Download 2016.1121 盧彥伸treatment of early breast cancer(1)

Treatment of
Early Breast Cancer
臺大醫院 腫瘤醫學部
盧彥伸
Outlines
• Overview:
– 重要性 (significance)
– Inside breast tissues
– Types of breast
cancer
• Work-up:
– Diagnosis
– Staging
g g
• Treatment modalities
– Surgery
– Radiotherapy
– Systemic therapies:
hormonal therapy,
therapy
chemotherapy,
antibody against
HER2, and others.
• Treatment
T t
t off various
i
subgroups of breast
cancer
台灣男女性10大癌症發生分率, 民國93、94年
（發生人數）部位
百分比
百分比
部位（發生人數）
(7,051、 7,159)肝
18、18
21、22
乳房 (6,176、6,593人)
(5,426、5,497 )結腸及直腸
14、14
14、14
結腸及直腸(4,109、4,107人)
( 5,537、 5,566)肺
14、14
10、9
肝(2,779、 2,757人)
(4,363、4,310)口腔
11、11
9、9
肺(2,605、 2,746人)
(2,660、2,704)攝護腺
7、7
8、7
子宮頸(2,292、 1,977人)
(2,380、2,288)胃
6、6
5、4
胃(1,338、 1,292人)
(1,374、1,403)食道
4、4
4、4
甲狀腺 (1,132、 1,146人)
(1,380、1,363)膀胱
4、3
3、4
皮膚(965、 1,039人)
(1,196、1,139)皮膚
3、3
3、3
子宮體(877、 987人)
(1,123、1,123)鼻咽
3、3
3、3
卵巢 (841、 894人)
(6,585、6,879)其他癌症
16、17
20、20
其他癌症(5,707、5,938人)
男性共（39,075、 39,431人）
備註:口腔癌含下咽及口咽
女性共（28,821、29,476人）
民國95年主要癌症死亡原因
順位
1
2
3
4
5
6
7
8
9
10
癌症死亡原因
肺癌
肝癌
結腸直腸癌
女性乳癌
胃癌
口腔癌
攝護腺癌
子宮頸癌
食道癌
胰臟癌
其他
所有癌症死亡原因
死亡人數
7,479
7,415
4,284
1,439
2 398
2,398
2,202
957
792
1,304
1,247
8,481
37,998
每十萬人口 死亡百
死亡率
分比%
32.8
19.7
32.5
19.5
18.8
11.3
12.8
3.8
10 5
10.5
63
6.3
9.6
5.8
8.3
2.5
7.0
2.1
5.7
3.4
5.5
3.3
37.2
22.3
166.5 100.0
Breast cancer: incidence increases;
mortality declines in developed countries
Taiwan Case No.
Incidnce
Mortality
Patients diagnosed with
breast cancer
Patients died of
breast cancer
5,339*
1,439
48.38*
12.9
212,930
,
40,870
,
~ 150
~ 28
Crude rate
5
(per 10 population)
U.S.#
Case No.
Crude rate
5
(per 10 population)
* data of year 2002; the other data are for year 2005.
# Estimated data of the American Cancer Society for US in year 2005
Note: In US, breast cancer is the most common malignancy in women and is second only to lung
cancer as a cause of cancer death.
Age-specific
g p
Breast Cancer Incidence
600.0
500.0
American
Caucasion
400.0
台灣1994
300.0
台灣1998
台灣2002
200.0
台灣2005
100.0
00
0.0
0
5
10 15 20 25 30 35 40 45 50 55 60 65 70 75 80 85+
年齡
Introduction
Breast tissue and draining
g lymphatics
y p
„
„
„
„
I
Increase
meatt consumption
ti
Decrease of fertility rate
Increase age at firstfirst-term pregnancy
and decrease
dec ease n
number
mbe of pa
parity
it
Decrease age
g at menarche
急速增加的台灣年輕女性乳癌是否
單純是西方化生活方式所造成??
單純是西方化生活方式所造成
台灣女性乳癌年齡別發生率
140.0
120.0
100 0
100.0
台灣女性結腸、直腸、乙狀結腸
連結部及肛門癌年齡別發生率
350.0
19811985
19861990
300.0
19811985
19861990
250 0
250.0
80.0
200.0
60.0
150 0
150.0
40.0
100.0
20.0
50 0
50.0
0.0
0.0
年齡（歲）
依發生年代分，1981-2005年
年齡（歲）
每十萬人口發生率
MacMahon et al, 1970
Age--specific rate: Female
Age
Korea 2006
許多亞洲國家有類似鐘型的乳癌年齡別發生率曲線
Shin HR et al, Cancer Causes Control. 2010 Nov;21(11):1777-85.
