Early Breast Cancer:
Updates from the 34th Annual San
Antonio Breast Cancer Symposium
December 6-10, 2011
Stephen Y. Chui, M.D.
Assistant Professor of Medicine
Division of Hematology and Medical Oncology
Director of Breast Cancer Clinical Research (Acting)
Knight Cancer Institute
Oregon Health & Science University
Portland, Oregon
Topics for discussion
• Partial breast irradiation:
– Are we treating the right patients?
• Can we better stratify DCIS to receive appropriate
therapies?
– “DCIS Score” to predict DCIS recurrence risk after surgery
• Pre-operative chemotherapy
– Update of the GEPAR-TRIO pre-operative clinical trial
• Do bisphosphonates provide direct anti-tumor effects?
– 7-yr update of ABCSG-12
– 5-yr update of ZO-FAST
– NSABP B-34: clodronate vs placebo
– GAIN: ibandronate vs placebo
Partial Breast Brachytherapy Is Associated with
Inferior Effectiveness and Increased Toxicity
Compared with Whole Breast Irradiation in
Older Patients
Smith GL, Xu Y, Buchholz TA, Giordano SH, Smith BD.
San Antonio Breast Cancer Symposium – 2011 Annual Meeting
Abstract # S2-1
Partial breast radiation therapy
• Medicare billings claims > 66 yrs diagnosed with
breast cancer between 2000-2007
• All treated with breast conserving surgery
followed by Accelerated Partial Breast Irradiation
(APBI) alone versus Whole Breast Irradiation
(WBI)
• In 130,535 women, use of APBI increased from
<1% in 2000 to 13% of patients in 2007
• APBI less likely to not have axillary lymph node
involvement or to have received chemotherapy.
Smith GL et al. SABCS 2011. Abstract S2-1
Should be have concerns about Partial Breast
Radiation Therapy?
• Endpoint of study:
Subsequent MASTECTOMY
(a surrogate for local failure)
Incidence of subsequent mastectomy at five years
Accelerated Partial
Breast Irradiation
Whole Breast
Irradiation
P value
4%
2.2%
<0.001
Smith GL et al. SABCS 2011. Abstract S2-1
Pick your patient carefully!
• American Society of Radiation Oncology (ASTRO)
opinion-based consensus statement published in 2009
identifies who can be safely treated with APBI>
Accelerated partial breast irradiation consensus statement from the American
Society for Radiation Oncology (ASTRO).
Smith BD et al. Int J Radiat Oncol Biol Phys. 2009 Jul 15;74(4):987-1001.
•
From the SEER database, TWO-THIRDS of women
treated with breast brachytherapy between 2000-2007
would have been classified as “cautionary/unsuitable” as
defined by ASTRO guidelines
Accelerated partial breast irradiation using brachytherapy for breast cancer:
patterns in utilization and guideline concordance.
Hattangadi JA et al. J Natl Cancer Inst. 2012 Jan 4;104(1):29-41. Epub 2011 Dec 1
Can we better stratify DCIS to
receive appropriate therapies?
A quantitative multigene RT-PCR assay for
predicting recurrence risk after surgical excision
alone without irradiation for ductal carcinoma in situ
(DCIS): A prospective validation study of the DCIS
score from ECOG E5194
Solin LJ, Gray R, Baehner FL, Butler S, Badve S, Yoshizawa C, Shak S,
Hughes L, Sledge G, Davidson N, Perez EA, Ingle J, Sparano JA, Wood W
San Antonio Breast Cancer Symposium – 2011 Annual Meeting
Abstract # S4-6
Ductal carcinoma in-situ (DCIS)
• 45,000 new cases annually in United States
(estimated)
• Most patients (~75%) treated with breast
conservation surgery
– Radiation and tamoxifen reduce risk
• Reliable methods to select treatment with
surgery alone have not been well-established
using clinical and pathologic factors
Oncotype DX® 21-Gene Recurrence Score (RS)
Assay for early breast cancer
16 Cancer and 5 Reference Genes From 3 Studies
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN RS =
ER
PR
Bcl2
SCUBE2
GSTM1
INVASION
Stromelysin 3
Cathepsin L2
HER2
GRB7
HER2
BAG1
CD68
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
+ 0.47 x HER2 Group Score
- 0.34 x ER Group Score
+ 1.04 x Proliferation Group Score
+ 0.10 x Invasion Group Score
+ 0.05 x CD68
- 0.08 x GSTM1
- 0.07 x BAG1
Category
RS (0 -100)
Low risk
RS <18
Int risk
RS 18 - 30
High risk
RS ≥ 31
Paik et al. N Engl J Med. 2004;351:2817-2826.
