Update Management Breast

Cancer inline BPJS role

Dr Faison SpB(K) Onk

Divisi Bedah Onkologi RS Doris Sylvanus

Palangka Raya
 Introduction
Breast cancer is a heterogeneous disease
Can not be explained only by clinical parameters or
by biomarkers(IHC)
Vary in prognosis and response to therapy
The advent of HIGH-THROUGHPUT technologies
development of gene signature to predict the
outcome of breast cancer patients
The concept of Personalized medicine in BC patients
Several study high-throughput technologies is
feasible in the context of daily practice.
 What is Cancer?

The uncontrolled, abnormal growth of cells

Cancer may spread to other parts of the body

BIOLOGI MOLEKULAR
BIOLOGI MOLEKULAR
What is the Structure of the Breast?
The breast is composed mainly of
fatty tissue, which contains a
network of lobes made up of tiny,
tube-like structures called lobules
that contain milk glands

Tiny ducts connect the glands,

lobules, and lobes, and carry the
milk from the lobes to the nipple

Blood and lymph vessels run

throughout the breast

About 90% of all breast cancers

originate in the ducts or lobes of the
breast
 What is Breast Cancer?
The most common type of cancer in women in the
United States (excluding cancers of the skin) and the
second most frequent cause of death from cancer in
women

A disease in which normal cells in the breast begin to

change, grow without control

Cancer that has not spread is called in situ, meaning in

place

Cancer that has spread is called invasive or infiltrating

 Breast Cancer Incidence

Breast cancer incidence

rates per 100,000

Reproduced with permission Ferlay J., Soerjomataram I., Ervik M., Dikshit R., Eser S., Mathers C., Rebelo M., Parkin D.M., Forman D., Bray, F.
GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide:IARC CancerBase No. 11 [Internet]. Lyon, France: International Agency for 8
Research on Cancer; 2013.Available from: http://globocan.iarc.fr, accessed on 02/06/2015.
 Breast cancer is by far the most frequent cancer among women with an
estimated
1.6 million new cases diagnosed with more than 500,000 deaths
each year
(GLOBOCAN 2012)

Ferlay J, et al. Cancer incidence and mortality worldwide : source, methods and major pattern in globocan 2012. IJC. 2014. 136: E358-E386
 Incidence and
mortality of breast
cancer is the biggest
among cancer in
Indonesia

International Agency for research on cancer. http://globocan.iarc.fr/Pages/fact_sheets_population.aspx 2.

10 downloaded 6/27/2016
Breast Cancer Has Different Clinico-pathologic Features in
Developing Countries

Clear lines of demarcation versus developed countries:

More advanced stages
Younger age
Somewhat more aggressive subtypes...?
Poorer survival
The Ultimate Challenge Breast Cancer in Eastern
Countries:
No proper registry
Late diagnosis
Different age and pathology to western data
Decreased survival probability

11
MANAGEMENT of BREAST CANCER
1. DIAGNOSIS
2. STADIUM
3. PERFORMANCE STATUS
4. THERAPY PLANNING
5. THERAPY IMPLEMENTATION
6. EVALUATION
 Diagnosis
TRIPLE DIAGNOSTIK
1. KLINIS
2. IMAGING/RADILOGI
3. HISTOPATOLOGI

13
 KLINIS
ANAMNESIS
KELUHAN PAYUDARA DAN AXILLA
KELUHAN DITEMPAT LAIN
FAKTOR RESIKO
PEMERIKSAAN FISIK
STATUS GENERALIS
STATUS LOKALIS
PAYUDARA /IPSILATERAL dan KONTRALATERAL
MASA TUMOR : LOKASI,UKURAN,KONSISTENSI,PERMUKAAN,BENTUK
DAN BATAS TUMOR, JUMLAH TUMOR, FIKSASI TUMOR DI DINDING
DADA dan KULIT
PERUBAHAN KULIT
PAPILLA MAMA
KGB REGIONAL : AXILLA, INFRA CLAVICULA, SUPRA CLAVICULA
PEMERIKSAAN ORGAN LAIN (METASTASIS)
DIAGNOSA KLINIS : TUMOR PAYUDARA D SUSPECT
GANAS TNM
14
 IMAGING/RADIOLOGI
USG
MAMOGRAFI
MRI
PET SCAN/PET CT

