Transcript Breast cancer overview

Overview of breast cancer
Sun Yat-Sen Cancer Center
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Outline
現況
 Epidemiology
 Diagnosis, stage
 Treatment

Surgery
 Radiation
 Hormone therapy
 Chemotherapy

Breast cancer (乳癌)
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是世界重要的健康公共議題
台灣地區主要癌症死亡原因。乳癌的發生率為第一位，死
亡率是排名第4位的女性癌症。
民國98年，女性及男性乳房惡性腫瘤發生個案數分別占全
部惡性腫瘤發生個案數的10.24%及0.06%，女性及男性乳房
惡性腫瘤死亡人數占全部惡性腫瘤死亡人數的3.98%及
0.03%。發生率的排名於女性為第1位、男性為第32位；死
亡率的排名於女性為第4位、男性為第34位。
民國98年初次診斷為女性及男性 乳房惡性腫瘤者分別為
8,926人及48人；當年死因為女性及男性乳房惡性腫瘤 者
分別為1,588人及10人。
從1970–1996 之間，乳癌發生率增加2-3倍。
Cancer Registry Annual Report in Taiwan Area 2001 Department of Health, Executive Yuan, ROC 2009

臺灣乳癌好發年齡在40~50歲之間，較歐美
國家的好發年齡約提早十歲。
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Taiwan: Cancer Registration (year of diagnosis is 2002; a total of 10 hospitals reported 2,174 cases
that includes complete follow-up data for five years)
USA: National Cancer Database, Survival Report, 2008 (years of diagnosis are 1998-1999 for a total
of 299,900 cases that covers complete follow-up data for five years)
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Normal Breast
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A. Breast Duct System
B. Lobules
C. Breast Duct System
D. Nipple
E. Fat
F. Chest Muscle
G. Ribs
A. Cells lining duct
B. Basement membrane
C. Open central duct
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Invasive ductal carcinoma(IDC)
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A. Breast Duct System
B. Lobules
C. Breast Duct System
D. Nipple
E. Fat
F. Chest Muscle
G. Ribs
A. Cells lining duct
B. Cancer cells, breaking
through the basement
membrane
C. Basement membrane
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DCIS and LCIS
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DCIS（Ductal Carcinoma in situ,管內癌），
及
Premalignant change
 Turn out to be cancer in ongoing years
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LCIS (Lobular carcinoma is situ,原位小葉
癌）
Not a premalignent change
 A sign, which indicate risk of breast ca
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Symptoms
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In early breast ca
Easily self palpated
 Nipple discharge
 May accompanied with axillary LN
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Late breast ca
Local usually symptomatic
 Depends on metastatic sites
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Epidemiology
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Increases with age, although the rate of increase
slows after menopause.
Early menarche, late menopause, and nulliparity
increase the risk of breast cancer.
Atypical lobular or ductal hyperplasia.
Other risk factors
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Early exposure to ionizing radiation
long-term postmenopausal estrogen-replacement therapy
Alcohol consumption.
The most important risk factor is a family history of
breast cancer.( 5 to 10%)
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breast–ovarian cancer syndrome, the Li–Fraumeni
syndrome, and Cowden's disease.
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Biology
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BRCA1 and BRCA2 germ-line mutations ( 50 – 85%
lifetime risk of breast cancer, ovarian cancer, or
both ).
In sporadic breast cancer (including p53, bcl-2, c-myc,
and c-myb),
HER-2/neu and cyclin D1 are overexpressed.
Factors that stimulate or inhibit growth and
proliferation of breast-cancer cells.
 Gonadal steroid hormones (estrogens, progestins,
and androgens)
 Growth factors (epidermal growth factor,
transforming growth factors and insulin-like growth
factors I and II)
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How to describe a breast ca
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TNM stage
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Tumor morphology
Grade
 VLI
 PNI
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Special receptor
Hormone receptor: ER and PR
 Her2/Neu
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TNM
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N
N0: no axilla LAPs
 N1:1-3
 N2:4-9
 N3>10
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M: M0 or M1
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I
IIA
IIB
IIIA
IIIB
IIIC
T1N0