DCIS Score
7 Cancer-related and 5 Reference Genes
PROLIFERATION
Ki-67
STK15
Survivin
Cyclin B1
MYBL2
ESTROGEN
PR
GSTM1
Category
REFERENCE
Beta-actin
GAPDH
RPLPO
GUS
TFRC
RS (0 -100)
Low risk
RS <39
Int risk
RS 39 - 54
High risk
RS ≥ 55
Solin LJ, et al. SABCS 2011. Abstract S4-6.
DCIS Score: Determining Risk of Recurrence
After DCIS Resection
• DCIS Score: gene-based score designed to predict for
local recurrence[1]
– Developed using subset of genes prognostic in both tamoxifentreated and tamoxifen-untreated patients
• Proliferation group: Ki67, STK15, survivin, CCNB1 (cyclin
B1), MYBL2
• Hormone receptor group: PgR
• GSTM1
• Reference group: ACTB (β-actin), GAPDH, RPLPO, GUS,
TFRC
• Evaluated using samples and data from ECOG E5194
trial[2]
1.
2.
Solin LJ, et al. SABCS 2011. Abstract S4-6.
2. Hughes LL, et al. J Clin Oncol. 2009;27:5319-5324.
E5194: Lumpectomy alone for low risk DCIS
“low risk” defined by clinical & pathologic criteria
DCIS
Lumpectomy (711 pts)
Group I
Low/int grade <2.5cm
Group II
High grade <1cm
Post-op mammogram clear for calcifications
Margins>3mm
Observation
30% Tamoxifen
Hughes L et al, SABCS 2006 Abstract #29
Lumpectomy alone for low risk DCIS
5 year results of intergroup trial E5194
Hughes L et al, SABCS 2006 Abstract #29
16%
13.70%
14%
12%
Ipsilateral events
10%
8%
Contralateral events
6.80%
6%
4%
3.50%
4.20%
30% of subjects
declared intent to
take tamoxifen
2%
0%
Low-Int Grade (n=580)
Median size 6 mm
Median margin 5-10 mm
50% DCIS
50% invasive
High Grade (n=102)
Median size 7 mm
Median margin 5-10 mm
NOTE:
• Dana Farber data shows ↑ recurrence without RT: IBTR 12% at 5 years, with low/int
grade and margins >1 cm (TAM not allowed)
J Clin Oncol Mar 1 2006 24(7):1031-6
• Van Nuys data demonstrates low recurrence rates overall if margins >1 cm, IBTR
13.9%, invasive IBTR 3.4% at 12 years (higher recurrence rates with Grade 3 DCIS)
Am J Surg Oct 2006 192(4):420-2
DCIS Score primary endpoint:
Risk of Ipsilateral Breast Events (DCIS + Inv ca)
Factor
HR (95% CI)
P Value
2.34 (1.15-4.59)
.02
21-gene RS
0.70 (0.15-2.65)
.62
Tamoxifen use
0.56 (0.24-1.15)
.12
DCIS Score
DCIS Score
n
Group
High
36
Intermediate 45
Low
246
50
45
40
35
30
25
20
15
10
5
0
10-Yr Risk, % (95% CI)
27.3 (15.2-45.9)
24.5 (13.8-41.1)
12.0 (8.1-17.6)
Log-rank P = .02
0
2
4
6
Yrs
8
10
Invasive IBE
Any IBE
10-Yr IBE by Risk Group
DCIS Score
n
Group
High
36
Intermediate 45
Low
246
50
45
40
35
30
25
20
15
10
5
0
10-Yr Risk, % (95% CI)
19.1 (9.0-37.7)
8.9 (2.9-25.8)
5.1 (2.8-9.5)
Log-rank P = .01
0
2
4
6
8
10
Yrs
Solin LJ, et al. SABCS 2011. Abstract S4-6.
DCIS Score: Multi-variable models of risk for
ipsilateral breast events
Hazard Ratio (95% C.I.)
