1. Endocrine Therapy for Metastatic Breast Cancer
Joyce O’Shaughnessy, MD
Co-Director, Breast Cancer Research Baylor Charles A. Sammons Cancer Center Texas Oncology US Oncology Dallas, Texas

2. This activity is supported by educational grant from Genentech
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3. Faculty Disclosures
Joyce O’Shaughnessy, MD, has disclosed that she has received consulting fees from Arno Therapeutics, Genentech, GlaxoSmithKline, Johnson & Johnson, Roche, and sanofi-aventis US.
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5. First-line Letrozole vs Tamoxifen, Then Crossover
1.0
Median OS Letrozole: 34 mos Tamoxifen: 30 mos
Time to Crossover Letrozole: 17 mos Tamoxifen: 14 mos
0.9
0.8
0.7
0.6
Proportion Alive
0.5
0.4
0.3
P = .53 (long-rank test)
Patients treated with Femara® demonstrated a 4 month longer median survival compared to those treated with tamoxifen (median survival 34 vs 30 months).
As expected, the difference in the overall survival curves is not significant because of the crossover design of the study.
0.2
0.1 6 12 18 24 30 36 42 48 54 60
Mos
Letrozole 1st
Tamoxifen 1st
Mouridsen H, et al. J Clin Oncol. 2003;21:

6. In the CONFIRM trial, 500 mg of monthly fulvestrant was superior to 250 mg for which survival endpoints?
PFS, but not OS
Both PFS and OS
Neither PFS nor OS

7. In the CONFIRM trial, 500 mg of monthly fulvestrant was superior to 250 mg for which survival endpoints?
PFS, but not OS
Both PFS and OS
Neither PFS nor OS

8. Postmenopausal women with ER-positive advanced breast cancer (N = 736)
CONFIRM: Fulvestrant 500 mg vs 250 mg in Postmenopausal Women With ER+ MBC
Fulvestrant 250 mg* (n = 374)
Postmenopausal women with ER-positive advanced breast cancer (N = 736)
Fulvestrant 500 mg† (n = 362)
*Fulvestrant 250 mg: 1 injection of fulvestrant 250 mg IM + 1 placebo injection on Day 0; 2 placebo injections on Day 14; 1 injection of fulvestrant 250 IM + 1 placebo injection on Day 28, then every 28 days thereafter.
†Fulvestrant 500 mg: 2 injections of fulvestrant 250 mg IM on Days 0, 14, 28, then every 28 days thereafter.
ER, estrogen receptor; IM, intramuscular; MBC metastatic breast cancer.
DiLeo A, et al. SABCS Abstract S1-4.

9. CONFIRM: Effect of Fulvestrant 500 mg vs 250 mg on Survival in Postmenopausal Women
Baseline characteristics appeared well balanced between treatment arms
Subsequent therapies were well balanced between arms, with approximately 60% of patients receiving subsequent chemotherapy and approximately one third receiving other hormonal therapy
Outcome
Timing of Analysis
Fulvestrant
500 mg
250 mg
HR (95% CI)
Median PFS
First*
6.5 mos
5.5 mos
0.80‡ ( )
Median OS
25.1 mos
22.8 mos
0.84§ ( )
Final†
26.4 mos
22.3 mos
0.81¶ ( )
*First analysis was performed at 50% maturity.
†Final analysis was performed at 75% maturity.
‡ P = §P = ¶P = .016
DiLeo A, et al. SABCS Abstract S1-4.

10. Fulvestrant 500 mg IM on Days 0, 14, 28, and every 28 days thereafter
FIRST Study Design
Open-label first-line ER+ postmenopausal patients with advanced breast cancer (target, N = 200; actual, N = 205)
Endpoints at primary data cutoff
Primary endpoint
Clinical benefit rate
Secondary endpoints
ORR
TTP
Duration of response
Duration of clinical benefit
Safety
Exploratory endpoint
Best response to subsequent therapy
Fulvestrant 500 mg IM on Days 0, 14, 28, and every 28 days thereafter
Anastrozole 1 mg/day PO
Progression
Progression
Follow-up
Follow-up
Robertson JF, et al. Clin Oncol. 2009;27:

11. FIRST: TTP at Follow-up Analysis
1.0
Fulvestrant 500 mg Anastrozole 1 mg
0.8
0.6
Proportion of Patients Alive and Progression Free
0.4
0.2
HR: 0.66 (95% CI: ; P = .01) 6 12 18 24 30 36 42 48
Mos
Pts at Risk, n Fulvestrant 500 mg Anastrozole 1 mg
74 69
65 55
52 39
45 30
34 21
20 8
6 2
0 0
Robertson JF, et al. Breast Cancer Res Treat. 2012;136:

12. SWOG S0226: Study Design Primary endpoint: PFS
Secondary endpoints: OS, safety
Stratified by previous adjuvant tamoxifen
Treatment until disease progression
Anastrozole 1 mg/day PO + Fulvestrant 500 mg on Day 1, 250 mg on Days 14 and 28, 250 mg every 28 days thereafter (n = 355)
Postmenopausal women with hormone receptor–positive MBC (N = 707)
Anastrozole 1 mg/day PO (n = 352)
Women with progression encouraged to cross over to receive fulvestrant
Mehta RS, et al. N Engl J Med. 2012;367:

