (local)• Chemotherapy (systemic)• Hormonal agents (systemic)

• Each therapy adds to reduction of recurrent disease.

• Therapy is individualized

ErbB Receptor Tyrosine Kinases

• Four receptors:– ErbB-1 (EGFR, HER-

1)– ErbB-2 (HER-2/neu)– ErbB-3 (HER-3)– ErbB-4 (HER-4)

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

2. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913.3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35.

1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217.

4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538.

Common Mechanisms of ErbB Activation in Tumors – Receptor Overexpression

• Gene amplification results in overexpression of normal receptors

• Receptors spontaneously homodimerize

• Drives tumour growth

2. Holbro T, et al. Exp Cell Res. 2003a;284:99-110.3. Marmor M, et al. Int J Radiat Oncol Biol Phys. 2004;58:903-913.

4. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35.

1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217.

5. Yarden Y, Sliwkowski M. Nat Rev Mol Cell Biol. 2001;2:127-137.

Monoclonal Antibodies• Trastuzumab is humanized

monoclonal antibody against EC domain of the HER-2 protein

• Mechanism of action:– Inhibit TK activation– Induce receptor

endocytosis and degradation

– Induce immune-mediated cytotoxicity

1. Arteaga C. Breast Cancer Res. 2003b;5:96-100. 2. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217.3. Rowinsky E. Horizons in Cancer Therapies: From Bench to Bedside. 2001;2:3-35.4. Zwick E, et al. Endocr Relat Cancer. 2001;8:161-173.

Endocrine Therapy for Breast Cancer

• Ovarian ablation—surgery, radiation, LHRH agonists

• Selective estrogen receptor modulators (SERMs) —tamoxifen, toremifene, fulvestrant

• Aromatase inhibitors—anastrozole, letrozole, exemestane

• Additive—progestins, estrogens, androgens

Estrogenbiosynthesis

Cancer cell

Nucleus

Inhibition ofEstrogen-Dependent Growth

Inhibition of growth

Estrogenbiosynthesis

Antiestrogens

Aromataseinhibitors