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

February 27, 2013

Modified from Peto et al.

Lancet 355:1822, 2000

Improvements

Breast CA Early

Detection and

Treatment

Good News:

Overall Declining Breast Cancer Mortality Rates!

Improvements in

Outcome are a

Direct Result of

Partnership and

Multidisciplinary

Care

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

Overall

Survival Local Recurrence

Trial # Pts

Max

tumor

size Mast BCT Mast BCT

Milan Cancer

Institute 701 2 cm 76% 79% 6% 5%

EORTC 868 5 cm 66% 65% 12% 20%

U.S. NCI 237 5 cm 79% 78% 8% 13%

NSABP

B-06 1855 4 cm 71% 71% 8%

Lumpectomy +

XRT: 10%

Lumpectomy

only: 39%

Clinical Trials of Mastectomy vs.

Breast Conservation Therapy

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

Clin Cancer Res (2008) 14 : 8010

Breast Cancer : Intrinsic Subtypes Predict Survival

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

H&E ER-Neg PR-Neg HER2/neu-Neg

ER-Pos PR-Pos HER2/neu-Pos H&E

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

TNBC : Prevalence

5 negative + Core basal phenotypes = TNBC

Plos Medicine (2010) 7 : e1000279

TNBC accounts for approximately 15% of

all breast cancers

Clin Cancer Res (2007) 13 : 4429

Characteristics of TNBC

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

N Engl J Med (2010) 363 : 1938

TNBC : Pattern of First Distant Recurrence

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

International Journal of Breast Cancer (2012) 2012 : 1

TNBC & PARP Inhibition

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 Non-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 No Association

Yang, 2011

Breast Cancer Association Consortium

Phipps, 2011

Women’s Health Initiative

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 high-risk 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

N=1,008

AA

N=581

Ghana

N=75

PValue

Mean Age 62.4 60.7 48.0 0.002

Tumor Size 1.95 2.30 3.20 <.001

Grade 3 (%) 29% 45% 76% .007

ER neg 22% 36% 76% <0.001

TNBC 16% 26% (37/45) 82.2% <0.001

Cancer, 2010 Results unchanged on updated studies of nearly 200

Ghanaian specimens (unpublished)

Korle Bu Teaching Hospital 2010

Accra, Ghana

58% 26%

5% 4%

2% 2%

2%

1%

Molecular Marker Pattern

ER neg/PR neg/HER2 neg (TNBC)

ER neg/PR neg/HER2 pos

ER pos/PR neg/HER2 neg

ER neg/PR pos/HER2 neg

ER neg/PR pos/HER2 pos

ER pos/PR pos/HER2 neg

ER pos/PR pos/HER2 pos

ER pos/PR neg/HER2 pos

Courtesy, Dr. Edmund Der

N=219

Breast Cancer in African Americans, Sub-Saharan Africans, and

White Americans

45

57 62

Average Age at Diagnosis (years)

African

African

American

White

American

0%

20%

40%

60%

80%

100%

Proportion with

TNBC

Proportion with

High-Grade

Tumors

Proportion with

ER-Negative

Tumors

4%

2%

1%

Frequency of Male Breast Cancer

TNBC in Developing Countries

Study Country Region TNBC (%)

Trinkaus 2011 Kenya East Africa 32%

Roy 2011 Uganda Southern, sub-Saharan Africa 36%

Stark 2010 Ghana Western, sub-Saharan Africa 82%

Bird 2008 Kenya East Africa 44%

Der, 2012 Ghana Western, sub-Saharan Africa 58%

Awadelkarim 2011 Sudan Northern Africa 16%

Abdelkrim 2010 Tunisia Northern Africa 18%

Ambroise 2011 India South Asia 25%

Teoh 2011 Malaysia Southeast Asia 15%

Tan 2009 Malaysia Southeast Asia 18%

Ghosh 2011 India South Asia 29%

Ng 2011 Indonesia Southeast Asia 21%

Research Project: UM International Breast Cancer Registry

Overarching Goal: To evaluate association between

African ancestry & high-risk breast cancer subtypes

• Step 3: Explore novel aspects of tumor biology

– Breast cancer stem cells; ALDH1

– Are there differences in the oncogenic potential of

mammary tissue that are associated with ancestry?

“ALDH1 Is a Marker of Normal

and Malignant Human

Mammary Stem Cells and a

Predictor of Poor Clinical

Outcome” Ginestier, Wicha

Cell, 2007

ALDH-1 Staining by Race/Ethnicity (Cancer, 2012)

• Consistent with results in Uganda breast cancer pts (Nalwoga et al, Br J Cancer 2010)

• 69 benign Ghanaian breast specimens studied at UM

– 58% ALDH1-positive

0%

10%

20%

30%

40%

50%

60%

70%

80%

Ghanaian CA HFH AA CA HFH WA CA French/Eur CA UM WA CA

EZH2 and Breast Cancer:

