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Jeffrey N. Weitzel, M.D.
Germline Mutations
Hereditary Breast and
Ovarian Cancer Risk and
Management Issues
Cancer Screening &
Prevention Program
Kesselheim A and Mello M. N Engl J Med 2010;10.1056/NEJMp1004026
Timeline of Important Events in DNA Patenting (Top) and the Discovery and Use
of Genes Conferring Susceptibility to Breast and Ovarian Cancer (Bottom)
June 2013 - U.S. Supreme
Court rules that as nature,
genes cannot be patented
BRCA1- and BRCA2-Associated Cancers: Lifetime Risk
Breast cancer 50%-85% (often early age at onset)
Second primary breast cancer 40%-60%
Ovarian cancer 15%-45%
Absolute risk likely to be higher than 10%
- Prostate cancer
Absolute risk 10% or lower
- Male breast cancer
- Fallopian tube cancer
- Pancreatic cancer
BRCA1 and BRCA2
On chromosomes 17 and 13, respectively
Autosomal dominant transmission
Proteins have a role in genomic stability
>2,000 different mutations, polymorphisms, and
variants distributed over both genes
Breast Cancer Information Core
Nonsense Missense Splice-site
BRCA1
5
BRCA: Selected Examples of Founder Mutations
Population BRCA1 Mutations BRCA2 Mutations
Ashkenazi
Jewish
185delAG 5382insC 6174delT
Icelandic 999del5
British 6-kb duplication of exon 13
4184del4
6503delTT
Dutch
(Netherlands)
2804delAA
Large deletions of exons 13 & 22
Chinese 1081delG
Russian 5382insC 4153delA
African A. 1832del5 5296del4
Hispanic 185delAG deletion exons 9-12 3492insT
Inherited Genomic Rearrangements of BRCA1 and BRCA2
35/300 (12%) sequence negative high risk families
Walsh et al, JAMA 295:1379-1388, 2006
Other:
CHEK2 n=14 (5%)
TP53 n=3 (1%)
k Comprehensive genetic testing includes full sequencing of BRCA1/BRCA2 and detection of large genomic rearrangements.
Influence of BRCA1 Genotype on
Histopathology in Breast Cancer (BC)
• Less likely to express estrogen receptor or Her2/neu
• Have a high nuclear grade
• Show less tubule formation
• Have a higher mitotic count
• Medullary histology more common (~ 6%)
• More BRCA1 mutations in “triple negative”
• DCIS is less associated with BRCA1 than BRCA2
• BRCA testing may be appropriate for triple negative BC or
early onset DCIS, especially if family history of BC and/or OC
Eisinger et al. Cancer Res 56:471, 1996; Claus et al, JAMA 293:964-969, 2005;
Breast Cancer Linkage Consortium. Lancet 349:1505, 1997; Kandel (ASCO), 2006
Contribution of known genes to explaining
familial aggregation of breast cancer
Other familial risk factors
(genes, environment)
BRCA1
BRCA2
TP53
PTEN
ATM
CHEK2,BRIP1,PALB2
8 WGA SNPs
CASP8
ASCO
Li-Fraumeni Syndrome
Bilateral Breast, 40
Leukemia, 33
Brain tumor, 32
Breast, 40 Osteosarcoma, 42
Breast, 35
Soft tissue sarcoma, 7
Leukemia, 6
Affected with cancer
TP53-mutation carrier 50
Cowden Syndrome Pedigree
Multinodular goiter,
dx 25
Follicular thyroid
cancer, dx 35
Trichilemmomas, dx 21
Breast cancer, dx 35
Macrocephaly
Papillomatous papules
Multinodular goiter, dx 22
Affected
Noncarrier
Eng C. J Med Genet. 2000;37:828-830
Risk for uterine,
but not ovarian
ca in CS
Emerging Breast Cancer Phenotype in
Women with TP53 Germline mutations
Cohort of TP53
Carriers
N ER+ Her2/neu+
LiFE Consortium 32 84% 63% Masciari et al.
BCRT 2012
UK 9 83% Wilson et al. J Med
Genet 2010
MDACC/Chi 30 70% 67% Melhem-Bertrandt et
al. Cancer 2012
Women < 40 BC,
unselected for FHx
- 52-66% 22-33% Collins et al. BCRT
2011; Gonalez-
Angulo et al. Cancer
2012
Genetic Predisposition Testing Is a Multi-Step Process
Identify at-risk
patients
Provide pretest
counseling
Obtain informed consent
Select and offer test
Disclose results
Provide post-test
counseling and
follow-up
Cancer Screening & Prevention Program
Estimating Cancer Risk
Family History
Empiric Data
Genetic Testing
Limited Paternal Family Structure
Br 47
Breast Cancer
57 y 65 y
85 y
60 y d. 55 y d. 36 y
MVA
87 y 88 y d. 73 y
62 y 55 y
Adequate Family Structure for both
Maternal and Paternal Lineage
57 y 65 y
85 y
55 y 60 y
87 y 88 y d. 73 y
55 y 58 y 62 y
Br 47
Breast Cancer
Weitzel et al. JAMA 297(2007) 2587-2595
Br-47
41
31 23 33
Ov-38 47
81
Br- 45
Br- Pm
43
30
Br-49
28 25
45
21 25 24 18 26 1 9 9 11
Pr- 50
71
Br- Pm
HEREDITARY BREAST AND OVARIAN CANCER
+ - - + ex9-12del
Clinical Management of BRCA
Mutation-Negative Patients
Negative BRCA1 and/or BRCA2 test result
Member of family w/ known BRCA1 or BRCA2 mutation?