T1N1
T2N0
T2N1
T3N0
T1N2
T2N2
T3N1
T3N2
T4N0
T4N1
T4N2
N3
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疾病種類
乳癌但無浸潤的情形
包括管內癌（Ductal Carcinoma in situ, DCIS），及原
位小葉癌（Lobular carcinoma is situ,LCIS）
輔助療法
不需要
乳癌有浸潤的情形，無淋巴轉移腫瘤小於1mm 。
不需要
最大直徑小於1cm浸潤性腺管癌，及浸潤性小葉癌
不需要
浸潤性腫瘤，但組織病理預後相對是較好，如髓質癌、不需要
黏液素癌、小管癌。腫瘤最大直徑小於3cm。
腫瘤最大直徑大於1cm浸潤性腺管癌，及浸潤性小葉
癌。
化療、荷
爾蒙療法
浸潤性腫瘤，但組織病理預後相對是較好，如髓質癌、化療、荷
黏液素癌、小管癌。腫瘤最大直徑大於3cm。
爾蒙療法
乳癌有浸潤的情形且有腋下淋巴轉移
無論腫瘤大小、或病理報告的任何腫瘤
化療、荷
爾蒙療法
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Tumor morphology
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Grade
Tubule Formation
 Nuclear Pleomorphism
 Mitotic Count
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Vascular lymphatic invasion(VLI)
 Perineural invasion(PNI)
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Both indicate aggressive behavior
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VLI
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A. Veins in breast
B. Lymph channels in breast
A. Cells lining duct
B. Cancer cells, breaking through
the basement membrane.
C. Broken basement membrane
D. Cancer entering a lymph
channel.
E. Cancer entering a vein.
F. Normal breast tissue.
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Receptor status
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Hormone receptor
Estrogen receptor (%)
 Progesterone receptor (%)
>10% predict response to hormone tx
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Her2/neu
Associate with invasion, metastasis…
 Predict poor prognosis
 IHC stain, FISH
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The EGFR (erbB) family
Ligands
EGF
TGF-
Amphiregulin
No specific
ligands
Heregulins
NRG2
NRG3
Heregulins
Receptor
domain
Extracellular
Membrane
Tyrosine
kinase
domain
Intracellular
K
K
erbB1
HER1
EGFR
erbB2
HER2
neu
K
erbB3
HER3
erbB4
HER4
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Current assay of HER2/neu
 Immunohistochemistry
‘0’ (negative)
‘1+’ (negative)
‘2+’ (equivocal)
‘3+’ (positive)
 Fluorescence in situ hybridization (FISH)
HER2 gene no amplification
FISH negative
HER2 gene amplification
FISH positive
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Definition of risk categories for patients with
node-negative breast cancer
Annals Oncol 2005; 16: 1669-1583
Low risk
Node negative AND all of the following features:
Pathologic tumour size ≤2cm, AND Grade 1 AND
Absence of peritumoural vascular invasion, AND
HER2/neu gene neither over-expressed nor amplified, AND
Age ≥35 years
Intermediate risk
Node negative AND at least one of the following features:
Pathologic tumour size >2cm, OR Grade 2-3, OR
Presence of peritumoural vascular invasion, OR
HER2/neu gene over-expressed or amplified, OR
Age <35 years
High risk
Node positive (1-3 nodes involved) AND
HER2/neu gene neither over-expressed nor amplified
Node positive (1-3 nodes involved) AND
HER2/neu gene over-expressed or amplified
Node positive (4 or more involved nodes)
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Diagnostic Approaches
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Mammography
25 to 30 % decrease in mortality (>= age of 50
years and probably also in women between the
ages of 40 and 50 years.
 High-risk families ( BRCA1 or BRCA2 mutations)
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 start
at 25 years of age
 5 years earlier than the earliest age at which breast
cancer was diagnosed in a family member
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The American Cancer Society and the National
Cancer Institute recommend annual screening
mammography for women older than 40 years who
have a standard risk of breast cancer.
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Diagnostic Approaches
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20years ago, incisional or excisional biopsies
were the standard methods for confirming the
diagnosis.
Today, fine-needle aspiration or core needle
biopsy is the standard.
Ultrasound-guided core needle biopsy,
stereotactic biopsy, and magnetic resonance–
directed biopsy have become important
diagnostic tools, especially for women with
suspicious but nonpalpable breast masses.
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Treatment
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Localized breast cancer
Surgery is mainstay
 Halsted, 1882, radical mastectomy
