An Interactive Webcast Featuring
Discussion of Key Presentations and
Posters from the 2011 San Antonio Breast
Cancer Symposium
Thursday, January 12, 2012
7:30 PM - 9:00 PM ET
Hope S Rugo, MD
Professor of Medicine
Director, Breast Oncology and Clinical Trials Education
University of California, San Francisco
Helen Diller Family Comprehensive Cancer Center
San Francisco, California
Antonio C Wolff, MD
Professor of Oncology
Breast Cancer Program
The Johns Hopkins Kimmel Cancer Center
Baltimore, Maryland
Neil Love, MD
Research To Practice
Miami, Florida
Disclosures for Moderator Neil Love, MD
Dr Love is president and CEO of Research To Practice, which
receives funds in the form of educational grants to develop CME
activities from the following commercial interests: Abbott
Laboratories, Allos Therapeutics, Amgen Inc, ArQule Inc, Astellas,
Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals Inc,
Biodesix Inc, Biogen Idec, Boehringer Ingelheim Pharmaceuticals
Inc, Bristol-Myers Squibb Company, Celgene Corporation,
Cephalon Inc, Daiichi Sankyo Inc, Dendreon Corporation, Eisai Inc,
EMD Serono Inc, Genentech BioOncology, Genomic Health Inc,
ImClone Systems, a wholly owned subsidiary of Eli Lilly and
Company, Lilly USA LLC, Medivation Inc, Millennium: The Takeda
Oncology Company, Mundipharma International Limited, Novartis
Pharmaceuticals Corporation, Regeneron Pharmaceuticals, Sanofi,
Seattle Genetics and Teva Pharmaceuticals.
Disclosures for Hope S Rugo, MD
Paid Research
Genentech BioOncology,
GlaxoSmithKline, Novartis
Pharmaceuticals Corporation, Pfizer
Inc, Roche Laboratories Inc, Sanofi
Speakers Bureau
Genomic Health Inc
Disclosures for Antonio C Wolff, MD
Paid Research
Genentech BioOncology
Agenda
• Module 1: HER2-Positive Breast Cancer
– CLEOPATRA, TEACH, APHINITY, others
• Module 2: Multigene/Biomarker Assays
– Oncotype DX® in DCIS, RxPONDER study, PAM50,
VeriStrat®
• Module 3: Advanced ER-Positive Disease
– SWOG-S0226, BOLERO-2, others
• Module 4: HER2-Negative, BRCA1/2 Mutant
– PARP inhibitors
– Other chemotherapy ± biologics
• Module 5: Bone-Targeted Therapy
– NSABP-B-34, ABCSG-12 update, denosumab, others
Module 1: HER2-Positive
Breast Cancer
A Phase III, Randomized, Double-Blind,
Placebo-Controlled Registration Trial to
Evaluate the Efficacy and Safety of
Placebo + Trastuzumab + Docetaxel vs
Pertuzumab + Trastuzumab + Docetaxel
in Patients with Previously Untreated
HER2-Positive Metastatic Breast Cancer
(CLEOPATRA)
Baselga J et al.
SABCS 2011;Abstract S5-5.
N Engl J Med 2012;366(2):109-19.
Pertuzumab and Trastuzumab:
Complementary Mechanisms of Action
Pertuzumab:
• Inhibits ligand-dependent
HER2 dimerization and
signaling
• Activates ADCC
HER1/3/4
Pertuzumab
Dimerization
domain
HER2
Subdomain IV
Trastuzumab:
• Inhibits ligand-independent
HER2 signaling
• Activates ADCC
• Prevents HER2 ECD
shedding
Trastuzumab
ADCC, antibody-dependent cell-mediated cytotoxicity; ECD, extracellular domain
Adapted from Baselga J et al. SABCS 2011;Abstract S5-5.
CLEOPATRA Study Design
Centrally confirmed HER2positive locally recurrent,
unresectable or metastatic BC
Docetaxel (>6 cycles recommended)
N = 406
≤1 hormonal regimen for mBC
(Neo)adjuvant systemic rx,
incl trastuzumab and/or
taxane if DFS ≥12 mos
Trastuzumab
Placebo
R
Baseline LVEF ≥ 50%; no
CHF or LVEF < 50% during or
after trastuzumab
1:1
Docetaxel (>6 cycles recommended)
N = 402 Trastuzumab
Pertuzumab
Primary endpoint: Independently
assessed progression-free survival
Baselga J et al. SABCS 2011;Abstract S5-5.
