breast cancer başak oyan-uluç, md yeditepe university hospital department of medical oncology
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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
ide
nc
e R
ate
sIn
cid
en
ce
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
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