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 John
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Hopkins
Metastatic breast cancer
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Systemic treatment
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Radical mastectomy
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A. Entire breast and a
chest wall muscle is
removed.
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LNs in the level 1 (B) and
level 2 (C ), and even
sometimes more distant
lymph node groups (D, E
and F) were also
removed.
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Modified radical mastectomy (MRM)
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A. Entire breast is
removed
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Classically some
lymph nodes in the
level 1 (B) and level 2
(C ) were removed,
called an axillary
lymph node
dissection.
MRM = simple mastectomy + ALND
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Breast conserving surgery
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Also called
lumpectomy
RT should be
followed
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Surgical evolution
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Radical mastectomy
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1885 ~ 1960s
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Modified radical mastectomy: 1970s
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Lumpectomy + RT, 1970s
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NSABP B-06, NEJM 1985
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Lumpectomy vs. MRM
Milan Cancer Institute, NEJM 1977
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Lumpectomy vs. RM
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Radical mastectomy : breast
Conserving therapy
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Equivalent survival with BCT (breast-conserving
therapy) as compared to mastectomy.
lumpectomy (wide excision of the tumor with
preservation of the breast) with radiotherapy is the
preferred treatment.
Radiotherapy, an integral part of BCT, is
inappropriately withheld from some women, especially
those older than 65 years.
Noninvasive (in situ) ductal and lobular breast cancer
can also be treated adequately with lumpectomy and
radiotherapy.
Early Breast Cancer Trialists' Collaborative Group. N Engl J Med 1995; 333:1444.
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Individual and Pooled Odds Ratios for Survival at 10
Years in Women with Breast Cancer Treated by BreastConserving Therapy as Compared with Mastectomy.
Cancer 1977;40:Suppl:574-587
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Axillary Lymph-Node Dissection
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Recurrence is higher with positive axillary lymph nodes and
increases with each additional positive node.
Axillary lymph-node dissection
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only provides prognostic information
most of the morbidity associated with breast surgery.
remains the standard of care for all women with invasive breast
cancer or large noninvasive tumors (>2.5 cm).
Sentinel-lymph-node mapping ( radioactive substance or a
blue dye is injected into the area around the tumor)
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The lower ipsilateral axilla is explored through a small incision
and the lymph node that has taken up the dye or radioactive
substance is excised.
The positive predictive value (100 %), negative predictive value
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(> 95 %).
Adjuvant Radiotherapy
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Radiotherapy is an integral part of breast-conserving
treatment.
Administering chemotherapy before radiotherapy resulted in
higher survival rates when given postoperatively.
Postmastectomy radiotherapy reduces the incidence of local
and regional recurrences by 50 to 75 % ( not increase
survival).
Only for women at high risk for local or regional recurrence
( large tumors invading the skin of the breast, chest wall,
positive axillary lymph nodes).
Benefit for high-risk premenopausal women. Fewer local and
regional recurrences and overall survival was significantly
better among the women treated with radiotherapy and
chemotherapy.