NO YES
Emphasize empirically increased risk of breast and/or ovarian cancer
Provide individualized risk-management plan
Encourage adherence to population screening
guidelines
Emphasize risk of sporadic cancer
Clinical Management of BRCA Mutation-Positive Patient
Cancer Screening & Prevention Program
Positive BRCA1 or BRCA2
test result
Possible testing for
other adult relatives
Increased
surveillance
Prophylactic
surgery
Lifestyle
changes
Chemo-
prevention
Dense Breast Tissue
Mammo
Size
Time
?
MRI and Breast Cancer Detection in BRCA Carriers - Sensitivity
N with mutations
Invasive cancers % by MRI % by
mammogram
Warner
(2004) 236 16 81% 31%
Kriege
(2004) 358 20 80% 33%
MARIBS (2005) 120 12 92% 23%
TOTAL 714 48 83% 30%
Breast MRI may be considered the
standard of care for high risk patients
Cumulative incidence of early-stage (stages 0 to I)
breast cancer in magnetic resonance imaging (MRI)
Warner E et al. JCO 2011;29:1664-1669
Is risk reduction mastectomy (RRM) effective?
Skin-Sparing Mastectomy With Immediate Reconstruction
Comparison of 214 high risk
women who underwent RRM
(1960-1993) to sister
controls:
3 cases BC observed vs.
37.4 expected = 92% Risk
Reduction Hartmann L. et al, NEJM, 340:77, 1999;
JNCI 93:1633, 2001
Study of 483 BRCA carriers:
>90% risk reduction Rebbeck, T.R., et al. JCO 22:1055, 2004
New Primary Cancer Risk and Modifiers Among 491 BRCA Carriers
10-year contralateral breast cancer risk
43.4% for BRCA1; 34.6% for BRCA2
Age 50 at diagnosis: HR 0.63; 95% CI 0.36-1.10
Tamoxifen use: HR 0.59; 95% CI 0.35-1.01
Oophorectomy: HR 0.44; 95% CI 0.21-0.91
10-year ovarian cancer risk after breast cancer:
12.7% for BRCA1, 6.8% for BRCA2 (p=0.03)
Ovarian cancer was the cause of death in 25% of the Stage I breast cancer patients
Metcalfe et al. J Clin Oncol 2004, 22:2328-2335. Gyn Onc 2005; 96:222-226
Options for breast cancer patients
with BRCA mutations
• Surgical options for the breast – therapeutic mastectomy versus breast conservation
therapy on affected breast
– risk reduction mastectomy on contralateral breast
• Hormonal risk reduction options – BSO
– tamoxifen
• Screening – mammography
– MRI
Genetic Cancer
Risk Assessment
Prevention Treatment
Oncologic
Consultation
Decisions, decisions…
Prophylactic
Oophorectomy
CA125 Screening
Chemoprevention
Options for BRCA1, BRCA2 Carrier
CASH study. N Engl J Med 316:650, 1987.
Rosenberg L et al. Am J Epidemiol
139:654, 1994. Ursin G et al. Cancer Res
57:3678, 1997. Narod et al, NEJM
339:424, 1998Narod SA, et al. Oral
contraceptives and the risk of breast
cancer in BRCA1 and BRCA2 carriers. J
Natl Cancer Inst 2002;94:1773-9.
