2. Sites of oestrogen synthesis
Miller WR. Best Pract Res Clin Endocrinol Metab 2004; 18(1): 1–32
Premenopausal women
• Oestrogen produced in the ovaries
• At some stages of the menstrual cycle,
up to 50% may be produced elsewhere
Postmenopausal women
• Ovaries no longer produce oestrogens
• Synthesis takes place in adipose tissue,
skin, liver, muscle and breast tissue
3. Hormonal therapy
• Hormonal treatments are only effective in
HR+ve tumours1
• Two thirds of postmenopausal breast cancers are
oestrogen dependent2
• Two major strategies for affecting oestrogen
deprivation:
1. ER blockade
2. inhibition of oestrogen synthesis
1. Miller WR. Best Pract Res Clin Endocrinol Metab 2004; 18(1): 1–32
2. Brueggemeier R. Breast Cancer Res Treat 2002; 74(2): 177–185
4. The role of tamoxifen
• The benchmark for newer treatments
• 5 years of tamoxifen therapy was the current gold standard
for adjuvant hormonal therapy in postmenopausal ER+ve
breast cancer1
• Early Breast Cancer Trialists’ Collaborative Group (EBCTCG)
meta-analyses (15 year follow-up):
– Annual recurrence rate almost halved (recurrence rate ratio
0.590.03)2
– Breast cancer mortality rate reduced by one third (death rate ratio
0.66 0.04)2
• The efficacy of tamoxifen can be improved upon
1. Ravdin PM. Medscape Hematology-Oncology 2004: 7(2)
2. Early Breast Cancer Trialists’ Collaborative Group (EBCTCG). Lancet 2005; 365(9472): 1687–1717
5. Current Endocrine Therapy Protocol
for Early Breast Cancer
• Premenopausal
– Tamoxifen
– Ovarian ablation
• Intolerant of Tam or
??high risk patients
6. Current Endocrine Therapy Protocol
for Early Breast Cancer
• Post-menopausal
– PATIENTS AT FIRST PRESENTATION:
– There are no clear data to guide management in this group
– International guidlines support the use of either an initial aromatase
inhibitor, or the initiation of tamoxifen with a subsequent switch to
an aromatase inhibitor after 2-3 years. (NCCN, St. Gallen)
– It is suggested that the majority of patients are treated with
TAMOXIFEN FOR 2-3YRS FOLLOWED BY EXEMESTANE OR
ANASTRAZOLE OR FOR 2-3YRS FOR A TOTAL TREATMENT
DURATION OF 5YRS.
– Patients with contraindications to TAMOXIFEN should continue to
be treated with ANASTRAZOLE for 5years.
– Given the current uncertainties regarding the optimal use of
aromatase inhibitors in the adjuvant setting, the choice of
treatment should be made after discussion between the responsible
clinician and the woman about the risks and benefits of each option
7. Adjuvant Hormonal Therapy Trial Designs
SUPPORTING TRIALS
• ATAC
• BIG 1-98 straight arm
• TEAM (not yet reported)
EARLY ADJUVANT (START)
Randomization
SUPPORTING TRIALS
• IES
• ITA
• ARNO/ABCSG combined analysis*
SWITCHING
Randomization
*
EXTENDED ADJUVANT
SUPPORTING TRIALS
• MA-17
• ABCSG 6a
Randomization
* Note that some patients from the original newly diagnosed population
are lost due to recurrence or adverse events prior to randomization
SUPPORTING TRIALS
• ABCSG 8 alone (arms A & C)
• BIG 1-98 sequencing arms (arms C&D)
Randomization
SEQUENCING
A
B
C
D
8. ATAC trial design
Tamoxifen
(n = 3116)
ITT population
n = 3125
Safety population
n = 3092
HR+ subpopulation
n = 2618
ITT population
n = 3116
Safety population
n = 3094
HR+ subpopulation
n = 2598
ITT, intent-to-treat; HR+, hormone receptor-positive
Anastrozole
(n = 3125)
Combination
n=3125
Discontinued following
initial analysis as no
efficacy or tolerability
benefit compared with
tamoxifen arm
Postmenopausal women with invasive breast cancer
(n = 9366)
Surgery radiotherapy chemotherapy
Randomisation 1:1:1 for 5 years
10. †included as a non-predefined adverse event of interest
Predefined adverse events
at any time on treatment or any severity
Hot flushes
Nausea and vomiting
Fatigue / tiredness (asthenia)
Mood disturbances
Musculo-skeletal disorders
Vaginal bleeding
Vaginal discharge
Ischaemic cardiovascular disease
Ischaemic cerebrovascular event
Venous thromboembolic events
Deep venous thromboembolic events
Cataracts
Carpal tunnel syndrome†
1102 (35.6)
394 (12.7)
578 (18.7)
599 (19.4)
1104 (35.7)
167 (5.4)
110 (3.6)
130 (4.2)
64 (2.1)
87 (2.8)
48 (1.6)
189 (6.1)
79 (2.5)
1263 (40.8)
358 (12.4)
544 (17.6)
555 (17.9)
915 (29.6)
319 (10.3)
409 (13.2)
106 (3.4)
91 (2.9)
141 (4.6)
75 (2.4)
218 (7.0)
22 (0.7)
Anastrozole
(N = 3092)
Tamoxifen
(N = 3094)
11.
