Transcript Novel Biologic Agents with Clinical Promise - ANCO On-Line

Updates from the San
Antonio Breast Cancer
Symposium 2007: Medical
Oncology
Hope S. Rugo, MD
Michelle Melisko, MD
UCSF Helen Diller Family
Comprehensive Cancer Center
1
Prognostic and Predictive Value of the 21-Gene
Recurrence Score Assay in Postmenopausal, NodePositive (N+), ER-Positive (ER+) Breast Cancer
SWOG 8814, TBCI 0100
#10: Albain et al
 The 21-gene Recurrence Score assay (RS) is
prognostic for women with node(-), ER+ breast
cancer on 5 years of tamoxifen*
 A high RS predicts large benefit from
chemotherapy in node(-) disease, but no
improvement if the RS is low**
 There are no RS data in a N+ population with a
tamoxifen-alone control
 SWOG 8814 is an ideal trial to explore this
question
*Paik, et al. NEJM, 2004
**Paik, et al. J Clin Oncol, 2006
Phase III SWOG 8814 (TBCI 0100)
Postmenopausal, N+, ER+
RANDOMIZE
tamoxifen x 5 yrs
(n = 361)
n = 1477
CAF x 6, with CAF x 6, then
tamoxifen
concurrent tam
(n = 550)
(n = 566)
Superior Disease-Free
Survival (DFS) and Overall
Survival (OS) over 10 Years
Albain, et al. Breast Cancer Res Treat 2005
SWOG 8814/TBCI 0100 Correlative
Science Study
Two co-primary objectives
were
to determine if the RS:
1) provides prognostic information for
women with N+ disease treated only
with tamoxifen, and
2) allows prediction of a N+ group that does
not derive benefit from chemotherapy
SWOG 8814/TBCI 0100 Correlative Science
METHODS - II
 Limited to tamoxifen and sequential CAF-T arms
(eliminated inferior concurrent CAFT)
 Stratified log-rank tests by nodes (1-3 vs 4+), due to
strong prognostic effect in main trial
 Conducted Cox regression analyses on continuous
RS and its interaction with treatment
-
Found violation of the proportional hazards
assumption (hazard ratio not constant over time)
-
Therefore, analyses done with a split time axis:
≤ 5 and > 5 years
70 Gene Profile in Patients with 1-3+
Axillary Lymph Nodes
#50: Mook et al
 70 gene profile
– Independent prognostic factor in node negative patients
– Prognostic value in node+ (NEJM 02)
 Overall survival 92 vs 60%
 In 1-3 node+ subset
– 98 vs 64% (#1064, SABC 2007)
– Independent validation
 241 pts diagnosed between 2004-2001
– Treated at Netherlands Cancer Inst and Europ Inst Oncol
– 53% chemotherapy, 64% hormonal therapy
– Median follow-up 7.8 years
SWOG 8814/TBCI 0100
Sample Size for This Analysis
Patients with samples - 666
(45% of parent trial)
RT-PCR obtained - 601 (90%)
Tamoxifen alone
148
CAFT (concurrent)
234
CAF-T (sequential)
219
Final sample for primary analysis
148 + 219 = 367 (40% of parent trial)
Outcomes in RS Subset Mirror Those
Reported in Main Trial: Superiority of CAF-T
0.75
0.50
0.25
Stratified log-rank p-value = 0.054 at 10 years
(adjusted for nodal status)
Tamoxifen (n=148, 63 events)
CAF-T
(n=219, 74 events)
0.00
Disease-free survival
1.00
Disease-Free Survival
0
2
4
6
Years since registration
8
10
Comparative Distribution of RS
SWOG 8814: Less Low RS, More High RS
Study
NSABP B14*
NSABP B20*
Low Risk
(RS < 18)
Int. Risk High Risk
(RS 18-30) (RS ≥ 31)
51%
54%
22%
21%
27%
25%
Kaiser controls* 56%
19%
25%
ECOG 2197**
SWOG 8814***
31%
28%
20%
32%
49%
40%
*node(-): Paik, et al. NEJM 2004 & JCO 2006; Habel, et al. Breast Ca Res Treat 2006
**node- or 1-3+: Goldstein, et al. Proc ASCO 2007
***node+, postmenopausal: this analysis - no difference by age
SWOG 8814/TBCI 0100
21-Gene Recurrence Score is Prognostic for
DFS and OS in Tamoxifen Arm
Overall Survival by Risk Group
Disease-Free Survival by Risk Group
2
4
6
1.00
8
Years since registration
10-yr: 60%, 49%, 43%
0.25
Stratified log-rank p = 0.003 at 10 years
Low RS <18 (n=55)
Intermediate RS 18-30 (n=46)
High RS ≥31 (n=47)
0.00
Low RS <18 (n=55)
Intermediate RS 18-30 (n=46)
High RS ≥31 (n=47)
0
(tamoxifen alone)
Overall Survival
