African Ancestry and

High-Risk/Triple Negative Breast Cancer:From Tuskegee and Race Medicine to

Precision Medicine and Oncologic Anthropology

Lisa A. Newman, MD, MPH, FACS, FASCO

Henry Ford Health System

Director, Breast Oncology Program

Director, International Center for the Study of Breast Cancer Subtypes

Adjunct Professor of Surgery, M.D. Anderson Cancer Center

Adjunct Professor of Health Policy Management, UM SPH

Beyond Flexner 2016:

Push for Change

I have no disclosures

Tuskegee Study and “Race Medicine”:

“Study of Untreated Syphilis in the Negro Male”

• 1932: Study initiated

• 1943: Penicillin accepted as

standard treatment, but withheld

from study subjects

• 1972: Study details reported by

news media

• 1973: Study discontinued

Treatment instituted and all

medical expenses paid for the rest

of the subjects’ lives

1997: President Clinton formally apologizes to trial participants and their families on behalf of the U.S. government

SOCIOECONOMIC DISPARITIES

8%

11%

24%

19%

22%

33%

27%28%

10%

18%

0%

5%

10%

15%

20%

25%

30%

35%

Proportion with Poverty-Level Income Proportion with No Medical Insurance

White American

African American

Latino American

American Indian/AlaskanNativeAsian American

Breast Cancer Burden of African Americans

• Socioeconomic

Disparities

• Tumor biology

• Genetics

• Lifestyle & Reproductive

Experiences

• Environmental exposures

• Diet/Nutrition

• Higher mortality

• Advanced stage

distribution

• Lower lifetime incidence

• Younger age distribution

• Increased frequency of adverse

tumor features

• Higher incidence of male breast

cancer

SES-Adjusted Meta-Analysis, 2006>13K AA & 75K WA Breast CA Pts; 19 Studies

mortality hazard.1 .5 1 5 10

Combined

Crowe

Jatoi 1995-99

Bradley

Polednak

Albain Postmen

Albain Premen

Roetzheim

El Tamer

Yood

Wojcik

Howard

Franzini

Simon (<50 yo)

Simon (>49 yo)

Perkins

Eley

Neale

Ansell

Gordon

Coates

Bassett

AA Mortality Risk: 1.28 (95% CI 1.18-1.38)Newman et al, JCO 2006

Breast Cancer Burden of African Americans

• Socioeconomic

Disparities

• Delivery of Care

• Tumor biology

• Genetics

• Lifestyle &

Reproductive

Experiences

• Environmental

exposures

• Diet/Nutrition

• Higher mortality

• Advanced stage distribution

• Lower lifetime incidence

• Younger age distribution

• Increased frequency of

adverse tumor features

• Higher incidence of male

breast cancer

Disentangling SES and Inherent Racial/Ethnic Cancer Risks

Clinical Trials Data

• Albain et al, JNCI 2009: Pooled analyses of SWOG adjuvant therapy trials

– Equal treatments delivered through clinical trials

resulted in equal outcomes for all cancers (regardless of

race/ethnicity) except for African Americans with

hormonally-driven cancers (breast & prostate cancers)

Recurrence Mortality

Premenopausal 1.39

(1.12-1.73)

1.41

(1.10-1.82)

Postmenopausal 1.45

(1.27-1.66)

1.49

(1.28-1.73)

TIME.com Aug 22, 2009

“Why Racial Profiling Persists in

Medical Research”By Catherine Elton

0

20

40

60

80

100

120

140

160

1973

1975

1977

1979

1981

1983

1985

1987

1989

1991

1993

1995

1997

1999

2001

2003

2005

2007

African American Incidence

White American Incidence

African American Mortality

White American Mortality

SEER Program: Breast Cancer Incidence and

Mortality Rates, 1973-2007

0

20

40

60

80

100

120

140

160

1973

1975

1977

1979

1981

1983

1985

1987

1989

1991

1993

1995

1997

1999

2001

2003

2005

2007

African American Incidence

White American Incidence

African American Mortality

White American Mortality

SEER Program: Breast Cancer Incidence and

Mortality Rates, 1973-2007

Tamoxifen

Disparities in Breast Tumor Biology:ER-Negative Breast Cancer in the U.S.

22%

39%

25%

31%32%

0%

5%

10%

15%

20%

25%

30%

35%

40%

45%

White American African

American

American Indian Asian/Pacific

Islander

Hispanic/Latina

American

Pro

port

ion

ER

-Neg

ativ

e B

reas

t C

ance

r

Li et al; SEER Data, 1992-98

Arch Int Med 2003

Copyright restrictions may apply.

Carey, L. A. et al. JAMA 2006;295:2492-2502.