Molecular classification of breast cancer
Carey et al, JAMA. 2006;295:2492-2502
Nielsen et al, CCR 2004; 10: 5367-5374
Molecular subtype distributions among African
A
Americans,
i
non-African
nonAf i
Americans
A
i
and
d Taiwanese
T i
Age ≤ 50 years or premenopausal women
Carey et al, JAMA. 2006;295:2492-2502
Lin CH et al, Cancer Epidemiol Biomarkers Prev. 2009 ;18(6):1807-14
年齡別ER表現率的變遷: 由台大醫院兩個
已發表的研究世代所做的比較
P = 0.08
P < 0.001
P=0
0.40
40
Cohort 1 (n=481): Oncologist. 2008 Jul;13(7):751-60.
Cohort 2 (n=1028): Cancer Epidemiol Biomarkers Prev. 2009 ;18(6):1807-14
Breast cancer in Taiwan does not fit the ER and
age relationship described in textbook.
Breast cancer- an evolving model of two diseases
飲食及飲食相關因子
賀爾蒙及生育因子
• 停經後肥胖
• 初經較早
• 停經前過瘦
• 停經較晚
• 西方飲食
輻射曝露
• 無生產紀錄
• 飲酒
• 較晚生第一胎
•少攝取蔬果
• 使用口服避孕藥
環境賀爾蒙 ?? 乳癌發生
家族乳癌病史
良性乳房疾病
Breast
Cervix
Uterus
Ovary
U
US
Taiwan
n
證實荷爾蒙相關癌症於台灣年輕女性急速增加，也將
病因指向雌激素相關基因多樣性及環境荷爾蒙曝露
第一型子宮內膜癌
(雌激素依賴型腫瘤)
第二型子宮內膜癌
(雌激素不相關的腫瘤)
Lin CH et al, Int J Cancer. 2011 Jun 23 [Epub ahead of print]
Dx: pathology
Types of breast malignancy diagnosed
in Taiwan
Dx: pathology
Pathologic classification of
carcinoma of the breast
• Non-invasive carcinoma
–Ductal carcinoma in situ
–Lobular carcinoma in situ
~ WHO classification of carcinoma of
the breast
• Invasive carcinoma
–Invasive ductal carcinoma
–Invasive lobular carcinoma
–Mucinous
Mucinous carcinoma
–Medullary carcinoma
–Papillary
Papillary carcinoma
–Tubular carcinoma
–Adenoid cystic carcinoma
–Secretory (juvenile) carcinoma
–Apocrine carcinoma
–Metaplastic
Metaplastic carcinoma
–Inflammatory carcinoma
Others (specify)
–Others
• Paget’s disease of the nipple
Dx: clinical
Cancer treatment bases on full
knowledge of diagnosis and extent of
disease….
• P
Presentation:
t ti symptoms
t
and
d signs
i
• Diagnosis:
– Diagnostic procedures
– Pathology
• Extent of disease (Staging):
– Axillary
A ill nodal
d l status
t t
– Systemic evaluation
Dx: clinical
A breast lump or mass:
the most common sign of breast cancer
• Not everyy lump
p is cancerous,, but it should p
prompt
p a
medical evaluation.
p , other signs
g of breast cancer
• In addition to lumps,
include:
– Swelling
g in part
p of the breast
– Skin irritation or dimpling
– Pain in the nipple or the nipple turning inward
– Redness, itching or scaling of the nipple or breast
skin
– Discharge other than breast milk
Dx: clinical
Evaluation of a breast lump….
p
• Medical history
• Physical examination, including systemic and local
examinations
• Breast imaging studies
– Mammography
– Ultrasound and sonogram
– MRI
• Biopsy
Any area that appears suspicious by being palpably
abnormal or by radiological criteria deserves biopsy
biopsybased diagnosis.
