What We've Learned from Studying Hereditary Cancer Families BRCA1, BRCA2, and NonBRCA: A Tale of Thr

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What We've Learned from Studying Hereditary
Cancer FamiliesBRCA1, BRCA2, and Non-BRCA A
Tale of Three Cancers

• Timothy R. Rebbeck
• University of Pennsylvania

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• What Were Finding (ca. 2008)
• Other factors influence risk among BRCA1/2
  mutation carriers.
• Risk factors for BRCA1/2 and non-BRCA cancers
  differ.
• Risk and mortality can be reduced, but better
  strategies are needed.

• What We Thought (ca. 1994)
• BRCA1/2 mutation status would be sufficient to
  predict risk.
• Risk factors for BRCA1/2 and non-BRCA cancers
  might be similar.
• Not clear if and how cancer could be prevented.

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BRCA1-Associated CancersLifetime Risk
Breast cancer 60-80
Second primary breast cancer 40-60
Ovarian cancer 30-45
Increased risk of other cancers Colon
10-15 Male breast cancer 1-5 Pancreatic
2-3 Uterine and cervical cancer Slightly
increased risk
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BRCA2-Associated CancersLifetime Risk
breast cancer (60-80)
breast cancer (5-10)
ovarian cancer (10-20)
Increased risk of other cancers Prostate
15-25 Pancreatic 3-5 Melanoma 3-5
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Factors that Define Differential Risk in BRCA1,
BRCA2 and non-BRCA Mutation Carriers

• Pathology and Tumor Markers
• Epidemiology / Exposures
• Susceptibility Genes
• Prevention

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Estrogen Receptor Positivity and BRCA Mutation
Status
Data from Foulkes et al. 2004
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Genomic Expression Differences(Sorlie 2003, van
t Veer 2003, West 2003)
Basal-Like Profile
BRCA1
BRCA2
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Factors that Define Differential Risk in BRCA1,
BRCA2 and non-BRCA Mutation Carriers

• Pathology and Tumor Markers
• Epidemiology / Exposures
• Susceptibility Genes
• Prevention

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Selected Reproductive Factors
Factor (Effect in Pop) Effect in B1/2
References Early Menarche (?) ? Kotsopolous
2005 0 Chang-Claude 2007 High Parity (?)
0 Rebbeck 2001, Cullinane 2005, Andrieu 2006,
Kotsopoulos 2006 46 ? Antoniou 2006 38
? Cullinane 2005 (4 births B1) 53 ? Cullinane
2005 (2 births B2) Late AFLB (?) 300
? Rebbeck 2001 0 Andrieu 2006 42 ? Andrieu
2006 (B1, 30 vs ? Jernström 2004 (B1) 0 Andrieu 2006
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Selected Exposure
Factor (Effect in Pop) Effect in B1/2
References Medical Radiation (?) 54 ? IBCCS
2006 80 ? (B1) Gronwald 2008 Mammography
(0) 0 Narod 2006 Smoking (??) 50 ? Brunet
1998 0 Ghadirian 2004 25 ? Colilla 2005 260
? (B1) BCFR 2008 230 ? (B2)
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Oral Contraceptive Use(Complex Association with
Risk in General Population)
Effect on Cancer
Risk Reference N Breast Ovarian Narod
1998 368 - 50 ? Modan 2001 240 - 0 Narod
2002 1311 20 ? - Haile 2006 804 0 - Haile
2006 (B2 5y) 307 210 ? - Compared with
non-carriers
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Factors that Define Differential Risk in BRCA1,
BRCA2 and non-BRCA Mutation Carriers

• Pathology and Tumor Markers
• Epidemiology / Exposures
• Susceptibility Genes
• Prevention

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GWAS Hits and Breast Cancer Risk
Per-Allele HR or OR Gene Gen
Pop B1 B2 FGFR2 1.3 NS 1.3 TNRC9 1.1 1.1 1.2
MAP3K 1.1 NS 1.1 Reference Easton 2007
Antoniou 2008
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BRCA1/2 Interactors
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Validated BRCA1 Interactors Breast Cancer
(N4400)
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BRCA1 Interactors Ovarian Cancer (n1602)
HAPLO
SNP
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BRCA2 Interactors Ovarian Cancer (n881)
HAPLO (rare)
SNP
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Factors that Define Differential Risk in BRCA1,
BRCA2 and non-BRCA Mutation Carriers

• Pathology and Tumor Markers
• Epidemiology / Exposures
• Susceptibility Genes
• Prevention

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Take-Home Message Genetic Testing for BRCA1/2
is warranted because cancer risk and mortality
can be reduced
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Risk Reduction and Screening Strategies
Approach Examples B1/2 Pop Screening Mammography Y
es Yes MRI Yes Maybe Chemoprevention SERMs Yes Y
es Surgery Risk-Reducing
Oophorectomy Yes No Mastectomy Yes No
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BRCA1/2 Screening Issues

