1. Is there a
State-of-the-art Endocrine
Therapy for ER+ HER2- MBC?
Olivia Pagani
Institute of
Oncology of
Southern
Switzerland

2. “Mostly” agreed indications
• Luminal A and B MBC
• Indolent disease (RFI)
• Low tumour burden/oligosymptomatic
Pitfalls
• Change in hormone expression
• Non homogeneous population:
Patients relapsing after Adj Tam (so few?)
Patients relapsing after Adj TAM and AIs
• Endpoints/subsequent therapies

4. Complex scenarios
1.1°-line ET
2.2° line ET
3.Beyond the 2° line…(no man’s land…)
4.Postmenopausal
Pre and perimenopausal
• Patients relapsing under Adj ET
Intrinsic/acquired resistance
• Role and timing of Chemotherapy

5. First-line AIs Versus Tamoxifen
in Postmenopausal women

6. ORR
Significant difference in favouring AIs over TAM
ORR (OR, 1.56; 95% CI, 1.17-2.07; P .002) and
CB (OR, 1.70; 95% CI, 1.24-2.33; P .0009)
Hong-Bin Xu et al Clinical Breast Cancer 11 (4); 246, 2011

7. OS
Trend toward an improved OS not significant
(OR, 1.95; 95% CI, 0.88-4.30; P .10).
Hong-Bin Xu et al Clinical Breast Cancer 11 (4); 246, 2011

8. Are all the AIs
the same?

9. No significant differences
in clinical activity
103 pts

10. What about
Fulvestrant?

11. FIRST: Study design
Randomization (1:1), open-label first-
line ER+ postmenopausal patients with
advanced breast cancer
(target, n=200; actual, n=205) Endpoints at primary DCO
Primary endpoint
 Clinical benefit rate
Secondary endpoints
Fulvestrant 500 mg Anastrozole 1 mg  Objective response rate
(500 mg IM on Days (1 mg PO daily)  Time to progression
0, 14, and 28, and every 28  Duration of response
days thereafter)  Duration of clinical benefit
 Safety
Exploratory endpoints
Progression Progression  Best response to
subsequent therapy
Follow-up Follow-up No Prior ET for ABC
Adj ET ≥ 12 months
DCO = data cut-off Robertson JF et al. Cancer Res 2010;70(24 Suppl): abstract S1-3

12. FIRST: Fulvestrant 500 mg vs
anastrozole as 1°-line therapy
1.0
Significantly longer TTP
Proportion of patients alive
0.8
and progression-free
Fulvestrant 500 mg
Anastrozole 1 mg
0.6
0.4
0.2 HR = 0.66 (95% CI: 0.47–0.92)
P = 0.01
0.0
0 6 12 18 24 30 36 42 48
Time (months)
No. at risk:
Fulvestrant 500 mg 102 74 65 52 45 34 20 6 0
Anastrozole 1 mg 103 69 55 39 30 21 8 2 0
Robertson JF et al. JCO 2009 27:4530

13. FIRST: Response to first subsequent
endocrine therapy
No. (%) of patients
Fulvestrant Anastrozole
No. of patients who progressed 63 79
Patients who received subsequent 34 50
endocrine breast cancer therapy
Complete response 0 0
Partial response 3 (8.8) 7 (14.0)
Total responders 3 (8.8) 7 (14.0)
Stable disease ≥24 weeks 11 (32.4) 14 (28.0)
Total with clinical benefit 14 (41.2) 21 (42.0)
Stable disease <24 weeks 10 (29.4) 16 (32.0)
Progressive disease 3 (8.8) 8 (16.0)
Not evaluable 7 (20.6) 5 (10.0)
Robertson JF et al. Cancer Res 2010;70(24 Suppl): abstract S1-3

16. 2° line therapy

17. AI as 2°-line therapy
• Significant benefit in terms of
OS (HR 0.80, 95% CI 0.66 to 0.96)
• But not for
PFS (HR 1.08, 95%CI 0.89 to 1.31)
CB (OR 1.00, 95% CI 0.87 to 1.14)
OR (OR 0.96, 95% CI 0.81 to 1.14).
• This is difficult to interpret due to the
extreme heterogeneity across AIs for
PFS but not the other endpoints.
Cochrane Database Syst Rev. 2007

18. 28 patients

21. Relapse on adjuvant
ET or within 1 year
from completion of
adjuvant ET
Relapse >1 year from
completion of
adjuvant ET or
de novo MBC
after 1° line with either
an antiestrogen or AI

22. Statistically significant increase in PFS No crossover yet to the higher dose

23. Premenopausal women

24. ANA +LH-RH TAM +LH-RH P-value
Monica Castiglione ESM0 2011

25. 1°-Line Phase II Parallel Group Study
Premenopausal MBC Pts
Treated With Letrozole Plus Goserelin and
Postmenopausal Pts Treated With Letrozole
TTP (P .89) OS (P .76)
73 patients overall In Hae Park, JCO 28:2705, 2010

26. Beyond the 2° line….

27. Is it worthwhile?
• New drugs and approaches!
Trials needed!
• When switching to CT?
• When “only” palliative care?
• Old drugs:
High dose AIs
Megestrol acetate
High dose estrogens
• QoL issues!

28. Pharmaco-economics
Cost of 6 months’ therapy with:
• Tamoxifen 75 Eu
• Megace 400 Eu
• Anastrozole 1.025 Eu
• Letrozole 1.043 Eu
• Exemestane 1.050 Eu
• Fulvestrant 250mg 3.762 Eu
Prue Francis Berlin 2010

29. Conclusions
• No “universal” standards
• Many questions still open
• Patients’ preferences
• QoL issues underscored
• New endpoints important in indolent
disease
• Integration with supportive care

30. Thank you