0.50
0.75
0.75
0.50
0.25
Stratified log-rank p = 0.017 at 10 years
0.00
Disease-free survival
1.00
(tamoxifen alone)
10
0
2
4
6
8
Years since registration
10-yr: 77%, 68%, 51%
10
Disease-Free Survival by Treatment
Disease-free survival
0.25
0.50
0.75
1.00
No benefit to
CAF over time
if low RS
Stratified log-rank p = 0.97 at 10 years
Tamoxifen (n=55, 15 events)
CAF-T
(n=91, 26 events)
0.00
Strong benefit
if high RS
Low risk (RS < 18)
0
2
4
6
8
10
Disease-Free Survival by Treatment
Disease-Free Survival by Treatment
1.00
1.00
0.25
Stratified log-rank p = 0.033 at 10 years
0
2
4
6
Years since registration
8
0.75
0.50
Stratified log-rank p = 0.48 at 10 years
Tamoxifen
CAF-T
0.00
Tamoxifen (n=47, 26 events)
CAF-T
(n=71, 28 events)
Intermediate risk (RS 18-30)
0.25
0.50
0.75
Disease-free survival
High risk (RS ≥31)
0.00
Disease-free survival
Years since registration
10
0
2
4
(n=46, 22 events)
(n=57, 20 events)
6
Years since registration
8
10
SWOG 8814/TBCI 0100
Ten-Year DFS Point Estimates (95% CI)
Recurrence Score
Risk Category
Tamoxifen
Alone
CAF followed
by tamoxifen
Low (< 18)*
60%
(40%, 76%)
64%
(50%, 75%)
Intermediate (18-30)
49%
(32%, 63%)
63%
(48%, 74%)
High (≥ 31)
43%
55%
(28%, 57%)
(40%, 67%)
*40% event rate over 10 years and resistance to CAF
SWOG 8814/TBCI 0100 Predictive Effect
Linear Recurrence Score for DFS
Interaction
Recurrence Score by
Chemotherapy
(adjusted for nodal
status)
Planned
analysis
Unplanned
analysis
first 5 years
p = 0.053
p = 0.029
Significance retained in Cox models adjusted for covariates
(age, race, tumor size, PgR, grade, HER2)
Significance lost when ER Allred score added to model (p=0.145)
The RS is Also Predictive for Overall Survival
in SWOG 8814/TBCI 0100
 No benefit to CAF in low RS in first 5 years (HR 1.05) or over
entire time period (HR 1.18)
1.00
Overall Survival by Treatment
0.50
0.75
High risk (RS ≥31)
0.25
Stratified log-rank test p = 0.027 at 10 years
Tamoxifen (n=47, 22 deaths)
CAF-T
(n=71, 20 deaths)
0.00
Overall survival
 Strong impact of CAF
in high RS first 5 years
HR 0.43 (0.21, 0.90)
and over entire period
HR 0.56 (0.31, 1.01)
10-year estimates:
Tam 51% (35%, 65%)
CAF-T 68% (51%, 79%)
0
2
4
6
Years since registration
8
10
No DFS Benefit from CAF if Central IHC
is Both HER2 Negative and ER Level High*
0
Stratified log-rank p = 0.81 at 10 years
Tamoxifen (n=57, 20 events)
CAF-T
(n=85, 30 events)
2
4
6
Years since registration
Disease-free survival
0.25
0.50
0.75
1.00
HER2 Positive or ER Allred <7
0.00
0.00
Disease-free survival
0.25
0.50
0.75
1.00
HER2 Negative and ER Allred 7-8
8
10
0
Stratified log-rank p = 0.011 at 10 years
Tamoxifen (n=73, 36 events)
CAF-T
(n=112, 39 events)
2
4
6
8
Years since registration
*Interaction p=0.052; if add mitotic grade, p=0.024
10
Single Gene Analyses might “Misclassify”
the Dominant Biology of the Tumor
Example: High ER (by either Allred Score
or RT-PCR) could have High RS
SWOG 8814/TBCI 0100 Correlative Science
CONCLUSIONS on PRIMARY ANALYSIS
 The 21-gene RS is prognostic for
tamoxifen-treated patients with positive
nodes
 Chemotherapy benefit is predicted when
the RS is high, dominating in the first 5
years, but carried over long-term
 A low RS may define a group of women
with positive nodes who do not appear to
benefit from anthracycline-based
chemotherapy
SWOG 8814/TBCI 0100 Correlative Science
OTHER PERSPECTIVES
 New strategies in endocrine/biologic therapy are
needed given event rate of 40% over 10 years
if low RS
 Biology should drive treatment decisions, since
for high RS chemotherapy is beneficial
regardless of age
 These data (both RS and IHC) challenge
chemotherapy mandates for patients with N+,
ER+ disease: not all benefit from
chemotherapy, whereas others derive greater
benefit than previously predicted
 A prospective trial should be a high priority.