Staging
Staging
g g of breast cancer
• Staging= grouping of patients
– Extent
E t t off disease
di
ÆDifferent prognosis Æ ÆDifferent treatment
strategies
t t i
• Based on history, physical exam, and the following
t t may include:
tests
i l d
– Blood tests
– Chest
Ch t X-ray
X
– Bone scan
– CT
– MRI
– PET
Staging
AJCC staging of breast cancer,
6th edition
diti published
bli h d iin 2002
T CATEGORIES
Tis
T1
T2
T3
T4
Carcinoma in situ
≤ 2 cm in greatest diameter
> 2 cm, but ≤ 5 cm
> 5 cm
Any size, with direct extension to
chest wall or skin
Stage
N CATEGORIES
g
LN metastasis
N0 No reginal
Clinical
N1 Ipsilateral axillary node(s), movable
N2 Ipsilateral axillary node(s), fixed;
Ipsilateral internal mammary nodes
N3 Ipsilateral infraclavicular node(s);
Ipsilateral supraclavicular node(s);
Ipsilateral internal mammary nodes +
axillary nodes
M CATEGORIES
M0 No distant metastasis
M1 Distant metastasis
T
N
M
0
Tis
N0
M0
I
T1
N0
M0
IIA
T0
T1
T2
T2
T3
N1
N1
N0
N1
N0
M0
M0
M0
M0
M0
IIIB
T0
T1
T2
T3
T3
T4
IIIC
Any T
N2
N2
N2
N1
N2
N1
N2
N3
M0
M0
M0
M0
M0
M0
M0
M0
IV
Any T
Any N
M1
IIB
Pathological
pN1 1~ 3 lymph nodes
pN2 4~ 9 lymph nodes
IIIA
pN3 ≥ 10 lymph nodes
Prognostic factors
Prognosis of breast cancer:
markers on cancer cells
• Markers on cancer cells
// potential or risk of occult metastasis
// susceptibility
p
y to current anti-cancer therapies
p
– Histologic type
– Histologic grading: grade 1 to 3
– Proliferation rate
– Lymphovascular invasion
– ER and PR
– HER2/neu
– Others: tumor angiogenesis, p53, occult metastasis in
bone marrow,
marrow other molecular or genomic profiles….
profiles
Non-invasive carcinomas
Operable,
p
, loco-regional
g
invasive
carcinomas
T CATEGORIES
Tis
T1
T2
T3
T4
Carcinoma in situ
≤ 2 cm in greatest diameter
> 2 cm, but ≤ 5 cm
> 5 cm
Any size, with direct extension to
chest wall or skin
Stage
N CATEGORIES
N0 No reginal LN metastasis
Clinical
N1 Ipsilateral axillary node(s), movable
N2 Ipsilateral axillary node(s), fixed;
Ipsilateral internal mammary nodes
N3 Ipsilateral infraclavicular node(s);
Ipsilateral supraclavicular node(s);
Ipsilateral internal mammary nodes +
axillary nodes
M CATEGORIES
M0 No distant metastasis
M1 Distant metastasis
T
N
M
0
Tis
N0
M0
I
T1
N0
M0
IIA
T0
T1
T2
T2
T3
N1
N1
N0
N1
N0
M0
M0
M0
M0
M0
IIIB
T0
T1
T2
T3
T3
T4
IIIC
Any T
N2
N2
N2
N1
N2
N1
N2
N3
M0
M0
M0
M0
M0
M0
M0
M0
IV
Any T
Any N
M1
IIB
Pathological
pN1 1~ 3 lymph nodes
pN2 4~ 9 lymph nodes
IIIA
pN3 ≥ 10 lymph nodes
Inoperable,
p
, loco-regional
g
invasive
carcinomas
Metastatic carcinomas
Treatment of cancer patients
G l Vs.
Goals
V Strategies
St t i
Goal
Parameters
做法(Strategies)
Cure
Long-term
竭盡所能達到
(痊癒)
Survival prolongation
(延長存活)
Symptom
y p
p
palliation
(症狀緩解)
disease-free
disease
free
治療的要求
Median survival
N-year survival
QOL
(Quality of life)
考量病人的需求及
生活品質
Chemotherapy
py for cancer patients
p
Goal
做法(Strategies)
Cure
竭盡所能達到治療的要求:
(痊癒)
標準的劑量, 強度, 療程,……
Survival prolongation
(
(延長存活)
)
Symptom palliation
(症狀緩解)
考量病人的需求及生活品質:
劑量, 強度,
劑量
強度 療程 相對的不是那麼
重要
Tx modality: op
Treatment of breast cancer
Surgery of breast
• Mastectomy: removal of the entire breast
– Simple (Total) mastectomy:
– Modified radical mastectom
mastectomy: pl
pluss axillary
a illar lymph
l mph
node dissection
• Radical mastectomy: plus removing all the muscle
under the breast
Radical mastectomyy is no longer
g a standard
procedure for breast cancer.