15
 HISTOPATOLGI

STANDAR BAKU EMAS

HANYA CURIGA GANAS
BIOPSI TERTUTUP
FNAB
CORE NEEDLE BIOPSY
STEREOTACTIC BIOPSY NON PALPABLE BREAST
CANCER
BIOSI TERBUKA
BIOPSI INSISIONAL
BIOPSI EKSISIONAL
IHC (FAKTOR PREDIKTOR dan PROGNOSTIK)
TERAPI DEFINITIF

16
 STAGING/STADIUM
TNM (UICC,AJCC)
KLINIS (PEMERIKSAAN KLINIS)
RADIOLOGI : RO THORAX, USG LIVER
BONE SCANNING, BONE SURVEY,
CT SCAN,
MRI,PET SCAN/CT

17
 PERFORMANCE STATUS
KARNOFSKY SCORE
WHO SCORE
ECOG SCORE

18
 How is Breast Cancer Treated?
Treatment depends on stage of cancer

More than one treatment may be used

Surgery

Radiation therapy

Chemotherapy

Hormone therapy

Targeted therapy
 Cancer Treatment: Adjuvant Therapy

Treatment given in addition to surgery to

reduce the risk of recurrence

May include radiation therapy, chemotherapy,

biologic therapy, and hormone therapy
 Cancer Treatment: Radiation Therapy

The use of high-energy x-rays or other particles to destroy cancer

cells

Usually used to treat breast cancer after surgery

Different methods of delivery

External-beam: outside the body

Internal: uses implants inside the body

Side effects may include fatigue, swelling, and skin changes

 Cancer Treatment: Chemotherapy

Drugs used to kill cancer cells

May be given before surgery to shrink a large tumor

(neoadjuvant chemotherapy) or after surgery to reduce
the risk of recurrence (adjuvant chemotherapy)

A combination of medications is often used

 Cancer Treatment: Hormone Therapy
Used to manage tumors that test positive for either estrogen or
progesterone receptors

May be used alone or together with chemotherapy

Tamoxifen (Nolvadex) is a common hormone therapy and is

effective in many premenopausal and postmenopausal women

Aromatase inhibitors are also used alone or following tamoxifen use

as treatment for postmenopausal women, including anastrozole
(Arimidex), letrozole (Femara), and exemestane (Aromasin)
 New Therapies: Targeted Therapy
Treatment designed to target cancer cells while minimizing damage
to healthy cells

Used to stop the action of abnormal proteins that cause cells to

grow and divide out of control

Trastuzumab (Herceptin) for women with a HER-2/neu-positive

breast cancer either with or after adjuvant chemotherapy

Bevacizumab (Avastin) blocks angiogenesis (the formation of new

blood vessels) and is under evaluation in clinical trials
Clinical Breast Cancer Subsets Today
(H. Burstein)

HR+
65-75%

All Breast Cancer

HER2+
15-20%

Triple
Neg 15%
 HORMONAL TREATMENT
FOR POSTMENOPAUSAL BREAST
CANCER

26
 Intrinsic subtype of breast cancer (St Gallen 2015) which is also
recommended by ESMO Clinical Practice Guidelines for making the
prognosis and treatment decision

Senkus E et al. Annals of Oncology. 2015. Downloaded from http://annonc.oxfordjournals.org/ at AZ Library on May 30,
2016 27
 Treatment recommendation
for early breast cancer subtypes

Senkus E et al. Annals of Oncology. 2015. Downloaded from http://annonc.oxfordjournals.org/ at AZ Library on May 30, 2016

28
 NCCN Guideline Version 2.2016
Adjuvant Endocrine Therapy For Postmenopausal Breast cancer

Aromatase inhibitors (AIs) and Tamoxifen are option for endocrine therapy for post
menopausal breast cancer patient.

NCCN Clinical practice guideline in oncology (NCCN Guidelines ). Version 2.2016. printed 6/2/2016 29
 ARIMIDEX (anastrozole) :
Long term efficacy and tolerability
 ATAC Trial Design
9366 postmenopausal women with localised
invasive breast cancer

Surgery radiotherapy chemotherapy

Randomisation 1:1:1 for 5 years

Anastrozole Tamoxifen Combination
n=3125 n=3116 n=3125
Discontinued

Regular follow-up

Primary trial endpoints: Secondary trial endpoints:
Disease-free survival Incidence of contralateral breast cancer
Safety / tolerability Time to distant recurrence
Overall survival
Time to breast cancer death