Risk Classification by 70-gene
Profile
 Out of 241 patients
– 99 (41%) had a good prognostic profile
– 142 (59%) had a poor prognositic profile
 Good prognostic tumors were more often
– ER+
– Low or intermediate grade
– Less than 2 cm
Significant in Multivariate Analysis
Results with Treatment?
Summary
 The 70 gene profile for 103 + nodes
– Significant prognostic marker
– Improves risk assessment
– Identifies a low risk group with an excellent prognosis
(41% of total population)
 Caveats
– Must have frozen or fresh tissue
– This population was not homogeneous
 Selection and treatment bias impacts evaluation
 Ongoing MINDACT trial
Extended follow-up and analysis by age
of the US Oncology Adjuvant Trial 9735:
docetaxel/cyclophosphamide is
associated with an overall survival
benefit compared to
doxorubicin/cyclophosphamide and is
well-tolerated in women 65 or older.
Jones SE, Holmes FA, O’Shaughnessy JA, Blum JL,
Vukelja SJ, McIntyre KJ, Pippen JE, Bordelon JH, Kirby RL,
Sandbach J, Hyman WJ, Khandelwal P, Negron AG, Richards
DA, Mennel RG, Boehm KA, Meyer WG, Asmar L, *Muss HB,
Savin MA.
US Oncology Research, Houston, TX; *Vermont Cancer Center,
USA
Research supported by sanofi-aventis, New York, NY
Extended FU and analysis by age of the USO
trial: TC compared to AC improves survival and is
well-tolerated in women 65 or older.
#12:Jones et al
R
A
N
D
O
M
I
Z
E
Doxorubicin
Day 1
Cyclophosphamide
Day 1
60 mg/m2 IV
600 mg/m2 IV
Every 21 days X 4 Cycles
Docetaxel
Day 1
Cyclophosphamide
Day 1
75 mg/m2 IV
600 mg/m2 IV
Every 21 days X 4 Cycles
Inclusion/Exclusion Criteria
 Stage I, II, or operable Stage III invasive
breast cancer
– Complete surgical excision of the primary
tumor
– Age >18 years
 No
– Invasive cancer > 7cm or < 1cm
– Prior chemotherapy
Demographics by Treatment and Age
<65 Years
TC
AC
Number of pts
428 Pts
428 Pts
>=65 Years
TC
AC
78 Pts
82 Pts
ER+
PR+
298 (70%) 275 (64%)
268 (63%) 258 (60%)
52 (67%)
47 (60%)
58 (71%)
49 (60%)
Nodes
0
1 to 3
4+
212 (50%) 217 (51%)
174 (41%) 174 (41%)
42 (10%)
37 (9%)
28 (36%)
35 (45%)
15 (19%)
31 (38%)
38 (46%)
13 (16%)
Median Age (yrs)
Range
50
49
69
68
(27 - 64)
(27 - 64)
(65 - 77)
(65 - 77)
Disease-free Survival by Treatment
1.00
0.95
0.90
TC
0.85
81%
0.80
P = 0.033
HR = .74
0.75
AC
Proportion DFS
75%
0.70
0.65
0.60
At Risk TC
AC
0
12
24
36
48
60
72
84
96
Months
506
510
495
498
47
477
454
442
442
422
434
412
425
401
420
396
418
392
Disease-free Survival by Treatment
and Age Group
1.0
0.9
<65TC
<65 AC
0.8
65+ TC
0.7
0.6
Proportion DFS
65+ AC
0.5
0.4
0
12
24
36
48
Months
60
72
84
96
Assessment of HER2 Status by
FISH* for 170 Patients
# of Patients
TC
AC
Total
83
87
170
Negative
55
69
124
(73%)
Positive
28
18
46 (27%)
*FISH+ = Gene copy ratio of 2.0 or greater
DFS For HER2 Positive Status
1.0
0.9
0.8
0.7
0.6
TC
0.5
0.4
AC
HR = .73
Proportion DFS
0.3
0.2
0.1
0.0
At Risk TC
AC
0
12
24
36
48
60
72
84
96
Months
28
18
27
17
21
14
20
10
17
9
17
8
16
8
16
8
16
8
DFS For HER2 Negative Status
1.0
0.9
TC
0.8
0.7
AC
0.6
0.5
HR = .56
0.4
Proportion DFS
0.3
0.2
0.1
0.0
At Risk TC
AC
0
12
24
36
48
