“Establishing a New Standard of Care

of Adjuvant hormonal treatment in

Early Breast Cancer”

Dr. Eddy Herman Tanggo, Sp.B(K)Onk

SMF Bedah FK UNAIR RSU Dr. Soetomo
SURABAYA
 Long-term risk of breast cancer recurrence
remains high following primary surgery

Annual 0.3
hazard rate
for ER/PgR+ (n=2257)
recurrence
(%) ER/PgR– (n=1305)
0.2
Need to give most effective treatment first

to reduce risk of recurrence

0.1

0
0 1 2 3 4 5 6 7 8 9 10 11 12
ER, oestrogen receptor Years
PgR, progesterone receptor Saphner et al. J Clin Oncol. 1996;14:2738.
 What we know…

 Tamoxifen treatment for 5 years reduces the risk of

reccurence compared to 2 years of therapy
 After 5 years of Tamoxifen, the risk begins to
outweight the benefit
 Aromatase Inhibitor have a proven efficacy benefit
compared to Tamoxifen in the advanced and early
breast cancer setting in postmenopausal woman

EBCTG ; Lancet 1998; 351:1451-67;

Scottish Cancer Trials Breast Group; J Natl Cancer Inst.; 2001:93: 456-462

Bonneterre J et al:Cancer 2001; 92:2247-58

 AIs Adjuvant Trial Designs
Randomisation
Initial
Tamoxifen
adjuvant
trial Aromatase inhibitor
Randomisation

Tamoxifen Aromatase inhibitor

Initial and Aromatase inhibitor Tamoxifen
sequencing Tamoxifen
trial Aromatase inhibitor
Randomisation

Switching 2–3 years’ prior Tamoxifen

trial tamoxifen Aromatase inhibitor
Randomisation

Extended Aromatase inhibitor

adjuvant 5 years’ prior tamoxifen
trial Placebo

0 Time (years) 5
 Patients Newly Diagnosed
Recurrence 16
rate/year
(%)
12

Node +ve
4
Node -ve
0
0 2 4 6 8 10
Time (years)
Randomisation

Tamoxifen ‘Anastrozole’, Tamoxifen Alone

Anastrozole or in Combination (ATAC)
Initial adjuvant
Tamoxifen Breast International
Letrozole Group (BIG) 1-98
Adapted from EBCTCG. Lancet 1998;352:930-942
 ATAC trial design
9366 Postmenopausal women with invasive breast cancer
mean age 64 years; 84% hormone receptor positive
61% node negative; 64% with tumour 2 cm in diameter

Surgery  radiotherapy  chemotherapy

Randomisation 1:1:1 for 5 years
   Combination was
Anastrozole Tamoxifen Combination
discontinued following initial
n=3125 n=3116 n=3125
analysis as no efficacy or
tolerability benefit compared
 with tamoxifen arm
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
The ATAC (‘Arimidex’, Tamoxifen, Alone or in
Combination) trial
 The largest reported adjuvant breast cancer trial

 Eligible patients were :

- postmenopausal women
- with operable invasive breast cancer
- who had completed primary surgery
- and chemotherapy (where given)
 Which problems does ATAC address?

 Is tamoxifen still the best adjuvant therapy for

early breast cancer (EBC)?
 How do we reduce recurrences in the first
few years of treatment?
 Can we improve upon the tolerability problems
associated with adjuvant tamoxifen?
 Is AI (anastrozole) superior to tamoxifen
in the adjuvant setting?
 Is there robust and mature data to
support the use of anastrozole in this setting?
 ATAC: patient characteristics
Anastrozole Tamoxifen
(n=3125) (n=3116)
Mean age (years) 64.1 64.1
Mean weight (kg) 70.8 71.1
Receptor status (%)
positive 83.7 83.4
negative 8.3 8.7
unknown 8.0 7.9
Primary treatment (%)
mastectomy 47.8 47.3
axillary surgery 95.5 95.7
radiotherapy 63.3 62.5
chemotherapy 22.3 20.8
prior tamoxifen 1.6 1.6
ATAC: baseline disease characteristics
Anastrozole Tamoxifen
(n=3125) (n=3116)
Primary tumour size (%)
T1 (2 cm) 63.9 62.9
T2 (2 cm to 5 cm) 32.6 34.2
T3 (5 cm) 2.7 2.2
Nodal status (%)
node-positive 34.9 33.6
Grading (%)
well differentiated 20.8 20.5
moderately differentiated 46.8 47.8
poorly / undifferentiated 23.7 23.3
not assessed / recorded 8.5 8.3
 Disease-free survival
(HR*-positive population)
25
HR 95% CI p-value

20 A vs T 0.83 (0.73–0.94) 0.005

Patients with reccurence (%)

15 Anastrozole (A)
Tamoxifen (T)
10

0 Absolute difference: 1.6% 2.6% 2.5% 3.3%

0 1 2 3 4 5 6
Follow-up time (years)
At risk:
A 2618 2540 2448 2355 2268 2014 830
T 2598 2516 2398 2304 2189 1932 774

*HR=hormone receptor
 Recurrence
(HR*-positive population)
25
HR 95% CI p-value

20 A vs T 0.74 (0.64–0.87) 0.0002

Patients with reccurence (%)

