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Title: An%20Interactive%20Webcast%20Featuring%20Discussion%20of%20Key%20Presentations%20and%20Posters%20from%20the%202011%20San%20Antonio%20Breast%20Cancer%20Symposium


1
An Interactive Webcast Featuring Discussion of
Key Presentations and Posters from the 2011 San
Antonio Breast Cancer Symposium
Thursday, January 12, 2012 730 PM - 900 PM ET
2
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
3
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.
4
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
5
Disclosures for Antonio C Wolff, MD
Paid Research Genentech BioOncology
6
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

7
Module 1 HER2-Positive Breast Cancer
8
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 2011Abstract S5-5. N
Engl J Med 2012366(2)109-19.
9
Pertuzumab and Trastuzumab Complementary
Mechanisms of Action
  • Pertuzumab
  • Inhibits ligand-dependent HER2 dimerization and
    signaling
  • Activates ADCC
  • Trastuzumab
  • Inhibits ligand-independent HER2 signaling
  • Activates ADCC
  • Prevents HER2 ECD shedding

HER1/3/4
Pertuzumab
Dimerization domain
HER2
Subdomain IV
Trastuzumab
ADCC, antibody-dependent cell-mediated
cytotoxicity ECD, extracellular domain
Adapted from Baselga J et al. SABCS 2011Abstract
S5-5.
10
CLEOPATRA Study Design
Centrally confirmed HER2-positive locally
recurrent, unresectable or metastatic BC 1
hormonal regimen for mBC (Neo)adjuvant systemic
rx, incl trastuzumab and/or taxane if DFS 12
mos Baseline LVEF 50 no CHF or LVEF lt 50
during or after trastuzumab
Docetaxel (gt6 cycles recommended)
N 406
Trastuzumab
Placebo
11
Docetaxel (gt6 cycles recommended)
N 402
Trastuzumab
Pertuzumab
Primary endpoint Independently assessed
progression-free survival
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)
Baselga J et al. SABCS 2011Abstract S5-5.
11
CLEOPATRA Efficacy Endpoints
Docetaxel, Trastuzumab,Pertuzumab (n 402) Docetaxel, Trastuzumab, Placebo (n 406) Hazard Ratio (95 CI) p-value
Median PFS (independently assessed) 18.5 mo 12.4 mo 0.62 (0.51-0.75) lt0.0001
Interim OS Not reported Not reported 0.64 (0.47-0.88) 0.005
Objective response rate 80.2 69.3 0.0011
Interim analysis of OS did not cross
OBrien-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 2011Abstract S5-5.
12
Prior Therapy for Breast Cancer
Docetaxel, Trastuzumab,Pertuzumab (n 402) Docetaxel, Trastuzumab, Placebo (n 406)
Prior (neo)adjuvant chemotherapy Yes No 45.8 54.2 47.3 52.7
Components of (neo)adjuvant therapy Anthracycline Taxane Trastuzumab Hormones 37.3 22.6 11.7 26.4 40.4 23.2 10.1 23.9
Baselga J et al. SABCS 2011Abstract S5-5.
13
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 lt 0.0001

Baselga J et al. SABCS 2011Abstract S5-5.
14
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
OBrien-Fleming stopping boundary therefore,
results are exploratory and nonsignificant
Baselga J et al. SABCS 2011Abstract S5-5.
15
Adverse Events
Docetaxel, Trastuzumab,Pertuzumab (n 402) Docetaxel, Trastuzumab, Placebo (n 406)
Cardiac Symptomatic LVSD (independent assessment) Fall in LVEF lt50 and by 10 from baseline 1.0 3.8 1.0 6.6
Grade 3 AEs Neutropenia Febrile neutropenia Leukopenia Diarrhea 48.9 13.8 12.3 7.9 45.8 7.6 14.6 5.0
Baselga J et al. SABCS 2011Abstract S5-5.
16
Adjuvant Pertuzumab and Herceptin IN Initial
TherapY in Breast Cancer APHINITY (BIG
4-11/BO25126/TOC4939g)
von Minckwitz G et al. SABCS 2011Abstract
OT1-02-04.
17
Phase II Trial of Adjuvant TC (Docetaxel/Cyclophos
phamide) plus Trastuzumab (HER TC) in HER2
Positive Early Stage Breast Cancer Patients
Jones S et al. SABCS 2011Abstract PD07-03.