13. SWOG S0226: PFS and OS Overall and by Previous Adjuvant Tamoxifen
Endpoint
Anastrozole + Fulvestrant
Anastrozole
HR (95% CI)
P Value
Median PFS (n = 694), mos
15.0
13.5
( )
.007
No previous adjuvant tamoxifen (n = 414)
17.0
12.6
( )
.0055
Previous adjuvant tamoxifen (n = 280)
14.1
( )
.37
Median OS (n = 694), mos
47.7
41.3
( )
.049
39.7
( )
.0362
49.6
44.5
( )
.59
Mehta RS, et al. N Engl J Med. 2012;367:

14. Aromatase Inhibitor + CDK4/6 Inhibitor Improves PFS in ER+ MBC
PD LET (n = 84) 21 (25) 26.1 ( )
LET (n = 81) 40 (49) 7.5 ( )
Events, n (%) Median PFS, mos (95% CI) HR (95% CI) P value
1.0
0.9
0.37 ( ) < .001
0.8
0.7
0.6
PFS Probability
0.5
0.4
0.3
0.2
0.1 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Mos
Pts at Risk, n PD LET LET
84 81
75 57
60 38
53 29
43 22
35 17
25 11
18 6
15 5
14 4
9 3
5 3
3 1
1 1
Finn RS, et al. SABCS Abstract S1-6.

15. EFFECT: Fulvestrant vs Exemestane After Progression of Nonsteroidal AI
1.0
Fulvestrant
Exemestane
Median, mos
3.7
3.7
PFS Probability
0.8
HR: (95% CI: ; P = .6531) Cox analysis, P = .7021
0.6
0.4
Fulvestrant
Exemestane
0.2
0.0 3 6 9 12 15 18 21 24 27
Mos
Pts at Risk, n Fulvestrant Exemestane
351
195 96 50 25 12 4 2
342
190 98 41 21 12 8 6 1
Chia S, et al. J Clin Oncol. 2008;26:

16. Patients with which site of metastatic disease had the longest PFS with exemestane + everolimus vs exemestane in the BOLERO-2 trial?
Bone only
Liver only
Lung only
Any visceral disease
No visceral disease

17. Patients with which site of metastatic disease had the longest PFS with exemestane + everolimus vs exemestane in the BOLERO-2 trial?
Bone only
Liver only
Lung only
Any visceral disease
No visceral disease

18. Mechanisms of Hormone Resistance
IGF1R
Increased signaling through EGFR and/or IGF1-R
VEGFR
EGFR/HER2 P P P P P P
SOS
PI3-K
RAS
RAF
akt
MEK
p90RSK
MAPK
Increased signaling through PI3-K pathway
SERD AI T ER E2 P
p160
Basal transcription machinery
CBP ER
Cytoplasm
ERE
ER target gene transcription
Nucleus
Plasma membrane
Reprinted by permission from the American Association for Cancer Research: Johnston SR. Clin Cancer Res. 2005;11:889s-899s.

19. BOLERO-2: Everolimus + Exemestane Improves PFS in HR+ MBC
Central Assessment
100
Everolimus + exemestane (median PFS: 10.6 mos)
Placebo + exemestane (median PFS: 4.1 mos) 90 80 70 60
Probability of Event (%) 50 40 30 20
HR: 0.36 (95% CI: ; log-rank P < .001) 10
PFS, progression-free survival. 6 12 18 24 30 36 42 48 54 60 66 72 78
Wks
Patients at Risk, n
Everolimus
Placebo
485
239
385
168
281 94
201 55
132 33
102 20 67 11 43 11 28 6 18 3 9 3 3 1 2
Baselga J, et al. N Engl J Med. 2012;366:

20. BOLERO-2: Final PFS Analysis (18-Mo Follow-up)
PFS, Mos
EVE + EXE
PBO + EXE
HR (95% CI)
P Value
Local review
7.8
3.2
0.45
( )
< .0001
Central review
11.0
4.1
0.38
( )
With visceral mets
6.83
2.76
0.47
( ) --
Without visceral mets
9.86
4.21
0.41
( )
Bone-only mets
12.88
5.29
0.33
( )
Progression after neo/adj therapy
11.50
4.07
0.39
( )
OS data still not mature (HR: 0.77; 95% CI: )
Most common grade 3/4 AEs were stomatitis (8%), hyperglycemia (5%), fatigue (4%)
Piccart, M, et al. SABCS Abstract P

21. Case
A 68-yr-old woman presents with a T4N2 left breast mass with associated contraction and fibrosis that had been developing over 3-4 yrs
Breast biopsy shows ER+/PgR+, HER2- IDC, grade 2
Staging evaluation shows bone metastases and multiple pulmonary nodules
The patient has mild DOE but no bone pain

22. An IV bisphosphonate or SC denosumab is recommended for this patient, but which of the following endocrine therapies is NOT recommended?
Fulvestrant 500 mg
Letrozole
Exemestane + everolimus
Fulvestrant + a nonsteroidal AI

23. An IV bisphosphonate or SC denosumab is recommended for this patient, but which of the following endocrine therapies is NOT recommended?
Fulvestrant 500 mg
Letrozole
Exemestane + everolimus
Fulvestrant + a nonsteroidal AI

24. Endocrine Therapy Sequencing in MBC: Which Order Is Best?
AI or fulvestrant are most effective first-line single agents; fulvestrant ± AI reasonable choice for endocrine therapy– naive patients with MBC
Continue endocrine therapies until resistance
mTOR inhibition with everolimus + exemestane is best second-line therapy after progression on nonsteroidal AI
After everolimus, back to anti-ER therapy alone or enhanced blockade of PI3K pathway
Addition of CDK4/6 inhibitor to first-line letrozole may become a new SOC; phase III trial under way