ATAC Trialists' Group. Lancet Oncol. 2008; 9: 45-53

After 10 years of follow-up...
 ARIMIDEX upfront significanly reduces the risk of
recurrence by 21%

Cuzick J, et al. Lancet Oncol. 2010; 11:1135-1141

33
 ARIMIDEX upfront significantly reduces the time
to distant recurrence by 15%

Cuzick J et al. Lancet Oncol. 2010; 11:1135-1141

34
ARIMIDEX significantly reduces the risk of contralateral
breast cancer by 38% (HR=0,62 (0.45-0.85), p=0,003)

Cuzick J, et al. Lancet Oncol. 2010; 11:1135-1141

 ARIMIDEX is associated with lower incidence of
endometrial cancer compare with tamoxifen
p = 0.001

Tamoxifen Arimidex

36 Cuzick J, et al. Lancet Oncol. 2010; 11:1135-1141

ATAC 10 years tolerability profile

ARIMIDEX is proven to have a better tolerability profile in serious adverse

event than tamoxifen during treatment period. The increased fracture rate
with ARIMIDEX during treatment didnt continue after treatment.

Cuzick J, et al. Lancet Oncol. 2010; 11:1135-1141

 Lipid profile in premenopausal,
postmenopausal women and breast cancer
patient

38
 Comparison of lipid profile in
premenopausal and postmenopausal
women

Total cholesterol, triglycerides and LDL-C

in postmenopausal significant higher than
premenopausal

Bade G et al. 2014. Downloaded free from http://www.cysonline.org on Tuesday, May 31, 2016.
 A case-control study conducted in 2001-2003 in department of Surgical
Oncology in New Delhi.

The study involved 160 patients diagnosed with breast cancer which have not
received any treatment specific for breast cancer

Total cholesterol level in breast cancer patients

Result significantly higher than control (p<0.001).

A significant difference (p=0.013) also observed

in triglyceride level of BC patients (170 67
mg/dL) vs control (149 81 mg/dL)

Kapil U et al. J Breast cancer. 2013 March ; 16(1) : 129-130

ARIMIDEX is NOT the same with other
AIs in lipid profile
 1. Michallaki V, et al. Mollecullar and cellular biochemistry. 2005. 268 : 19-24
2. Buzdar A, et al. Cancer. 2002 ; 95: 2006-2016
3. PI Arimidex version 22nd January 2014
4. Letrozole. PIO Nas (internet). http : //pionas.pom.go.id. Printed 6/27/2016
42 5. Aromasin. PIO Nas (internet). http://pionas.pom.go.id. Downloaded 6/27/2016
 SUMMARY
ARIMIDEX as upfront adjuvant therapy is significantly more superior than
tamoxifen in reducing risk of recurrence, time to distant recurrence and
contralateral breast cancer1

ARIMIDEX associated with lower incidence of endometrial cancer compare

with tamoxifen1

ARIMIDEX is proven to have a better tolerability profile in serious

adverse event than tamoxifen during treatment period. The increased
fracture rate with ARIMIDEX during treatment didnt continue after
treatment1

ARIMIDEX is a non steroid aromatase inhibitor which has shown no

significant impact on patients lipid profile compared to other AIs2

1. Cuzick J, et al. Lancet Oncol. 2010; 11:1135-1141

2. Buzdar A, et al. Cancer. 2002 ; 95: 2006-2016
43
 Management of Breast Cancer
in Premenopausal Patients

372893 / AUGUST 2018

 Age-specific breast cancer incidence rates in selected cancer registries

Asia : Rates in Singapore, particularly among the Chinese, are also relatively high
for the region
Bray F et al. Breast Cancer Research. 2004; 6:229-239
 Recovery from Chemotherapy-induced Amenorrhea: According
to Age
Proportion patient with Amenorrhea decreasing for Age < 40

Kim HA et al. The Incidence of Chemotherapy-induced Amenorrhea and Recovery in Young (<45-year-old) Breast Cancer Patients.
J Breast Cancer. 2009 Mar;12(1):20-26 (South Korea)
 Chemotherapy-Induced Amenorrhea (CIA) for
Hormone Receptor Positive (HR +) & Prognosis
DFS OS

Patient no CIA showed poor Disease Free Survival (DFS) and Over all Survival (OS)

Jung M et al. The clinical outcome of chemotherapy-induced amenorrhea in premenopausal young patients with breast cancer with
long-term follow-up. Ann Surg Oncol. 2010 Dec;17(12):3259-68. (South Korea)
ZOLADEX in the management
of breast cancer
St Gallen 2013

