SABCS 2011
Metastatic Breast Cancer
Shiuh-Wen Luoh MD PhD
Clinical Associate Professor
Comprehensive Breast Cancer Clinic
Hematology and Medical Oncology
Knight Cancer Institute, OHSU
Portland VA Medical Center
BOLERO-2
SWOG-0226
A phase III randomized trial of
anastrozole versus anastrozole and
fulvestrant as first-line therapy for
postmenopausal women with metastatic
breast cancer: SWOG S0226
Mehta RS, Barlow WE, Albain KS,Vandenberg TA,
Dakhil SR, Tirumali NR,
Lew DL, Hayes DF, Gralow JR,
Livingston RB, and Hortobagyi GN
Background

Anastrozole lowers estrogen levels and fulvestrant
down-regulates the estrogen receptor

The combination of anastrozole and fulvestrant may
be additive in postmenopausal breast cancer

Fulvestrant has a high efficacy in low-estrogen in
vivo model (Osborne JNCI 1995)

The combination of fulvestrant and anastrozole
down-regulates several resistance proteins in in vivo
model (Macedo et al. Cancer research 2008)
S0226: Main Eligibility Criteria
• Postmenopausal women with metastatic breast cancer
(measurable or non-measurable)
• ER-positive or PgR-positive by local institutional standards
• No prior chemotherapy, hormonal therapy, or
immunotherapy for metastatic disease
• Prior adjuvant tamoxifen allowed (stratification factor)
• Prior adjuvant AI allowed if completed 12 months earlier
• Neoadjuvant or adjuvant chemotherapy completed more
than 12 months prior
• Patients were not allowed chemotherapy or other hormone
therapy while on treatment
• Must have given informed consent
S0226: Schema
Arm 1
R
A
N
D
O
M
I
Z
E
Anastrozole only: 1 mg PO daily
Treat until progression; crossover to fulvestrant
strongly encouraged after progression
Arm 2
Anastrozole: 1 mg PO daily
First cycle of 28 days:
Fulvestrant 500mg IM ( 2 x 5 mL) Day 1
Fulvestrant 250mg IM ( 1 x 5 mL) Day 14
Fulvestrant 250mg IM ( 1 x 5 mL) Day 28
Subsequent cycles of 28 days:
Fulvestrant 250mg IM ( 1 x 5 mL) Day 28
Treat until progression
S0226: Statistical Design
• Accrual goal: 690 eligible patients equally allocated and
stratified by use of adjuvant tamoxifen
• Primary endpoint: Progression-free survival (PFS)
– 90% power to detect an increase in median PFS from
10 months (monotherapy) to 13 months (combination)
with 2-sided α = 0.05 overall
• Planned analyses of the primary endpoint
– Two interim analyses at 50% and 75% of the events
– Final analysis at 2-sided α = 0.04
• Subset analyses were not planned and are not
adjusted for multiplicity
• Overall survival is a secondary endpoint
Primary Comparisons
• Intent-to-treat analysis of eligible patients
• Analysis stratified by prior adjuvant tamoxifen
• Results to be presented today:
– Population characteristics
• 707 patients randomized in the period
June 2004 to June 2009
• 694 analyzed excluding 12 ineligible patients
and one who withdrew consent
– Progression-free survival
– Overall survival
– Toxicity
Patient Characteristics
Characteristic
Anastrozole
Anastrozole +
Fulvestrant
Total
352
355
707
7 (2.0%)
6 (1.7%)
13 (1.8%)
345
349
694
65 (36-91)
65 (27-92)
65 (27-92)
Prior adjuvant tamoxifen
139 (40.3%)
141 (40.4%)
280 (40.3%)
Prior adjuvant chemo
103 (29.9%)
129 (37.0%)
232 (33.4%)
Measurable
54.5%
53.9%
54.2%
Bone only
22.0%
21.5%
21.8%
De novo metastatic disease
41.8%
36.0%
38.9%
> 10 years since previous dx
26.1%
30.7%
28.4%
HER2-positive
8.5%
10.4%
9.5%
Randomized
Ineligible or withdrew consent
Analyzed
Age median (range)
Disease characteristics
Use of adjuvant AI is being determined retrospectively, but only 12 users of
adjuvant AI’s have been identified.
Crossover
• Patients in the anastrozole arm were strongly
encouraged to crossover to fulvestrant after
progression
• After Feb 15, 2011 patients on either arm could
crossover to 500 mg fulvestrant dosing after
progression
• 143 of 345 patients (41%) on anastrozole did
crossover to fulvestrant after progression
(including 5 who took the 500 mg dosing)
• 9 of 349 patients on the combination took
500 mg dosing after progression
Progression-Free Survival in S0226
1.00
All eligible patients (n=694)
0.75
Anastrozole + Fulvestrant (268 events)
Anastrozole (297 events)
Stratified log-rank p = 0.0070
0.50
Median PFS
Anastrozole 13.5 mos (95% CI 12.1-15.1)
0.00
0.25
Combination 15.0 mos (95% CI 13.2-18.4)
HR = 0.80 (95% CI 0.68 - 0.94)
0
N at risk
AN 349
AN + FV 345
12
24
36
48
Months since registration
60
72
199
193
114
92
8
3
2
0
53
39
21
11
Progression-Free Survival in S0226
1.00
Prior adjuvant tamoxifen (n=280)
0.75
Anastrozole + Fulvestrant (114 events)