Study dosing q3wk:
Trastuzumab: 8 mg/kg loading, 6 mg/kg maint
Pertuzumab: 840 mg loading, 420 mg maint
Docetaxel: 75 mg/m2 (escalating to 100 mg/m2)
CLEOPATRA: Efficacy Endpoints
Median PFS
(independently
assessed)
Interim OS*
Objective
response rate**
Docetaxel,
Trastuzumab,
Pertuzumab
(n = 402)
Docetaxel,
Trastuzumab,
Placebo
(n = 406)
18.5 mo
12.4 mo
0.62
(0.51-0.75)
<0.0001
Not reported
Not reported
0.64
(0.47-0.88)
0.005
80.2%
69.3%
—
0.0011
Hazard
Ratio
(95% CI)
p-value
* Interim analysis of OS did not cross O’Brien-Fleming stopping boundary; therefore, results
are exploratory and nonsignificant (n = 165 OS events, 19.3 mo follow-up).
** Response evaluation prespecified to occur after OS; therefore, results are exploratory.
Baselga J et al. SABCS 2011;Abstract S5-5.
Prior Therapy for Breast Cancer
Prior (neo)adjuvant chemotherapy
Yes
No
Components of (neo)adjuvant therapy
Anthracycline
Taxane
Trastuzumab
Hormones
Baselga J et al. SABCS 2011;Abstract S5-5.
Docetaxel,
Trastuzumab,
Pertuzumab
(n = 402)
Docetaxel,
Trastuzumab,
Placebo
(n = 406)
45.8%
54.2%
47.3%
52.7%
37.3%
22.6%
11.7%
26.4%
40.4%
23.2%
10.1%
23.9%
Primary Endpoint: Independently
Assessed PFS (n = 433 PFS events)
• Median PFS, pertuzumab + trastuzumab + docetaxel:
18.5 mos
• Median PFS, placebo + trastuzumab + docetaxel:
12.4 mos
• Hazard ratio = 0.62
• p < 0.0001
Baselga J et al. SABCS 2011;Abstract S5-5.
Overall Survival: Predefined Interim
Analysis (Median Follow-Up:
19.3 Months, n = 165 OS Events)
• Pertuzumab + trastuzumab + docetaxel, 69 events
• Placebo + trastuzumab + docetaxel, 96 events
• Hazard ratio = 0.64
• p = 0.005
Interim analysis of OS did not cross O’Brien-Fleming stopping
boundary; therefore, results are exploratory and nonsignificant
Baselga J et al. SABCS 2011;Abstract S5-5.
Adverse Events
Cardiac
Symptomatic LVSD (independent
assessment)*
Fall in LVEF <50% and by ≥10%
from baseline
≥Grade 3 AEs
Neutropenia
Febrile neutropenia
Leukopenia
Diarrhea
Baselga J et al. SABCS 2011;Abstract S5-5.
Docetaxel,
Trastuzumab,
Pertuzumab
(n = 402)
Docetaxel,
Trastuzumab,
Placebo
(n = 406)
1.0%
1.0%
3.8%
6.6%
48.9%
13.8%
12.3%
7.9%
45.8%
7.6%
14.6%
5.0%
Adjuvant Pertuzumab and
Herceptin IN Initial TherapY in
Breast Cancer: APHINITY
(BIG 4-11/BO25126/TOC4939g)
von Minckwitz G et al.
SABCS 2011;Abstract OT1-02-04.
Phase II Trial of Adjuvant TC
(Docetaxel/Cyclophosphamide) plus
Trastuzumab (HER TC) in HER2
Positive Early Stage Breast Cancer
Patients
Jones S et al.
SABCS 2011;Abstract PD07-03.
Survival and Select Adverse Events (AEs)
DFS
OS
Survival
2-year
3-year
2-year
3-year
Overall safety population (n = 486)
97.8%
96.3%
99.4%
98.5%
Pts with node-positive ESBC (n = 101)
96.9%
91.9%
100%
96.5%
Pts with node-negative ESBC (n = 385)
98.1%
97.7%
99.2%
99.2%
Pts with node-negative tumor < 1.0 cm (n = 94)
100%
100%
100%
100%
AEs (n = 486)
All Grades
Grade 3/4
Neutropenia
51.4%
47.1%
Febrile neutropenia
7.0%
6.2%
Anemia
27.0%
1.0%
Thrombocytopenia
3.3%
0.2%
Fatigue
58.4%
4.3%
Diarrhea
38.3%
3.3%
Cardiac dysfunction
6.0%
0.4%
DFS, disease-free survival; OS, overall survival; ESBC, early-stage breast cancer
Jones S et al. SABCS 2011;Abstract PD07-03.
