Breast Cancer Risk and Prevention

Diagnosis and Treatment of Patients
with Primary and Metastatic Breast Cancer
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Guidelines Breast
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Breast Cancer Risk and
Prevention
Breast Cancer Risk and Prevention
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Guidelines Breast
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 Versions 2003–2012:
Schmutzler with Albert / Blohmer / Fehm /
Kiechle / Maass / Mundhenke / Thomssen
 Version 2013:
Schmutzler / Thomssen
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Principles in Prevention
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Guidelines Breast
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• Women at increased risk for breast cancer are not
considered patients but healthy women or
counselees
• A comprehensive informed consent taking into
consideration all potential side effects and risks is
warranted prior to offering preventive measures
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• Highest priority: „First, do no harm!“
(Primum nil nocere)
Who Should be Tested for BRCA1/2
Mutations?
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GR: B
AGO: ++
Families with
at least three women with breast cancer independent of age or
at least two women with breast cancer, one < 51 yrs. or
at least one woman affected by breast and one by ovarian cancer or
at least one woman affected by breast and ovarian cancer or
at least two women affected by ovarian cancer or
at least one woman affected by bilateral breast cancer, first < 51 yrs. or
at least one woman affected by breast cancer < 36 yrs. or
at least one man affected by breast cancer and one additional relative
affected by breast or ovarian cancer* #
* in one side of the family
#Inclusion
criteria of the German Consortium of Hereditary Breast and Ovarian Cancer
(GCHBOC) based on a mutation detection rate ≥ 10%
Use of a Screening Checklist*
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*online tool provided by the Ärztekammer Westfalen-Lippe based on the inclusion criteria of the GC-HBOC
www.aekwl.de/brustzentren-download
Recruitment of the German Consortium for Hereditary
Breast and Ovarian Cancer (GC-HBOC), Stand 9/2012
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28.417
16.692
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Empirical Mutation Detection Rates
in BRCA1 and BRCA2 Based on 12.662
Families from 1997–2013
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Familial constellation
Deleterious mutations %
>= 3 BrCa
23%
>= 2 BrCa, 1 > 51 y.
22%
>= 1 BrCa and >= 1 OvCa (in two women)
39%
>= 1 BrCa and >= 1 OvCa (in one woman)
48%
>= 2 OvCa
54%
>= 1 male BrCa and >= 1 Br- or OvCa
33%
>= 1 BrCa < 36 y.
30%
1 bil. BrCa, first < 51 y.
35%
Legend: BrCa = breast cancer, OvCa = ovarian cancer;
female cancer if not speficied
Third High Risk Gene Identified within the
GC-HBOC
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Nature Genetics April 18, 2010
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• 1.100 BRCA1/2 negative risk families:
670 breast only, 430 breast and ovarian cancer
• 6 deleterious mutations in BC/OC families only ( 1.5%)
Current Clinical Impact of Other Risk
Genes
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Further high risk genes, e.g RAD51C and RAD51D have recently been identified.
However, due to the low mutation detection rate, the predominant
identification of mutations in families with breast and ovarian cancer and
insufficient data on genotype / phenotype correlation genetic testing should
only be performed within studies like the GC-HBOC
Based on the hypothesis that cancer susceptibility may also be transmitted by
a oligo- or polygenic trait, new susceptibility genes (e.g. ATM, CHEK2,
PALB, FGFR2, TNRC9…) that confer low to moderate risk have been
identified by association studies. However, risk profiles of the known
variants do not yet allow risk stratification for the provision of clinical
prevention or surveillance strategies
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Clinical genetic testing for RAD51C
Clinical genetic testing for CHEK2 founder mut.
Clinical genetic testing for low risk variants
Refer mutation carriers to specialized centers
2b
2a
3b
5
B
B
D
D
+/+/-++
Genetically Defined Subtypes are
Distinct Tumor Entities
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Distinct genetic subtypes of breast cancer may show
distinct clinical features. Prior to the offer of prophylactic
measures the following questions should be adressed:
•Typical histopathological features?
•Sensitivity to current screening modalities?
•Better survival of early detected tumors?
•Natural disease course?
•Response to anti-tumor therapy?
Genotype-phenotype-correlations must be
employed
Requirements for the Introduction of New
Diagnostic or Predictive Genetic Testing
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• The risk collective is clearly defined by risk criteria
• The positive predictive value of risk critiera with respect
to the identification of the genetic risk factor is known
• The cut-off values for genetic testing evolved through a
transparent consensus process
• The genetic test is valide and reliable
• A spectrum bias is excluded or defined
• A clinical prevention strategy exists that leads to early
detection or prevention and mortality reduction of the
genetically defined subset of the disease
Non Directive Counseling for the Uptake
of Preventive Measures
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• According to the Genetic Diagnostic Law
• According to the Medical Devices Act, e.g. risk
assessment requires professional training and
expertise
• Communicate absolute risks within a manageable
timeframe
• Communicate competing risks, e.g. risk of progressive
disease in relation to the risk of a secondary primary in
case women have already been affected by primary
breast cancer
• Allow for appropriate time for consideration
Definition of Women at High Risk
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 Deleterious mutation in the BRCA1,
BRCA2 or RAD51C gene
 Heterozygous risk of >= 20% or
remaining life time risk of >=30% acc.
to a validated standard risk prediction
model
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 Childhood cancer survivors after chest
irradiation in adolescence (e.g.
Hodgkin disease)
1a
A
++
2b
B
+
2a
B
++
Surveillance Program for Women at High
Risk*
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Guidelines Breast
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Multimodal intensive surveillance program*