Fisher s theory : operable breast cancer has
Fisher’s
distant micrometastasis at very early stages
of breast cancer.
cancer
Levels
Types
yp of evidence
I
Meta analysis of multiple well
Meta-analysis
well-designed,
designed, controlled studies.
Randomized trials with low-false positive and low falsenegative errors (high power)
II
At least one well-designed experimental study. Randomized
trials with high false-positive and/or negative errors (low
power)
III
Well-designed, quasi-experimental studies such as nonrandomized, controlled, single group, pre-post, cohort, and
time or matched case
case-control
control series
IV
Well-designed non-experimental studies such as
comparative and correlational descriptive and case studies
V
Case reports
Levels
Types
yp of evidence
I
多個隨機臨床試驗 (Randomized controlled trials) 經由綜合
分析 ( Meta-analysis) 所獲得的結論
II
至少一個設計完整的隨機臨床試驗所獲得的結論
III
非隨機分配或無對照組的臨床試驗
流行病學或公共衛生的觀察、分析
IV
V
病例報告
Op for early-stage
Treatment of breast cancer
Operable loco
Operable,
loco-regional
regional invasive Ca.
Ca
• Local treatment:
– Modified radical mastectomy ~~Breast-conserving
surgery (lumpectomy+ axillary dissection+ whole
breast irradiation)
Table 33.2-11: Breast-Sparing Surgery with Radiation versus Mastectomy: 1995
National Cancer Institute Update Conference
Deaths/Patients
Study
BCT with RT
Mastectomy
Difference
/
90/430
77/429
/
None
107/456
89/422
None
17/88
18/91
None
NCI—Bethesda
NCI
Bethesda
14/121
17/116
None
NCI—Milan
74/352
84/349
None
176/515
188/492
None
478/1962
473/1899
None
Denmark
EORTC
Institut Gustave Roussy
NSABPa
Total
~ Table 33.2-11 in Principle and Practice of Oncology, 7th ed., Page 1436.
Op for early-stage
Treatment of breast cancer
Operable loco
Operable,
loco-regional
regional invasive Ca.
Ca
• Breast-conserving surgery:
Absolute contraindications
• Previous mod
mod- or high
high- dose
RT to breast or chest wall
• Pregnant
• Diffuse suspicious or
malignancy-appearing
g
y pp
g
microcalcifications on
mammography
• Widespread ds for which
cosmetically single-excision is
i
impossible
ibl
Relative contraindications
• Connective tissue ds
ds. of skin
• Tumors > 5 cm
• Focally positive pathologic
margins
~ NCCN treatment guidelines version2, 2006.
Tx modality: RT
Treatment of breast cancer
Radiotherapy
• As part of breast-conserving surgery:
– Whole breast irradiation +/- a boost
– Nodal irradiation?
• Post-mastectomy radiation:
– Radiation
R di ti to
t chest
h t wallll + one or more regional
i l
lymph node areas
• Palliative measures for symptomatic sites in advanced
diseases
Tx modality: RT
• Simulation films for
definitive RT to left
breast tangent fields
– A. Fluoroscopic
simulation film
– B. CT-simulated
film.
~ Figure 33.2-4.
in Principle and Practice of Oncology, 7th
ed., Page 1440.
RT for early-stage
Treatment of breast cancer
Operable loco
Operable,
loco-regional
regional invasive Ca.
Ca
• Radiotherapy
py
– Mandatory for breast-conserving surgery
– Post-mastectomy
Post mastectomy radiation: irradiation to chest wall +
one or more regional lymph node areas
Postmastectomy
radiotherapy
↓loco-regional
recurrence
↑disease-free
↑overall survival
↑Cardio-pulmonary
mortalityy
~ NCCN treatment guidelines version2, 2006.
RT for early-stage
Treatment of breast cancer
Operable loco
Operable,
loco-regional
regional invasive Ca.
Ca
• Post-mastectomy radiation: irradiation to chest wall +
one or more regional
i l llymph
h node
d areas
– Lymph nodes ≥ 4(+)
– Lymph nodes 1~ 3, but T≥ 5 cm or positive pathologic
margins
– Lymph node-negative, but T≥ 5 cm and positive or very
close ((< 1 cm)) pathologic
p
g margin
g
• Timing: after finishing adjuvant chemotherapy
? Any lymph nodes 1~ 3
p
internal mammaryy field
? Inclusion of ipsilateral
~ NCCN treatment guidelines version2, 2006.