18
Survival and Select Adverse Events (AEs)
Survival DFS DFS OS 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 lt 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 2011Abstract PD07-03.
19
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 2011Abstract S4-7.
20
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
R
Adjuvant chemo
Diagnosis
Placebo qd x 1 y
Median time since initial diagnosis 2.7 y
Primary endpoint Disease-free survival
Goss P et al. SABCS 2011Abstract S4-7.
21
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/PR- Central 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 2011Abstract S4-7.
22
Common Adverse Events Maximum NCI CTC Toxicity
Grades
Max Tox Grade, n () Lapatinib (Lap) (n 1,573) 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 (lt1)
1
6
5
18
19
Percentage of Patients ()
1
37
1
1
1
35
1
3
3
2
3
1
3
1
13
14
13
10
12
10
Lap
Plac
Lap
Plac
Lap
Plac
Lap
Plac
Diarrhea
Rash
Nausea
Fatigue
Goss P et al. SABCS 2011Abstract S4-7.
23
Phase II Study Evaluating Lapatinib in
Combination with nab-Paclitaxel in Women Who
Have Received 1 Chemotherapy Regimen for
HER2-Overexpressing Metastatic Breast Cancer
Yardley DA et al. SABCS 2011Abstract P1-12-10.
24
Efficacy Analysis and Adverse Events
Endpoint Lapatinib nab paclitaxel (n 60)
Overall response rate Complete response Partial response 53 7 47
Median progression-free survival 39.7 weeks
Serious Adverse Events Serious Adverse Events
Diarrhea 5
Anemia 3
Febrile neutropenia 3
Yardley DA et al. SABCS 2011Abstract P1-12-10.
25
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 2011Abstract S4-8.
26
Efficacy Endpoints
Endpoint Trastuzumab Docetaxel (n 208) Trastuzumab Docetaxel Bevacizumab (n 216) Hazard Ratio p-value
Median PFS Investigator assessed Independent review 13.7 mo 13.9 mo 16.5 mo 16.8 mo 0.82 0.72 0.0775 0.0162
Median OS (interim) Unstratified Stratified 38.3 mo 38.5 mo 1.01 0.94 0.9543 0.7078
Objective response rate Investigator assessed Independent review 69.9 65.9 74.3 76.5 0.3492 0.0265
Unstratified Stratified, censored for
nonprotocol therapy
Gianni L et al. SABCS 2011Abstract S4-8.
27
PFS According to Baseline Plasma VEGF-A
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) H DOC BEV better H DOC better
median 0.83 (0.50-1.36)
gt median 0.70 (0.43-1.14)
Estimated probability
0.2 0.5 1 2 5
HR
16.6 16.5
13.6
8.5
Time (months)
With permission from Gianni L et al. SABCS
2011Abstract S4-8.
28
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
29
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
4
Trastuzumab (T) alone
Paclitaxel/T
34
Nanoparticle albumin- bound (nab) paclitaxel/T
10
10
Lapatinib/capecitabine
31
Lapatinib/trastuzumab
Chemotherapy/trastuzumab/ bevacizumab
4
Other
7
0
5
10
15
20
25
30
35
30
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
31
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
32
Module 2 Multigene/Biomarker Assays
33
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 2011Abstract S4-6.
34
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 (lt39),
    intermediate (39-54), high (55)

Solin LJ et al. SABCS 2011Abstract S4-6.
35
10-Year IBE Outcomes with the New Oncotype DX
DCIS Score
Primary Endpoint Any IBE
Secondary Endpoint Invasive IBE
DCIS Score Group N 10-Year Risk
High 36 19.1
Intermediate 45 8.9
Low 246 5.1
DCIS Score Group N 10-Year Risk
High 36 27.3
Intermediate 45 24.5
Low 246 12.0
Log rank p 0.02
Log rank p 0.01
Solin LJ et al. SABCS 2011Abstract S4-6.
36
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 2011Abstract
OT1-03-01.
37
SWOG-S1007 (RxPONDER) Study Design
Chemotherapy appropriate endocrine therapy
HR-positive, HER2-negative, nodes 1-3 early
breast cancer with RS 25 (N 4,000)
11
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 2011Abstract
OT1-03-01.
