Triple-Negative Breast Triple-Negative Breast Cancer :Cancer :

An emerging EntityAn emerging EntityLouis J. Auguste, MD, FACSLouis J. Auguste, MD, FACS

Associate Clinical Professor of SurgeryAssociate Clinical Professor of Surgery

Albert Einstein College of MedicineAlbert Einstein College of Medicine

XXXVIIth Annual AMHE ConventionChateau Montebello, Quebec, Canada

The Jean-Claude Remy, MD Series

Sources: National Cancer institute, SEER Program. National Center for Health Statistics, public use tape

Breast CA:Breast CA:Stage at Stage at Diagnosis by RaceDiagnosis by RaceUS, 1995 - 2000US, 1995 - 2000

0%

10%

20%

30%

40%

50%

60%

70%

Localized Regional Distant

All races

Caucasian

Afro-Amer

CA Canc. J. Clin 2005;55:10-30

Five-year relative survival rates among patients with Breast cancer by race and stage at diagnosis: 1996 - 2002

Jemal, A. et al. CA Cancer J Clin 2007;57:43-66.

Disparities in Outcome of Disparities in Outcome of Breast CA in Afro-American Breast CA in Afro-American

WomenWomen• Health Care systemHealth Care system

• Distribution of health care facilitiesDistribution of health care facilities• Distribution of medical manpowerDistribution of medical manpower• Clinical competency of physiciansClinical competency of physicians• Cultural sensitivity – Institutional Cultural sensitivity – Institutional

racism?racism?• Government impactGovernment impact

• Political prioritiesPolitical priorities• Enforcing health policiesEnforcing health policies

Racial and Ethnic Racial and Ethnic differences in Poverty differences in Poverty Rate– Rate– US Census Bureau - US Census Bureau -

20042004

8.2%

24.4%22.5%23.2%

0.0%

5.0%

10.0%

15.0%

20.0%

25.0%

2003

Caucasian

Afro-Amer.

Hispanics

Americannatives

Prevalence(%) of Recent Cancer Prevalence(%) of Recent Cancer Screening among US Adults < 65Screening among US Adults < 65

(2000 US Census)(2000 US Census)

Overall

Have Health

Insurance

No Health Insurance

Mammogram 61.3 64.0 36.6

Mammogram & CBE

54.0 58.4 31.4

CA Canc. J. Clin 2005;55:10-30

Disparities in Outcome of Disparities in Outcome of Breast CA in Afro-American Breast CA in Afro-American

WomenWomen• Socio-cultural factorsSocio-cultural factors• Historic backgroundHistoric background

• Mistrust of the systemMistrust of the system

• Level of educationLevel of education• Economic disparitiesEconomic disparities

• Health insurance vs. Government insurance Health insurance vs. Government insurance vs. no insurancevs. no insurance

• Do we have a two-tiered system?Do we have a two-tiered system?

• Intrinsic differences in disease Intrinsic differences in disease patternspatterns

Age specific Br. CA Age specific Br. CA incidence rates 1973 - incidence rates 1973 -

19971997

Swanson GM et al., Cancer 2003, 97 : 273

Age specific female breast Age specific female breast CA mortality 1973-1997 CA mortality 1973-1997

(Rates per 100.000)(Rates per 100.000)

Swanson GM et al., Cancer 2003, 97 : 273

Breast CA Rate Ratio in Breast CA Rate Ratio in African American vs African American vs Caucasian womenCaucasian women

Age Group RR

0 – 24 2.0

25 –29 1.5

30 – 34 1.4.

35 – 39 1.1

40 – 44 1.0

45 - 59 0.9

= / > 60 0.8

SEER Stat 3.0. Bethesda: NCI, 2000

Comparison of Stage Comparison of Stage Distribution and by ER statusDistribution and by ER status

African-American Caucasian

Stage No(%) ER+ No(%) ER+

I 5724(30.6) 55.8 78,706(44.1) 71.3

II 7524(40.2) 46.8 63,619(35.6) 64.8

III 1976(10.6) 39.2 10,980( 6.1) 55.3

IV 1358( 7.3) 36.7 7,581 ( 4.2) 48.0

NCI – SEER Data 1995 – 2002

N = 197,279

Immunohistochemistry Results Immunohistochemistry Results by Race–TJUH 1995 – 2002 by Race–TJUH 1995 – 2002

(All stages – n=2230pts)(All stages – n=2230pts)

ER+ (%) Ki67+ (%) P53+ (%)

Afro-American 147 (51.9) 120(42.2) 55 (18.4)

Caucasian 1228(63.1) 559(28.7) 255(13.1)

P value .0003 <.0001 .0039

Morris, GJ et al., Cancer Aug. 2007

Breast Cancer Breast Cancer in Black and Whitein Black and White

Feature African-American Caucasian

Menopausal status Pre Post

Palpable mass +++ +

Lymphatic metastasis ++ +Tumor dedifferentiation +++ +ER & PR receptors + ++Survival ++ +++

Gene expression Gene expression profiling using profiling using

microarray analysismicroarray analysis

Van de Vijver, M.J. MD, Dis. Of the Breast, 7(3) 2004

Microarray analysis of Microarray analysis of human neoplasmhuman neoplasm

• Tumor cell behavior must be determined by Tumor cell behavior must be determined by the coordinate expression of genes the coordinate expression of genes controlling cell growth.controlling cell growth.