Results of the TEACH Trial.
Lapatinib in Women with
Early-Stage HER2-Overexpressing
Breast Cancer: A Double-Blind,
Placebo-Controlled, Phase III Trial
Goss P et al.
SABCS 2011;Abstract S4-7.
TEACH Study Design
Eligibility:
Stage I-IIIC HER2+ local ICH3+ or FISH+
No prior trastuzumab
Neo(adjuvant) CMF, anthracycline or taxane
Appropriate endocrine therapy
N = 3,147 from 33 countries
Lapatinib 1500 mg qd x 1 y
Diagnosis
Adjuvant
chemo
R
Placebo qd x 1 y
Median time since
initial diagnosis: 2.7 y
Primary endpoint: Disease-free survival
Goss P et al. SABCS 2011;Abstract S4-7.
Survival Analysis: ITT and Centrally
Confirmed FISH+ (Median F/U: 4 Years)
Endpoint
Hazard ratio
p-value
Disease-free survival
ITT (N = 3,147)
ER/PR+
ER/PRCentral HER2 (N = 2,490)
0.83
0.98
0.68
0.82
0.053
0.886
0.006
0.04
Overall survival
ITT
0.99
0.966
Goss P et al. SABCS 2011;Abstract S4-7.
Common Adverse Events: Maximum
NCI CTC Toxicity Grades
Percentage of Patients (%)
Max Tox
Grade, n (%)
1
6
5
18
37
Placebo (Plac)
(n = 1,574)
Grade 1
414 (26)
558 (35)
Grade 2
674 (43)
505 (32)
Grade 3
333 (21)
104 (7)
Grade 4
21 (1)
15 (<1)
19
1
3
Plac
1
2
1
13
Plac
35
13
Lap
Lapatinib (Lap)
(n = 1,573)
Lap
Diarrhea
Goss P et al. SABCS 2011;Abstract S4-7.
Rash
3
1
3
1
3
14
1
1
10
12
10
Lap
Plac
Lap
Plac
Nausea
Fatigue
Phase II Study Evaluating Lapatinib in
Combination with nab®-Paclitaxel in
Women Who Have Received ≤1
Chemotherapy Regimen for HER2Overexpressing Metastatic Breast
Cancer
Yardley DA et al.
SABCS 2011;Abstract P1-12-10.
Efficacy Analysis and Adverse Events
Endpoint
Overall response rate
Complete response
Partial response
Median progression-free survival
Lapatinib + nab paclitaxel
(n = 60)
53%
7%
47%
39.7 weeks
Serious Adverse Events
Diarrhea
5%
Anemia
3%
Febrile neutropenia
3%
Yardley DA et al. SABCS 2011;Abstract P1-12-10.
AVEREL, A Randomized Phase III Trial
to Evaluate Bevacizumab in
Combination with Trastuzumab +
Docetaxel as First-Line Therapy for
HER2-Positive Locally Recurrent/
Metastatic Breast Cancer
Gianni L et al.
SABCS 2011;Abstract S4-8.
Efficacy Endpoints
Endpoint
Median PFS
Investigator assessed*
Independent review**
Median OS (interim)
Unstratified
Stratified
Trastuzumab +
Docetaxel
(n = 208)
Trastuzumab
+ Docetaxel
+ Bevacizumab
(n = 216)
Hazard
Ratio
p-value
13.7 mo
13.9 mo
16.5 mo
16.8 mo
0.82
0.72
0.0775
0.0162
38.3 mo
38.5 mo
1.01
0.94
0.9543
0.7078
—
—
0.3492
0.0265
Objective response rate
Investigator assessed
Independent review
69.9%
65.9%
* Unstratified
** Stratified, censored for nonprotocol therapy
Gianni L et al. SABCS 2011;Abstract S4-8.
74.3%
76.5%
PFS According to Baseline
Plasma VEGF-A
Estimated probability
H + DOC low VEGF-A (n = 45)
H + DOC high VEGF-A (n = 37)
H + DOC + BEV low VEGF-A (n = 36)
H + DOC + BEV high VEGF-A (n = 43)
Plasma
VEGF-A
HR (95% CI)
≤ median
0.83 (0.50-1.36)
> median
0.70 (0.43-1.14)
H + DOC +
BEV better
0.2
0.5
H + DOC
better
1
HR
8.5
13.6
16.6
16.5
Time (months)
With permission from Gianni L et al. SABCS 2011;Abstract S4-8.