P value
Tumor size
1.54 (1.14, 2.02)
0.01
Postmenopausal
0.49 (0.27, 0.90)
0.02
DCIS Score
2.41 (1.15, 4.89)
0.02
Tumor size
1.52 (1.11, 2.01)
0.01
Postmenopausal
0.49 (0.27, 0.90)
0.02
Excluding the DCIS Score
Including the DCIS Score
For study cohort, surgical margins, grade, comedo necrosis, and
DCIS pattern, all p > 0.46. For tamoxifen, p = 0.09
Solin LJ, et al. SABCS 2011. Abstract S4-6.
Exploratory analysis of DCIS Score across
different subgroups of DCIS
Solin LJ, et al. SABCS 2011. Abstract S4-6.
DCIS Score: Summary
• DCIS Score preliminarily appears to be a
predictor of the risk of (i) ipsilateral breast events
and (ii) invasive breast cancer
• DCIS score provides independent prognostic
information on IBE risk provided above that
attained with clinical and pathologic variables
• Including Tamoxifen, Grade, and Negative Margin
Width
• How do we use DCIS Score to guide treatment
selection for patients with newly diagnosed
DCIS?
Do bisphosphonates provide
direct anti-cancer benefits?
Bisphosphonates
• Analogs of pyrophosphate that bind to
hydroxyapetite at bone surface
• Osteoclast inhibition and apoptosis
• Prevent cancer cell adhesion to bone?
• Anti-angiogenesis activity?
• Direct anti-tumor activity?
• Immune activation?
Long-term follow-up in ABCSG-12:
Significantly improved overall survival with
adjuvant zoledronic acid in premenopausal
patients with endocrine-receptor-positive early
breast cancer
Gnant M, Mlineritsch B, Luschin-Ebengreuth G, Stoeger H, Dubsky P,
Jakesz R, Singer C, Eidtmann H, Fesl C, Eiermann W, Marth C, Greil R.
San Antonio Breast Cancer Symposium – 2011 Annual Meeting
Abstract # S1-2
ABCSG-12 Trial – 7 year median followup
Evaluation of Anastrozole vs. Tamoxifen in Premenopausal Women,
Alone or In Combination With Zoledronic Acid
N = 1803
Stage I & II, <10 positive LNs
ER+ and/or PgR+
Tamoxifen (TAM) 20 mg/d
n= 451
Anastrozole (ANA) 1 mg/d
n= 453
Surgery
+/- XRT
Goserelin
3.6mg q28d
Randomize
1:1:1:1
Key Endpoints:
• Primary:
Disease-free survival
(TAM vs. ANA; ZOL vs. No-ZOL)
• Secondary:
Recurrence-free survival
Overall survival
(TAM vs. ANA; ZOL vs. No-ZOL)
Tamoxifen (TAM) 20 mg/d
+ Zoledronic Acid (ZOL) 4mg q6m
n= 449
Anastrozole (ANA) 1 mg/d
+ Zoledronic Acid (ZOL) 4mg q6m
n= 450
Treatment duration: 3 years
Gnant M et al. SABCS 2011. Abstract S1-2
ABCSG-12 DFS events NO ZOL vs. ZOL (SABCS 2011)
ITT population: Median f/u 84 mo
HR 0.72 (0.56-0.94) p=.014
Death without
previous recurrence
Secondary
malignancy
First Event/Patient (n)
140
120
100
3
18
13
14
11
80
65
60
56
40
20
Contralateral
breast cancer
Distant
recurrence
Locoregional
recurrence
36
19
0
No ZOL
(n = 903)
ZOL
(n = 900)
Benefit of ZOL consistent across ER/PgR Node/Grade/Size/TAM vs ANA subgroups
ABCSG-12 (84 Mos): Age Effect on DFS
40 Yrs of Age or Younger
Older Than 40 Yrs of Age
100
80
80
60
60
DFS (%)
100
Univariate
40
Events, n
20
HR (95% CI)
P Value
vs no ZOL
(Log-rank)
0.87 (0.55-1.36)
.525
No ZOL 42/213
ZOL
35/200
Univariate
40
Events, n
20
No ZOL 90/690
ZOL
0
63/700
HR (95% CI)
P Value
vs no ZOL
(Log-rank)
0.66 (0.48-0.92)
.013
0
0
12
24
36
48
60
72
84
96 108
0
12
Mos Since Randomization
Pts at Risk, n
No ZOL 213 202
200 192
ZOL
194
185
189
180
177
169
157
148
127
125
102
94
24
36
48
60
72
84
96 108
Mos Since Randomization
52
48
Pts at Risk, n
No ZOL 690 656
700 670
ZOL
639
656
616
642
581
619
496
526
394
419
303
325
139
160
Gnant M, et al. SABCS 2011. Abstract S1-2.