60
72
84
96
Months
55
68
53
61
49
51
45
47
42
45
42
44
42
44
41
40
40
38
Overall Survival by Treatment
1.00
0.95
TC
0.90
87%
0.85
AC
P = 0.032
HR = .69
0.80
82%
0.75
Proportion Surviving
0.70
0.65
0.60
At Risk TC
AC
0
12
24
36
48
60
72
84
96
Months
506
510
502
504
495
493
481
476
466
459
461
448
454
432
449
429
448
427
Overall Survival by Treatment
and by Age Group
1.0
<65TC
0.9
<65AC
0.8
65+TC
Insert graphics
here
0.7
65+AC
0.6
Proportion Survi
0.5
0.4
0
12
24
36
48
Months
60
72
84
96
Grade 3-4 Hematologic Toxicity by
Treatment and Age (%)
<65 Years
TC
AC
Adverse Event
Anemia
Neutropenia
Thrombocytopenia
Febrile Neutropenia
428 Pts 428 Pts
<1
1
60
54
<1
1
4
2
>=65 Years
TC
AC
78 Pts
<1
52
0
82 Pts
5
59
<1
8
4
Grade 3-4 Nonhematologic Toxicity
by Treatment and Age (%)
<65 Years
TC
AC
Adverse Event
Asthenia
Edema
Fever
Infection
Myalgia
Arthralgia
Stomatitis
Diarrhea
Nausea
Vomiting
Phlebitis
428 Pts
3
1
4
7
2
1
1
2
2
1
<1
428 Pts
4
<1
3
10
1
1
2
1
7
6
<1
>=65 Years
TC
AC
78 Pts
6
0
6
6
0
<1
0
5
3
0
<1
82 Pts
9
<1
4
2
<1
<1
<1
1
5
0
0
3 Additional Long-term Fatal Toxicities
All on the AC arm
CHF (45 yrs - AC)
myelodysplastic syndrome (63 yrs AC)
myelofibrosis (66 yrs - AC)
Conclusions
 At 7 years median FU
–
–
–
–
TC was superior to AC for DFS and OS
Efficacy across age groups
Less long term toxicities with TC
Short term
 Slightly more FN with TC, more anemia with AC
– Ongoing US oncology trial is evaluating the role of
anthracyclines:
 TAC vs TC – both given for 6 cycles
– Effective regimen to use for lower risk tumors where
chemotherapy is planned
ATAC Trial: 100 month update:
#41: Forbes et al
Postmenopausal women with invasive breast cancer
(n = 9366)
Surgery  radiotherapy  chemotherapy
Randomisation 1:1:1 for 5 years
Anastrozole
(n = 3125)
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
Discontinued
following
Combination
initialn=3125
analysis as no
efficacy or tolerability
benefit compared with
tamoxifen arm
Summary of endpoints (A vs T)
(HR+ patients)
Endpoint
No. events
Hazard ratio
95% CI
p-value
Disease-free survival
618 v 702
0.85
(0.76-0.94)
0.003
Time to recurrence
391 v 494
0.76
(0.67-0.87) 0.0001
Time to distant recurrence
305 v 357
0.84
(0.72-0.97)
0.022
Contralateral breast cancer
50 v 80
0.60
(0.42-0.85)
0.004
Death − all causes
472 v 477
0.97
(0.86-1.11)
0.7
Death after recurrence
245 v 269
0.90
(0.75-1.07)
0.2
Death without recurrence
227 v 208
1.05
(0.87-1.26)
0.6
A, anastrozole; T, tamoxifen; HR+, hormone receptor-positive; CI, confidence interval
Disease-free survival
HR+ patients
Patients 30
(%)
25
HR
95% CI
HR+ 0.85 (0.76, 0.94)
20
Tamoxifen (T)
Anastrozole (A)
29.9%
p-value
0.003
30
25
25.8%
20
16.4%
15
15
10
10
13.9%
5
5
Absolute difference 2.5%
0
0
1
2
3
4
5
6
Follow-up time (years)
4.1%
7
8
At risk:
A
2618 2541 2453 2361 2278 2159 1995 1801 1492
T
2598 2516 2400 2306 2196 2075 1896 1711 1396
HR, hazard ratio; CI, confidence interval
9
608
547
0
Time to recurrence
HR+ patients
Patients 30
(%)
25
HR
95% CI
30
p-value
HR+ 0.76 (0.67, 0.87) 0.0001
21.8%
20
Tamoxifen (T)
Anastrozole (A)
15
25
20
