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BREAST CANCER
Başak Oyan-Uluç, MD
Yeditepe 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*
INCIDENCE
Women
678,060
•26% Breast
MORTALITY
Women
270,100
•26% Lung & bronchus
•15% Breast
•15% Lung & bronchus
•10% Colon & rectum
•11% Colon & rectum
• 6% Pancreas
•6%
• 6% Ovary
Uterine corpus
• 4% Non-Hodgkin
lymphoma
•4%
• 4%
Melanoma of skin
Thyroid
• 4% Leukemia
• 3% Non-Hodgkin
lymphoma
• 3% Uterine corpus
• 3% Ovary
• 2% Brain/ONS
• 3% Kidney
• 2% Liver & intrahepatic
bile duct
•3%
Leukemia
•21% All Other Sites
•23%
All other sites
*Excludes basal and squamous cell skin cancers and in situ carcinomas except urinary bladder.
Source: American Cancer Society, 2007.
Lifetime Probability of Developing Cancer,
by Site, Women, US, 2001-2003*
Site
Risk
All sites†
Breast
1 in 3
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
† All Sites exclude basal and squamous cell skin cancers and in situ cancers except urinary bladder.
* For those free of cancer at beginning of age interval. Based on cancer cases diagnosed during 2001 to 2003.
‡ Includes invasive and in situ cancer cases
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
Incidence varies among different populations
Age-specific incidence (per 100,000)
Incidence Rates
420
400
300
United
States
England
and Wales
200
Italy
France
100
Japan
0
20
24
25
29
30
34
35
39
40
44
45
49
50
54
55
59
60
64
65
69
70
74
75
79
80
84
85+
Age
Adapted from New Horizons in Cancer Management, SRI International, 1990.
5-year Relative Survival
Site
•
•
•
•
•
•
•
•
•
•
•
•
All sites
Breast (female)
Colon
Leukemia
Lung and bronchus
Melanoma
Non-Hodgkin lymphoma
Ovary
Pancreas
Prostate
Rectum
Urinary bladder
1975-1977
50
75
51
35
13
82
48
37
2
69
49
73
1984-1986
1996-2002
53
79
59
42
13
86
53
40
3
76
57
78
66
89
65
49
16
92
63
45
5
100
66
82
*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 and
Population Sciences, National Cancer Institute, 2006.
†
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
• Breast disease
• Parity and lactation
• Radiation
• Alcohol
• 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
25
55
75
80
All
Risk
19.6008
1/33
1/11
1/10
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 breast
duct
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
Location
Most are located in upper outer quadrant
Upper inner
Upper outer
Nipple
Axillary tail
Central portion
Lower inner
Lower outer
RIGHT
Spread to lymph nodes
Supraclavicular
Subclavicular
Mediastinal
Distal (upper)
axillary
Internal mammary
Central (middle)
axillary
Interpectoral
(Rotter’s)
Proximal (lower)
axillary
Sites of distant metastases
Brain
Lymph nodes
Skin
Liver
Bone
Pleura
Lung
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
examination
Mammography—the
only modality shown
to decrease mortality
American Cancer Society
Screening 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
Age
Mortality Reduction (%)
40-49
17%
50-69
25%-30% 10-12 years post-screening
70+
Insufficient data
15 years post-screening
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 pain
in the axilla

Palpable mass

Thickening

Pain

Nipple discharge

Nipple retraction

Edema or erythema
of 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,
Breast cancer– Intrinsic subtypes
Diffreneces between subtypes
• Risk of recurrence
• Sites of metastases
• Response to treatment
• İncidence varies between different
populations
Biyolojik sınıflama
Immünhistokimya (IHC)
Hormone receptor positive
• Luminal A
• Luminal B
HER2+
Bazal (triple negatif)
ER+ &/or PR+
ER+ &/or PR+
ER–/PR–
ER–/PR–
HER2 (–), Ki67 low
Ki67 high or HER2+
HER2+
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, HER1)
– ErbB-2 (HER-2/neu)
– ErbB-3 (HER-3)
– ErbB-4 (HER-4)
ErbB-1
ErbB-2
ErbB-3
1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217.
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.
4. Vlahovic G, Crawford J. Oncologist. 2003;8:531-538.
ErbB-4
Common Mechanisms of ErbB Activation in
Tumors – Receptor Overexpression
• Gene
amplification
results in
overexpression of
normal receptors
• Receptors
spontaneously
homodimerize
• Drives tumour
growth
1. Holbro T, Hynes NE. Annu Rev Pharmacol Toxicol. 2004;44:195-217.
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.
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 immunemediated 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
Inhibition of
Estrogen-Dependent Growth
Antiestrogens
Estrogen
biosynthesis
Nucleus
Estrogen
biosynthesis
Inhibition
of growth
Aromatase
inhibitors
Cancer cell