Part VI – Triple-Negative Breast Cancer:
Current Clinical Management
Tuesday, July 19, 2011
7:30 PM - 8:30 PM ET
Neil Love, MD
Research To Practice
Miami, Florida
Harold J Burstein, MD, PhD
Associate Professor of Medicine, Harvard Medical School
Breast Oncology Center
Dana-Farber Cancer Institute
Boston, Massachusetts
Charles E Geyer Jr, MD
Director of Medical Affairs
National Surgical Adjuvant Breast and Bowel Project
Vice-Chair, Department of Human Oncology
Allegheny General Hospital
Pittsburgh, Pennsylvania
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: Allos
Therapeutics, Amgen Inc, Astellas Pharma Global Development
Inc, AstraZeneca Pharmaceuticals LP, Aureon Laboratories Inc,
Bayer HealthCare Pharmaceuticals/Onyx Pharmaceuticals 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, Millennium: The Takeda Oncology Company,
Mundipharma International Limited, Myriad Genetics Inc, Novartis
Pharmaceuticals Corporation, OSI Oncology, Sanofi and Seattle
Genetics.
Disclosures for Harold J Burstein, MD, PhD
No financial interests or affiliations to disclose
Disclosures for Charles E Geyer Jr, MD
No financial interests or affiliations to disclose
Agenda — Triple-Negative Breast Cancer:
Current Clinical Management
• Module 1: Metastatic TNBC
– Case A: Dr Burstein
– ASCO 2011 review
– Case B: Dr Geyer
• Rapid-Fire Questions 1
• Module 2: Management of Patients Who Are BRCA-Positive
– Case C: Dr Burstein
• Rapid-Fire Questions 2
• Module 3: Adjuvant/Neoadjuvant Therapy for TNBC
– Case D: Dr Geyer
– Case E: Submitted by Dr William Adler
• Questions and answers
TNBC Comprised of Diverse Molecular
Subtypes
0.3
Preliminary*
0.25
0.2
0.15
0.1
0.05
0
Basal Claudin-low ERBB2 Luminal A Luminal B Normal-like
* Validation ongoing
Affymetrix gene expression profiling of FFPE samples
Intrinsic subtypes assigned using Sorlie et al, PNAS, 2003 data set and claudin-low classifier
(Prat et al, BCR, 2010) [courtesy of J Theilhaber and D Bergstrom, Sanofi]
With permission from O’Shaughnessy J et al.
Proc ASCO 2011;Abstract 1007.
Triple Negative is Biologically
Heterogeneous
ER+/HER2+
100%
Claudin-low
100%
Basal-like
83%
ER+/HER2-
ER-/HER2+
ER-/HER2-
80% 71% 80%
60%
40%
20%
0%
2%
13% 13%
60%
40%
20%
0%
2%
7% 8%
• Triple-negative eligibility enriches for subtype of biologic interest
(basal-like) but will misclassify some.
• However, we have no reason to think this happened in a differential manner across the 2 trials.
HER2-enriched
100%
80%
60%
40%
20%
15% 16%
0%
51%
18%
Luminal B
100%
80%
60%
40%
20%
20%
0%
72%
1%
7%
Prat A and CM Perou. Mol Oncol 2011;5(1):5-23.
100%
Luminal A
87%
80%
60%
40%
20%
7%
0%
2% 5%
Dr Burstein (Case A)
• 2/2010: 73 yo healthy, married woman with mammogram changes confirmed by ultrasound