ABCSG-12 at 7 year median followup: Summary
• Survival benefits (DFS, OS) with addition of ZOL
to endocrine therapy first reported at median
follow-up of 48 months are still present at 84
months
• Subset analysis suggests that survival benefits
of ZOL may be restricted to patients older than
40 yrs of age
ABCSG-12 enrolled a very unique (and good
prognosis?) pre-menopausal patient population
• VERY endocrine-responsive tumors.
– ER +++/++ (80%) and PgR +++/++ (75%).
• Most of these were smaller tumors
– 75% of tumors were T1 in size.
• Although LN+ pts could be enrolled,
two-thirds of patients were actually axillary
lymph node negative.
• Mostly low- and intermediate-grade tumors.
– 76% were Grade 1 or 2.
DFS/OS events are occurring very infrequently on
ABCSG-12 (Is the data from this study underpowered?)
ABCSG-12 ATAC
IES
CALGB B31 /
BIG 1-98
9741 N9831
Zol vs. none ANA vs. TAM/EXE
q2wk vs. AC-T +/LET vs. TAM
TAM vs. ANA
TAM
vs. TAM
q3wk
Tras
Median f/u
84 mo
68 mo 58 mo
51 mo
67 mo
36mo
DFS
OS
87%
95%
80% 82%
87% 95%
84%
92%
74% 87%
81% 91%
Adjuvant Treatment with Zolderonic Acid in
Stage II/III Breast Cancer:
The Azure Trial (BIG 01/04)
Coleman RE, Cameron TH, Dodwell D, Burkinshaw R, Keane M, Gil M,
Houston SJ, Grieve RJ, Barrett-Lee PJ, Ritchie D, Davies C, Bell R
On Behalf of the AZURE Investigators
San Antonio Breast Cancer Symposium – 2010 Annual Meeting
Abstract # S4-5
AZURE: Adjuvant Zolendronate to Reduce Recurrence
(Neo)Adjuvant chemotherapy +/- zolendronate
Stage II / III early
breast cancer
Stratification:
Node pos vs. Node neg
<2 cm vs. 2-5 cm vs. >5 cm
Hormone receptor status
Chemotherapy type
Pre / Post-menopausal
R
A
N
D
O
M
I
Z
E
N=3360
Primary endpoint: DFS
Secondary Endpoints: OS, Invasivedisease free survival, Bone met
free-survival, Safety
Chemotherapy per local practice
Placebo infusion
Chemotherapy per local practice
Zolendronate 4 mg IV*
6 doses
(q3-4 wks)
8 doses
(q3 mos)
5 doses
(q6 mos)
5 years (60 months)
AZURE: 5-year median follow-up
Disease-free survival
Invasive disease-free survival
Coleman RE et al. SABCS 2010. Abstract S4-5.
AZURE: Survival by menopausal status*
Coleman RE et al. SABCS 2010. Abstract S4-5.
AZURE Summary
• Adjuvant zoledronate did not improve DFS in a
broad population of Stage II/III breast cancer
patients treated with adjuvant chemotherapy.
• The AZURE results are strikingly different to
those observed in ABCSG-12.
• In subgroup analysis, hypothesis-generating
heterogeneity of effect by menopausal status was
seen:
– Improved DFS and OS in those >5 years post
menopause
– Hypothesis: Adjuvant bisphosphonate efficacy is
dependent on low estrogen concentrations within the
bone/other microenvironment?
Long-term survival outcomes among
postmenopausal women with hormone
receptor-positive early breast cancer receiving
adjuvant letrozole and zoledronic acid: 5-year
follow up of ZO-FAST
de Boer R, Bundred N, Eidtmann H, Neven P, von Minckwitz G, Martin N,
Modi A, Coleman R.
