Post on 11-Jan-2016
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