2
5
A 42-year-old premenopausal woman
presents 1 year after completing adjuvant
TCH for ER-negative, HER2-positive IDC with
asymptomatic lung mets. Your likely
recommendation:
A 42-year-old premenopausal woman presents 1 year
after completing adjuvant TCH for an ER-negative,
HER2-positive IDC with asymptomatic lung mets.
Your likely recommendation:
Trastuzumab (T) alone
4%
Paclitaxel/T
34%
Nanoparticle albuminbound (nab) paclitaxel/T
10%
Lapatinib/capecitabine
10%
Lapatinib/trastuzumab
Chemotherapy/trastuzumab/
bevacizumab
Other
31%
4%
7%
0% 5% 10% 15% 20% 25% 30% 35%
A 42-year-old premenopausal woman with an
ER-positive, HER2-positive tumor presents
1 year after completing adjuvant TCH, on
tamoxifen with asymptomatic lung mets.
Your likely recommendation:
A 42-year-old premenopausal woman with an
ER-positive, HER2-positive tumor presents 1 year
after completing adjuvant TCH, on tamoxifen with
asymptomatic lung mets. Your likely recommendation:
Endocrine treatment (E)
6%
E/anti-HER2 treatment
63%
E/anti-HER2
treatment/chemotherapy
12%
Chemotherapy/antiHER2 treatment
Other
14%
5%
0%
10%
20%
30%
40%
50%
60%
70%
Module 2: Multigene/Biomarker
Assays
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 et al.
SABCS 2011;Abstract S4-6.
Methods for DCIS Score
Validation Study
Patients with DCIS from ECOG-E5194 (n = 670)
• Treated with surgical excision (≥3-mm negative margins) without irradiation
• Some received tamoxifen (n = 96)
• DCIS grade: low/intermediate ≤2.5 cm or high ≤1 cm
Oncotype DX assay by RT-PCR on formalin-fixed, paraffin-embedded tumors
(n = 327)
Calculated: DCIS score, Recurrence Score®
• DCIS score based on an optimized gene expression algorithm
• DCIS score calculated in 2 ways:
• Continuous variable
• 3 prespecified risk groups: low (<39), intermediate (39-54), high (≥55)
Solin LJ et al. SABCS 2011;Abstract S4-6.
10-Year IBE Outcomes with the New
Oncotype DX DCIS Score
Primary Endpoint:
Any IBE
DCIS Score
Group
Secondary Endpoint:
Invasive IBE
N
10-Year
Risk
High
36
19.1%
24.5%
Intermediate
45
8.9%
12.0%
Low
246
5.1%
N
10-Year
Risk
High
36
27.3%
Intermediate
45
Low
246
Log rank p = 0.02
Solin LJ et al. SABCS 2011;Abstract S4-6.
DCIS Score
Group
Log rank p = 0.01
SWOG S1007: A Phase III,
Randomized Clinical Trial of Standard
Adjuvant Endocrine Therapy +/Chemotherapy in Patients with 1-3
Positive Nodes, Hormone Receptor
(HR)-Positive and HER2-Negative
Breast Cancer with Recurrence Score
(RS) of 25 or Less
Gonzalez-Angulo AM et al.
SABCS 2011;Abstract OT1-03-01.
SWOG-S1007 (RxPONDER)
Study Design
HR-positive, HER2negative, nodes
1-3+ early breast
cancer with RS ≤ 25
(N = 4,000)
Chemotherapy*;
appropriate endocrine therapy**
1:1
R
No chemotherapy*;
appropriate endocrine therapy**
* Various 2nd- or 3rd-generation regimens (physician/patient choice)
** Various options, dependent on menopausal status (physician/patient choice)
Primary Objective
Determine the effect of chemo in patients with node-positive BC who do not
have high RS by Oncotype DX
1. DFS for patients treated with chemo compared to no chemo and
dependence on the magnitude of RS
2. Determine the optimal cut-point for recommending chemo or not
Gonzalez-Angulo AM et al. SABCS 2011;Abstract OT1-03-01.
Impact of the Recurrence Score on
Adjuvant Decision-Making in ERPositive Early Breast Cancer —
Results of a Large Prospective
Multicentre Decision Impact Study
in Node Negative and Node
Positive Disease
Rezai M et al.
SABCS 2011;Abstract P2-12-26.
Summary
• 366 evaluable German patients with N0 and N+
(1-3 positive nodes) early breast cancer and no
contraindication to chemo.
• Physician recommendations assessed before and after
Oncotype DX assay.
• Initial treatment recommendation changed in 33.1% of all
cases:
– 30.3% in N0 disease
– 38.5% in N+ disease
• Treatment recommendations predominantly changed from
chemoendocrine therapy to endocrine therapy alone:
– 18.4% in N0 disease
– 27.9% in N+ disease
Rezai M et al. SABCS 2011;Abstract P2-12-26.