San Antonio Breast Cancer Symposium – 2011 Annual Meeting
Abstract # S1-3
ZO-FAST: Immediate vs. Delayed Bisphosphonate
Eligibility:
• ER+/PR+ early breast
cancer
• Postmenopausal
• T score ≥= -2
Stratification:
• Adjuvant chemo
• T score
• Established vs. recent
post-menopausal
IMMEDIATE (n = 532)
R
A
N
D
O
M
I
Z
E
Letrozole 2.5 mg/day
Zolendronic acid 4 mg IV q6 mo
DELAYED (n = 532)
Letrozole 2.5 mg/day
Add zolendronic acid if
BMD T score < -2 or clinical or
asymptomatic fracture at 36 mo
1065 pts in 128 centers in Asia Pacific, Central
and South America, Egypt and Europe
Treatment duration:
5 years
ZO-FAST (Primary Endpoint): Median Change
in Lumbar Spine BMD
Change in LS (LS-L4) BMD (%)
6
Immediate ZOL
Delayed ZOL
P < .0001 for each
4
2
0
290
313
339
264
360
Δ 5.9%
Δ 8.2%
Δ 8.8%
Δ 9.2%
Δ 10.0%
343
311
294
264
36 mos
48 mos
60 mos
-2
369
-4
-6
12 mos
24 mos
De Boer R, et al. SABCS 2011. Abstract S1-3.
ZO-FAST: Final 5-Yr Disease-Free Survival
100
100
90
90
80
70
DFS (%)
70
DFS (%)
80
ITT Population
60
50
40
HR: 0.66; log-rank P = .0375
30
Censored Analysis*
60
50
40
HR: 0.62; log-rank P = .024
30
IM-ZOL 4 mg (42 events)
D-ZOL 4 mg (62 events)
20
20
10
10
0
0
0
6 12 18 24 30 36 42 48 54 60 66
Time on Study (Mos)
Pts at Risk, n
518
500
488
475
376
IM-ZOL 532
511
491
475
463
368
D-ZOL 533
IM-ZOL 4 mg (42 events)
D-ZOL 4 mg (53 events)
0 6 12 18 24 30 36 42 48 54 60 66
Time on Study (Mos)
Pts at Risk, n
IM-ZOL 532
518
500
488
475
376
D-ZOL 533
459
402
376
350
267
*Censored patients at initiation of delayed ZOL (n = 144) – approximately 27% of subjects in “delayed” group
De Boer R, et al. SABCS 2011. Abstract S1-3.
ZO-FAST: Disease recurrence
Disease Recurrence
70
50
41
30
20
29
6
10
0
60
Patients (n)
Patients (n)
60
40
70
Distant
Contralateral
Local
12
D-ZOL
(n = 533)
Key Sites of Distant
Recurrence*
3
5
IM-ZOL
(n = 532)
50
9
40
11
30
11
20
10
0
24
Liver
Lung
Lymph node
Bone
9
9
5
14
D-ZOL
(n = 533)
IM-ZOL
(n = 532)
*Multiple sites may be recorded within the same patient.
De Boer R, et al. SABCS 2011. Abstract S1-3.
ZO-FAST: Overall survival (ITT)
100
90
80
OS (%)
70
60
50
40
HR: 0.69; log-rank P = .196
30
IM-ZOL 4 mg (26 events)
D-ZOL 4 mg (36 events)
20
10
0
0
Pts at Risk, n
IM-ZOL
532
D-ZOL
533
6
12
522
519
18
24
30
36
42
Time on Study (Mos)
511
502
505
491
48
485
480
54
60
66
406
407
De Boer R, et al. SABCS 2011. Abstract S1-3.
ZO-FAST 5-yr followup: Summary
• Immediate initiation of ZOL at start of letrozole
prolonged DFS vs delayed initiation of ZOL in
postmenopausal women with endocrineresponsive EBC
– Continued to improve BMD after 5 yrs of follow-up
– 34% improvement in DFS
• Findings consistent with those observed in
ABCSG-12 and subset of patients > 5 years
postmenopause in AZURE
NSABP Protocol B-34: A Clinical Trial
Comparing Adjuvant Clodronate vs. Placebo in
Early Stage Breast Cancer Patients Receiving
Systemic Chemotherapy and/or Tamoxifen or
No Therapy – Final Analysis
Paterson AHG, Anderson SJ, Lembersky BC, Fehrenbacher L, Falkson CI,
King KM, Weir LM, Brufsky AM, Dakhil S, Lad T, Baez-Diaz L, Gralow JR,
Robidoux A, Perez EA, Zheng P, Geyer CE, Swain SM, Costantino JP,
Mamounas EP, Wolmark N.