Goldhirsch A et al. Annals of Oncology. 2013; 24: 22062223

 Why Endocrine Therapy?
Adjuvant hormone therapy (tamoxifen) was not associated with survival benefits in very
young patients (age <35 years), when compared with the significant benefits in older
patients1
Younger patients (<35 years) showed worse prognosis than older pre- and peri-menopausal
patients (35-50 years) in the HR(+) group, not in the HR(-) group, regardless of LN status or tumor
size1

It suggests that adjuvant tamoxifen alone may not be very effective in very young HR(+) patients

Early breast cancer can be treated with ovarian suppression using the GnRH analogue
(goserelin)2
Adjuvant or after adjuvant chemotherapy in pre-/peri-menopausal women

Goserelin (ZOLADEX) as monotherapy or in combination with tamoxifen is as effective as

cytotoxic chemotherapy in patients with HR(+) tumors2

Note :
HR: hormone receptor
GnRH: Gonadotropin hormone-releasing hormone

1. Ahn, SH et al. J Clin Oncol. 2007 Jun 10;25(17) : 2360-8.

2. Jonat, W British Journal of Cancer. 2001; 85(Suppl. 2) : 15.
 ZOLADEX: Mechanism of Action
(1/2)
ZOLADEX
downregulation
of LHRH
receptors
Estrogen
Progesterone

Pituitary gland
LHRH
(hypothalamus)
Breast
Gonadotrophins
(FSH + LH)

Ovary

Adapted from : LHRH, luteinizing hormone-releasing hormone;

Kovacs M. PNAS. 2001; 98(21):1219712202 FSH, follicle-stimulating hormone; LH,
Emons et al. Trend in Endocrinology and metabolism. 1997. Vol.8,No.9 luteinizing hormone.
 ZOLADEX: Mechanism of Action
(2/2)
Hypersecretion of LH following acute Hyposecretion of LH following chronic
administration of ZOLADEX administration of ZOLADEX
goserelin

Pituitary Pituitary
Cell LH Cell LH

Adapted from :
Kovacs M. PNAS. 2001; 98(21):1219712202
Emons et al. Trend in Endocrinology and metabolism. 1997. Vol.8,No.9 LH : luteinizing hormone.
 ZOLADEX 3.6 mg suppresses serum oestradiol to
postmenopausal level by the eighth day.

Matta WH, et al. Endocrinologic and clinical evaluation following a single administration of a GnRH agonist (ZOLADEX),in a depot formulation to premenopausal
women.Fertil Steril. 1988;49:163-165
 IBCSG VIII: Trial Design
Objective
To examine the role of adjuvant treatment using chemotherapy, ovarian suppression with
goserelin, or the sequential combination of both modalities in pre- and peri-menopausal
patients with lymph nodenegative breast cancer
Pre-/Peri-menopausal
Stratification R
a
n
ZOLADEX 3.6 mg/28 days for 2 years
d
ER+ or ER or ER o
unknown m 1:1:1
Surgery i CMF* x 6 cycles
Planned
z (N=1063)
radiotherapy
a
(Yes/No)
t
CMF* x 6 cycles followed by ZOLADEX
Institution i
o
3.6 mg/28 days for 18 months
n
Primary Outcome:
*CMF: Cyclophosphamide 100 mg/m2 oral on
Disease-free survival days 1-14; Methotrexate 40 mg/m2 IV on days
1, 8; 5-Fluorouracil 600 mg/m2 IV on days 1, 8
Castiglione-Gertsch M et al. J Natl Cancer Inst. 2003;95:18331846.
IBCSG VIII Result : DFS in ER+ Patients by Age
ZOLADEX 3.6 mg demonstrated similar efficacy to CMF with respect to DFS in
pre-/peri-menopausal women with hormone-sensitive, node-negative disease

ER+, Age 39 Years ER+, Age 40 Years

100 100
disease-free patients (%)
Percentage of alive and

80 80

60 60

40 n Events 5-Yr % p 40 n Events 5-Yr% p

38 14 62 0.02 191 36 85 0.99
20 47 17 64 0.94 20 200 38 85 0.90
41 6 85 0.02 203 38 87 0.83
0 0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Years Years
*Retrospective analysis ZOLADEX 3.6 mg CMF CMF ZOLADEX 3.6 mg