– Core biopsy: Poorly differentiated, triple-negative
IDC
– Exam: Palpable ALN
• FNA: Positive for breast cancer
• Days later: Red rash develops on underside of breast
– Skin biopsy: Dermal lymphatic invasion
• Staging CT scans: Positive axillary LNs, suspicious liver lesion
– Liver FNA: Positive for breast cancer
Baseline Scans
1. Generally what first-line, off-protocol therapy would you recommend?
Single-agent taxane 3%
Taxane/bevacizumab 71%
Other chemotherapy
Other chemotherapy/bevacizumab
Other 0%
8%
18%
0% 10% 20% 30% 40% 50% 60% 70% 80%
Dr Burstein (Case A)
• CALGB-40502
– Randomly assigned to ixabepilone/bevacizumab
– Tolerates initial therapy well
• 11/2010: Colitis symptoms, nausea, abdominal pain
– CT: Non-specific colitis
– Ixabepilone/bevacizumab discontinued
• Paclitaxel
• Summer 2011: Axillary lymphadenopathy and liver lesion decreased in size but still seen
• CT: New subclinical changes in the original breast
Restaging After ~Four Months
Summer 2011
CALGB-40502/NCCTG N063H: A Phase III Trial of Bevacizumab with Paclitaxel, Nab Paclitaxel or Ixabepilone in Patients with Stage IIIC-IV
Breast Cancer
Target accrual = 900 (temporarily closed 7/8/11)
Eligibility
• Stage IIIC-IV measurable disease ≥1 cm by CT scan or ≥2 cm by conventional techniques
• Known ER, PR and
HER2 status
•
No prior chemotherapy for metastatic disease
R
1
2
3
Paclitaxel 90 mg/m 2 IV d1,
8 and 15 + bevacizumab* d1 and
15 q28 days
Nab paclitaxel 150 mg/m 2 IV d1,
8 and 15 + bevacizumab* d1 and
15 q28 days
Ixabepilone 16 mg/m 2 IV d1,
8 and 15 + bevacizumab* d1 and
15 q28 days
* The treating physician and patient must decide prior to registration whether the patient will receive or not receive bevacizumab www.clinicaltrials.gov, July 2011.
Breast Cancer Subtypes
ER+, HER2-
ER+, HER2+
ER-, HER2+ 5%
15%
60%
ER-, HER2-
0%
20%
10% 20% 30% 40% 50% 60% 70% a Li CI et al. J Clin Oncol 2003;21:28-34; b Allred DC et al. Breast Cancer Res
2004;6:240-5; c Yaziji H et al. JAMA 2004;29(16):1972-7.
Estimated New Cancer Cases per Year in the US
Breast
Triple-negative subset 1
Pancreas
CNS
Ovarian
Gastric
Multiple myeloma
Hodgkin lymphoma
Chronic myeloid leukemia
Estimated new cases
232,620
~34,893
44,030
22,340
21,990
21,520
22,520
8,830
5,150
1 Value estimated by multiplying the number of new breast cancer cases by reported 15% incidence (Stead, Breast Cancer Res 2009) of TNBC.
Siegel R et al . CA Cancer J Clin 2011;61(4):212-36.
Hazard Rate for Distant Recurrence
“…there is a sharp decrease in survival during the first 3 to 5 years after diagnosis, but distant relapse after this time is much less common. After 10 years, relapse is more likely among patients with ER-positive cancers than among patients with ER-negative cancers.
”
Foulkes WD et al. N Engl J Med 2010;363(20):1938-48. Copyright © 2011 Massachusetts
Medical Society. All rights reserved.
Published Guidelines for the Management of TNBC
• NCCN: No specific algorithm
– NCCN Guidelines 2010, v.2
• ESMO: No specific algorithm
– Cardoso F et al. Ann Oncol 2010;21(Suppl):v15v19
– Aebi S et al. Ann Oncol 2010;21(Suppl):v9-v14
– Balmana J et al. Ann Oncol 2010;21(Suppl):v20v22
• St Gallen: No specific algorithm
– Goldhirsch A et al. Ann Oncol 2009;20:1319-29
Bear HD et al.
Proc ASCO 2011;Abstract LBA1005.
NSABP B-40: Chemotherapy ± Bevacizumab in Patients with Operable HER2-Negative
Breast Cancer
Tissue for
Biomarkers
Tissue for
Biomarkers
Operable
Breast
Cancer
R
S
U
R
G
E
RY
+/-
X10
+/-
T
X
G
B docetaxel capecitabine gemcitabine bevacizumab
NSABP B-40: Effect on pCR Rates of Docetaxel
Alone or in Combination with Capecitabine or
Gemcitabine pCR breast
(n = 395; 394; 391) pCR breast + nodes
(n = 393; 390; 388)
T = docetaxel; X = capecitabine; G = gemcitabine
T - AC
32.7%
26%
TX - AC
29.7%
23.3%
TG - AC
32.0%
27.3%
Bear HD et al . Proc ASCO 2011;Abstract LBA1005.
NSABP B-40: Benefit of Adding Bevacizumab to
Standard Chemotherapy
• Benefit of bev predominant in HR+ and not TNBC patient subgroup
• pCR breast
(with bev vs without bev):
– HR+ patients: 23.3 vs 15.2% ( p = 0.008)
– TNBC patients: 51.3 vs 47.3% ( p = 0.44)
Bear HD et al. Proc ASCO 2011;Abstract LBA1005.
Gerber B et al.
Proc ASCO 2011;Abstract 1006.
