February 27, 2013

TRIPLE NEGATIVE BREAST CANCER Lisa A. Newman, M.D., M.P.H., F.A.C.S. Professor of Surgery Director, Breast Care Center University of Michigan Ann Arbor, MI

Good News: Overall Declining Breast Cancer Mortality Rates!

Improvements Breast CA Early Detection and Treatment

Improvements in Outcome are a Direct Result of Partnership and Multidisciplinary Care

Modified from Peto et al. Lancet 355:1822, 2000

SURGERY FOR BREAST CANCER: Evolution

• Radical Mastectomy • Extended Radical Mastectomy • Modified Radical Mastectomy • Breast Conservation Therapy

MANAGEMENT OF BREAST CANCER Three Principles • Eradicate the primary focus of disease • The entire breast must be treated – risk of microscopic multicentric foci of disease

• The axillary nodal basin must be staged

MANAGEMENT OF BREAST CANCER: Standard of Care • Modified Radical Mastectomy/Total Mastectomy – Removal of breast with axillary surgery

• Breast Conservation Therapy – Lumpectomy, axillary surgery, and breast XRT

• Breast cancer treatment trials: – women randomized to lumpectomy vs mastectomy – women randomized to surgery + CTX vs surgery alone

• Systemic therapy (chemotherapy and/or hormonal therapy), depending on tumor stage & features

Clinical Trials of Mastectomy vs. Breast Conservation Therapy

Trial

Overall Survival

Max # Pts tumor size Mast

Local Recurrence

BCT

Mast

BCT

Milan Cancer 701 Institute

2 cm

76%

79%

6%

5%

EORTC

868

5 cm

66%

65%

12%

20%

U.S. NCI

237

5 cm

79%

78%

8%

13%

8%

Lumpectomy + XRT: 10% Lumpectomy only: 39%

NSABP B-06

1855

4 cm

71%

71%

MANAGEMENT OF BREAST CANCER: Standard of Care • Modified Radical Mastectomy/Total Mastectomy – Removal of breast with axillary surgery

• Breast Conservation Therapy – Lumpectomy, axillary surgery, and breast XRT

• Breast cancer treatment trials: – women randomized to lumpectomy vs mastectomy – women randomized to surgery + CTX vs surgery alone

• Systemic therapy (chemotherapy and/or hormonal therapy), depending on tumor stage & features

Key Strategies for Improving Breast Cancer Survival Rates • Early detection • Systemic therapy to eliminate microscopic disease in distant organs (micrometastases) • Extent and volume of micrometastases lowest when breast cancer is diagnosed at early stage • Note: Elimination of primary disease on the chest wall via surgery with/without radiation is essential in rendering the patient disease-free, but control of micrometastases (with systemic therapy) is critical for long-term survival

Adjuvant Systemic Therapy for Breast Cancer • Chemotherapy • “Targeted” therapy – Endocrine Therapy – Trastuzamab

All systemic therapies have toxicities, which can be minimized by: • limiting use to patients at highest risk for micrometastatic disease • utilizing targeted therapy

Adjuvant Systemic Therapy for Breast Cancer • Chemotherapy – Non-targeted systemic therapy; chemotherapy damages any hyper-proliferative tissue

• Endocrine Therapy: – targets ER/PR-positive tissue – Tamoxifen – Aromatase inhibitors for postmenopausal patients • Arimidex; Letrozole; Exemestane

• Trastuzamab: – targets HER2/neu

Breast Cancer : Intrinsic Subtypes Predict Survival

Clin Cancer Res (2008) 14 : 8010

Proc Natl Acad Sci USA (2001) 98 : 10869

Triple Negative Breast Cancer

Plos Medicine (2010) 7 : e1000279

Triple-negative breast cancer: Range of histology.