About how many patients, if any, do you have
in your practice with metastatic disease who
had DCIS as their original diagnosis?
About how many patients, if any, do you have in your
practice with metastatic disease who had DCIS as their
original diagnosis?
None
63%
26%
1
2
3-5
9%
2%
6-10 0%
>10 0%
0%
10%
20%
30%
40%
50%
60%
70%
For how many patients with node-positive
disease in your practice have you ordered
an Oncotype DX assay?
For how many patients with node-positive disease in
your practice have you ordered an Oncotype DX assay?
33%
None
11%
1
16%
2
27%
3-5
10%
6-10
>10
0%
3%
5%
10%
15%
20%
25%
30%
35%
Module 3: Advanced ER-Positive
Breast Cancer
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 et al.
SABCS 2011;Abstract S1-1.
SWOG-S0226 Study Design
Postmenopausal,
ER/PR-positive
metastatic breast
cancer
(N = 690)
Anastrozole - 1 mg PO daily
Treatment until progression; crossover
to fulvestrant strongly encouraged
after progression
R
Primary endpoint:
Progression-free survival
Anastrozole – 1 mg PO daily
First cycle of 28 days:
Fulvestrant – 500 mg IM (2x5mL) Day 1
Fulvestrant – 250 mg IM (1x5mL) Day 14
Fulvestrant – 250 mg IM (1x5mL) Day 28
Subsequent cycles of 28 days:
Fulvestrant – 250 mg IM (1x5mL) Day 28
Treat until progression
Mehta RS et al. SABCS 2011;Abstract S1-1.
Primary Endpoint:
Progression-Free Survival
Anastrozole + Fulvestrant (268 events)
Anastrozole (297 events)
Stratified log-rank p = 0.0070
Median PFS
Anastrozole 13.5 mos (95% CI 12.1-15.1)
Combination 15.0 mos (95% CI 13.2-18.4)
HR = 0.80 (95% CI 0.68-0.94)
With permission from Mehta RS et al. SABCS 2011;Abstract S1-1.
Secondary Endpoint:
Overall Survival
Median OS
Anastrozole 41.3 mos (95% CI 37.2-45.0)
Combination 47.7 mos (95% CI 43.4-55.7)
HR = 0.81 (95% CI 0.65-1.00)
Anastrozole + Fulvestrant (154 deaths)
Anastrozole (176 events)
Stratified log-rank p = 0.049
With permission from Mehta RS et al. SABCS 2011;Abstract S1-1.
SWOG-S0226 Study Design
Postmenopausal,
ER/PR-positive
metastatic breast
cancer
(N = 690)
Anastrozole - 1 mg PO daily
Treatment until progression; crossover
to fulvestrant strongly encouraged
after progression
R
Primary endpoint:
Progression-free survival
Anastrozole – 1 mg PO daily
First cycle of 28 days:
Fulvestrant – 500 mg IM (2x5mL) Day 1
Fulvestrant – 250 mg IM (1x5mL) Day 14
Fulvestrant – 250 mg IM (1x5mL) Day 28
Subsequent cycles of 28 days:
Fulvestrant – 250 mg IM (1x5mL) Day 28
Treat until progression
Mehta RS et al. SABCS 2011;Abstract S1-1.
Everolimus for Postmenopausal
Women with Advanced Breast
Cancer: Updated Results of the
BOLERO-2 Phase III Trial
Hortobagyi GN et al.
SABCS 2011;Abstract S3.7.
Baselga J et al.
N Engl J Med 2011;[Epub ahead of print].
Mechanism of Action of mTOR Inhibitors
Adapted from Atkins MB et al. Nat Rev Drug Discov 2009;8(7):535-6.
Crosstalk between ER and mTOR
Signaling
Adapted from Di Cosimo S, Baselga J. Nat Rev Clin Oncol 2010;7(3):139-47.
BOLERO-2 Study Design
Postmenopausal,
ER-positive locally
advanced or
metastatic breast
cancer
Progression on
letrozole or
anastrozole
(n = 724)
Everolimus – 10 mg daily
+
Exemestane – 25 mg daily
R
(n = 485)
Placebo
+
Exemestane – 25 mg daily
(n = 239)
Stratification: Sensitivity to prior hormonal therapy and presence of visceral metastases
Endpoints:
• Primary: Progression-free survival (PFS) by local assessment
• Secondary: Overall survival, overall response rate, quality of life,
safety, bone markers, pharmacokinetics
Hortobagyi GN et al. SABCS 2011;Abstract S3-7.