38
Impact of the Recurrence Score on Adjuvant
Decision-Making in ER-Positive Early Breast
Cancer Results of a Large Prospective
Multicentre Decision Impact Study in Node
Negative and Node Positive Disease
Rezai M et al. SABCS 2011Abstract P2-12-26.
39
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 2011Abstract P2-12-26.
40
About how many patients, if any, do you have in
your practice with metastatic disease who had
DCIS as their original diagnosis?
41
About how many patients, if any, do you have in
your practice with metastatic disease who had
DCIS as their original diagnosis?
63
None
26
1
9
2
2
3-5
0
6-10
0
gt10
0
10
20
30
40
50
60
70
42
For how many patients with node-positive disease
in your practice have you ordered an Oncotype DX
assay?
43
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
3
gt10
0
5
10
15
20
25
30
35
44
Module 3 Advanced ER-Positive Breast Cancer
45
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 2011Abstract S1-1.
46
SWOG-S0226 Study Design
Anastrozole - 1 mg PO daily Treatment until
progression crossover to fulvestrant strongly
encouraged after progression
Postmenopausal, ER/PR-positive metastatic breast
cancer (N 690)
R
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 Fulvestrant 250 mg IM
(1x5mL) Day 28
Primary endpoint Progression-free survival
Subsequent cycles of 28 days
Treat until progression
Mehta RS et al. SABCS 2011Abstract S1-1.
47
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
2011Abstract S1-1.
48
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
2011Abstract S1-1.
49
SWOG-S0226 Study Design
Anastrozole - 1 mg PO daily Treatment until
progression crossover to fulvestrant strongly
encouraged after progression
Postmenopausal, ER/PR-positive metastatic breast
cancer (N 690)
R
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 Fulvestrant 250 mg IM
(1x5mL) Day 28
Primary endpoint Progression-free survival
Subsequent cycles of 28 days
Treat until progression
Mehta RS et al. SABCS 2011Abstract S1-1.
50
Everolimus for Postmenopausal Women with Advanced
Breast Cancer Updated Results of the BOLERO-2
Phase III Trial
Hortobagyi GN et al. SABCS 2011Abstract S3.7.
Baselga J et al. N Engl J Med 2011Epub ahead
of print.
51
Mechanism of Action of mTOR Inhibitors
Adapted from Atkins MB et al. Nat Rev Drug Discov
20098(7)535-6.
52
Crosstalk between ER and mTOR Signaling
Adapted from Di Cosimo S, Baselga J. Nat Rev Clin
Oncol 20107(3)139-47.
53
BOLERO-2 Study Design
Everolimus 10 mg daily Exemestane 25 mg
daily (n 485)
Postmenopausal, ER-positive locally advanced or
metastatic breast cancer Progression on letrozole
or anastrozole (n 724)
R
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 2011Abstract S3-7.
54
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 lt1 x 10-16

Hortobagyi GN et al. SABCS 2011Abstract S3-7.
55
Response and Clinical Benefit
Everolimus Exemestane Placebo Exemestane
50.5
P lt 0.0001
Percent
25.5
12.0
P lt 0.0001
1.3
Response
Clinical Benefit
Hortobagyi GN et al. SABCS 2011Abstract S3-7.
56
Common Adverse Events
Everolimus Exemestane (n 482) Everolimus Exemestane (n 482) Placebo Exemestane (n 238) Placebo Exemestane (n 238)
All Grades Grade 3/4 All Grades Grade 3/4
Stomatitis 59 8 11 lt1
Rash 39 1 6 0
Fatigue 36 lt5 27 1
Diarrhea 33 lt3 19 lt1
Decreased appetite 30 1 12 lt1
Nausea 29 lt2 28 1
Noninfectious pneumonitis 15 3 0 0
Hyperglycemia 14 lt6 2 lt1
Hortobagyi GN et al. SABCS 2011Abstract S3-7.
57
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)?
58
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)?
0
None
66
AI
Fulvestrant
4
21
AI/fulvestrant
4
AI/everolimus
2
AI/everolimus/fulvestrant
2
Chemotherapy
Other
1
0
10
20
30
40
50
60
70
59
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)?
60
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)?
13
Exemestane
23
Fulvestrant
24
Exemestane/fulvestrant
Exemestane/everolimus
35
0
Exemestane/everolimus/fulvestrant
4
Chemotherapy
Other
1
0
5
10
15
20
25
35
30
61
Module 4 HER2-Negative BRCA1/2 Mutant Breast
Cancer
62
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 2011Abstract P5-19-03.