Hudis C A , Gianni L The Oncologist 2011;16:1-11 ©2011 by AlphaMed Press

Clinical Relevance of “Triple-Negative” Breast Cancer (TNBC) • Risk of metastatic spread exists for ALL breast cancers Risk lower for early stage breast cancer Micrometastases can be controlled with systemic therapy Systemic therapy options determined by ER, PR, HER2/neu

• Fewer systemic therapy options for TNBC

Inherently aggressive biologic behavior (basal-like) Endocrine therapy and trastuzamab will be ineffective H&E

H&E

ER-Pos

PR-Pos

HER2/neu-Pos

ER-Neg

PR-Neg

HER2/neu-Neg

TNBC : Prevalence 5 negative + Core basal phenotypes = TNBC

Plos Medicine (2010) 7 : e1000279

TNBC accounts for approximately 15% of all breast cancers

Characteristics of TNBC

Clin Cancer Res (2007) 13 : 4429

TNBC: Clinical Features • Younger age at breast cancer diagnosis – Average age 5-10 years younger than with non-TNBC

• “Interval” breast cancer – TNBC more common among tumors detected as palpable lumps following a “normal” mammogram

• BRCA1 mutation carrier • African ancestry

TNBC & Survival- Early Detection Critical!!!

J. Clin. Oncol. (2011) 29 : 2628

TNBC : Pattern of First Distant Recurrence

N Engl J Med (2010) 363 : 1938

TNBC: More common in African American compared to White American breast cancer patients

Breast Cancer Res Treat (2009) 113 : 357

TNBC : Novel Targets

Int J Clin Oncol (2010) 15 : 341

TNBC & PARP Inhibition

International Journal of Breast Cancer (2012) 2012 : 1

Can we prevent TNBC??? • What do we know about risk factors for TNBC (identifying women at highest risk for developing TNBC)? • What do we know about chemoprevention of TNBC?

Reproductive History and TNBC Risk Study

Effect of Multiparity on Risk

TNBC Millikan, 2008 Carolina Breast Cancer Study Ma, 2010 Women’s Contraceptive and Reproductive Experiences Study

No Association

Shinde, 2010 M.D. Anderson Cancer Center Phipps, 2011 Breast Cancer Surveillance Consortium Yang, 2011 Breast Cancer Association Consortium Phipps, 2011 Women’s Health Initiative

No Association

Non-TNBC

TNBC Prevention • Currently-available medications to prevent breast cancer (tamoxifen, raloxifene, exemestane) will only reduce risk of estrogen receptor-positive breast cancer • Preliminary epidemiologic data suggests that lactation/nursing appears to lower risk of TNBC

High-Risk Breast Cancer/TNBC and African Ancestry • Parallels between hereditary breast cancer and breast cancer in women with African ancestry – younger age distribution – increased prevalence of ER-neg, aneuploid tumors – higher risk of male breast cancer

• Is African ancestry associated with a heritable marker for highrisk breast cancer subtypes?

•Unique opportunity to gain insights regarding etiology of breast cancer disparities and the pathogenesis of triple-negative breast cancer

Research Project: UM International Breast Cancer Registry To systematically evaluate African ancestry as a risk factor for ER/triple-negative, early onset breast cancer • Multicenter/international study – African Americans – White Americans – Ghanaians

• Document correlation between quantified extent of ancestry (via genotyping) and risk for ER-negative/triple-negative breast cancer (via tumor studies)

UM-Ghana Research Project Overarching Goal: To evaluate association between African ancestry & high-risk breast cancer subtypes

• Step 1: Characterize the breast cancer burden of Sub-Saharan Western Africa – Komfo Anoyke Teaching Hospital, Kumasi Ghana

UM-Ghana Breast Cancer Research Collaborative Overarching Goal: To evaluate association between African ancestry & high-risk breast cancer subtypes

• Step 2: Compare WA, AA, and Ghanaian breast CA pts – Henry Ford Hospital, Detroit; KATH, Ghana WA AA Ghana N=1,008 N=581 N=75 Mean Age 62.4 60.7 48.0

Tumor Size Grade 3 (%) ER neg TNBC

1.95 29% 22% 16%

2.30 45% 36% 26%

PValue 0.002

3.20 76% 76% (37/45) 82.2%

Results unchanged on updated studies of nearly 200 Ghanaian specimens (unpublished)