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Ten-Year Cancer-free Survival and Overall Survival among
Women Treated with Chemotherapy with or without Radiotherapy
after Mastectomy
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Hortobagyi, G. N. N Engl J Med 1998;339:974-984
Impact of surgical evolution
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Local control: no survival benefit
Local control: RM>MRM>BCT+RT>BCT
 Survival no different
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 Why?
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distant metastasis is the main cause
Distant “micrometastasis”
Not from local residual dz
 Does exist at diagnosis
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 Adjuvant
systemic treatment
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Adjuvant systemic treatment
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Hypothesis:
Eradicate micrometastasis
 From effective tx for overt(macro) metastasis
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Chemotherapy
 Hormone therapy
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Adjuvant chemotherapy
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CMF, first generation, 1970s
Cyclophosphamide
 Methotrexate
 5-FU
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Benefit in
 Distant
recurrence
 Survival
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Adjuvant chemotherapy
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CAF or CEF, 2nd generation, 1980s
Cyclophophamide
 Adramycin(or Epirubicin)
 5-FU
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More toxic than CMF
 CAF better than CMF in high-risk group
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 Axilla
LN+
 LN-, but tumor large or other risk factor
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Adjuvant chemotherapy
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Benefits both premenopause and postmenopause
Benefit is greater in younger as compared to older
women.
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Age 50 to 69, the risk of relapse or death was
decreased by 19 and 12 %.
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< 50 , polychemotherapy reduced the risk of disease
relapse and death by 37 and 30%, respectively.
10 % absolute improvement in 15-year survival (42 versus
32 %).
3 % absolute gain in 15-year survival (50 versus 47 %).
> age 70 , the benefits of chemotherapy are still
uncertain because few studies have included
women in this age group.
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Lancet 2005; 365:1687
Early Days: Alkylating Agents and
Antimetabolites
In 1976, Bonadonna and colleagues from
Milan, Italy, reported that postoperative
CMF improved DFS and OS
in women with node-positive breast cancer
 At the same time, the NSABP was
evaluating adjuvant
L-phenylalanine mustard and fluorouracil
 In Scandinavia, Nissen Meyer was
evaluating adjuvant cyclophosphamide
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Duration of Chemotherapy
CA Cancer J Clin 1995;45:199-226
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less than 3 months was inferior to treatment for 4 to 6 months
Longer than 6 months was no more effective than treatment
for four to 6 months.
The combinations standard therapy
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EBCTCG. Lancet 1992;339:71-85
fluorouracil, doxorubicin, and cyclophosphamide (FAC 6 cycles)
fluorouracil, epirubicin, and cyclophosphamide (FEC 6 cycles)
(AC 4 cycles); and CMF (6 cycles).
intermittently at intervals of three to four weeks.
Addition of 4 cycles of paclitaxel (duration, 12 to 16 weeks) to
4 cycles of AC improved both disease-free survival and
overall survival rates.
In premenopausal women
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Ovarian ablation = combination chemotherapy or tamoxifen.
This benefit persists for 15 years after treatment.
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The choice of regimen
Ththere is a modest but significant benefit
for anthracycline-containing compared to
nonanthracycline-containing adjuvant
chemotherapy (CMF).
 Both premenopausal and postmenopausal
women with node-positive breast cancer
should consider a taxane-containing
chemotherapy regimen.
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Adjuvant chemotherapy
Incorporate Taxane
 TAC, 3rd generation, mid-1990s

