Download - Breast Ca1
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BREAST CANCER
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EPIDEMIOLOGY
Risk factors
increasing age: rate slows after menopause
early menarche, late menopause , nulliparity
atypical lobular or ductal hyperplasia(benign breast disease)
early exposure to ionizing radiation
long-term postmenopausal estrogen-replacement therapy
alcohol consumption
family history of breast ca.( most important )
- 5 to 10% occur in high-risk families
- familial breast ca. syndrome : breast-ovarian cancer syndLi-Fraumeni synd
Cowden's ds
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BIOLOGY
Genetic abnormalities(1) familial breast ca
BRCA1andBRCA2 germ line mutation
. 50 to 85 % lifetime risk breast ca, ovarian ca, or both
. genetic screening and counseling programs are ongoing
(2) sporadic breast ca
p53, bcl-2, c-myc,c-myb gene abnormality
HER-2/neu
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DIAGNOSTIC APPROACHES
Screening by mammography and physical examination
- early diagnosis
25 to 30 % decrease in mortality over age of 50 yrs
& probably in btw age of 40-50 yrs
American Cancer Society, the National Cancer Institute recommend
1) annual mammography for > 40 yrs2) high-risk families, withBRCA1 orBRCA2 mutant
: at 25 yrs of age
or 5 yrs earlier than earliest age at which breast ca diagnosed
in family member
Standard method for confirming diagnosis
fine-needle aspiration or core needle biopsy
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THERAPY
1. Primary Breast Cancer Local disease without distant spread
curable with local or regional treatment alone
but, most pts have subclinical metastasis
distant metastasis ultimately develop
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1) Local and Regional Treatment
early breast cancer
lumpectomy
(wide excision of tumor with preservation of breast)
with radiotherapy
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2) Axillary Lymph-Node Dissection standard for invasive or large non-invasive tumors (>2.5 cm)
Prognosis information
- recurrence is higher for histologically positive axillary LNs responsible for morbidity associated with surgery
alternative method
: Sentinel-lymph-node mapping
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3) Postop. Adjuvant Therapy
(1) Chemotherapy
(2) Hormone therapy
(3) Radiotherapy
Prognostic factors
Gold Standard
Axillary lymph node status
Tumor size
Histologic subtype, Histologic or nuclear grade
ER and PgR status
Potential
proliferation marker (S-phase fraction, Ki67, TLI )
c-erbB-2(HER-2/neu)
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Axillary LN status and recurrence rate
Positive nodes(No.) 10 year recurrence rate(%)
0 201-3 47
4-6 59
7-12 69
>13 87
Hormone receptor and response to endocrine therapy
Receptor status Response rate(%)
ER -, PR - 10
ER -, PR + 33
ER +, PR - 34
ER +, PR + 74
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Risk categories for pts with node-negative breast ca.
Factors Low Intermediate High
(has all listed factors) (at least one factor)
Tumor size < 1cm 1-2 cm > 2 cm
ER and PgR + - -
Grade Grade I Grade 1-2 Grade 2-3
Age > 35 yrs < 35 yrs
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(1) Adjuvant Systemic Chemotherapy
combination chemotherapy- more effective than single-drug treatment
- effects : marked in < 60 yrs ( esp. premenopausal )
- reduce annual risk of death by 20%
duration of chemotherapy
- usually used combination regimens
: FAC, FEC, CMF ( 6 cycles )
AC ( 4 cycles )
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(2) Adjuvant Hormone Therapy
Tamoxifen- breast ca. is estrogen-dependent
- antiestrogenic activity mediated by competitive inhibition
of estrogen binding to estrogen receptors
- inhibits expression of estrogen-regulated genes including
growth factors and angiogenic factors secreted by tumor
reduce recur & death in all age group
- when to estrogen-receptor-positive tumor
- when for about 5 yrs, rather than 1 to 3 yrs
( for more than 5 yrs is no more effective than for 5 yrs )
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Adjuvant therapy fornode-negative breast ca.
(1998 International Consensus)
Pt group Low risk Intermediate risk High risk
Premenopausal, ER or PgR + None or TMF TMF + CTX CTX + TMF
ER and PgR - NA NA CTX
Postmenopausal, ER or PgR + None or TMF TMF + CTX TMF + CTX
ER and PgR - NA NA CTX
Elderly None or TMF TMF TMF
ER: estrogen receptor, PgR: progesteron receptor
TMF : tamoxifen, CTX : chemotherapy, NA : not applicapable
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Adjuvant therapy fornode-positive breast ca.