Anastrozole (119 events)
Log-rank p = 0.37
0.50
Median PFS
Anastrozole 14.1 mos (95% CI 12.0-16.8)
0.25
Combination 13.5 mos (95% CI 11.0-19.3)
0.00
HR = 0.89 (95% CI 0.69 - 1.15)
0
N at risk
AN 141
AN + FV 139
12
24
36
48
Months since registration
60
72
74
80
43
32
2
1
1
0
17
17
5
3
Progression-Free Survival in S0226
1.00
No prior adjuvant tamoxifen (n=414)
0.75
Anastrozole + Fulvestrant (154 events)
Anastrozole (178 events)
Log-rank p = 0.0055
0.50
Median PFS
Anastrozole 12.6 mos (95% CI 11.2-15.6)
0.00
0.25
Combination 17.0 mos (95% CI 13.8-19.9)
HR = 0.74 (95% CI 0.59-0.92)
0
N at risk
AN 208
AN + FV 206
12
24
36
48
Months since registration
60
72
125
113
71
60
6
2
1
0
36
22
16
8
Overall Survival in S0226
1.00
All eligible patients (n=694)
0.50
0.75
Median OS
Anastrozole 41.3 mos (95% CI 37.2-45.0)
Combination 47.7 mos (95% CI 43.4-55.7)
0.25
HR = 0.81 (95% CI 0.65 - 1.00)
0.00
Anastrozole + Fulvestrant (154 deaths)
Anastrozole (176 deaths)
Stratified log-rank p = 0.049
0
N at risk
AN 349
AN + FV 345
12
24
36
48
Months since registration
60
72
315
306
259
239
26
22
4
4
145
136
62
54
Overall Survival in S0226
1.00
Prior adjuvant tamoxifen (n=280)
0.50
0.75
Median OS
Anastrozole 44.5 mos (95% CI 38.0-54.8)
Combination 49.6 mos (95% CI 37.9-71.2)
0.25
HR = 0.91 (95% CI 0.65-1.28)
0.00
Anastrozole + Fulvestrant (63 deaths)
Anastrozole (68 deaths)
Log-rank p = 0.59
0
N at risk
AN 141
AN + FV 139
12
24
36
48
Months since registration
60
72
125
125
101
100
13
10
3
2
54
59
28
24
Overall Survival in S0226
1.00
No prior adjuvant tamoxifen (n=414)
0.50
0.75
Median OS
Anastrozole 39.7 mos (95% CI 33.1-43.9)
Combination 47.7 mos (95% CI 43.4-58.3)
0.25
HR = 0.74 (95% CI 0.56-0.98)
0.00
Anastrozole + Fulvestrant (91 deaths)
Anastrozole (108 deaths)
Log-rank p = 0.0362
0
N at risk
AN 208
AN + FV 206
12
24
36
48
Months since registration
60
72
190
181
158
139
13
12
1
2
91
77
34
30
Prior tamoxifen as a predictive factor?
• Overall planned analysis is highly significant
• Unplanned analysis by prior tamoxifen may suggest
benefit only in the tamoxifen naive group
• Prior tamoxifen use is confounded with time between
adjuvant diagnosis and metastatic diagnosis
• Need to better understand other possible predictive
factors since the prior tamoxifen factor could be a false
lead from an unplanned analysis
Forest Plot
PFS treatment hazard ratio with 95% confidence interval
Unplanned subset analysis
Overall HR = 0.80
Age 65+
Age < 65
HER2-positive
HER2-negative
Non-visceral
Visceral
Bone only
Non-measurable
Measurable
10 years+
5-10 years
0-5 years
De novo
No prior chemo
Prior chemo
No prior tam
Prior tam
Overall
Combination better
.4
.6
.8
Hazard ratio
Combination worse
1
1.2
1.4
1.6
S0226 Toxicity: Grade 4 and 5
•
•
•
Three patients on the combination had grade 5
toxicities:
–
two had pulmonary embolism
–
one had cerebrovascular ischemia
Two other patients on the combination had grade
4 toxicities:
–
one had pulmonary embolism
–
one had neutropenia and lymphopenia
Four patients on anastrozole alone had Grade 4
toxicities (thrombosis/embolism, arthralgia,
thrombocytopenia, dyspnea)
S0226 Toxicity
•
Grade 3 toxicities:
–
46 (13%) on the combination
–
38 (11%) on anastrozole alone
•
Includes musculo-skeletal pain, fatigue, hot
flashes, mood alterations and gastrointestinal
symptoms with frequency 1-4%
•
Adverse events did not differ significantly by
treatment group
•
Few patients went off treatment early due
to adverse events or side effects
(anastrozole alone 4; combination 11)
First-Line Hormonal Agent Phase-III Studies
in Breast Cancer: Overall Survival
Study
N
Control Arm
(months)
Experimental
Arm (months)
HR for OS
P-value
S0226
694
Anastrozole
(→fulvestrant
(41.3)
Anastrozole +
Fulvestrant
(47.7)
0.80
0.049
Bergh SABCS
2009
514
Anastrozole
1.00
1.00
(38.2)
Anastrozole +
Fulvestrant
(37.8)
Nabholtz
2003 Eur J C
1021
Tamoxifen
(40.1)
Anastrozole
(39.2)
0.97
?
Mouridsen
2003 JCO
916
Tamoxifen
(30)
Letrozole
(34)
?
0.53
Paridaens
JCO 2008
371
Tamoxifen
(43.3)
Exemestane
(37.2)
1.04
0.82
Howell
JCO 2004
587
Tamoxifen
(38.7)
Fulvestrant
(36.9)
1.29
0.04
S0226 Conclusions:
• The combination of anastrozole and fulvestrant
improves PFS and OS, the primary and
secondary endpoints, respectively, in first-line
therapy of hormone receptor positive breast
cancer in postmenopausal women
• The toxicity of the combination treatment is
comparable to single agent treatment though
Grade 5 toxicity was seen only with the
combination
CLEOPATRA
AVEREL