*CMF = Cyclophosphamide 50 mg/m2 IV on

days 1, 8 or 100 mg/m2 oral on days 1-14;
Methotrexate 40 mg/m2 on days 1, 8; 5-
Castiglione-Gertsch M et al. J Natl Cancer Inst. 2003;95:18331846. Fluorouracil 600 mg/m2 IV on days 1, 8
ZEBRA: Trial Design
Objective
To compare the efficacy and tolerability of ZOLADEX with CMF chemotherapy in
pre-/peri-menopausal women with node(+) early breast cancer

R
a ZOLADEX 3.6mg/28 days for
n 2 years
Tumor recurrence
d
o
m
1:1
Surgery
i Death
radiotherapy
z
Eligibility criteria: a
Pre- or peri-menopausal t
Age: 50 years i CMF* x 6 cycles (each cycle
Node-positive Stage II o of 28 days)
early breast cancer n

*CMF = Cyclophosphamide 500 mg/m2 IV on days 1, 8

or 100 mg/m2 oral on days 1-14; Methotrexate 40 mg/m2
on days 1, 8; 5-Fluorouracil 600 mg/m2 IV on days 1, 8
Jonat W et al. J Clin Oncol. 2002; 20: 462835.
ZEBRA : Zoladex Early Breast Cancer Research Association
IBCSG VIII Result : DFS in ER+ Patients by Age
ZOLADEX 3.6 mg demonstrated similar efficacy to CMF with respect to DFS in
pre-/peri-menopausal women with hormone-sensitive, node-negative disease

ER+, Age 39 Years ER+, Age 40 Years

100 100
disease-free patients (%)
Percentage of alive and

80 80

60 60

40 n Events 5-Yr % p 40 n Events 5-Yr% p

38 14 62 0.02 191 36 85 0.99
20 47 17 64 0.94 20 200 38 85 0.90
41 6 85 0.02 203 38 87 0.83
0 0
0 1 2 3 4 5 6 7 8 0 1 2 3 4 5 6 7 8
Years Years
*Retrospective analysis ZOLADEX 3.6 mg CMF CMF ZOLADEX 3.6 mg

*CMF = Cyclophosphamide 50 mg/m2 IV on

days 1, 8 or 100 mg/m2 oral on days 1-14;
Methotrexate 40 mg/m2 on days 1, 8; 5-
Castiglione-Gertsch M et al. J Natl Cancer Inst. 2003;95:18331846. Fluorouracil 600 mg/m2 IV on days 1, 8
ZEBRA: Trial Design
Objective
To compare the efficacy and tolerability of ZOLADEX with CMF chemotherapy in
pre-/peri-menopausal women with node(+) early breast cancer

R
a ZOLADEX 3.6mg/28 days for
n 2 years
Tumor recurrence
d
o
m
1:1
Surgery
i Death
radiotherapy
z
Eligibility criteria: a
Pre- or peri-menopausal t
Age: 50 years i CMF* x 6 cycles (each cycle
Node-positive Stage II o of 28 days)
early breast cancer n

*CMF = Cyclophosphamide 500 mg/m2 IV on days 1, 8

or 100 mg/m2 oral on days 1-14; Methotrexate 40 mg/m2
on days 1, 8; 5-Fluorouracil 600 mg/m2 IV on days 1, 8
Jonat W et al. J Clin Oncol. 2002; 20: 462835.
ZEBRA : Zoladex Early Breast Cancer Research Association
ZEBRA: KaplanMeier Plots of Overall Survival
ZOLADEX is an effective alternative to chemotherapy in hormone receptor-
positive premenopausal patients with early breast cancer

(A) Kaplan-Meier curve of OS in the ER-positive (B) Kaplan-Meier curve of OS in the ER-negative
patient subgroup patient subgroup
A 1.0
Goserelin B 1.0
Goserelin
CMF CMF
0.9 0.9

0.8 0.8

0.7 0.7
Proportion alive

Proportion alive
0.6 0.6

0.5 0.5
HR=0.94:95% CI:0.75-1.18 HR=1.64:96% CI:1.13-2.39
0.4 0.4

0.3 0.3

0.2 Patients at risk at the start of each year 0.2 Patients at risk at the start of each year

0.1 591 573 554 521 487 450 374 262 174 83 Goserelin 0.1 144 136 125 107 95 81 64 53 33 16 Goserelin
598 584 555 535 512 455 377 261 166 89 CMF 160 154 140 124 119 108 97 74 51 22 CMF
0 0
0 1 2 3 4 5 6 7 8 9 10 0 1 2 3 4 5 6 7 8 9 10
Time (years) Time (years)