Microarray and Immunohistochemistry to Identify of Breast Tumor Subtypes

26%16%

39%

16%14%16%

0%

10%

20%

30%

40%

50%

AA All WA All AA Premen WA Postmen AA Postmen WA Postmen

Carolina Breast Cancer Study: Frequency of “basal subtype” by IHC

Dataset/Sample Size Frequency of TNBC

AA WA P

Carey, 2006 97 premenopausal AA vs 164

premenopausal WA women;

Carolina Breast Cancer Study

39% 16% <0.001

Morris, 2007 2230 Thomas Jefferson Univ Hosp

pts; 197,274 SEER pts 20.8% 10.4% <0.0001

Lund, 2008 Population-based Atlanta GA cohort

of 116 AA, 360 WA pts46.6% 21.8% <0.001

Lund, 2008 167 AA and 23 WA from Grady

Hospital; Atlanta, GA 29.3% 13.0% 0.05

Moran, 2008 99 AA; 968 WA BCS pts from Yale

Univ School of Medicine21% 8% <0.0001

Chavez-

MacGregor

2013

606 cases of male breast cancer,

population-based California

Cancer Registry9% 3% NR

Population-Based Incidence Rates of TNBC,

by Race/Ethnicity and Age:

Implications for Screening Recommendations

Delayed mammography screening may worsen breast

CA outcome disparities between AA and WA women (Amrikia and Newman, 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)

White

Black

Kohler B et al, April 2015

TNBC WA

TNBC AA

TNBC Asian/PI TNBC Hispanic

“Annual report to the nation on the status of cancer,

1975-2011, featuring incidence of breast cancer subtypes

by race/ethnicity, poverty, and state”

“Breast cancer statistics, 2015: Convergence of incidence rates between

black and white women”

CA: A Cancer Journal for Clinicians29 OCT 2015

Systemic therapy

advances:

• Endocrine Tx

• Anti-HER2 therapy

• Mortality disparity

Δ=42%

Precision MedicineBreast cancer precursors revisited:

molecular features & progression pathways

Reis-Filho J et al; Histopathology 2010

Prior benign

breast biopsies

and fibrocystic

histopathology

are risk factors

for non-TNBC;

What are the

TNBC

precursors?

HFHS Benign Breast Disease Cohort

• HFHS female patients 1994-2005

– Age 40-70 years

– Prior cancer history excluded

– Minimum six months HFHS

interaction/affiliation

– 2,588 African Americans

– 3,566 White Americans

Variable

African-

Americans

N= 2,588 (%)

White-

Americans

N=3,566 (%)

P-Value

95% CI

Mean age at diagnosis of BBD (± SD) 51.7 (± 8.3) 52.1 (±8.4) 0.0692

Method of BBC Detection

Asymptomatic/Screening

Mammogram

Clinical Breast Examination

Symptomatic

Pain and Tenderness

Lump

Clear Discharge

Bloody Discharge

2,019 (78.4)

48 (1.9)

89 (3.5)

310 (12.0)

51 (2.0)

33 (1.3)

2,799 (78.9)

126 (3.5)

94 (2.6)

436 (12.3)

53 (1.5)

20 (0.6)

0.468

Extent of BBC Treatment

Excision/Lumpectomy

Biopsy (Needle/Core)

376 (14.7)

2,216 (83.3)

583 (16.5)

2,799 (79.4)

0.653

Histology of Benign Lesions

Non-Proliferative

Hyperplasia with Atypia

Ductal

Lobular

Ductal and Lobular

Lobular Carcinoma In Situ

2,438 (94.2)

122 (4.7)

19 (0.7)

6 (0.2)

3 (0.1)

3,283 (92.0)

207 (5.8)

52 (1.5)

21 (0.6)

3 (0.1)

0.0012

African

Americans

White/Caucasian

Americans

Henry Ford Health System

Benign Breast Disease Cohort: TNBC Incidence

High-Risk Breast Cancer 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

International Breast Cancer Research Collaborative

Overarching Goal: To evaluate association between

African ancestry & high-risk breast cancer subtypes

Characterizing the breast cancer burden of Sub-

Saharan Western Africa

– Komfo Anoyke Teaching Hospital, Kumasi Ghana

Michigan-Ghana Breast Cancer Research Collaborative

Overarching Goal: To evaluate association between African

ancestry & high-risk breast cancer subtypes

Comparison of WA, AA, and Ghanaian ptsHenry Ford Hospital, Detroit; KATH, Ghana

WA

N=321

AA

N=272

Ghana

N=234PValue

Average

Age63 60 48.0 0.002

TNBC 16% 26% 53% <0.001

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

Der and Newman, The Breast J, 2015

N=219

TNBC: International Patterns

• USA; Europe: 10-20% of all invasive cancers

• Canada: 11%

– Dent et al, Clin Cancer Res, 2007

• Turkey: 12%

– Turkoz et al, The Breast, 2013

• Greece: 8%

– Fostira et al, Br Cancer Res Tr, 2012

• China: 22%

– Song et al, PLoS One, 2013

ALDH-1 Staining by Race/Ethnicity (Newman et al 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