12.
13.
14. The Intergroup Exemestane Study
Coombes RC, Hall E, Gibson LJ et al
N Engl J Med 2004; 350(11): 1081–1092
Coombes RC, Hall E, Snowdon CF et al. Updated survival analysis. Data
presented at the 27th San Antonio Breast Cancer Symposium, December
2004
15. Disease-free survival
Coombes RC, Hall E, Snowdon CF et al. Data presented at the 27th San Antonio Breast Cancer
Symposium, December 2004
* Events occurring more than 4 years after randomisation
Women surviving
event free (%)
Years from randomisation
0 1 2 3 4
0
25
50
75
100
Number of events/at risk
Hazard ratio = 0.73 (95% CI: 0.62–0.86)
Log-rank test: p=0.0001
Exemestane
Tamoxifen
0/2,352 57/2,233 65/2,081 75/1,413 41+24*/661
0/2,372 82/2,243 105/2,062 96/1,359 47+23*/650Tamoxifen
Exemestane
(262 events)
(353 events)
16. Overall survival
Coombes RC, Hall E, Snowdon CF et al. Data presented at the 27th San Antonio Breast Cancer
Symposium, December 2004
0 1 2 3 4
0
25
50
75
100
Hazard ratio: 0.83
95% CI: 0.67–1.02
Log-rank test: p=0.08
Exemestane (152 deaths)
Tamoxifen (187 deaths)
Patientsalive(%)
18/2,270 41/2,137 41/1,469 37+15*/690
23/2,300 53/2,165 49/1,465 41+21*/701Tamoxifen
Exemestane
* Events occurring more than 4 years after randomisation
0/2,352
0/2,372
Years from randomisationNumber of events/at risk
17. Switching to Arimidex
• ABCSG trial 8 and ARNO 95
• Reported in The Lancet 6th August 05
• Similar results
– Median follow up 30.1 months
– 40% reduction in risk of an event (local or distant
metastases or contralateral breast primary)
– Similar survival benefit to that seen in IES for switch
18. Case 1
• 57 yr old post-menopausal female, Chief Executive of
a local manufacturing company
• Gr 3 4.5 cm Ductal Ca Left Breast – mastectomy and
ANC. Margins all clear >5mm
• 3 out 11 level one LN involved, all 8 level two and
level three LN clear
• ER +ve, PR +ve and Her-2 +ve
• Baseline CXR, USS Liver and IBS – no mets identified
• PHx of DVT 3 years after a flight from the Bahamas –
received Warfarin for 6 months
19. Q1. What is the most appropriate standard
management of this lady?
1. Adjuvant Chemotherapy followed by radiotherapy followed
by Herceptin, followed by hormone therapy
2. Adjuvant Chemotherapy followed by hormone therapy
followed by Herceptin therapy
3. Adjuvant Chemotherapy and Radiotherapy concurrently
followed by Herceptin and Hormone therapy
4. Adjuvant Chemotherapy followed by Radiotherapy followed
by Herceptin together followed by Hormone therapy
5. Adjuvant Chemotherapy followed by Herceptin and
Hormone therapy
22. Q1. Answer
Adjuvant Chemotherapy followed by Herceptin
and Hormone therapy
Radiotherapy not routinely indicated in 1 to 3
nodes positive group. However could offer
entry into the Supremo trial.
23. Sequencing of Adjuvant Therapy
• Give the therapy with the most impact up front – Hence
chemo given first.
• Do not combine chemo (particularly anthracyclines) with RT
• Do not combine Herceptin with RT, risk of cardiotoxicity
• Do not combine Chemo with Hormone therapy – increased
risk of thrombo-embolism
• Hence usually:
– Chemo
– RT
– Herceptin and Hormones
24. Q2. What Adjuvant Chemotherapy Would
you chose?