Primary Endpoint: PFS by Local
Assessment
• Median PFS, everolimus plus exemestane: 7.4 mos
• Median PFS, placebo plus exemestane: 3.2 mos
• Hazard ratio = 0.44
• p-value <1 x 10-16
Hortobagyi GN et al. SABCS 2011;Abstract S3-7.
Response and Clinical Benefit
Everolimus + Exemestane
Placebo + Exemestane
50.5%
Percent
P < 0.0001
25.5%
12.0%
P < 0.0001
1.3%
Response
Hortobagyi GN et al. SABCS 2011;Abstract S3-7.
Clinical Benefit
Common Adverse Events
Everolimus +
Exemestane
(n = 482)
All Grades Grade 3/4
Placebo +
Exemestane
(n = 238)
All Grades
Grade 3/4
Stomatitis
59%
8%
11%
<1%
Rash
39%
1%
6%
0
Fatigue
36%
<5%
27%
1%
Diarrhea
33%
<3%
19%
<1%
Decreased appetite
30%
1%
12%
<1%
Nausea
29%
<2%
28%
1%
Noninfectious
pneumonitis
15%
3%
0
0
Hyperglycemia
14%
<6%
2%
<1%
Hortobagyi GN et al. SABCS 2011;Abstract S3-7.
A 64-year-old woman has a 2-cm ER-positive,
HER2-negative primary breast cancer and
asymptomatic bone and nodal mets. What
systemic treatment would you recommend
(cost and reimbursement aside)?
A 64-year-old woman has a 2-cm ER-positive,
HER2-negative primary breast cancer and asymptomatic
bone and nodal mets. What systemic treatment would you
recommend (cost and reimbursement aside)?
None 0%
AI
66%
Fulvestrant
4%
21%
AI/fulvestrant
AI/everolimus
4%
AI/everolimus/fulvestrant
2%
Chemotherapy
2%
Other
1%
0%
10%
20%
30%
40%
50%
60% 70%
A 64-year-old woman has ER-positive,
HER2-negative asymptomatic bone and
nodal mets during year 4 of adjuvant
anastrozole. What would you recommend
(cost and reimbursement aside)?
A 64-year-old woman has ER-positive, HER2-negative
asymptomatic bone and nodal mets during year 4 of
adjuvant anastrozole. What would you recommend
(cost and reimbursement aside)?
Exemestane
13%
Fulvestrant
23%
Exemestane/fulvestrant
24%
Exemestane/everolimus
Exemestane/everolimus/fulvestrant
Chemotherapy
Other
35%
0%
4%
1%
0% 5% 10% 15% 20% 25% 30% 35%
Module 4: HER2-Negative; BRCA1/2
Mutant Breast Cancer
Nab-Paclitaxel Versus
Docetaxel for the First-Line
Treatment of Metastatic Breast
Cancer: Overall Survival and
Safety Analysis of a
Randomized Phase 2 Trial
Gradishar WJ et al.
SABCS 2011;Abstract P5-19-03.
Final Overall Efficacy Analysis
Nab paclitaxel
Docetaxel
300 mg/m2
q3w
(n = 76)
100 mg/m2
qw3/4
(n = 76)
150 mg/m2
qw3/4
(n = 74)
100 mg/m2
q3w
(n = 74)
46%
63%
74%
39%
Median progressionfree survival†
10.9 mo
7.5 mo
14.6 mo
7.8 mo
Median overall
survival‡
27.7 mo
22.2 mo
33.8 mo
26.6 mo
Endpoint
Overall response
rate*
* Investigator-assessed endpoint. Overall p-value among 4 treatment arms < 0.001.
† Investigator-assessed endpoint. Overall p-value among 4 treatment arms = 0.008.
‡ Overall p-value among 4 treatment arms = 0.047.
Gradishar WJ et al. SABCS 2011;Abstract P5-19-03.
PARP Inhibition After
Preoperative Chemotherapy in
Patients with Triple-Negative
Breast Cancer (TNBC) or Known
BRCA1/2 Mutations: Hoosier
Oncology Group BRE09-146
Miller KD et al.
SABCS 2011;Abstract OT3-01-05.