African Ancestry and TNBC

Heterogeneity: Xenograft Creation

- NOD/SCID mice humanized at UM

with fibroblasts from reduction

mammoplasty cases prior to travel

De novo creation of lab at KATH for

preparation of tumor specimens

procured directly from OR

Implantation into mice mammary fat

pads immediately upon return to UM

African Ancestry and TNBC Heterogeneity:

TNBC Subtypes

• Vanderbilt University (Pietenpol; Lehmann)

• Gene expression profiles; 21 breast CA datasets

– >3,000 cases, including 587 TNBC (18% TNBC)

• Geographic sources: US (predominately Caucasian cases);

UK; Sweden; Germany; Singapore; Netherlands

– 6 subtypes; varying degrees of stem cell-like versus

Luminal Androgen Receptor (LAR)-like properties• Treatment response/predictive value of TNBC subtype

– MD Anderson

• TNBC subtype associated with response to neoadjCTX

• LAR subtype with lowest response

– Therapeutic implications

• bicalutamide/anti-androgen therapy in LAR subtype

Associations with AR level among TNBC samples (n=80)

AR Level

1 2-4 p-value

ALDH1 Negative 38 (86.4) 6 (13.6)0.019

ALDH1 Positive 23 (63.9) 13 (36.1))

Androgen Receptor positivity associated with

ALDH1 expression: Novel, as-yet undefined

additional TNBC subtype featuring joint

expression of AR and ALDH-1???

Proctor and Newman, Ann Surg Onc, 2015

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 in Ghana

KATH Surgical Suite

Michigan-Ghana Collaboration:Academic Exchange

Growth and Evolution of

Weekly KATH

Multidisciplinary Breast CA

Tumor

Board/Teleconference

Michigan-Ghana Collaboration: Investment in Ghana Community

Donation of

medical supplies

and educational

materials to KATH

hospital school

Michigan-Ghana Collaboration: Investment in Ghanaian Healthcare

Resources, supplies, and

support for KATH Breast

Clinic staff

Establishment of KATH

dedicated breast

clinicopathology team

Michigan-Ghana Collaboration:Academic Exchange

Core Needle

Biopsy Training

Program (AnnSurgOnc 2010)

Establishment of

Immunohistochemistry

Program at KATH

Expansion of International Registry:

Addis Ababa, Ethiopia

Results: Phenotype Distribution

19.8%16.7% 15.5%

37.1%

18.7%

29.8%

67.5%

20.1%

53.2%

28.7%

33.3%

15.0%

0%

10%

20%

30%

40%

50%

60%

70%

80%

ER-negative HER2-positive TNBC

White American African American

Ghanaian EthiopianP 0.0001

P =0.0048

P <0.0001

GHANA

ETHIOPIA

Biologic Plausibility: African Diaspora/

Patterns of Forced Population Migration

• Breast cancer is a heterogeneous disease

– Subtypes vary in treatment needs and prognosis

– Subtypes vary in genetic risk

– Subtypes vary in prevalence within population subsets

• Eliminating breast cancer is dependent upon our ability to

understand and define its diverse nature

– Obligation to study to diverse populations worldwide

– Oncologic Anthropology

• ICS BCS Mission Statement:

– “To reduce the global breast cancer burden through advances in

research and delivery of care to diverse populations worldwide”

SURVIVAL RATES

• 60%

• 43%

• 20%

R.M.S. TITANIC

20%3rd Class

43%2nd Class

60%1st Class

Survival RatePassenger Status

Outcome is dependent on access to care

“Of all the forms of injustice, inequality in health care is

the most shocking and inhumane”

Rev. Dr. Martin Luther King, Jr.

“No quality without access”

American College of Surgeons, National Institute of

Minority Health and Disparities, and American Cancer

Society Collaborate to address unequal healthcare

May, 2015

Bethesda, MD

THANK YOU!!!!!!

Acknowledgements

Colleagues in Ghana:

Dr. Baffour Awuah

Dr. Joseph Oppong

Dr. Frances Aitpillah

Dr. Ishmael Kyei

Dr. Francis Abantaga

Dr. Ernest Adjei

Dr. Ernest Osei-Bonsu

Dr. Michael Ohene-Yeboah

Dr. Emmanuel Amankwaa-Frempong

Patients of the Komfo Anokye

Teaching Hospital

Colleagues in Ethiopia:

Dr. Aisha Suleiman-Jibril

Dr. Abebe Engida

Dr. Bekele Mahteme

Dr. Abebe Zerihun

Patients of the St. Paul’s Millenium Teaching Hospital

Dr. Kofi Gyan

Dr. Jessica Bensenhaver

Dr. Erica Proctor

Dr. David Nathanson

Dr. Dhanitale Chitale

Barbara Salem

Dr. Azadeh Stark

Dr. Evelyn Jiagge

Dr. Max Wicha

Dr. Celina Kleer

Dr. Sofia Merajver

Kathy Toy

Dr. Mark Hoenerhoff