15 Anastrozole (A)
Tamoxifen (T)
10

0 Absolute difference: 1.7% 2.4% 2.8% 3.7%

0 1 2 3 4 5 6
Follow-up time (years)
At risk:
A 2618 2540 2448 2355 2268 2014 830
T 2598 2516 2398 2304 2189 1932 774

*HR=hormone receptor
 Overall survival
(HR*-positive population)
25
HR 95% CI p-value

20 A vs T 0.97 (0.83–1.14) 0.7

Patients (%)

15 Anastrozole (A)
Tamoxifen (T)
10

0
0 1 2 3 4 5 6
Follow-up time (years)
At risk:
A 2618 2566 2505 2437 2377 2117 867
T 2598 2549 2502 2430 2333 2080 855

*HR=hormone receptor
Incidence of new (contralateral) breast
primaries in HR*-population
HR 95% CI p-value
AN vs TAM 0.47 0.29–0.75 0.001

Number 60
53
of cases
50 5 DCIS

40

30 26
5 DCIS 48
20 Invasive*
21
10 Invasive*

0
Anastrozole (AN) Tamoxifen (TAM)
(n=3125) (n=3116)

*p=0.001 for invasive cancers.

*HR=hormone receptor
 Anastrozole demonstrates
superior efficacy to tamoxifen

 Anastrozole is more effective than tamoxifen in

reducing the risk of recurrence, distant
recurrence and contralateral breast cancer
 The absolute difference between anastrozole and
tamoxifen continues to increase over time, and
extends beyond completion of treatment
 As expected, overall survival is similar for both
treatments, with a trend in favour of anastrozole
for breast cancer death
 Added benefit versus tamoxifen
EBCTCG ATAC
 
Hormone receptor-positive Benefit for Additional benefit
population tamoxifen vs of anastrozole vs
placebo tamoxifen

Reduction in risk of 50% 26%

recurrence
Reduction in risk of breast 28% 13%
cancer mortality

*hormone receptor-positive and -negative patients

EBCTCG = Early Breast Cancer Trialists’ Collaborative Group
Added benefit versus tamoxifen
38% risk of recurrence with no adjuvant treatment
50% reduction in risk with tamoxifen

Further 26% risk

reduction with
anastrozole

Tam vs placebo Tam vs Anastrozole

EBCTCG ATAC
 Pre-defined adverse events
Completion p-value
analysis
A T
Hot flushes 35.7 40.9 <0.0001
Vaginal bleeding 5.4 10.2 <0.0001
Vaginal discharge 3.5 13.2 <0.0001
Endometrial cancer* 0.2 0.8 0.01
Ischaemic cerebrovascular 2.0 2.8 0.03
event
Venous thromboembolic 2.8 4.5 0.0004
events
Deep venous 1.6 2.4 0.02
thromboembolic events
Joint symptoms 35.6 29.4 <0.0001
Total fractures 11.0 7.7 <0.0001
*Excludes patients with prior hysterectomy and includes on- and off-therapy AEs
 Bone health is predictable and
manageable
 “AI-associated bone loss may represent a
preventable and treatable condition…
intravenous bisphosphonates as well as oral
bisphosphonates, clodronate and
risedronate, are effective in maintaining bone
density in breast cancer patients on hormonal
therapy”
 baseline bone mineral density evaluation is
recommended in high-risk patients
Winer E et al. J Clin Oncol 2005;23:619-629
 Tamoxifen is associated with
life-threatening side effects

 “some toxicities such as

thromboembolic events and stroke,
life-threatening side effects seen
with tamoxifen may lead to death
– Other side effects of tamoxifen :
endometrial cancer.

Winer E et al. J Clin Oncol 2005;23:619-629

 ATAC summary
 ATAC Completed Treatment Analysis extends
and strengthens the evidence that 5 years of
anastrozole is significantly more effective and
better tolerated than 5 years of tamoxifen
 Overall risk:benefit profile remains clearly in
favour of anastrozole
 The absolute benefits for anastrozole over and
above those of tamoxifen continue to increase
with time and extend beyond the completion of
therapy
 ASCO Technology Assessment
 “Adjuvant therapy for post-menopausal women with
hormone receptor-positive breast cancer should
include an aromatase inhibitor (AI)”
 “…optimal adjuvant hormonal therapy for a post-
menopausal woman with hormone receptor-positive
breast cancer includes an AI as initial therapy or after
treatment with tamoxifen”
– five years’ tamoxifen is no longer optimal
– ATAC, IES, ITA,BIG,ARNO and MA 17 trials used in decision-
making process

ATAC = ‘Anastrozole’, Tamoxifen Alone or in

Combination
IES = Intergroup Exemestane Study; ITA = Italian
Tamoxifen Anastrozole; BIG = Breast International Winer E et al. J Clin Oncol 2005;23:619-629
Group;ARNO = ‘Anastrozole’/’Tamoxifen’
 Conclusions
 Adjuvant therapy for postmenopausal women with hormone receptor-
positive breast cancer should include an aromatase inhibitor (AI)
 Giving an aromatase inhibitor at the earliest opportunity is the best
option to prevent recurrence in the first 5 years
 ATAC completed treatment analysis (68 months) confirms the benefits of
Anastrozole as initial adjuvant therapy
 The absolute benefits for Anastrozole over and above those of tamoxifen
continue to increase with time and extend beyond the completion of therapy
thank you