OS : over all survival;

Kaufmann et al. Eur J Cancer. 2003;39:1711-1717
ER : estrogen receptor.
ZEBRA: KaplanMeier Plot of DFS in
ER+ Patients
ZOLADEX is an effective alternative to chemotherapy in hormone receptor-
positive pre-menopausal patients with early breast cancer

1.0
ZOLADEX 3.6 mg
0.9
Proportion alive and free

CMF
0.8
0.7
of disease

0.6
0.5
0.4
0.3
0.2
HR=1.05, 95% CI 0.881.24; p=0.597
0.1
0
0 1 2 3 4 5 6 7 8 9 10
Time (years)

Kaufmann et al. Eur J Cancer. 2003;39:1711-1717

 Incidence of Adverse Events
ZOLADEX is well tolerated compared to chemotherapy in hormone receptor-positive
pre-menopausal patients with early breast cancer

Adverse event (%)

24 weeks 2 years 3 years
ZOLADEX ZOLADEX ZOLADEX
CMF CMF CMF
3.6mg 3.6mg 3.6mg

Nausea/vomiting 5.4 57.9 3.8 2.3 3.7 2.4

Alopecia 3.6 44.9 3.4 2.8 2.4 1.6

Infection 4.9 13.4 1.5 3.0 3.5 3.0

Vaginal dryness 25.6 15.2 25.9 13.5 9.5 14.1

Hot flushes 74.6 44.6 60.4 42.4 18.6 39.6

More than 97% of patients received anti-emetics at each cycle of CMF

Jonat W et al. J Clin Oncol 2002; 20: 462835.

 INT0101 Trial: Study Design
Primary End Points :
Time to recurrence, disease-free interval, and survival in pre-
menopausal node +ve, receptor +ve breast cancer

R
a CAF
n
6 x 28-day cycles
d
o
Multicenter, US m
comparative trial
1:1:1 CAF x 6 cycles followed by
i
Surgery ZOLADEX 3.6mg/28 days for 5 years
z
radiotherapy
a
t CAF x 6 cycles followed by ZOLADEX
i
3.6mg/28 days for 5 years + tamoxifen
o
n
10 mg p.o bid for 5 years

1503 eligible patients (29% aged younger than 40 years)

Median follow-up 9.6 years (551 recurrences)
CAF = Cyclophosphamide 100 mg/m2/d orally on
days 1-14; Doxorubicin 30 mg/m2 IV on days 1 and
Davidson NE et al. J Clin Oncol. 2005;23:59735982. 8; Fluorouracil 500 mg/m2 IV on days 1 and 8
 INT-0101 Trial: Disease-free Survival
ZOLADEX + tamoxifen after chemotherapy shows significant improving DFS than chemotherapy
alone in young and pre-menopausal patients with node +ve, high-risk breast cancer
1.0
CAFZ vs CAF: p=NS
CAFZT vs CAFZ: p<0.01
0.8
Probability

0.6

9-yr DFS
0.4
CAF 57%

0.2 CAF + Zoladex 3.6mg (CAFZ) 60%

CAF + Zoladex 3.6mg + tamoxifen (CAFZT) 68%
0.0
0 1 2 3 4 5 6 7 8 9 10

Disease-free survival (years)

DFS, disease-free survival;

Davidson NE et al. J Clin Oncol. 2005;23:59735982.
INT-0101 Trial: Disease-Free Survival
For Women < 40 years
1.0

0.8
Probability

0.6

9yr DFS
0.4
CAF 48%
0.2 CAFZ 55%
CAFZT 64%
0
0 1 2 3 5 6 7 8 9 10
Disease Free Survival (years)
For women < 40 years seemed to benefit from the addition of ZOLADEX to CAF

Davidson NE et al. J Clin Oncol. 2005;23:59735982.