Oophorectomy Reduces
Ovarian Cancer, Breast Cancer,
and all cause mortality
Greatest breast cancer risk
reduction among BRCA1
mutation carriers without a prior
dx of breast cancer who had
their oophorectomy < age 50
HR: 0.15 (95% CI 0.04-0.63)
Genetic status is on the cusp of
helping to determine composition
of breast and ovarian cancer
treatment regimens
PARP inhibition and tumor-selective synthetic
lethality
DSB, double-strand break; HR, homologous recombination
SSB, single-strand break
PARP
DNA damage (SSBs)
DNA replication
(accumulation of DNA DSBs)
Normal cell
with functional HR pathway HR-deficient tumor cell
(e.g. BRCA 1/2-/-)
Cell survival Cell death
HR-mediated
DNA repair
Impaired HR-
mediated
DNA repair
Tumor-selective cytotoxicity
PARP inhibition
Farmer H et al. Nature 2005;434:917–921
Bryant HE et al. Nature 2005;434:913–917
McCabe N et al. Cancer Res 2006;66:8109–8115
PARP inhibitors in cancer therapy
Agent Company Single / Combination
therapy
Route of
administr
ation
Disease Clinical status
AG014699 Pfizer (New
York, NY)
Single IV Advanced BC
and OC
Phase 1 in solid
tumors, phase 2 in
BC and OC
AZD2281
(Olaparib)
AstraZeneca/Ku
DOS (London,
UK)
Single, combinations with
carbo/paclitaxel or
paclitaxel alone
Oral Advanced BC
and OC
Phase 2, 3
ongoing
ABT-888
(Veliparib)
Abbott
Laboratories
(North Chicago,
IL)
Combination with carbo,
temozolomide, or
cisplatin/vinorelbine
Oral Advanced BC Phase 1, 2, 3
ongoing
BSI-201
(Iniparib)
Sanofi-Aventis
(Bridgewater,
NJ)
Gemcitabine/carboplatin IV Triple-negative
BC
Phase 2, 3
ongoing
GPI 21016 MGI Pharma
(Bloomington,
MN)
Combination with
temozolomide
Oral Solid tumors Phase 1 planned
Phase II trial of the oral PARP
inhibitor olaparib in BRCA-deficient
advanced breast cancer: Best %
change from baseline in target BC
lesions by prior chemotherapy
–100
–80
–60
–40
–20
0
20
40
60
80
100
Previous anthracycline, taxane and capecitabine
Increasing tumor shrinkage
Best %
change from
baseline
*Prior platinum Tx
* *
* *
*
*
Tutt et al. Lancet 2010
Olaparib 400 mg bid cohort
ORR, n (%) 11 (42)
CR, n (%) 1 (4)
PR, n (%) 10 (39)
Protocol NCI #8264: ABT-888 +/- Carbo
Adv/Mets BRCA- Breast Cancer
ABT-888 400 mg
BID >2 cycles
ABT-888 150 mg BID
+ Carbo AUC=5
Safety Lead-In
21 patients
Endpoints: BRCA1 vs. BRCA2 •RECIST Criteria •PFS ABT-888 single agent; post-progression for combination •Safety & Tolerability, Pharmacokinetics •Correlative studies will include biomarkers of PARP and carboplatin effect, as well as prospective analyses of mechanism(s) of resistance •in vivo selection for BRCA “reversion” mutants that restore the reading frame and functional domains such as HRR may be one mechanism of drug resistance
Post-progression
How Much Breast and Ovarian Cancer Is Hereditary? It depends on what tests you use to answer the question
Sporadic
Family clusters
Hereditary
Ovarian Cancer Breast Cancer
5%–7% 10-23%
15% -20%
Proportions ovarian, fallopian tube, or peritoneal cancer
patients with respective germ-line loss-of-function mutations
Walsh T et al. PNAS 2011;108:18032-18037
Domchek SM, et al. Multiplex
genetic testing for cancer
susceptibility: out on the high
wire without a net? J. Clin.
Oncol. 2013;31(10):1267-
1270.
Weitzel et al. Genetics, Genomics, and Cancer Risk Assessment: State of the Art and
Future Directions in the Era of Personalized Medicine. CA Cancer J Clin 2011;61:327–359
clinical utility
accepted
clinical utility
unclear
directed by
HCP high
penetrance
intermediate
penetrance
directed by
individual DTC
testing
low penetrance
variants
Clinical Utility and professional
mediation of genetic testing
American Society of Clinical Oncology Policy Statement Update: Genetic
and Genomic Testing for Cancer Susceptibility. J Clin Oncol, 2010.
Key advances and evidence for advice:
• There are advances in protocols for screening (MRI), risk reduction
(RRSO, RRM), and targeted treatment
Warner et al, 2004; Kriege et al, 2004; Rebbeck et al, 2002, Kauff et al, 2002;
Weitzel et al, 2007
• GCRA influences surgical decisions in a risk-appropriate way and
should be considered for women with newly diagnosed early stage
breast cancer and suspicion of BRCA gene mutation
• Timing of GCRA in the sequence of events in cancer diagnosis
and treatment is dependent on both patient and provider
variables and limitations
Weitzel et al, 2003; Schwartz et al, 2004, 2005.
Cancer Screening & Prevention Program
Breast and Ovarian Cancer Screening and Prevention
Key advances and evidence for advice:
• BRCA testing for early onset DCIS, and for single cases of BC
<50 years if limited family structure; <60 if “triple negative”
Claus et al, 2005; Kandel et al, 2006; Weitzel et al, 2007
• Large rearrangements account for a significant proportion of
high risk families without sequence detected BRCA mutations
Walsh et al, 2006; Weitzel et al, 2007; MGL 2012
• Documented efficacy of interventions for BRCA mutation
carriers drives medical necessity and liability issues, making
GCRA a standard of care
• GCRA along with risk reduction interventions are cost-effective
tools for increasing quality-adjusted life
Cancer Screening & Prevention Program
Breast and Ovarian Cancer Screening and Prevention