12.5%
17.0%
10
15
10
9.7%
5
5
Absolute
difference 2.8%
0
0
1
2
3
4
5
6
Follow-up time (years)
4.8%
7
8
At risk:
A
2618 2541 2453 2361 2278 2159 1995 1801 1492
T
2598 2516 2400 2306 2196 2075 1896 1711 1396
9
608
547
0
Time to distant recurrence
HR+ patients
Patients 30
(%)
25
HR
95% CI
HR+ 0.84 (0.72, 0.97)
20
p-value
30
0.022
25
20
Tamoxifen (T)
Anastrozole (A)
15.6%
15
15
9.1%
10
13.2%
7.8%
5
5
Absolute difference 1.3%
0
0
1
2
3
4
5
6
Follow-up time (years)
10
2.4%
7
8
At risk:
A
2618 2551 2470 2393 2320 2201 2042 1854 1536
T
2598 2533 2440 2363 2263 2151 1982 1809 1484
9
636
591
0
Contralateral breast cancer
HR+ patients
Patients
(%)
5
HR
95% CI
HR+ 0.60 (0.42, 0.85)
5
p-value
0.004
4.2%
4
Tamoxifen (T)
Anastrozole (A)
3
4
3
2.5%
1.8%
2
2
1.0%
1
1
AD 0.8%
0
0
1
2
3
4
5
6
Follow-up time (years)
1.7%
7
8
At risk:
A
2618 2541 2453 2361 2278 2159 1995 1801 1493
T
2598 2516 2400 2306 2196 2075 1896 1711 1396
AD, absolute difference
9
608
547
0
Death: all causes
HR+ patients
Patients 30
(%)
25
HR
95% CI
HR+ 0.97 (0.86, 1.11)
20
p-value
30
0.70
25
20
Tamoxifen (T)
Anastrozole (A)
15
15
10
10
5
5
0
0
0
1
2
3
4
5
6
Follow-up time (years)
7
8
At risk:
A
2618 2567 2511 2445 2389 2274 2102 1911 1586
T
2598 2549 2504 2432 2339 2227 2068 1888 1551
9
659
620
Deaths according to treatment
group (ITT population)
No. patients (%)
Cause of death
Anastrozole
(n = 3125)
Tamoxifen
(n = 3116)
Total deaths
629 (20)
624 (20)
Deaths after recurrence
350 (11)
382 (12)
Deaths without recurrence
279 (9)
242 (8)
Cardiovascular
67 (2)
66 (2)
Cerebrovascular
25 (1)
29 (1)
Second primary non-breast cancer
84 (3)
60 (2)
Other
103 (3)
87 (3)
Fractures
(occurring at any time before recurrence)
Fractures before recurrence
A
T
N=3092 N=3094
(%)
(%)
Odds ratio
A vs T
95% CI
p-value
Patients with one or more
fracture episodes
421
(13.6)
311
(10.1)
1.41
1.21-1.65 <0.0001
Hip
49
(1.6)
42
(1.4)
1.17
0.75-1.82
0.46
Spine
60
(1.9)
37
(1.2)
1.64
1.08-2.48
0.02
Wrist / colles
94
(3.0)
83
(2.7)
1.14
0.84-1.54
0.4
All other sites
270
(8.7)
191
(6.2)
1.46
1.20-1.77
0.0001
A, anastrozole; T, tamoxifen
Fracture episode rates
throughout the study
Annual
fracture
episode
rates (%)
4
Tamoxifen (T)
Anastrozole (A)
3
2
1
0
0
1
At risk:
A
2984
T
2976
2
2859
2824
3
4
5
6
7
Time since randomisation (years)
2745
2699
2640
2572
2496
2419
2306
2208
2077
2000
8
9
1713
1645
702
659
Conclusions
 At 100-month median follow-up, data show anastrozole is significantly
superior to tamoxifen at preventing recurrence:
– Locoregional
– Contralateral
– Distant
 The absolute difference in recurrence rates persists after treatment
completion:
– HR+ population: 2.8% at 5 years increased to 4.8% after 9 years
– HR = 0.75; p=0.01
 Anastrozole is well-tolerated long term:
– No excess fracture rate seen after treatment completion
– Risk of fracture on treatment needs to be taken into consideration and can
be managed according to established guidelines
– No new morbidity or mortality increases seen after treatment completion
 Lack of survival benefit in aging population – role of competing
morbidities?