• The expression pattern is also determined by The expression pattern is also determined by gene expression in fibroblasts, endothelial, gene expression in fibroblasts, endothelial, inflammatory cells, etc.inflammatory cells, etc.

• All 30,000 to 40,000 human genes can be All 30,000 to 40,000 human genes can be analyzed.analyzed.

• The function of encoded proteins is being The function of encoded proteins is being elucidatedelucidated

• Sophisticated software required to analyze Sophisticated software required to analyze large database. large database.

Van de Vijver, M.J. MD, Dis. Of the Breast, 7(3) 2004

Immuno-histochemical assay and Immuno-histochemical assay and Tissue Microarray definition of Tissue Microarray definition of

Intrinsic Sub-types of Breast cancerIntrinsic Sub-types of Breast cancer

Basal Breast Cancer Basal Breast Cancer MarkersMarkers

• In addition…In addition…• Over expression of Ki-67Over expression of Ki-67• Caveolin-1Caveolin-1• άB-Crystallin (heat-άB-Crystallin (heat-

shock protein)shock protein)• Frequent P53 mutationsFrequent P53 mutations• C-KITC-KIT• Genomic instability(as in Genomic instability(as in

BRCA-1 deficient BC)BRCA-1 deficient BC)

Heterogeneity of potentially Heterogeneity of potentially relevant features of TNBCrelevant features of TNBC

TNBC

P53 mutation

BasalBRCA1mutation

Immune Response

άBcristallin

Schneider, B et al.Clin. Canc. Res. 2008;14

Breast Cancer Sub-TypesBreast Cancer Sub-Types according to Gene Expression according to Gene Expression

AnalysisAnalysisTypes ER PR HER2 Cyto

keratin

Luminal A + + -

Luminal B + + +

HER2 + - - +

Basal-like - - - +

Unclassified - - - -

Copyright restrictions may apply.

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

Adjusted Odds Ratios for Patient and Tumor Characteristics by Breast Cancer Subtype*

Distribution of Triple Negative Breast Cancer

By Race and Ethnicity

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

Copyright restrictions may apply.

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

Prevalence of Breast Cancer Subtypes According to Race and Menopausal Status

Epidemiology of TNBCEpidemiology of TNBC• Incidence: 10-15 % of all BC in USIncidence: 10-15 % of all BC in US

• 20,000 – 25,000 cases/year20,000 – 25,000 cases/year

• More common in African-AmericansMore common in African-Americans• More common pre-menopausallyMore common pre-menopausally• Associated with ObesityAssociated with Obesity• Associated with BRCA1 mutationAssociated with BRCA1 mutation• Not associated with traditional hormonal Not associated with traditional hormonal

risk factorsrisk factors• Mortality: > 10 – 15 % of BC deaths in USMortality: > 10 – 15 % of BC deaths in US

Pathology and Pathology and PresentationPresentation• 90% = Basal-like90% = Basal-like

• High nuclear and histologic gradeHigh nuclear and histologic grade• High mitotic and proliferation indicesHigh mitotic and proliferation indices• Pushing BordersPushing Borders• Scant or absent in-situ componentScant or absent in-situ component

• More likely: “Interval” presentationMore likely: “Interval” presentation• More likely to present as a mass More likely to present as a mass

rather than microcalcificationsrather than microcalcifications

Carey LA et al. Clin. Canc. Res. 2007;13(8)

Patients with residual tumorPatients with residual tumorfollowing Neo-adjuvant following Neo-adjuvant

chemotherapychemotherapy

Carey LA et al. Clin. Canc. Res. 2007;13(8)

PARP pathway of DNA PARP pathway of DNA repairrepair

activated by metabolic, chemical or ionizing radiation DNA damage

OlaparibOlaparib

• Poly(ADP-Ribose) Poly(ADP-Ribose) Polymerase inhibitorPolymerase inhibitor

• Inhibitor of both Inhibitor of both PARP-1 and PARP-2PARP-1 and PARP-2

• Oral bioavailabilityOral bioavailability• Stand alone activity Stand alone activity

vs BRCA1 deficient vs BRCA1 deficient breast cancer cell breast cancer cell lineslines

4-[3-(4-Cyclopropane carbonylpiperazine-1-carbonyl) -4-fluorobenzyl]-2H-phthalazin-1-one

Fong P et al. N Engl J Med 2009;361:123-134

Results of Pharmacokinetic and Pharmacodynamic Studies of Olaparib

125 women with metastaticTNBC125 women with metastaticTNBCs/p 0 – 2 prior chemotherapys/p 0 – 2 prior chemotherapywell balanced for Performance Statuswell balanced for Performance StatusSites of recurrence and Prior therapySites of recurrence and Prior therapy