Tx modality: op
Treatment of breast cancer
Surgery of (axillary) lymph nodes
• Removing lymph nodes:
X improve the chance of long-term survival
√pro ide prognostic information and help select
√provide
further therapy
• Side effects:
– Numbness in the skin on the inside of the upper arm
– Limitation of shoulder movements
– Lymphedema: 10% of women receiving axillary
lymph node dissection
Op for early-stage
Treatment of breast cancer
Operable loco
Operable,
loco-regional
regional invasive Ca.
Ca
• Axillaryy lymph
y p node dissection
– Standard approach: a formal level I and level II
dissection of ≥ 10 lymph nodes; level III nodes need to
be dissected when gross disease is apparent.
– Sentinel lymph node dissection: considered as an
option for certain group of patients.
~ NCCN treatment guidelines version2, 2006.
Tx modality: op
Treatment of breast cancer
Surgery of (axillary) lymph nodes
• Sentinel lymph node dissection:
手術後的全身性輔助性
(adjuvant) 治療
Fisher’s theoryy : operable
p
breast cancer has
distant micrometastasis at very early stages
of breast cancer.
Introduction
• Adjuvant systemic treatment: (chemotherapy /
endocrine therapy)
– Aim: to eradicate “micrometastasis”
• No target to evaluate efficacy
– End-point:
End point:
• Disease-free survival
• Overall survival
– Long
g wayy to g
go
乳癌術後的輔助性治療
•
•
•
•
化學治療
荷爾蒙治療
放射線治療
其他
• 減少局部復發及
遠處轉移
• 延長無病存活期
間 (disease-free
survival)
i l)
• 增加治癒率
Systemic Tx
Treatment of breast cancer
Systemic therapy
• Types:
– Hormonal therapy
– Chemotherapy
– Antibody against HER2
– ……..
• Timing:
– Adjuvant
– Neoadjuvant
– For metastatic disease
Treatment,, based on considering:
g
• Diagnosis
• Disease extent
(staging)
• Prognostic
factors:
– Tumor
type/grade;
– Tumor size;
– LN status;
– ER/PR?
– HER2/neu?
– …..
Disease
Host
=
• Age
g
• Co-morbid
disease
• Patient
preference
Annuall Hazard
A
H
d off Recurrence
R
b
by
Estrogen
g Receptor
p
Status
Recu
urrence haazard ratte
0.3
Negative (n=1305)
Positive (n=2257)
0.2
0.1
0
0
1
2
3
4
5
6
Years
Saphner et al. J Clin Oncol. 1996;14:2738.
1. Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451.
2. Update of Houghton. J Clin Oncol. 2005;23(16S):24s. Abstract 582.
7
8
9
10 11 12
Recurrence Hazard Rates Are Dependent
on Known Prognostic Factors
Haz
zard of re
ecurrenc
ce by yea
arly
iinterval
Prominent early peak of recurrences (~ 3 yrs)
in absence of adjuvant therapy, particularly in ER- disease
25
Total
Node 0
20
Node 1-3
Node (4+)
15
Tumour size (<1cm)
Tumour size (1.1-3cm)
10
Tumour size (>3cm)
ER+
5
ERPremen
Postmen
0
0.5
1.5
2.5
3.5
4.5
5.5
6.5
7.5
8.5
9.5 10.5
Year
Early Breast Cancer Trialists’ Collaborative Group. Lancet. 1998;351:1451 ; Update of Houghton. J Clin Oncol. 2005;23(16S):24s. Abstract 582 ; Saphner et al., J Clin Oncol. 14:
2738-2746, 1996
Adjuvant Tx for earlystage
Adjuvant systemic therapy
for early
early-stage
stage breast cancer
ER+ or PR+
ER-- or PR--
T1a or T1b & N0
±Tamoxifen
±Combination
py
chemotherapy
T1c-T2 & N0
Combination
chemotherapy
Ætamoxifen x 5 years
Any T & N1
Combination
chemotherapy
± Taxane
± Dose dense
Ætamoxifen x 5 years
± Aromatase
A
t
inhibitor
i hibit
Combination
chemotherapy
Combination
chemotherapy
py
± Taxane
± Dose dense
~ Modified from Table 33,2-19B, Chapter 33.2 of Cancer: PPO 7th Ed.
Adjuvant Tx for earlystage
Estimate risk of recurrence
by computer
computer-based
based model:
Online: www.adjuvantonline.com
Adjuvant Tx for earlystage
Treatment of early-stage breast cancer
What is adjuvant therapy for..
for
• ↓chance of recurrence, ↑chance of cure
不用做也
會好!
做了也不
會好!