 Role of cyp2D6 needs to be further defined
Outcome Prediction with Neoadjuvant
Hormone Therapy
#5072: Ellis et al
Letrozole
ER+ Stage 2/3
Tamoxifen
Final accrual 337
S
U
R
G
E
R
Y
Continued therapy
with tamoxifen
radiotherapy
chemotherapy
discretionary
P024: Efficacy of letrozole versus tamoxifen
Letrozole
Confirmed (ER+/PgR+)
Tamoxifen
P Value1
124 (100%) 126 (100%)
Overall tumor response
(CR+PR)
Clinical
Ultrasound
Mammography
Breast-conserving surgery
Clinical disease progression
1Stratified
74 (60%)
48 (39%)
47 (37%)
60 (48%)
10 (8%)
52 (41%)
37 (29%)
25 (20%)
45 (36%)
15 (12%)
Mantel-Haenszel chi-squared test
Ellis MJ et al. J Clin Oncol. 19:3808-3816, 2001.
0.004
0.119
0.002
0.036
0.303
Stage 1/0 versus Stage 2/3
Node Status
Clinical Response
Histological Grade
Post treatment ER - RFS
Post treatment ER - OS
Ki67 Absolute Cut Offs Pre and Post treatment
Final Multivariate analysis for RFS including Clinical Response
RFS
Factor definitions
Clinical Response
HR
OS
HR
Multivar’te
95% CI
Multivar’te
P Value
95% CI
P Value
1.72
0.07
1.12
0.78
(0.96-3.09)
Tumor size
2.8
(T1/2 v T3/4)
(1.51-5.22)
Node status
2.06
(Yes v No)
(1.09-3.9)
Ki67 level
1.2
per log (2.7 fold)
increase
(1.02-1.42)
ER Allred
2.44
(0,2 v 3-8)
(1.15-5.2)
Grade
2.7
(1 v 2/3)
(1.07-7.02)
(0.51-2.45)
0.001
3.73
0.001
(1.68-8.28)
0.03
1.48
0.4
(0.65-3.38)
0.03
1.27
0.03
(1.02-1.59)
0.02
4.66
0.001
(1.86-11.7)
0.04
3.49
(0.8-15.1)
0.1
Risk Score
Pathology, Biomarkers and
Response Factors
Clinical Res
Tumor size
HR
Points
-
0
No
1.72
1
T1/2
-
0
T3/4
2.80
3
No
-
0
Yes
2.06
2
0- 1
-
0
Yes
Node status
Ln Ki67 level
ER Allred
Grade
RFS
1+ - 4
1.2-1.73
1
4+
2.07
2
0-2
2.44
2
3-8
-
0
1
-
0
2.7
3
2/3
Risk score
0-1
2-5
6-9
10-13
Total
Relapse
1(7%)
15(21%)
31(55%)
5(100%)
43
Total
14(10%)
71(49%)
56(38%)
5(3%)
146
Conclusion
 Assessment of risk following neoadjuvant
chemotherapy may be a useful tool to
determine use of subsequent chemotherapy
 Neoadjuvant endocrine therapy followed by
surgical staging can be used to assess
baseline risk
 Further data is needed to determine the
benefit of subsequent chemotherapy
Z-FAST: 36 month follow-up
#27: Brufsky et al
Eligibility
• Early BCa
• ER+ or PgR+
• PMW
• T score ≥ -2
Stratification
• Adjuvant chemo
(yes or no)
• T score ( > -1 or
between -1 and -2)
R
A
N
D
O
M
I
Z
E
D
UPFRONT Zoledronic acid 4 mg IV q 6 mo
+
Letrozole 2.5 mg po qd*
DELAYED† Zoledronic acid 4 mg IV q 6 mo
+
Letrozole 2.5 mg po qd*
• n=602
• In 94 Canadian and US sites
•Median age 60, 46-48% prior adjuvant chemotherapy
•Baseline T score -1 tp -2: 28%
*Plus daily calcium (500–1200 mg) and vitamin D (400–800 IU)
†Initiation determined by any postbaseline T score < -2, any clinical fracture unrelated to trauma, or an asymptomatic
fracture at 36 mo
Chemo=chemotherapy; ER=estrogen receptor; PgR=progesterone receptor
Zoledronic Acid Initiation in Delayed Group
Delayed Group Patients Who Initiated Zoledronic Acid
No. of Patients (%)
12-mo visit
All patients
44 (14.7)
Per protocola
28 (9.3)
24-mo visit
All patients
54 (18.0)
Per protocola
37 (12.3)
36-mo visit
All patients
62 (20.7)
Per protocola
45 (15.0)
aInitiation
of zoledronic acid determined by postbaseline T score < -2.0, any clinical fracture, or any asymptomatic
fracture at 36 mo.