San Antonio Breast Cancer Symposium – 2011 Annual Meeting
Abstract # S2-3
NSABP B-34: Phase III Study of Adjuvant
Clodronate in Breast Cancer
 Primary endpoint: DFS (mean follow-up: 8.4 yrs)
 Two thirds aged 50 yrs or older; 25% node positive
Stratified by age, number of positive
nodes, and ER/PgR status
Women with
stage I-III breast
cancer
(N = 3323)
3 Yrs
Clodronate 1600 mg/day*
(n = 1662)
Placebo*
(n = 1661)
*All patients could receive adjuvant systemic chemotherapy with or without tamoxifen or no adjuvant
therapy at investigator discretion.
Paterson A, et al. SABCS 2011. Abstract S2-3.
NSABP B-34: Disease-Free Survival
100
Disease Free (%)
80
60
N
Events
40
Placebo
1656
Clodronate 1655
20
312
286
HR: 0.91; P = .27
0
0
2
4
Yrs after Randomization
6
8
Paterson A, et al. SABCS 2011. Abstract S2-3.
NSABP B-34 Subset Analysis: DMFI, RFI, BMFI,
NBMFI in Pts Aged > 50 Yrs
Endpoint for Patients Aged 50
Years or Older
Distant metastasis free interval
Relapse free interval
Bone metastasis free interval
Non-bone metastasis free interval
HR
P Value
0.62
0.76
0.61
0.63
.003
.05
.024
.015
Paterson A, et al. SABCS 2011. Abstract S2-3.
NSABP B34: Summary
• No significant benefit in DFS (primary endpoint) with oral
clodronate in women with early breast cancer[1]
• Clodronate significantly reduced NBMFI vs placebo
– HR: 0.743; 95% CI: 0.554-0.996; P = .046
• In patients aged 50 yrs or older, clodronate associated
with significant improvements in RFI, BMFI, NBMFI vs
placebo[1]
– Findings consistent with those observed in older,
postmenopausal women in other adjuvant
bisphosphonate studies
GAIN Study: A Phase III Trial To Compare ETC
vs. EC-TX and Ibandronate vs. Observation in
Patients with Node-Positive Primary Breast
Cancer – 1st Interim Efficacy Analysis
Möbus V, Diel IJ, Elling D, Harbeck N, Jackisch Ch, Thomssen C, Untch M,
Conrad B, Schneeweiss A, Kreienberg R, Huober J, Müller V, Lück HJ,
Bauerfeind I, Loibl S, Nekljudova V, von Minckwitz G, on Behalf of the GBG /
AGO-B / NOGGO Study Groups
San Antonio Breast Cancer Symposium – 2011 Annual Meeting
Abstract # S2-4
German Adjuvant Intergroup Node Positive
(GAIN) Trial: Bisphosphonate Study Design
Randomized 2:1*
Patients aged 65 yrs or
younger with previously
untreated node-positive
primary breast cancer
(N = 3023)
Yr 2
Ibandronate 50 mg/day PO
(n = 2015)
Observation
(n = 1008)
*Patients in trial also randomized 1:1 to receive ETC vs epirubicin/cyclophosphamide followed by paclitaxel/capecitabine
(EC-TX).
ECT regimen: epirubicin 150 mg/m2 every 2 wks for 3 cycles, followed by paclitaxel 225 mg/m2 every 2 wks for 3 cycles,
followed by cyclophosphamide 2000 mg/m2 every 2 wks for 3 cycles.
EC-TX regimen: concurrent epirubicin 112.5 mg/m2 and cyclophosphamide 600 mg/m2 every 2 wks for 4 cycles, followed
by concurrent paclitaxel 67.5 mg/m2 wkly for 10 wks and capecitabine 2000 mg/m2 on Days 1-14 every 3 wks for 4 cycles.
During chemotherapy, all patients received primary prophylaxis with pegfilgrastim and either epoetin or darbepoetin.
Möbus V, et al. SABCS 2011. Abstract S2-4.
GAIN: Disease-free and Overall Survival
Product-Limit Survival Estimates
With Number of Subjects at Risk
+ Censored
Product-Limit Survival Estimates
With Number of Subjects at Risk
1.0
+ Censored
0.8
0.8
Survival Probability
1.0
0.6
0.6
0.4
3-yr DFS:
Ibandronate 87.6%
Observation: 87.2%
0.2
Cox regression:
HR: 0.945 (95% CI: 0.768-1.16; P = .59)
0 Pts at risk, n
1996
998
1814
871
1590
727
0
12
24
1057
483
555
264
210
105
36
48
DFS (Mos)
60
Ibandronate
0.4
3-yr OS:
Ibandronate 94.7%
Observation: 94.1%
0.2
Cox regression:
HR: 1.04 (95% CI: 0.763-1.42; P = .80)
0 Pts at risk, n
1996
998
1836
886
1653
756
0
12
24
1121
506
586
277
219
112
36
48
OS (Mos)
60
Observation
Möbus V, et al. SABCS 2011. Abstract S2-4.