BRE09-146 Study Design
Stage I-III TNBC or
BRCA1/2 mutant
BC with residual
R
disease after
anthracycline
and/or taxane
neoadjuvant Rx
(N = 128)
Cisplatin 75 mg/m2 IV D1 q3wk x 4
(Cisplatin 75 mg/m2 IV D1 q3wk +
rucaparib 24 mg* IV D1,2,3 q3wk) x 4
*(30 mg IV cycles 2-4)
Rucaparib
100 mg PO
x 24 wk
Rucaparib is a potent IV and oral inhibitor of
PARP1 and PARP2
Primary Objective: 2-year DFS
Secondary Objectives: Safety and tolerability, 1-year DFS, 5-year OS,
pharmacokinetics, correlatives of benefit from DNA damaging chemo and
PARP inhibition
Miller KD et al. SABCS 2011;Abstract OT3-01-05.
Randomized, Double-Blind, PlaceboControlled Phase II Trial of Low-Dose
Metronomic Cyclophosphamide Alone
or in Combination with Veliparib
(ABT-888) in Chemotherapy-Resistant
ER and/or PR-Positive, HER2/neu-Negative
Metastatic Breast Cancer: New York
Cancer Consortium Trial P8853
Andreopoulou E et al.
SABCS 2011;Abstract OT3-01-17.
NYC Consortium P8853 Study Design
ER- and/or PRpositive, HER2negative mBC
R
progressing on ≥1
line of endocrine Rx
and 2 lines of
chemo (N = 62)
Cyclophosphamide 50 mg
PO daily + placebo
Cyclophosphamide 50 mg PO daily
+ veliparib 60 mg PO daily
Primary Objective: PFS
Secondary Objectives: ORR, clinical benefit rate, OS
Andreopoulou E et al. SABCS 2011;Abstract OT3-01-17.
A 55-year-old woman with a node-negative,
triple-negative IDC receives adjuvant
docetaxel/cyclophosphamide (TC) but then
develops asymptomatic bone and nodal mets
18 months later. What is your preferred
treatment?
A 55-year-old woman with a node-negative, triple-negative
IDC receives adjuvant docetaxel/cyclophosphamide (TC)
but then develops asymptomatic bone and nodal mets 18
months later. What is your preferred treatment?
28%
Paclitaxel
21%
Paclitaxel/bevacizumab
22%
Nab paclitaxel
Nab paclitaxel/bevacizumab
6%
Platinum/paclitaxel/bevacizumab
6%
Platinum/nab
paclitaxel/bevacizumab
4%
13%
Other
0%
5%
10%
15%
20%
25%
30%
When using nab paclitaxel, what dose and
regimen do you use?
When using nab paclitaxel, what dose and regimen
do you use?
300 mg/m2
q3wk
3%
100 mg/m2
qwkly 3/4
80%
150 mg/m2
qwkly 3/4
17%
0%
10%
20%
30%
40%
50%
60%
70%
80%
In the next 5 years, how likely is it that PARP
inhibitors will become incorporated into the
management of breast cancer?
In the next 5 years, how likely is it that PARP
inhibitors will become incorporated into the
management of breast cancer?
Very likely
28%
Somewhat likely
44%
25%
Somewhat unlikely
Very unlikely
0%
3%
10%
20%
30%
40%
50%
Module 5: Bone-Targeted Therapy
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 et al.
SABCS 2011;Abstract S2-3.
NSABP-B-34 Study Design
Stratification:
Age (<50 vs ≥50)
Number of positive
nodes (0, 1-3, 4+)
ER/PR status
(N = 3,323)
Clodronate
1,600 mg/day x 3 years
R
Placebo* x 3 years
* Alone or in addition to adjuvant chemotherapy or hormone therapy at the discretion of the
investigator
Key Endpoints:
Primary: Disease-free survival (DFS)
Secondary: Incidence of skeletal metastases, overall survival, relapse-free survival,
incidence of nonskeletal metastases and incidence of skeletal morbid events
Paterson AHG et al. SABCS 2011;Abstract S2-3.
Primary Endpoint: DFS
Treatment Arm
N
Events
Placebo
1,656
312
Clodronate
1,655
286
HR = 0.91 p = 0.27
Paterson AHG et al. SABCS 2011;Abstract S2-3.
Secondary Endpoints — Post-Hoc
Analysis: Benefits Observed in
Patients ≥50
Hazard Ratio
p-value
Relapse-free interval
0.76
0.05
Bone metastasis-free interval
0.61
0.024
Nonbone metastasis-free interval
0.63
0.015
Overall survival
0.80
0.10
Paterson AHG et al. SABCS 2011;Abstract S2-3.
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 et al.
SABCS 2011;Abstract S1-2.