Carboplatin +

Gemcitabine

Carboplatin+Gemcitabine +BSI-

201

Population 62 61

Overall Response Rate

16% 48% P < 0.002

Progression-free survival

3.3 months 6.3 months P<0.0001

Overall survival 5.7 months 9.2 months P=0.0005

O’Shaughnessy et al. ASCO Proceedings # 3, June 2009

Individualized Therapy Individualized Therapy Schemes for Breast Schemes for Breast

CancersCancersType of Cancer

Molecular Target

Chemotherapy

Luminal A Estrogen and Progesterone

receptors

Anthracyclin or Taxanes-

based(CAF or CA-

T)

+ SERMAromatase inhibitors

Luminal B and

HER2neu

ER, PR &/or HER2neu

Idem +Traztuzumab

Triple Negative

Genomic instability

NeoangiogenesisEGFR1

?PARP pathway

Platinating agents

?Anti-VEGF(bevacizumab)

?Anti-EGFR(cetuximab)? Olaparib

ConclusionsConclusions• The availability of gene array platforms The availability of gene array platforms

has allowed to identify different sub-has allowed to identify different sub-classes of Breast cancer.classes of Breast cancer.

• Triple negative breast cancer has a more Triple negative breast cancer has a more aggressive behavior and worse aggressive behavior and worse prognosis.prognosis.

• It is found more commonly in Pre-It is found more commonly in Pre-menopausal African-American women menopausal African-American women and may contribute to the poorer and may contribute to the poorer outcome in this group.outcome in this group.

Conclusions (2)Conclusions (2)• Better understanding of the genomics Better understanding of the genomics

and molecular biology of the tumor may and molecular biology of the tumor may lead to novel therapeutic approaches.lead to novel therapeutic approaches.

• Recent trials targeting the PARP DNA Recent trials targeting the PARP DNA repair pathway are very promising. repair pathway are very promising. They need to be confirmed by a larger They need to be confirmed by a larger study, which has completed enrollmentstudy, which has completed enrollment

• We are anxiously awaiting the We are anxiously awaiting the maturation of the data. maturation of the data.

T H E E N DT H E E N DAny Questions?Any Questions?

Breast Cancer in the Haitian Breast Cancer in the Haitian

CommunityCommunity Age Distribution Age Distribution

0

2

4

6

8

10

12

30- 40 41 -

50

51 -

60

61 -

70

71 -

80

> 80

Age

Breast CA in the Haitian Breast CA in the Haitian CommunityCommunity

0

2

4

6

8

10

12

14

T0 T1 T2 T3 T4

Tumor Size

Breast CA in the Haitian CommunityBreast CA in the Haitian Community

OverviewOverviewAge + LN ER/PR

Pos.Her2neu

Amp(3+)

SBR

<50 10 4/10

(40%)3/6

(50%)

2/6

(33%)

3-5 0 6-7 1

8-9 4

>50 29 11/27 (41%)

18/25 (72%)

4/24

(17%)

3-5 2 6–7 13

8-9 7

Total

39 37 31 30 27

Breast CA in the Haitian Community – Breast CA in the Haitian Community – Tumor CharacteristicsTumor Characteristics

< 50 > 50ER Status: Pos.

Neg.

3 50%

3 50%

18 76%

6 24%

HER2neu: Pos.

Neg.

2 33%

4 66%

3 13%

20 87%

SBR 3-5

6-7 1 20%

8-9 4 80%

2 10%

12 57%

7 33%

Breast Cancer in the Haitian Breast Cancer in the Haitian CommunityCommunity

Breast Tumor IHC Intrinsic Sub-TypesBreast Tumor IHC Intrinsic Sub-Types

Tumor Type < 50 > 50 Total

Luminal A 2 (33%) 14 (58%) 16 (53%)

Luminal B 1 (16%) 3 (13%) 4 (13%)

HER2 (+) 1 (16%) 1 (4%) 2 ( 7%)

Basal-like / unclassified

2 (33%) 6 (25%) 8 (27%)

Breast Cancer in the Breast Cancer in the Haitian CommunityHaitian Community

GOALSGOALS• To increase the patient populationTo increase the patient population• To ascertain health attitudes of To ascertain health attitudes of

Haitians toward Breast Cancer.Haitians toward Breast Cancer.• To compare Haitians to other To compare Haitians to other

communities.communities.• Major Problem: How do you define Major Problem: How do you define

race.race.

Breast CA: Five-Year Survival Breast CA: Five-Year Survival By Stage and RaceBy Stage and Race

US 1995 - 2000US 1995 - 2000

0%

20%

40%

60%

80%

100%

Localized Distant

All races

Caucasian

Afro-Amer

CA Canc. J. Clin 2005;55:10-30

Copyright restrictions may apply.

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

Survival Analysis of the Carolina Breast Cancer Study Cases Grouped Using the Refined Breast Tumor Immunohistochemical Intrinsic Subtypes

Slamon DJ et al. Science 1987;235: 177-182