GAIN: Subgroup analysis
DFS for Ibandronate in Subgroups
pN1
HR: 1.04 (95% CI: 0.652-1.65; P = .877)
pN2
HR: 0.875 (95% CI: 0.599-1.28; P = .490)
pN3
HR: 0.951 (95% CI: 0.710-1.27; P = .734)
ER and/or PgR positive
HR: 0.952 (95% CI: 0.736-1.23; P = .706)
ER and PgR negative
HR: 0.856 (95% CI: 0.604-1.21; P = .383)
HR: 1.02 (95% CI: 0.756-1.37; P = .912)
Postmenopausal
HR: 0.897 (95% CI: 0.671-1.20; P = .462)
< 60 yrs
HR: 1.02 (95% CI: 0.807-1.30; P = .842)
≥ 60 yrs
HR: 0.746 (95% CI: 0.490-1.14; P = .172)
0.5
Better with ibandronate
1.0
HR
1.5
Worse with ibandronate
Möbus V, et al. SABCS 2011. Abstract S2-4.
GAIN Adjuvant Ibandronate: Summary
• Adjuvant ibandronate did not improve DFS nor
OS following dose-dense chemotherapy in
patients with node-positive primary breast
cancer
• GAIN trial still ongoing to compare the 2 different
dose-dense chemotherapy regimens
Pre-operative chemotherapy
for breast cancer:
What is an appropriate
clinical endpoint?
In the historic development of early
breast cancer adjuvant treatment,
we have sequentially added newer
therapies to established therapies….
Surgery
Cytotoxic chemotherapy
Radiation therapy
Endocrine therapy
NSABP B-18 – Nine year update
Overall Survival and Disease-Free Survival
Potential Advantages to Pre-Operative
Systemic Therapy
• To improve the odds of breast conserving surgery.
– Inoperable
– Mastectomy
Operable
Breast conserving surgery
• To allow early assessment of treatment effect.
– Yes, but what does it truly mean in the long run?
– What are the optimal markers for various phenotypes?
– What is the true outcome of interest?
• To allow therapy adjustments to improve outcome
• Research:
– Provides opportunity to assess surrogate biologic endpoints
– May expedite drug development
Patients who achieve PathCR may have better
survival rates than patients who do not.
100
% Surviving
90
80
NSABP B27
Overall Survival
70
TRT
Non pCR
pCR
60
50
N
Deaths
1899 396
409 31
HR=0.33
p<0.0001
40
0
1
Bear, et al, SABCS 2004, #26
2
3
Years after Surgery
4
5
PathCR is not a perfect surrogate endpoint for
OS after pre-op chemotherapy
Anthracycline +
taxane preop chemo
Survival
PathCR
Cristofanilli Inv Ductal
JCO 2005
n=770
Inv Lobular
n=118
PathCR
15%
3%
5 yr OS
70%
93%
Guarneri
JCO 2006
ER-neg
ER-pos
PathCR
24%
8%
5 yr OS
84%
96%
Neoadjuvant chemotherapy adapted by interim
response improves overall survival of primary
breast cancer patients –
Results of the GeparTrio trial
von Minckwitz G, Blohmer JU, Costa S, Denkert C, Eidtmann H, Eiermann
W, Gerber B, Hanusch C, Hilfrich J, Huober J, Jackisch C, Kaufmann M,
Kümmel S, Paepke S, Schneeweiss A, Untch M, Zahm DM, Mehta K, Loibl
S.
San Antonio Breast Cancer Symposium – 2011 Annual Meeting
Abstract # S3-2
GEPAR-TRIO study design
SABCS 2006 - abstract 42
NX
NX
Vinorelbine
Capecitabine
Core biopsy:
uni/bilateral
cT2-4
cN0-3
size  2 cm*
Palpation /
sonography
NC R
TAC
TAC
Docetaxel
Adriamycin
Cyclophosphamide
+G-CSF
TAC x 6
CR/
PR R
TAC x 8
*excluding low risk (T2 + ER/PR pos. + cNO + G1/2 + > 35y.)