GEPARQUINTO: Benefit of Bevacizumab
Added to Neoadjuvant Chemotherapy in
TNBC Subgroup
• Benefit of bev limited to TNBC subgroup
• pCR breast
(with bev vs without bev)*
– TNBC patients: 36.4 vs 27.8% ( p = 0.021)
– All patients: 15.0 vs 17.5% ( p = NS)
* pCR breast
= no inv/non-inv in breast and nodes
Gerber B et al. Proc ASCO 2011;Abstract 1006.
Comparison of NSABP B-40 and
GEPARQUINTO: pCR Results* Differ in TNBC
Patient subgroup
All patients 1 p -value
TNBC 2 p -value
GEPARQUINTO 1,2
No bev
21%
NS
Bev
24%
NSABP B-40 3
No bev Bev
28.4% 34.5%
0.027
36.5% 44.6% 47.3% 51.3%
0.04
0.44
* pCR is defined as no inv in breast only. DCIS allowed in NSABP B-40.
1 von Minckwitz G et al. Proc SABCS 2010;Abstract S4-6;
2011;Abstract 1006;
2 Gerber B et al. Proc ASCO
3 Bear HD et al. Proc ASCO 2011;Abstract LBA1005.
CALGB-40603: The Triple-Negative Neoadjuvant
Trial (TNNT)
Target accrual = 362 (Open)
Eligibility
• Stage II-IIIA resectable breast cancer ≥1 cm
•
HER2-negative
(IHC 0-1+ or FISH
<2.0); ER-/PR-poor
•
Registered on CALGB-
150709 correlative tissue study
R
1
2
3
4
Paclitaxel 80 mg/m 2 x 12
dose dense (dd) AC x 4
Paclitaxel + dd AC as in arm 1; bevacizumab 10 mg/kg q2wk x 9
Paclitaxel + dd AC as in arm 1; carboplatin AUC 6 q3wk x 4
Paclitaxel + dd AC as in arm 1 + bevacizumab as in arm 2 + carboplatin as in arm 3 www.clinicaltrials.gov, July 2011.
Plasma Biomarker Analysis in the AVADO Phase III
Randomized Study of First-Line
Bevacizumab/Docetaxel
VEGF low
VEGF high
VEGFR2 low
VEGFR2 high
ICAM-1 low
ICAM-1 high
Bev 7.5 mg/kg
HR (95% CI)
Interaction
p-value
0.96 (0.62-1.48) p = 0.0136
0.52 (0.33-0.81)
1.10 (0.73-1.67)
0.46 (0.28-0.74)
0.67 (0.42-1.06)
0.78 (0.50-1.20) p = 0.0342
p = 0.7803
Bev 15 mg/kg
HR (95% CI)
Interaction
p-value
0.86 (0.56-1.32) p = 0.0808
0.49 (0.31-0.76)
0.75 (0.49-1.16)
0.54 (0.35-0.85)
0.71 (0.46-1.11)
0.62 (0.40-0.96) p = 0.2545
p = 0.9922
Miles D et al . SABCS 2011;Abstract P2-16-04.
Burstein HJ. J Clin Oncol 2011;29(10):1232-5.
Brufsky A et al.
Proc ASCO 2011;Abstract 1010.
RIBBON-2: PFS in TNBC Subgroup
PFS
Events, n (%)
Median, months
HR
Log-rank test
BEV + CT
(N = 112)
94 (84)
6.0
0.494
PLA + CT
(N = 47)
42 (89)
2.7
p = 0.0006
2.7
6.0
Time (months)
With permission from Brufsky A et al. Proc ASCO 2011;Abstract 1010.
RIBBON-2: Second-Line CT plus Bev for TNBC Subgroup (N = 159)
Overall response rate
Median PFS (mos)
Median interim OS
(mos)
CT + bev
(n = 112)
41%
CT + placebo
(n = 47)
18% p = 0.0078
6.0
2.7
HR = 0.494, p = 0.0006
17.9
12.6
HR = 0.624, p = 0.0534
No unanticipated side effects were observed, except neutropenia: bev + CT, 18.8% versus CT + placebo, 10.6%
Brufsky A et al. Proc ASCO 2011;Abstract 1010.
Anti-angiogenic Agents Under Investigation in
Breast Cancer
• Motesanib
• Aflibercept
• IMC-18F1
• HuMV833
• Ramucirumab
• AMG 386
• Pazopanib
• Cabozantinib
• Foretinib
• Tivozanib
• Sunitinib
• Sorafenib
• Vandetanib
• Vatalanib
• Axitinib
• Semaximab
• Cediranib www.clinicaltrials.gov, July 2011.