First Zoledronic Acid Infusion in Delayed Group
Mean (SD)
Time to Initiation, mo
13.5 (10.2)
Median
11.5
Range
0.03–37.1
Mean (SEM) Percentage Change in
Bone Mineral Density at 36 months
Percentage Change in Bone Mineral Density
5
Upfront
group
Delayed
group
n=189
n=204
4
3
n=251
n=189
2
n=251
n=206
1
0
-1
-2
n=256
-3
n=256
n=199
-4
n=188
P<.0001
n=197
n=187
P<.0001
-5
Month 12
Month 24
Lumbar Spine
Month 36
Month 12
Total Hip
Month 24
Month 36
Shift in LS T Score at 36 Months
in Patients with Normal Baseline
T Score (T Score > -1)
T Score > - 1
T Score between - 1 and - 2
100
P=.0024a
Patients
(%)
80
60
40
20
0
Upfront Group
(n=140)
aP
value corresponds to INTERGROUP comparison at 36 mo.
LS, lumbar spine.
Delayed Group
(n=133)
Shift in LS T Score at 36 Months in Patients With
Low Baseline T Score (T Score Between -1 to -2)
T Score > - 1
T Score between -1 and -2
T Score < - 2
100
Patients (%)
80
P=.0011a
60
40
20
0
Upfront Group
(n=47)
aP
value corresponds to INTERGROUP comparisons at 36 mo.
LS, lumbar spine.
Delayed Group
(n=52)
Fracture Rates at 36 months
No. of Patients (%)
Type of Fracture
Upfront Group
Delayed Group
(n=300)
(n=300)
Clinical
Significant trauma
11 (3.7)
12 (4.0)
2 (0.7)
3 (1.0)
Asymptomatic
2 (0.7)
1 (0.3)
Other
1 (0.3)
2 (0.7)
Radiological spine
1 (0.3)
1 (0.3)
17 (5.7)
19 (6.3)
Minimal or no trauma
Total
Additional Adverse Events
 Renal disorders
– Grade 1-2 renal insufficiency
 Upfront group, 2 patients
 Delayed group, 0 patients
– Both suspected to be related to zoledronic acid
 Atrial fibrillation
– Grade 1-2
 Upfront group: 3 patients
 Delayed group: 0 patients
– Grade 3-4
 Upfront group: 4 patients
 Delayed group: 4 patients
Conclusions
 Upfront administration of zoledronic acid (4 mg IV every 6
months) was effective in preventing bone loss in
postmenopausal women on AI therapy at 36 months of
follow-up
– Increased lumbar spine and total hip bone mineral
density
– Bone-specific alkaline phosphatase and serum NTX
were effectively suppressed
 No differences were seen in symptomatic or
asymptomatic fracture rates at 36 months with upfront
therapy
 Zoledronic acid was safe and well tolerated
 Identifying high risk patients is critical to determine who
should receive upfront therapy
Denosumab Binds Receptor Activator of Nuclear
Factor Kappa B Ligand and Inhibits Osteoclast
Formation, Function, and Survival
M-CSF
Colony Forming
Unit Macrophage
Receptor Activator of Nuclear
Factor Kappa B Ligand
Pre-Fusion
Osteoclast
Receptor Activator of
Nuclear Factor Kappa B
Osteoprotegerin
Denosumab
Hormones
Growth Factors
Cytokines
Osteoclast Formation, Function,
and Survival Inhibited
Osteoblasts
Bone Formation
Adapted from Boyle WJ, et al. Nature. 2003;423:337-342.