(1998 InternationalConsensus)
Pt group Minimal/low risk
Premenopausal, ER or PgR + CTX + TMF
ER and PgR - CTX
Postmenopausal, ER or PgR + TMF + CTX
ER and PgR - CTX
Elderly TMF
ER: estrogen receptor, PgR: progesteron receptor
TMF : tamoxifen, CTX : chemotherapy
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(3) Adjuvant Radiotherapy (RT)
Postmastectomy RT
- reduces local recur by 50-75%
but this reduction was not accompanied by increased survival
so, postop. RT indication
only for high risk local recur. pts
- large tumors > 5 cm
- invading the skin of the breast or chest wall
- many (> 4 ) positive axillary LNs
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4) Preoperative Chemotherapy
- large operable tumor
- 90% of tumor decrease in size by more than 50%
- lumpectomy possible
- survival benefit : no apparent advantage
as compared with postop. chemotherapy
5) Dose-Intensive and High-Dose Chemotherapy Regimens
- ongoing randomized trial should help to determine the efficacy
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2. Locally Advanced and Inflammatory Breast Ca.1) Stage III breast ca.
tumor > 5 cm in diameter
any size with invasion of skin of breast or chest wall
any tumors with fixed or matted axillary LNs
2) Inflammatory breast ca.
- should treat withpreoperative chemotherapy or hormonal therapy
- excellent local control achieved in 80 to 90% of pts
and 30% pts remain free of cancer after 10 yrs
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3. Metastatic Breast Cancer
clinical course is variable- large variation in growth rate and responsiveness
to systemic therapy
main goals of treatment- optimal palliation and prolongation of life
therapeutic strategy on basis of
age, disease-free interval, hormone-receptor status,
and extent of disease
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1) Hormonal intervention- 20 to 35% response to initial hormonal therapy
- 10 to 20% to second-line
- 15 to 30% to another
Hormonal Therapies for Metastatic Breast Ca.
Order of Tx. Premenopausal Postmenopausal
First line Antiestrogens or ovarian ablation Antiestrogens(chemical, surgical or postRT)
Second line Ovarian ablation after antiestrogens Aromatase inhibitors*
; antiestrgens after ovarian ablation
Third Liline Progestins ProgestinsForth line Androgens Androgens or estrogens
* Aromatase inhibitor: Formestane, Anastrozole(Arimidex), Letrozole(Femara)
Metastatic Breast Cancer
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2) Chemotherapy
- refractory to hormonal therapy
40 to 60% response to CMF
- anthracycline-containing combination superior to CMF
50 to 80% response to FAC
- new drugs
vinorelbine( third-generation vinca alkaloid )
taxanes (paclitaxel and docetaxel)
* Combinations of taxanes and anthracyclines
responses in 40 to 94%
complete remissions in 12 to 41%
Metastatic Breast Cancer
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Bone
- most common site of metastasis
cause of substantial morbidity, complication
* Bisphosphonate (pamidronate and clodronate)add to chemotherapy or homonal therapy
- reduce pain and complication
- prolong survival free of bone-related event
Metastatic Breast Cancer
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3) High-Dose Chemotherapy
I. single cycle of high-dose combination of cytotoxic drug(usually alkylating agent)
bone marrow damage is earliest limiting toxic effect
- eliminated by reinfusing autologous hematopoietic stem cell
II. 2 to 4 cycles of cytotoxic-drug combination
at dose higher than usual but not ablate bone marrow
higher complete remission (40 to 60%)
15 to 25% free of cancer for 3 to 5 yrs
Metastatic Breast Canc
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CHEMOPREVENTION
administration of adj. tamoxifen for 5yrs after primary Tx.
- reduce incidence of contralat. breast ca. by 47%
- endometrial ca. in twice
- increase in thromboembolic event
occured predominantly in older than 50 yrs
* overall beneficial effect of tamoxifen
outweighed adverse effect
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NOVEL THERAPIES
HER-2/neu oncogene overexpressed in 20 to 30%
- more aggressive
- more resistant to chemotherapy
13% of metastatic breast ca with HER-2/neu
- response to monoclonal antibody againstextracellular domain of HER-2/neu oncoprotein
chemotherapy combined with anti HER-2/neu antibody- increase response rate & prolongation of survival