Systemic Tx
Treatment of breast cancer
Hormonal therapy
LHRH
agonists
Pituitary gland
FSH/LH
Aromatase
inhibitors
Adrenal
Ovary
Ovarian
O
i
ablation
Anti--estrogens
Anti
↑Cell survival, proliferation…
Systemic Tx
Treatment of breast cancer
Hormonal therapies
Ovarian ablation by LHRH
agonists
Other ovarian ablations
Selective estrogen receptor
modulators (SERMs)
Progestins
Aromatase inhibitors
ER down-regulators (pure
anti estrogens)
anti-estrogens)
Goserelin ((Zoladex))
Leuprolide (Lupron)
Oophorectomy
Ovarian irradiation
Tamoxifen
Toremifene
Megestrol acetate (Megace)
Medroxyprogesterone
yp g
acetate
Anastrozole (Arimidex)
Letrozole (Femara)
Exemestane (Aromasin)
Fulvestrant (Faslodex)
Adjuvant HT for earlystage
Adjuvant hormonal therapy
Early stage breast cancer
Early-stage
• Previous standard:
tamoxifen x 5 years
• The role of
aromatase inhibitors
become increasingly
gy
important.
~ Koeberle D & Thurlimann B: The breast 2005; 14: 446.
Systemic Tx
Treatment of breast cancer
Chemotherapy: active drugs
Anthracyclines
Alkylating agents
Platinums
Vinca alkaloids &
related drugs
Taxanes
Anti-metabolites
Doxorubicin (adriamycin)
E i bi i
Epirubicin
Liposomal doxorubicin
Cyclophosphamide
Melphalan
Cisplatin
p
or carboplatin
p
Etoposide
Vinblastine
Vi
Vinorelbine
lbi
Paclitaxel (Taxol)
Docetaxel (Taxotere)
5-FU
Capecitabine
p
((Xeloda))
Methotrexate
Gemcitabine (Gemzar)
Development of Adjuvant Chemotherapy
Breast Cancer
1970s
•
•
1980s
•
1990s
•
2000s
Before anthracyclines
– CMF,
CMF CMFVP
With anthracyclines
– Combinations:
C bi ti
AC
AC, FAC
FAC, AVCMF,
AVCMF FEC,
FEC CEF
– Sequence and Alternating (Milan A & B)
– Dose intensity,dose
intensity dose density,
density HDCT
Taxanes (Paclitaxel/Docetaxel)
– Sequential: A⇒ T⇒ C or AC⇒ T
– Combinations: TA, TAC
Biologic Modifiers: Herceptin
– Integration in chemotherapy strategies
Nabholtz; May, 2002
Istituto Nazionale Tumori, Milan, Italy
Gianni Bonadonna et al.
1973 1975
1973-1975
386 pts
LN: positive
Menopausal: both
Hormone: N/A
RFS
CMF x 12
None
Classic CMF
C: 100mg/m2/d, D1-14
q4w
4
M: 40mg/m2,
0
/ 2 D1,8
8
F: 600mg/m2, D1,8
20 yrs follow-up
f ll
OS
20yr
RR
↓Risk
Recur
65%
35%
OS
76%
24%
New England Journal of Medicine 1976; 294: 405-410
New England Journal of Medicine 1995; 322: 901-966
Istituto Nazionale Tumori, Milan, Italy
Gianni Bonadonna et al.