1. FEC 60 for 6 cycles
2. FEC 100 for 6 cycles
3. FEC 100 for 4 cycles followed by Docetaxol
for 4 cycles
4. FEC 100 for 3 cycles followed by Docetaxol
for 3 cycles
5. Cyclophosamide and Docetaxol for 6 cycles
25. Q2 Answer
FEC 100 for 3 cycles followed by Docetaxol for 3
cycles
In node positive breast cancer the optimal
therapy is a Taxane and Anthracycline based
regimen
28. Taxane Trials
Trial N= Node
+ve
Trial
Design
Outcome
US ONC
9735
1015 4 AC vs 4 TC 94 VS 95 3 YR
NSABP
B28
3060 N+ 4AC vs
4AC + 4T
85 VS 85 **
BCIRG
001
1491 N+ 6 FAC vs
6 TAC
68 VS 75 **
CALGB
9344
3121 N+ 4 AC vs
4 AC + 4T
77 VS 80 **
MDACC
2022
0524 4 FAC + 4T
vs 8 FAC
79 VS 83 RFS
PACS 01 1999 N+ 3 FEC + 3T
vs 6 FEC 100
90.7% vs 86.7
5 yr OS ITT
29. Taxane Trials
Trial N= Node
+ve
Trial
Design
Outcome
US ONC
9735
1015 4 AC vs 4 TC 94 VS 95 3 YR
NSABP
B28
3060 N+ 4AC vs
4AC + 4T
85 VS 85 **
BCIRG
001
1491 N+ 6 FAC vs
6 TAC
68 VS 75 **
CALGB
9344
3121 N+ 4 AC vs
4 AC + 4T
77 VS 80 **
MDACC
2022
0524 4 FAC + 4T
vs 8 FAC
79 VS 83 RFS
PACS 01 1999 N+ 3 FEC + 3T
vs 6 FEC 100
90.7% vs 86.7
5 yr OS ITT
31. Overall Survival over time
No CT
CMF1970
+ 3%
Anthracyclins
+ 4.6%
1980
Taxanes+Antracyclins2000
+5.1%
?
32. Which hormone therapy would you offer?
1. Adjuvant Exemestane for 5 years
2. Adjuvant Anastrozole/Letrozole for 5 years
3. Adjuvant Tamoxifen for 2 years followed by
Exemestane for 3 years
4. Adjuvant Tamoxifen for 2 years followed by
adjuvant Anastrozole for 3 years
5. Adjuvant Tamoxifen for 5 years followed by
adjuvant Letrozole for 5 years
33. Q3. Answer
Adjuvant Anastrozole/Letrozole for 5 years
In the setting of a prior personal history of
venous thrombo-embolism, tamoxifen is
contra-indicated
Exemestane is not licensed for up-front usage
35. When to use an upfront AI in place of
Tamoxifen
• For those with contra-indications or increased
risk with Tamoxifen (DVT, Endometrial Ca)
• Previous separate breast primary treated with
Tamoxifen
• ? Those with high risk features (Her-2 +ve,
GrIII, Node Positive)
• ? All adjuvant Patients
36. Case 2
• 49 year old female, post-menopausal, optician
• Gr II 1.8cm ER positive, Her negative, ductal ca
– Right Partial Mastectomy
• Node negative, CXR, LFTs and Bone Profile
normal
• No significant PHx
37. Q4. What is the most appropriate
subsequent management?
1. FEC 60 followed by RT and Hormone therapy
2. FEC 100 followed by RT and Hormone
therapy
3. FEC-D followed by RT and Hormone therapy
4. RT and Hormone therapy
5. Cyclosphosphamide and Docetaxol followed
by Hormone therapy
39. An Answer
FEC 100 followed by RT and Hormone therapy
Although benefit of chemo very small, it is
above the 2% threshold and as such would
discuss chemo in this setting
40. Q5. Which hormone therapy would you chose?
1. Tamoxifen for 5 years
2. Adjuvant Anastrozole for 5 years
3. Adjuvant Tamoxifen for 2 years followed by
Exemestane for 3 years
4. Adjuvant Tamoxifen for 5 years followed by
adjuvant Letrozole for 5 years
42. Current Endocrine Therapy Protocol
for Early Breast Cancer
• Post-menopausal
– PATIENTS AT FIRST PRESENTATION:
– There are no clear data to guide management in this group
– International guidlines support the use of either an initial
aromatase inhibitor, or the initiation of tamoxifen with a
subsequent switch to an aromatase inhibitor after 2-3 years.
(NCCN, St. Gallen)
– It is suggested that the majority of patients are treated with
TAMOXIFEN FOR 2-3YRS FOLLOWED BY EXEMESTANE OR
ANASTRAZOLE OR FOR 2-3YRS FOR A TOTAL TREATMENT
DURATION OF 5YRS.
– Patients with contraindications to TAMOXIFEN should
continue to be treated with ANASTRAZOLE for 5years.
43. Given the current uncertainties regarding the
optimal use of aromatase inhibitors in the
adjuvant setting, the choice of treatment should
be made after discussion between the responsible
clinician and the woman about the risks and
benefits of each option