63
Final Overall Efficacy Analysis
Endpoint Nab paclitaxel Nab paclitaxel Nab paclitaxel Docetaxel
Endpoint 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)
Overall response rate 46 63 74 39
Median progression-free 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
 Investigator-assessed endpoint. Overall p-value
among 4 treatment arms lt 0.001.  Investigator-ass
essed endpoint. Overall p-value among 4 treatment
arms 0.008.  Overall p-value among 4 treatment
arms 0.047.
Gradishar WJ et al. SABCS 2011Abstract P5-19-03.
64
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 2011Abstract OT3-01-05.
65
BRE09-146 Study Design
Stage I-III TNBC or BRCA1/2 mutant BC with
residual disease after anthracycline and/or
taxane neoadjuvant Rx (N 128)
Cisplatin 75 mg/m2 IV D1 q3wk x 4
R
(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 2011Abstract OT3-01-05.
66
Randomized, Double-Blind, Placebo-Controlled
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 2011Abstract
OT3-01-17.
67
NYC Consortium P8853 Study Design
Cyclophosphamide 50 mg PO daily placebo
ER- and/or PR-positive, HER2-negative mBC
progressing on 1 line of endocrine Rx and 2
lines of chemo (N 62)
R
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 2011Abstract
OT3-01-17.
68
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?
69
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
Other
13
0
5
10
15
20
25
30
70
When using nab paclitaxel, what dose and regimen
do you use?
71
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
72
In the next 5 years, how likely is it that PARP
inhibitors will become incorporated into the
management of breast cancer?
73
In the next 5 years, how likely is it that PARP
inhibitors will become incorporated into the
management of breast cancer?
74
Module 5 Bone-Targeted Therapy
75
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 2011Abstract S2-3.
76
NSABP-B-34 Study Design
Clodronate 1,600 mg/day x 3 years
Stratification Age (lt50 vs 50) Number of
positive nodes (0, 1-3, 4) ER/PR status (N
3,323)
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 2011Abstract S2-3.
77
Primary Endpoint DFS
Treatment Arm N Events
Placebo 1,656 312
Clodronate 1,655 286
HR 0.91 p 0.27 HR 0.91 p 0.27 HR 0.91 p 0.27
Paterson AHG et al. SABCS 2011Abstract S2-3.
78
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 2011Abstract S2-3.
79
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 2011Abstract S1-2.
80
ABCSG-12 Study Design
Tamoxifen (Tam)
Tamoxifen zoledronic acid (ZDA)
Premenopausal, Stage I and II ER/PR-positive
breast cancer (N 1,803)
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
Anastrozole zoledronic acid
Gnant M et al. SABCS 2011Abstract S1-2.
81
OS ZDA versus No ZDA
Univariate Univariate Multiple Cox Regression Multiple Cox Regression
No. of events Hazard ratio (95 CI) p-value Hazard ratio (95 CI) p-value
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) 0.033
Gnant M et al. SABCS 2011Abstract S1-2.
82
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 2011Abstract S1-3.
83
ZO-FAST Study Design
Treatment duration 5 years
Letrozole immediate zoledronic acid (IM-ZDA)
Postmenopausal Stage I, II and III ER/PR-positive
breast cancer T-score -2.0 (N 1,065)
  • Letrozole
  • delayed zoledronic acid (D-ZDA)
  • If 1 of the following occurs
  • BMD T-score lt -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 2011Abstract S1-3.
84
DFS Comparison ZO-FAST, AZURE and ABCSG-12
Trial n Hazard Ratio p-value
ZO-FAST Truly postmenopausala 888 0.71 0.0998
AZURE1 gt5 y postmenopausal 1,041 0.75 0.02
ABCSG-122 Rendered postmenopausal (overall population) 1,803 0.68 0.008
a Defined as naturally occurring menopause prior
to diagnosis. 1 Data from Coleman RE, et al. N
Engl J Med 2011365(15)1396-1405 2 Data from
Gnant M, et al. Lancet Oncol 201112(7)631-641.
de Boer R et al. SABCS 2011Abstract S1-3.
85
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 gt5-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
20113651396-1405.
de Boer R et al. SABCS 2011Abstract S1-3.
86
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?
87
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?
88
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?
89
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?
90
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