RTP TV: An 8-Part Live CME

Webcast Series

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

The Effect of pCR of Bevacizumab and/or Antimetabolites Added to Standard

Neoadjuvant Chemotherapy:

NSABP Protocol B-40

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.

Neoadjuvant Bevacizumab and

Anthracycline-Taxane Based Chemotherapy in 684 Triple Negative Primary Breast

Cancers: Secondary Endpoint Analysis of the GEPARQUINTO Study (GBG 44)

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.

Impact of Bevacizumab (Bev) on Efficacy of Second-Line

Chemotherapy (CT) for Triple-Negative

Breast Cancer: Analysis of RIBBON-2

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

Oral Poly(ADP-ribose) Polymerase

Inhibitor Olaparib in Patients with BRCA1 or BRCA2 Mutations and Advanced Breast Cancer:

A Proof-of-Concept Trial

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.

Can We Define Tumors That Will

Respond to PARP Inhibitors? A

Phase II Correlative Study of

Olaparib in Advanced Serous

Ovarian Cancer and Triple-

Negative Breast Cancer

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.

A Randomized Phase III Study of

Iniparib (BSI-201) in Combination with

Gemcitabine and Carboplatin in

Metastatic Triple-Negative Breast

Cancer (mTNBC)

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