1973 1975
1973-1975
Dose delivery and efficacy
RFS
OS
New England Journal of Medicine 1976; 294: 405-410
New England Journal of Medicine 1995; 322: 901-966
Adjuvant Tx for earlystage
√
CMF- based chemotherapy
for breast cancer
Oral CMF
IV CMF
Cyclophosphamide, PO 100 mg /m2/d ↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓
↓
Methotrexate, IV
40 mg/m2/d ↓
↓
5-FU, IV
600 mg/m2/d ↓
W k 1 Week-2
Week-1
W k 2 Week-3
W k3
Cyclophosphamide, IV 600 mg /m2/d ↓
Cyclophosphamide
Methotrexate, IV
40 mg/m2/d ↓
5-FU, IV
600 mg/m2/d ↓
Week-1
x 6 cycles
W k4
Week-4
x 8 cycles
Week-2
↓
Cyclophosphamide, IV 600 mg /m2/d ↓
↓
Methotrexate, IV
40 mg/m2/d ↓
↓
5-FU, IV
600 mg/m2/d ↓
Week-1 Week-2
Week-3
x 6 cycles
Week-3
Week-4
Adjuvant Tx for earlystage
Anthracycline- based chemotherapy
for breast cancer
Cyclophosphamide,
C
l h h id IV 600 mg //m2/d ↓
Doxorubicin, IV
60 mg/m2/d ↓
Week-1
AC:
CAF
oral:
CAF
IV:
x 4 cycles
Week-2
Week-3
Cyclophosphamide, PO 100 mg /m2/d ↓↓↓↓↓↓↓ ↓↓↓↓↓↓↓
2
↓
Doxorubicin, IV
g /d ↓
25 mg/m
2
↓
5-FU, IV
500 mg/m /d ↓
Week-1 Week-2 Week-3
Cyclophosphamide, IV 500 mg /m2/d ↓
2
Doxorubicin, IV
50 mg/m /d ↓
↓
5 FU IV
5-FU,
500 mg/m2/d ↓
Week-1 Week-2
AC x 4 //
equivalent
to oral CMF
x 6 cycles
y
Week-4
x 6 cycles
Week-3
Note: Doxorubicin Æ Epirubicin (in 2 x dose)
6 cycles of Acontaining
regimen Æ
better than
CMF
Adjuvant Tx for earlystage
Taxane- containing adjuvant
chemotherapy for breast Cancer
AC followed by T
Cyclophosphamide, IV 600 mg /m2/d ↓
2
Doxorubicin, IV
60 mg/m /d ↓
Week-1
Paclitaxel, IV
175 or 225
2
mg/m /d
x 4 cycles
Week-2
Week-3
x 4 cycles
↓
Week-1
ee
Week-2
ee
Week-3
ee 3
Adjuvant Tx for earlystage
Taxane- containing adjuvant
chemotherapy for breast Cancer
• CALGB 9344 (INT
(INT-0148)
0148)
AC AC+T
AC T
Efficacy
Hazard
reduction
Node(+)
Breast Ca
~ Henderson IC et al: JCO 2003;21:976.
2003;21:976
5-year DFS 65% 70%
5-year OAS 77% 80%
↓ recurrence
↓17%
↓ death
↓18%
Adjuvant Tx for earlystage
Taxotere-containing adjuvant
chemotherapy for breast cancer
: BCIRG-001
R
A
N
D
Axillary LN(+) O
Breast cancer M
(1491 patients) I
After surgery Z
A
T
I
O
N
FAC x 6 cycles
2
Doxorubicin, IV
50 mg/m /d ↓
Cyclophosphamide, IV 500 mg /m2/d ↓
2
55-FU,
FU, IV
500 mg/m /d ↓
Week-1
x 6 cycles
Week-2
Week-3
TAC x 6 cycles
l
2
Doxorubicin, IV
g /d ↓
50 mg/m
Cyclophosphamide, IV 500 mg /m2/d ↓
Docetaxel, IV
75 mg/m2/d ↓
Week-1
x 6 cycles
Week-2
Week-3
Adjuvant Tx for earlystage
Taxotere-containing adjuvant
chemotherapy for breast cancer
: BCIRG-001
R
A
N
D
Axillary LN(+) O
Breast cancer
M
(1491 patients)
after surgery
g y I
Z
A
T
I
O
N
FAC
FAC x 6
cycles
TAC x 6
cycles
~ Martin M et al: N Engl J Med 2005;352:2302.
Efficacy
Hazard
reduction
TAC
5-year DFS
68% 75%
5-year OAS 81% 87%
↓ recurrence
↓28%
↓ death
↓30%
Adjuvant Tx for earlystage
Taxotere-containing adjuvant
chemotherapy for breast cancer
: BCIRG-001
Axillary LN(+)
Breast cancer
(1491 patients)
After surgery
R
A
N
D
O
M
I
Z
A
T
I
O
N
FAC x 6
cycles
Gr 3 or 4
toxicity
(%)
FAC
TAC
Neutropenia
49 3
49.3
Febrile neutropenia
2.5
Infection
6.3
Thrombocytopenia
1.2
Any non-hematologic 26.6
CHF
07
0.7
65.55
65
24.7
12.5
2.0
36.3
16
1.6
TAC x 6
cycles
~ Martin M et al: N Engl J Med 2005;352:2302.
毒性明顯增加!
I it worth?
Is
th? Any
A better
b tt way?
?
Adjuvant Tx for earlystage
Adjuvant chemotherapy for
early stage breast cancer
early-stage
• Anthracycline-based regimens better > conventional
CMF (annual odd of recurrence by CMF: 12%)
– ↓↓annual odd of recurrence: 11% further reduction
– Recommended for any node- positive, especially those
with HER2/neu
HER2/neu-overexpressing
overexpressing, cases
• More drugs are better (?): adding taxanes
• Alternating
Alt
ti dosing
d i is
i better
b tt (?)