Agents Currently Under Investigation for TNBC
• Tigatuzumab
• Eribulin mesylate
• P276-00
• Entinostat
• mTOR inhibitors
– Temsirolimus
– Everolimus
• Apatinib
• NK012
• Cediranib
• MetMAb
• PARP inhibitors
– Iniparib (BSI-201)
– Olaparib (AZD-2281)
– Veliparib (ABT-888)
– PF-01367338
• MK2206
• Irinotecan (patients with
CNS disease) www.clinicaltrials.gov, July 2011.
Dr Geyer (Case B)
• 11/2008: 42 yo premenopausal woman with moderately ER+, weakly PR+, HER2-neg T3N0M0 poorly differentiated breast carcinoma
• NSABP B-40: Completes docetaxel/gemcitabine + bevacizumab
AC + bevacizumab per protocol
• 7/2009: Lumpectomy + SLNB
– Multifocal ypT2N1a residual disease
• 3.6 x 2.5-cm: ER-neg, weakly PR+, HER2-neg
• 1.7 x 1.2-cm: Strongly ER+, moderately PR+, HER2-neg
– 1 out of 4 SLNs positive
• Post-operative seroma
– RT delayed, ALND not completed
– Resumed bevacizumab and RT after seroma improved
• Tamoxifen and clodronate (on SWOG-S0307)
• 9/2010: Elevated estradiol, initiated leuprolide
Dr Geyer (Case B)
• 3/2011: Hepatomegaly, increased LFTs
– CT CAP: Extensive hepatic mets, no other sites of disease
– Liver biopsy: Triple-negative IDC
• Asymptomatic, tumor markers normal,
CTCs = 142
• Initiated ixabepilone
Local versus Central Laboratory
Discrepancies in the Determination of
Triple-Negative Breast Cancer (TNBC)
Status in a Large Phase III (CIBOMA/
2004-01/GEICAM/2003-11) Trial Assessing
Adjuvant Capecitabine (C) Maintenance
Therapy After Standard Chemotherapy (CT) in Early Breast Cancer (EBC) Patients
Ruiz-Borrego M et al.
Proc ASCO 2011;Abstract 1022. (Poster Discussion)
Local versus Central Laboratory
Discrepancies in TNBC Status
(CIBOMA/2004-01/GEICAM/2003-11)
• N = 1,441 patient samples sent for central laboratory confirmation
• In 130 cases (9%) tumors were found to not be
TNBC by central determination
• 71% of discrepant results involved ER or PR status
• 22% of discrepant results involved HER2 status
Ruiz-Borrego M et al. Proc ASCO 2011;Abstract 1022.
Dr Burstein (Case C)
• 57 yo married woman with 2 children
– Family hx: Sister (40 yo), maternal grandmother
– Deleterious BRCA2 mutation
• 1997: DCIS + 4-mm focus of high-grade IDC
– Left mastectomy
• 1998: Right mastectomy for DCIS
• 2005: Left chest wall nodule
– Biopsy: High-grade triple-negative IDC
– Excision chest wall RT
2. Would you generally recommend “adjuvant” systemic treatment for this patient?
Yes, single-agent chemotherapy
Yes, other
37%
39%
No, just watch and wait
0% 10% 20%
24%
30% 40% 50%
Repeat Staging Scans
August 2008
January 2009
November 2009
Tutt A et al.
Lancet 2010;376(9737):235-44.
Phase II Study of Olaparib in BRCA1/2+
Advanced Breast Cancer: ER/HER2 Status
Olaparib 400 mg
ER+/HER2+
4%
ER-/HER2+
4%
ER+/HER2-
41%
Triple
Negative
50%
Olaparib 100 mg
ER-/HER2+
4%
ER+/HER2+
15%
ER+/HER2-
15%
Triple
Negative
64%
Tutt A et al . Lancet 2010;376(9737):235-44.
Efficacy of Olaparib by BRCA Mutation Status
Complete response, n (%)
Partial response, n (%)
Olaparib 400 mg bid
BRCA1
(n = 18)
1 (6%)
BRCA2
(n = 9)
0
Olaparib 100 mg bid
BRCA1
(n = 16)
0
BRCA2
(n = 11)
0
8 (44%) 2 (22%) 3 (19%) 3 (27%)
Tutt A et al . Lancet 2010;376(9737):235-44.
Gelmon KA et al.
Proc ASCO 2010;Abstract 3002.
Objective Response Rates to Olaparib in
Patients with Advanced OC or TNBC According to BRCA Mutation Status
Ovarian
Breast
BRCA mutation-positive
7/17 (41.2%)
0/8 (0)
BRCA mutationnegative*
11/46 (23.9%)
0/15 (0)
* BRCA mutation-negative patients in study were 46 patients with high-grade serous ovarian carcinoma and 15 patients with triple-negative breast cancer.