• MRI vs Mammography
• (Leach/MARIBS 2005) Sensitivity/Specificity
  Sensitivity
• Type BRCA1 BRCA2
• MRI 92 / 79 58 / 82
• Mammo 23 / 92 50 / 94
• Both 92 / 74 92 / 78
• Radiation Risk?
• Narod (2006) Screening mammography and breast
  cancer
• BRCA1 1.04 (95 CI 0.84-1.29)
• BRCA2 1.06 (95 CI 0.67-1.66)
• DCIS?
• Hagen (2007) Sensitivity for DCIS in BRCA1
• 33 for MRI
• 33 for Mammography

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Breast Cancer Risk Reduction by Tamoxifen Use in
BRCA1/2 Mutation Carriers
OR or HR Setting N (95 CI) Reference Contr
alateral 593 0.5 (0.3-0.9) Narod 2000 491 0.6
(0.4-1.0) Metcalfe 2004 1036 0.5 (0.3-0.9)
Gronwald 2006 (B1) 0.4 (0.2-1.0) Gronwald
2006 (B2) 0.8 (0.2-2.9) Gronwald 2006
(BPO) 0.4 (0.3-0.7) Gronwald 2006 (no
BPO) 1o Prevention 11 1.7 (0.3-10.7) King
2001 (BRCA1) 8 0.4 (0.1-1.6) King 2001 (BRCA2)
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Breast Cancer Risk Reduction After Prophylactic
Mastectomy in BRCA1/2 Mutation Carriers
HR Years of N (95 CI) Follow-up Reference
26 ? 13.4 Hartmann 2001
131 ? 3.0 Meijers-Heijboer 2001 483 0.05
(0.01-0.22) 7.5 Rebbeck 2004
Hartmann et al., JNCI 93(21)1633-7,
2001Meijers-Heijboer et al. NEJM 345(3)159-64,
2001Rebbeck et al. JCO, 22(6)1055-62 , 2004
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Impact of Risk-Reducing Salpingo Oophorectomy
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Post-BPO HRT Use and Subsequent Breast Cancer
Risk
N Surgery HRT Hazard Ratio (95 CI)
296 None None 1 62 BPO None 0.38
(0.09-1.59) 93 Any 0.37 (0.14-0.96) 50 E
only 0.44 (0.12-1.61) 34 PE 0.43 (0.07-2.68)
Rebbeck et al, JCO 2005
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Mortality With and Without Prophylactic
Oophorectomy in BRCA1/2 Mutation Carriers
Domchek et al, Lancet Oncology 2006
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What Hereditary Cancers Have Taught Us

• New biological pathways associated with breast
  cancer risk can be found.
• Exposures and preventive interventions may not
  have the same effects in all settings
• Context matters
• Suggests differences in risk conferred by low
  penetrance susceptibility genes may exist
• Cancer is complex it requires knowledge of
  genetic susceptibility and other factors.
• Prevention is critical but may differ by
  population.

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Multicenter PROSE/MAGIC Team
Baylor College of Medicine Sharon Plon Baylor
University Joanne Blum Beth Israel
(Boston) Nadine Tung Chaim Sheba Medical Center
Eitan Friedman City of Hope Jeff
Weitzel Creighton University Henry Lynch, Patrice
Watson Dana Farber Cancer Institute Judy
Garber Duke University Joellen Schildkraut Evansto
n-Northwestern Wendy Rubinstein Fox Chase Cancer
Center Mary Daly, Andrew Godwin Georgetown
University Claudine Isaacs KConFab Georgia
Chenevix-Trench Mayo Clinic Fergus Couch, Lynn
Hartmann Memorial Sloan Kettering Cancer
Center Noah Kauff, Ken Offitt Netherlands Cancer
Institute Laura van t Veer, Emiel Rutgers Royal
Marsden Hospital Ros Eeles St. Marys Hospital,
Manchester Gareth Evans University of
Pennsylvania Susan Domchek, Kate
Nathanson University of California, Irvine Hoda
Anton-Culver, Susan Neuhausen University of
California, Los Angeles Patricia Ganz University
of Chicago Funmi Olopade University of Texas,
Southwestern Gail Tomlinson University of
Vienna Theresa Wagner Womens College
Hospital Steven Narod Yale University Elizabeth
Claus, Ellen Matloff
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PROSE/MAGIC Team at Penn
Funded by R01-CA083855, R01-CA102776 Project
Manager Tara Friebel-Klingner Laboratory Saarene
Panossian Teo Tran Amy Walker Data
Management Stephen Gallagher Statistics/Analysis
Jinbo Chen Shannon Chuai Nandita Mitra Fei
Wan Co-Investigators Susan Domchek Kate
Nathanson