• Dose-dense is better?
越強, 越密集,越多, …….. Æ 似乎越好!
Tx for LABC
Patients with inflammatory breast cancer
(T4 disease)
• Aggressive combined modality therapy:
– A small and
real fraction of
patients have
long-term
o g e
survival.
~ Figure 33.2-8 in Principle and Practice of Oncology, 7th ed., Page 1453. Actuarial overall survival curves for patients
with inflammatory breast cancer undergoing combined modality treatment according to whether a pathologic complete
response (Path CR) was achieved based on the pathologic findings at the time of mastectomy. (From Harris EE, Schultz
D, Bertsch H, et al. Ten-year outcome after combined modality therapy for inflammatory breast cancer. Int J Radiat Oncol
Biol Phys 2003;55:1200, with permission.)
Systemic Tx
Targeting growth factor receptors or
signaling pathways
~ Gross ME, Shazer RL, and Agus DB: Targeting the HER-Kinase Axis in Cancer. Sem Oncol 2004; 31(Suppl 3):9.
Systemic Tx
Treatment of breast cancer
Monoclonal antibody against HER2
• Trastuzumab ((Herceptin):
p ) a humanized monoclonal
antibody against the EC domain of HER2/neu (c-erbB2).)
• In 1998, HerceptinTM , a monoclonal antibody against
HER2/neu was approved for the treatment of patients
with metastatic breast cancer whose tumors
overexpress the HER2 protein and who have received
one or more chemotherapy regimens for their
metastatic disease.
Adjuvant anti-HER2
for early-stage
Adjuvant Trastuzumab (Herceptin)
HER2 positive early breast cancer
HER2-positive
~ Baselga J et al: Oncologist 2006; 11 (suppl 1): 4-12.
Adjuvant anti-HER2
for early-stage
Adjuvant Trastuzumab (Herceptin)
HER2 positive early breast cancer
HER2-positive
• All showed ↓risk of recurrence
• All showed ↑cardiac events: slightly higher (0.6~ 3.3%) of CHF
~ Baselga J et al: Oncologist 2006; 11 (suppl 1): 4-12.
Adjuvant Tx for
early-stage
Adjuvant therapy for
early stage breast cancer
early-stage
• Chemotherapy: more drugs, more complex schedules
• Hormonal therapy: Aromatase inhibitors (AIs) should
be offered for menopausal women.
• Trastuzumab for HER2-positive cases
越強, 越密集, 越多, …….. Æ 似乎越好!
¾毒性!
¾適用的病人族群
Tx for early-stage
Treatment of breast cancer
Operable loco
Operable,
loco-regional
regional invasive Ca.
Ca
How to increase the chance of cure!
• Local treatment:
– Breast-conserving surgery Vs.
Vs mastectomy
• Regional treatment:
– Axillary
A ill llymph
h node
d dissection
di
i
– Radiation
• Systemic treatment: (adjuvant)
– Chemotherapy
– Hormonal therapy
– Herceptin
H
ti
~ NCCN treatment guidelines version2, 2006.
Tx for LABC
Inoperable, loco-regional invasive Ca.
or Locally advanced breast Ca.
Ca
To increase the chance of cure!
• Local treatment:
– Mastectomy
Start with highly
effective
– Breast-conserving surgery
chemotherapy Æ
• Regional
eg o a treatment:
ea e
– Axillary lymph node dissection
↑likelihood of proper
local control;;
– Radiation
• Systemic treatment: (Neoadjuvant)
↑elimination of occult
– Chemotherapy
py
systemic metastasis
– Hormonal therapy
– Herceptin
p
~ NCCN treatment guidelines version2, 2006.
Conclusion
Treatment of breast cancer
• 更多, 更強, 更密集, 更複雜, …….. • 更individualized,更target更i di id li d 更
or mechanism-based,……..
h i b d
Surgery
1. Breast-conserving
surgery
2. Mastectomy
Axiallry LN
1. LN dissection
2. Sentinel LN
dissection
Radiation
Systemic therapy
1. Hormonal therapy
2. Chemotherapy
3. Ab against HER2
Non-invasive carcinomas
Operable, loco-regional
invasive carcinomas
Inoperable, loco-regional
invasive carcinomas
Metastatic or recurrent
Multi-discipline
Teamwork
Dedicated & professional
Thank You
V
Very
M
Much
h