Gelmon KA et al. Proc ASCO 2010;Abstract 3002.
O’Shaughnessy J et al.
Proc ASCO 2011;Abstract 1007.
Efficacy Endpoints — ITT Population
PFS
GC
(N = 258)
GCI
(N = 261)
Median PFS 4.1 mos 5.1 mos
HR 0.79
p -value 0.027
OS
GC
(N = 258)
GCI
(N = 261)
Median OS 11.1 mos 11.8 mos
HR p -value
0.88
0.28
0.6
0.5
0.4
0.3
1.0
0.9
0.8
0.7
0.2
0.1
Prespecified alpha = 0.01
0.6
0.5
0.4
0.3
1.0
0.9
0.8
0.7
0.2
0.1
Prespecified alpha = 0.04
0
0 2 4 6 8 10 12 14 16
Months Since Study Entry
0
0 2 4 6 8 10 12 14 16
Months
With permission from O’Shaughnessy J et al.
Proc ASCO 2011;Abstract 1007.
Exploratory Analysis — Second- or Third-Line
ITT Population
Second- or third-line – 43% patients (222/519)
PFS
0.6
0.5
0.4
0.3
1.0
0.9
0.8
0.7
0.2
0.1
0
GCI
GC
4.3 mos
2.9 mos
HR = 0.67
0 2 4 6 8 10 12 14 16
Months Since Study Entry
With permission from O’Shaughnessy J et al.
Proc ASCO 2011;Abstract 1007.
OS
0.6
0.5
0.4
0.3
1.0
0.9
0.8
0.7
0.2
0.1
0
GCI
GC
10.8 mos
9.1 mos
HR = 0.65
0 2 4 6 8 10 12 14 16
Months
Dr Geyer (Case D)
• 3/2006: 75 yo woman with clinical T3N1M0 triplenegative, Grade III IDC
– 5.5-cm mass
– Ultrasound: 2 to 3 abnormal nodes
3. In general, what neoadjuvant therapy would you recommend?
Anthracycline/taxane
TAC
TC
Other
I would not recommend neoadjuvant therapy
0%
0%
5%
10%
19%
20%
37%
39%
30% 40% 50%
Dr Geyer (Case D)
• Neoadjuvant FEC x 3
– Mass reduced to 2 x 1.5 cm
• Weekly paclitaxel 80 mg/m 2
• Mastectomy
– pCR
– Free of disease after 5 years
Submitted by William Adler, MD (Case E)
• 86 yo woman with hypertension, severe kyphosis and moderate renal insufficiency
• Presents with a 3.5-cm, Grade III triple-negative breast cancer with 8 positive nodes
– No evidence of other disease
– Good performance status
• Patient desires adjuvant systemic therapy, even for modest benefit
4. In general, which adjuvant systemic therapy would you recommend for this patient?
TAC x 6 cycles
AC x 6 cycles
2%
0%
TC x 4 cycles
TC x 6 cycles
39%
18%
18% CMF x 6 cycles
Dose-dense AC followed by dosedense paclitaxel
Other
0%
7%
10%
16%
20% 30% 40% 50%
Beta Blocker Use and Survival in TNBC
Relapse-Free Survival
1.0
0.8
0.6
0.4
0.2
No beta blocker
Beta blocker p = .02
0
0 1 2 3 4 5 6
Time Since Diagnosis (years)
Overall Survival
1.0
0.8
0.6
0.4
0.2
0
No beta blocker
Beta blocker p = .03
0 1 2 3 4 5 6
Time Since Diagnosis (years)
Originally published by the American Society of Clinical Oncology. Melhem-Bertrandt A et al.
J Clin Oncol 2011;29(19):2645-52.
Beta Blocker Use and Survival in ER+ Breast Cancer
Relapse-Free Survival
1.0
0.8
0.6
0.4
0.2
No beta blocker
Beta blocker p = .40
0
0 1 2 3 4 5 6
Time Since Diagnosis (years)
Overall Survival
1.0
0.8
0.6
0.4
0.2
0
No beta blocker
Beta blocker p = .65
0 1 2 3 4 5 6
Time Since Diagnosis (years)
Originally published by the American Society of Clinical Oncology. Melhem-Bertrandt A et al.
J Clin Oncol 2011;29(19):2645-52.
Schedule of Events
Tuesday, July 26
NonHodgkin’s
Lymphoma/Chronic
Lymphocytic Leukemia
Stephanie A Gregory, MD
John P Leonard, MD
Tuesday, August 2
Chronic Myeloid
Leukemia
Susan M O’Brien, MD
Neil P Shah, MD, PhD