Taxotere
 Adriamycin
 Cyclophosphamide
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More toxic than CAF
 Better than CAF in high-risk group

 Need
more time to observe
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Adjuvant Herceptin
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Effective in Her2+ pts
ICH3+
 FISH+
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
Herceptin + adjuvant chemotherapy

Optimal role to be defined
 Concurrent
or sequential?
 Maintenance ? Duration ?
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Adjuvant hormone therapy
GNRH agonists
(A) Premenopausal
(B) Postmenopausal
LH
FSH
Antiestrogen
Breast
carcinoma
Breast
carcinoma
Adrenal
Estrogen
Adapted with permission from
Tellez C, et al. Surg Oncol Clin
North Am. 1995;4:751-777.
GNRH = Gonadotropin-releasing
hormone; LH = Luteinizing hormone;
FSH = Follicle-stimulating hormone.
Antiestrogen
Estrogen
Androstenedione
Aromatase
inhibitor
Ovary
Peripheral
aromatization
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Hormone therapy — Adjuvant
hormone therapy


For presence of ER or progesterone (PgR) receptors.
Premenopausal women
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Surgical removal (or irradiation) of the ovaries
Tamoxifen
Luteinizing hormone releasing hormone (LHRH) analogs
(eg, goserelin [Zoladex®], leuprolide [Lupron®]).
For postmenopausal women

Tamoxifen or aromatase inhibitors (anastrozole
[Arimidex®], letrozole [Femara®], exemestane
[Aromasin®]).
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Tamoxifen hormone therapy
EBCTCG The Lancet 2005; 365:1687-1717

ER (+) only

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5 yrs of adjuvant tamoxifen reduces the annual
breast cancer death rate by 31%, largely
irrespective of the use of chemotherapy and of age
(<50, 50–69, ≥70 years), progesterone receptor
status, or other tumor characteristics.
The annual breast cancer mortality rates are similar
during years 0–4 and 5–14.
The cumulative reduction in mortality is more than
twice as big at 15 years as at 5 years
5 years vs 1-2 yrs


2p<0·00001 for recurrence
2p=0·01 for breast cancer mortality
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Adjuvant hormone therapy

Aromatase inhibitor
Effective in post-menopausal state
 Aromatase, in fat tissue,

 Convert
androgen to estrogen
 Main estrogen source in post-menopausal
Exemestane : Aromasin
 Letrozole: Femara
 Anastrozole: Arimidex


More effective than Tamoxifen
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Comparative Toxicity: Tamoxifen
and Aromatase Inhibitors
ATAC
Significantly higher toxicity with tamoxifen vs anastrazole
• Vaginal bleeding or discharge
• Hot flashes
• Endometrial cancer
• Ischemic cerebrovascular events
• Venous thromboembolic events
Significantly higher toxicity with anastrozole vs tamoxifen
• Arthralgia
• Fractures
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Comparative Toxicity: Tamoxifen
and Aromatase Inhibitors
Significantly higher toxicity with tamoxifen vs exemestane
• Gynecologic symptoms
• Vaginal bleeding
• Muscle cramps
• Thromboembolic events
Significantly higher toxicity with exemestane vs tamoxifen
• Arthralgia, Myalgia, Arthritis/osteoarthritis
• Limb pain, Carpal tunnel, Paraesthesia
• Myocardial infarction
• Diarrhea
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Aromatase inhibitors

Upfront therapy (an AI initially instead of
tamoxifen)

Sequential therapy (switch to an AI after 23 years of tamoxifen)

Extended therapy (an AI after 5 years of
tamoxifen).
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Adjuvant ovarian suppression
Effective in pre-menopausal state
 Type

Surgical ablation
 RT ablation
 GnRH analogue: Goserelin, Leupride


Exact role to be defined
Combination with chemotherapy?
 Combination with AI or TAM?

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Concurrent chemotherapy :
Sequential chemotherapy
Proc Am Soc CLIN Oncol 21: 37a, 2002 (abstr 143)
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Does chemotherapy add benefit to
tamoxifen for postmenopasual women
with ER-positive disease ?

Combined chemotherapy and tamoxifen therapy
for postmenopausal women with node-positive
ER-positive disease. 2000 EBCTCG overview
analysis



Decreased the annual risk of recurrence and death by
35 and 34%, vs tamoxifen alone.
Tamoxifen should be started after chemotherapy is
completed, and not given concurrently.
The benefit of adding chemotherapy to
tamoxifen is less clear for women with ERpositive node-negative

are inconclusive
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Neoajuvant chemotherapy
Large operable tumors
 90% of primary operable tumors decrease
in size by more than 50 %.
 Lumpectomy a possibility for many women
who would otherwise have required a
mastectomy.
 No apparent advantage survival to
preoperative chemotherapy as compared
with postoperative chemotherapy.