Potential Target for TNBC Prognosis & Treatment

EZH2 plays a role in the

maintenance of breast stem cells in

Triple Negative breast cells

EZH2 downregulation in SUM149

(TN) cells decreases growth of

Aldefluor-positive breast cancer

stem cell in vivo

Normal epithelial cells are negative,

invasive carcinoma cells express

EZH2 protein, primarily in the nucleus

EZH2 and Ghanaian Breast Cancer

Br CA Res Tr, 2012

a. Fibroadenoma with occasional

epithelial cells expressing nuclear EZH2

b. Basal-like CA with high EZH2 nuclear

expression. EZH2 localization to mitotic

figures, consistent with suspected role of

EZH2 in mitosis

c. Previously unreported pattern of

EZH2 expression: Invasive CA with

cytoplasmic EZH2 expression. Nuclei of

cancer cells negative for EZH2

Ultimate Goal:

Eliminating the Threat of Breast Cancer Worldwide

International Collaborations:

•Opportunities to study

disparities in high-risk patterns

of disease

•Opportunities to improve the

standard of health care in

medically-underserved

populations

•Opportunities to cultural and

academic exchange

•Opportunities to forge

powerful friendships

Breast Cancer Disparities and

Screening Mammography Controversy

• Mammography clinical trials:

– healthy women randomized to receive regular

mammograms versus “usual medical care”

• 30% lower mortality in screened women ≥50 yrs

• Controversies:

– Extent of survival benefit in younger women (40-49 yrs)

– Mammography clinical trials data primarily based on

White American and European women

SCREENING FOR BREAST CANCER

Study Accrual

Interval

F/U

(yrs)

Mammo

Interval

Mammo

Views Mortality

40-49 yo

HIP 1963-66 18 12 2 22

Kopperberg 1977-89 15 24 1 22

Ostergotland 1978-89 14 24 1 8

Malmo 1977-90 13 18-24 1,2 28

Edinburgh 1978-85 13 24 1,2 18

Gothenberg 1982-84 12 18 1,2 29

Stockholm 1981-86 11 28 1 5

Canada NBSS 1980-85 11 12 2 0

Mammography Screening Controversy

• Recent controversy based upon USPSTF update on screening recommendations (Ann Int Med Nov 2009)

• USPSTF commissions multi-center expert statistical teams to review mammography data

– Model 1: mammography initiated at age 40 years results in more life-years gained

– Model 2: mammography initiated at age 50 years results in higher cancer diagnostic “yield”

– “USPSTF recommends against routine screening mammography in women aged 40-49 years...USPSTF recommends biennial screening mammography for women between the ages of 50 and 74 years.”

0

10

20

30

40

50

60

70

80

30-34 35-39 40-44 45-49 50-54 55-59

per 1

00,0

00 p

opul

atio

n

Age (years)

Age-Specific Mortality

AA Mort

WA Mort

Potential Impact of USPSTF Recommendations

on Breast Cancer Disparities

Younger age distribution for breast cancer in African Americans:

- Among women younger than age 45 yrs, breast cancer

incidence rates higher for AA compared to WA women

- 20% WA breast cancer patients are <50 years old

- 30-35% AA breast cancer patients are <50 years old

Population-Based Incidence Rates of TNBC,

by Race/Ethnicity and Age:

Implications for Screening Recommendations

USPSTF updated mammography recommendations

may worsen breast cancer outcome disparities

between AA and WA women (CANCER, 2011)

0

10

20

30

40

50

60

70

< 40 40-49 50-59 60-74 ≥75

Inci

de

nce

Rat

e (

pe

r 1

00

,00

0)

Age (years)

NH White

NH Black

Summary:

How TNBC differs from non-TNBC

• More common in young/premenopausal women

• More common in African American women

• More common in women with hereditary

susceptibility/BRCA mutation carriers

• More likely to present as a palpable breast lump with

normal mammogram

• More likely to require chemotherapy

• More likely to metastasize to brain

• Less likely to recur/metastasize after a five-year

disease-free survival

Summary:

How TNBC is similar to non-TNBC

• Early detection is critical!!!!

– More likely to be treated successfully, less

likely to require chemotherapy if detected early

• Surgical treatment options are similar

– Mastectomy with/without breast reconstruction

– Breast-conserving surgery (lumpectomy,

axillary surgery, breast radiation)

Summary:

What you need to know about TNBC in 2013

• Similar to general breast health awareness messages:

– Initiate yearly screening mammography at age 40

– If you detect a new finding on self examination, seek medical

attention promptly

– Know your family history

• Messages with heightened importance related to TNBC:

– Seek genetic counseling if you have hereditary susceptibility

• Male breast cancer; breast and/or ovarian cancer in close or multiple

relatives, or relatives diagnosed at young ages; Ashkenazi Jewish

• Women with hereditary susceptibility benefit from screening breast MRI in

addition to mammography

– If you are diagnosed with TNBC prior to age 50, seek genetic

counseling in addition to standard cancer treatment

Common Questions and Concerns

• Does breast pain indicate that I have cancer?

• Does breast pain indicate that I don’t have cancer?

• Should I get mammograms more frequently if I have a

family history of breast cancer?

• Does exposure to air make a tumor spread?

• Does stress cause cancer?

• Can I avoid breast cancer by following a special diet?

• Can I develop breast cancer by following a special diet?

• Do brassieres cause breast cancer?

• Is there any way to prevent breast cancer?

University of Michigan Health Center

THANK YOU!!!!!