ABCSG-12 Study Design
Tamoxifen (Tam)
Premenopausal,
Stage I and II
ER/PR-positive
breast cancer
(N = 1,803)
Tamoxifen +
zoledronic acid (ZDA)
Surgery
(+RT)
Goserelin
R
Anastrozole (A)
Primary endpoint: Disease-free survival
Study dosing:
Tamoxifen: 20 mg/day
Zoledronic acid: 4 mg q6m
Anastrozole: 1 mg/day
Goserelin: 3.6 mg q28d
Gnant M et al. SABCS 2011;Abstract S1-2.
Anastrozole +
zoledronic acid
OS: ZDA versus No ZDA
Univariate
Multiple Cox Regression
No. of
events
Hazard ratio
(95% CI)
p-value
Hazard ratio
(95% CI)
No ZDA
49/903
vs No ZDA
(Mantel-Cox)
vs No ZDA
ZDA
33/900
0.63
(0.40-0.99)
0.049
0.61
(0.39-0.96)
Gnant M et al. SABCS 2011;Abstract S1-2.
p-value
0.033
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 et al.
SABCS 2011;Abstract S1-3.
ZO-FAST Study Design
Treatment duration = 5 years
Postmenopausal Stage I,
II and III ER/PR-positive
breast cancer
T-score ≥ -2.0
(N = 1,065)
Letrozole +
immediate zoledronic acid (IM-ZDA)
R
Letrozole +
delayed zoledronic acid (D-ZDA)
If 1 of the following occurs:
• BMD T-score < -2.0
• Clinical fracture
• Asymptomatic fracture at 36 months
Key Endpoints:
Primary: Bone mineral density (BMD) at 12 months
Secondary: BMD at 36 and 60 months, disease recurrence, fractures, safety
de Boer R et al. SABCS 2011;Abstract S1-3.
DFS Comparison: ZO-FAST, AZURE and
ABCSG-12
Trial
n
Hazard Ratio
p-value
888
0.71
0.0998
AZURE1
>5 y postmenopausal
1,041
0.75
0.02
ABCSG-122
Rendered
postmenopausal
(overall population)
1,803
0.68
0.008
ZO-FAST
Truly postmenopausala
a
Defined as naturally occurring menopause prior to diagnosis.
1 Data
from Coleman RE, et al. N Engl J Med 2011;365(15):1396-1405; 2 Data from Gnant M, et al. Lancet Oncol
2011;12(7):631-641.
de Boer R et al. SABCS 2011;Abstract S1-3.
Osteonecrosis of the Jaw (ONJ)
• ZO-FAST (N = 1,065; 5-year follow-up)
– 3 confirmed cases (0.56%)a
• Other adjuvant ZDA trials
– Z-FAST (N = 601; 5-year follow-up)1
• No confirmed cases
– E-ZO-FAST (N = 527; 3-year follow-up)2
• 1 confirmed case (0.19%)
– ABCSG-12 (N = 1,803; >5-year follow-up)3
• No confirmed cases
– AZURE (N = 3,360; 5-year follow-up)4
• 17 confirmed cases (1.1%)
a
A total of 9 potential ONJ events from 7 patients were reported and independently adjudicated by an external
panel; 3 were confirmed, 2 had insufficient data, the remaining events were excluded.
1 Brufsky
A, et al. SABCS 2009. Abstract 4083. 2 Llombart A, et al. ASCO-BC 2009. Abstract 213. 3 Gnant M, et al.
ASCO 2011. Abstract 520. 4 Coleman RE, et al. N Engl J Med 2011;365:1396-1405.
de Boer R et al. SABCS 2011;Abstract S1-3.
A 42-year-old premenopausal woman has a
node-negative, ER-positive, HER2-negative
IDC with a low Recurrence Score (RS). The
patient is receiving tamoxifen and has normal
bone density. Would you add a
bisphosphonate?
A 42-year-old premenopausal woman has a node-negative,
ER-positive, HER2-negative IDC with a low Recurrence
Score (RS). The patient is receiving tamoxifen and has
normal bone density. Would you add a bisphosphonate?
No
Yes
Likely
Possibly
0%
84%
2%
9%
5%
10%
20%
30%
40%
50%
60%
70%
80%
90%
A 62-year-old woman has a node-negative,
ER-positive, HER2-negative IDC with a low
RS. The patient is receiving an AI and has
normal bone density. Would you add a
bisphosphonate?
A 62-year-old woman has a node-negative,
ER-positive, HER2-negative IDC with a low RS. The
patient is receiving an AI and has normal bone density.
Would you add a bisphosphonate?
No
72%
Yes
Likely
Possibly
0%
11%
7%
10%
10%
20%
30%
40%
50%
60%
70%
80%