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Neoajuvant chemotherapy





Emerging data supports a similar degree of benefit from
taxanes in the neoadjuvant setting.
4 cycles of induction AC plus vincristine and prednisolone
(CAVP); responders were then randomly assigned to continue
CAVP for a total of eight courses, or switch to four cycles of
docetaxel.
The number of pCRs (pathologic complete remission) sequential
docetaxel vs CAVP (34 versus 16 %).
Initial fail respond to CAVP had a cCR (complete clinical responses)
rate of 55% to subsequent docetaxel monotherapy.
Significant five-year OS (97 versus 78 %)
Presented at the 26th annual San Antonio Breast Cancer Symposiom, San Antonio,
TX, December 2003 (abstract 11).
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Treatment of metastatic dz


Usual sites: bone, lung, liver, brain
Incurable


Systemic treatment is mainstay



Goal: live with dz for longest time
Chemotherapy
Hormone therapy
Palliative local therapy


Radiotherapy
Palliative surgery
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Treatment strategy

Principle:
Save your bullet
 Right time, right treatment


Why?
Treatment effectiveness only in limited
duration
 To avoid unnecessary toxicity
 Ultimately incurable

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Chemotherapy

In general, chemotherapy
Single agent: RR: 20-30%
 Combination: doublet: 40-60%
triplet: 70-80%


Hormone therapy
Tamoxifen: RR 15-20%
 Aromatase inhibitor: RR 30-35%

69
Chemotherapeutic agents

Single agents:
Doxorubicin/Epirubucin
 Cyclophosphamide
 MTX
 5-FU
 Taxane(Paclitaxel, Docetaxel)
 Navelbine
 Gemcitabine

70
Chemotherapy regimens

Combination:
Navelbine-HDFL
 Paclitaxel-Cisplatin
 Doxorubicin-Cyclophosphamide
 Gemcitabine-Paclitaxel/-Trastuzumab/lapatinib


Combination C/T provide better RR, but
overall survival not different
71
Example - 1
55y/o woman, ER/PR +/+,
 Dz recurred 5yrs after surgery
 Only neck and mediastinum LNs
 Slowly progressed clinically(!)

Hormone therapy
May do RT for symptomatic site
72
Example - 2
45 y/o woman, ER/PR -/ Dz recurred 3 yrs after operation
 Only right supraclavicle LNs
 Slowly progressed

RT alone
Observation
73
Example - 3
50 y/o woman, ER/PR +/+
 Back, shoulder, hips pain, 3m, progress
 Massive bone mets over spine, pelvis,
shoulder, and ribs

Systemic chemotherapy, combination
RT for symptomatic sites
Bisphosphonate: Aredia or Zometa
74
Example - 4



55 y/o woman, ER/PR +/+
Dyspnea progressively
Lung mets bilaterally
Systemic chemotherapy, combination
75
Treatment principle

For visceral organ crisis
Combination chemotherapy
 Failure is not allowed
(high RR necessary)


For isolated LN or bone mets
Hormone tx (more chance to try)
 RT alone in hormone unresponder

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Trastuzumab
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20-30 % of breast cancers overexpress the
HER-2/neu protein.
Preliminary reports support a significant
disease-free survival and overall survival benefit
from the addition of trastuzumab to
anthracyclines and paclitaxel in the adjuvant
setting, particularly for women with node-positive
breast cancer.
Increase in the risk of cardiac events.
Trastuzumab at the earliest sign of cardiotoxicity
developed in 2 to 3 % over a two year period.
Long-term data in the adjuvant setting is lacking.
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SUMMARY
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Surgical resection is required in all invasive breast cancer.
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The status of the axillary lymph nodes provides important
prognostic information.
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Outcomes are similar with mastectomy and breast conserving
therapy (lumpectomy plus breast radiation therapy).
Sentinel lymph node dissection is replacing axillary lymph node
dissection.
there is no information about the long-term outcome (ie, cancerspecific survival). (compare to full axillary node dissection.)
With positive sentinel node require a completion axillary node
dissection.
Adjuvant systemic therapy (chemotherapy, hormone therapy,
trastuzumab or a combination) is recommended for node (+),
and tumors > 1 cm.
Adjuvant hormone therapy is for ER-positive or PR-positive.
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