GEPAR-TRIO primary endpoint:
Pathologic complete response
Responders
(n = 1344)
%
P=0.27
P=0.08
P<0.0001
%
Non-responders
(n = 604)
P=0.73
P=0.17
40
40
7.6
9.7
20
20
21.0
23.6
6.8
0
0
TAC X 6
TAC X 8
Path CR
6.3
1.7
6.0
TAC X 6
TAC NX
In-breast PathCR, but N+
SABCS 2006 - abstract 42
GEPAR-TRIO 1º endpoint summary
• Changing treatment to so-called non-cross
resistant cytotoxic agents does not improve
outcomes for “chemotherapy nonresponsive” tumors.
• Dose-intensification (i.e. “adding more
drugs”) does not improve outcomes for
“chemotherapy non-responsive” tumors.
SABCS 2006 – abstract 42
GeparTrio Trial: Disease-free survival and
Overall Survival
 Median follow-up: 62 mos
HR for Response-Guided vs
Conventional Chemotherapy (95% CI)
P Value
DFS
0.71 (0.60-0.85)
< .001
OS
0.79 (0.63-0.99)
.048
Endpoint
 DFS benefit in early responding and nonresponding patients who
received response-guided vs conventional chemotherapy
Patient
Subgroup
Treatment
Comparison
HR for DFS
(95% CI)
P Value
Responders
TAC x 8 vs TAC x 6
0.78 (0.62-0.97)
.026
Nonresponders
TAC-NX vs TAC x 6
0.59 (0.49-0.82)
.001
Von Minckwitz G, et al. SABCS 2011. Abstract S3-2.
GeparTrio Trial: DFS by Patient Subgroup
HR (95% CI)
Subgroup
N patients
Overall
2012
Age (yrs)
<40
353
≥ 40
1659
cT-stage
cT1-3
1737
cT4
267
cT-size
< 40 mm
775
≥ 40 mm
1212
cN status
Negative
894
Positive
NR
Histological type
Ductal or other
1571
Lobular
270
Grade
1 or 2
1176
3
725
Hormone receptor status
Negative
717
Positive
1295
HER2 status
Negative
1145
Positive
486
Breast cancer phenotype
Luminal A
572
Luminal B (HER2-)
211
Luminal B (HER2+)
281
HER2+ (nonluminal)
178
Triple negative
362
Test for
Interaction
0.74 (0.60-0.85)
0.2
0.4
0.6
0.8
Response-guided treatments better
1.0
1.2
0.66 (0.42-1.03)
0.73 (0.60-0.88)
0.67
0.70 (0.56-0.85)
0.79 (0.54-1.17)
0.66
0.62 (0.44-0.85)
0.79 (0.63-0.98)
0.22
0.84 (0.61-1.14)
0.66 (0.53-0.82)
0.19
0.73 (0.60-0.88)
0.61 (0.37-1.03)
0.71
0.79 (0.61-1.01)
0.65 (0.49-0.85)
0.25
0.94 (0.73-1.22)
0.56 (0.44-0.73)
0.008
0.63 (0.49-0.81)
0.72 (0.51-1.04)
0.54
0.55 (0.37-0.82)
0.40 (0.20-0.79)
0.56 (0.33-0.96)
1.01 (0.61-1.67)
0.87 (0.61-1.25)
0.12-0.01
1.4
Conventional treatments better
Von Minckwitz G, et al. SABCS 2011. Abstract S3-2.
GeparTrio Trial: PathCR by Breast Cancer Subtype
40
35
pCR (%)
30
25
20
15
10
5
0
Luminal A
(n = 572)
Luminal B
(HER2 neg)
(n = 211)
Luminal B
(HER2 pos)
(n = 281)
HER2+
“Triple Negative”
(Nonluminal)
(n = 362)
(n = 178)
Von Minckwitz G, et al. SABCS 2011. Abstract S3-2.
GEPAR-TRIO DFS and OS summary
• Adapting neoadjuvant chemotherapy based on
early response improved DFS and OS vs.
conventional chemotherapy
• Response-guided chemotherapy appeared to be
more effective in patients with luminal A or
luminal B tumors
– Low PathCR rates in these tumors
– PathCR not prognostic
• No DFS benefit with response-guided
chemotherapy in patients with HER2-positive or
triple-negative tumors