 ABCSG5: Study Design
Objective
To compare the efficacy of a combination endocrine treatment
with standard chemotherapy

R
a ZOLADEX 3.6 mg/28 days
n for 3 years +
d Tamoxifen 20 mg/day
Pre-menopausal women with o for 5 years
ER+ and/or PgR+ breast cancer m
Node +ve or node ve i
z
a
t
i CMF x 6 cycles
o
1034 assessable patient
Stage I & II n
CMF = Cyclophosphamide 600 mg/m2 ,Methotrexate 40 mg/m2
and Fluorouracil 600 mg/m2

Jakesz R et al. J Clin Oncol. 2002;20:46214627. ABCSG5 : Austrian Breast and Colorectal Cancer Study Group
Trial 5
 ABCSG5: Outcomes
ZOLADEX +Tamoxifen is more effective than chemotherapy in the adjuvant
treatment of HR+ pre-menopausal patients with stage I and II breast cancer

KaplanMeier plot of relapse-free

survival (RFS)
100 p = 0.017, generated Wilcoxon test;
p = 0.037, log-rank test

90
RFS (%)

80

70 ZOLADEX 3.6mg + Tamoxifen

CMF

0 12 24 36 48 60

Months

CMF = Cyclophosphamide 600 mg/m2 ,Methotrexate 40 mg/m2

and 5-Fluorouracil 600 mg/m2
Jakesz R et al. J Clin Oncol. 2002;20:46214627.
 ABCSG5: Outcomes
ZOLADEX +Tamoxifen is more effective than chemotherapy in the adjuvant
treatment of HR+ pre-menopausal patients with stage I and II breast cancer

CMF vs.ZOLADEX 3.6 mg+Tamoxifen

RR 95% CI p-value
Relapse-free survival (RFS) 1.35 1.021.79 0.0374

Local recurrence-free survival 1.86 1.13-3.08 0.0150

Overall survival 1.32 0.87-1.99 0.1948
Univariate analysis
Median follow-up was 5 years
RR, risk ratio; an RR>1.00 favors ZOLADEX 3.6 mg + tamoxifen

Jakesz R et al. J Clin Oncol. 2002;20:46214627.

 ZIPP : Study Design

Zoladex 3.6mg/28 days

for 2 years

Tamoxifen 2040mg/day
Standard randomise for 2 years
Surgery
. + 1:1:1:1
therapy
Zoladex 3.6mg/28 days +
tamoxifen 2040mg/day for 2 years

No further treatment

Randomised trials, from four collaborative groups, with an essentially

common protocol; 2,710 eligible patients
Node+ve or nodeve (stage I or II) disease; no exclusion based on
ER status
Standard therapy = radiotherapy chemotherapy

Baum et al. Eur J Cancer. 2006; 42:895-904 ZIPP : Zoladex in Pre-menopausal Patients
 ZIPP: Outcomes
ZOLADEX combined with standard therapy is more effective than standard
therapy alone in pre-menopausal women with early breast cancer1,2
Kaplan-Meier curve of event-free survival in patients Kaplan-Meier curve of overall survival in patients receiving
receiving goserelin or no goserelin in addition to standard goserelin or no goserelin in addition to standard adjuvant
adjuvant therapy. therapy.
Goserelin Goserelin
1.0 1.0
Control Control

0.8 0.8
Proportion alive and

Proportion alive
0.6 0.6
event-free

0.4 0.4
HR 0.81;95%, CI 0.67-0.99,
HR 0.80;95%, CI 0.69-0.92,
P=0.038
0.2 P=0.002 0.2

0.0 0.0
0 2 4 6 8 10 12 0 2 4 6 8 10 12
Time since randomisation (years) Time since randomisation (years)
Number at risk: Number at risk:

No goserelin 1356 1062 702 381 134 22 0 No goserelin 1356 1216 877 486 178 33 0
Goserelin 1354 1108 772 418 156 31 0
Goserelin 1354 1214 893 501 198 37 0

Baum M et al. Euro J Cancer. 2006;42:895-904.

Key Takeaways
ZOLADEX is an effective alternative to chemotherapy in hormone
receptor-positive premenopausal patients with early breast cancer
Patient < 40 years old have higher tendency to not achieved
Chemotherapy Induced Amenorrhea (CIA) and have poor prognosis (DFS
& OS)
Goserelin (ZOLADEX 3.6 mg) suppresses serum oestradiol to
postmenopausal level
Goserelin (ZOLADEX 3.6 mg) combined with standard therapy is more
effective than standard therapy alone in pre-menopausal women with
early breast cancer
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Mastektomi radikal
TRAM FLAP
Donor site
Mastektomi radikal
Rekonstruksi
Hari ke 5 paska operasi
Hari ke 5 paska operasi
Satu bulan paska operasi
4 bulan paska radioterapi