Bone Resorption
Inhibited
Phase 3 Trial of Denosumab on BMD in
Women Receiving AIs for Early Stage BC
#47: Ellis et al
 Fully human monoclonal antibody to receptor activator of
nuclear factor kappa B (RANK) ligand
 IgG2 immunoglobulin isotype
 High affinity for human RANK ligand
 No detectable binding to tumor necrosis factor 
(TNF)TNF TNF-related apoptosis-inducing ligand
(TRAIL), or CD40L
 Pharmacokinetic and phase 2 studies support the 60 mg
6-monthly dosing regimen selected for this bone loss trial
Bekker PJ, et al. J Bone Miner Res 2004;19:1059-1066. Boyle WJ, et al. Nature. 2003;423:337-342.
Peterson M, et al. J Bone Miner Res 2003;18 (Suppl. 2):S166. Abstract SA393 and poster.
Phase 3 Study of Denosumab in Women With NonMetastatic Breast Cancer Receiving Aromatase
Inhibitor Therapy
Study
Design:
Multi-center, randomized, double-blind,
placebo-controlled study conducted in
the United States and Canada
Women Receiving
AIs For HR+, NonMetastatic Breast
Cancer
N = 127 Denosumab 60 mg SC
every 6 months (x 4 doses)
T score -1.0 to -2.5
No oral bisphos.
No chemo.
25-OH vit D > 12
mg/ml
N = 125 Placebo SC every
6 months (x 4 doses)
Baseline
12 month
24 month
Treatment and Patients
 All patients instructed to take daily supplements
of calcium (1000 mg) and vitamin D (400 IU).
 Stratified by duration of prior AI rx (> or < 6
mo.)
 252 patients enrolled in 24 month study
– 99 (79%) completed placebo
– 106 (83%) completed denosumab
Patient Demographics and Disease
Characteristics at Baseline
Characteristic
Placebo
(N = 125)
Denosumab
(N = 127)
Age, mean years (SD)
59.7 (9.7)
59.2 (8.9)
White, n (%)
119 (95)
116 (91)
At least 10 yrs from last menstrual period, n
(%)
63 (50)
63 (50)
68 (54)
39 (31)
18 (14)
71 (56)
42 (33)
14 (11)
Duration of prior aromatase inhibitor therapy
> 6 months, n (%)
79 (63)
80 (63)
Prior chemotherapy - n (%)
78 (62)
83 (65)
Prior tamoxifen therapy - n (%)
53 (42)
58 (46)
Type of aromatase inhibitor therapy at
randomization, n (%)
Anastrozole
Letrozole
Exemestane
Percentage Change (± 95% CI) From Baseline
in Lumbar Spine Bone Mineral Density
Effect of Denosumab on Lumbar
Spine Bone Mineral Density
Placebo (N = 122)
8
*
7
6
*
5
4
*
3
2
Denosumab (N = 123)
*
5.5% Difference
at Month 12
*
1
0
-1
7.6% Difference
at Month 24
-2
-3
1
3
6
* P < 0.0001 versus Placebo
12
Months
24
Effect of Denosumab on Lumbar Spine
Bone Mineral Density at Month 24
Percentage Change
From Baseline
100%
Percentage of Patients
Gain (> 6%)
80% 34%
Moderate Gain
(> 3% to 6%)
Minimal Gain
(> 0% to 3%)
60%
95%
40%
20%
0%
Placebo (N = 122)
Denosumab (N = 123)
Loss ( 0%)
Incidence of Adverse Events Occurring at
≥ 10% in Any Treatment Group Over 24
Months
Placebo
(N = 120)
Denosumab
(N = 129)
Arthralgia
30 (25)
31 (24)
Pain in Extremity
14 (12)
19 (15)
Back Pain
15 (13)
18 (14)
Fatigue
17 (14)
17 (13)
Constipation
11 (9)
15 (12)
Cough
5 (4)
13 (10)
14 (12)
12 (9)
Event, n (%)
Insomnia
N = number of patients who received study drug
Conclusions
 60 mg of denosumab twice yearly increased
bone mineral density over 24 months in this
population
 Well tolerated
 Also has demonstrated effectiveness in
treating metastatic bone disease
 Additional studies are ongoing
Other Interesting Data to be Briefly
Discussed (UCSF)
 ISPY neoadjuvant trial (Esserman et al)
 Ixabepilone in triple negative metastatic
breast cancer (Rugo et al)
 Zoledronate as adjuvant therapy for patients
with occult tumor cells in bone marrow (Lin et
al)