For the detection of early stage breast cancers
2a
B

Clinical breast exam
>=25 years
semi-annually

Sonography
>=25 years
semi-annually

Mammography
>=30 years
annual

Breast MRI
>=25 years
annual
++
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
For mortality reduction
5
D
+
*Referral to specialized centres of the GC-HBOC is recommended
Surgical Prevention for
Healthy BRCA1/2 Mutation Carriers
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• Risk-reducing bilateral salpingo-oophorectomy
(RR-BSO, PBSO) around 40 years of age
2a B ++*
reduces OvCa incidence and mortality
reduces BrCa incidence and mortality
reduces overall mortality
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• Risk-reducing bilateral mastectomy (RR-BM,
PBM)
2a B +*
reduces BrCa incidence and mortality
RR-BSO is performed after completion of family planning
RR-BM revealed a high incidence of premalignant lesions
*Study participation recommended
Risk-reducing Interventions for BRCA1/2
Mutation Carriers Affected by Breast Cancer
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Guidelines Breast
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• Bilateral salpingo-oophorectomy (RR-BSO) 2b
B
+*
reduces OvCa incidence and mortality
reduces BrCa mortality
reduces overall mortality
(contradictory results for reduction of cl BrCa incidence)
• Bilateral mastectomy+ (RR-BM)
2b
B
+/-*
• Tamoxifen (reduces cl BrCa incidence)
2b
B
+/-*
• Indication for PBM should consider age
at onset of first breast cancer and the
affected gene
2a
B
++*
reduces cl BrCa incidence
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+ Overall prognosis has to be considered *Study participation recommended
Risk-reducing Salpingo-oophorectomy
and All-cause Mortality
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Domchek et al. JAMA 2010; Table 4.
Contralateral Cancer Risk in 6235 BRCA1/2
Positive and Negative Patients
(retrospektive)
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N=135 second cancer events
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Rhiem et al. BCR Dec. 2012
Therapy of BRCA1/2-associated Breast
Cancer+
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Limited prospective cohort studies with short follow-up time
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Guidelines Breast
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Breast conserving therapy:
Adequate local tumor control (10 years observation)
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2a B
+
Systemic therapy according to sporadic breast cancer 3a B
+
BRCA1 mutation status is predictive for chemotherapy 3b B
response
+
Platinum-based regimens
3
+/-*
PARP inhibitor in metastatic breast cancer
2b D
+ Overall prognosis has to be considered
B
+/-
*Study participation recommended
Medical Prevention for
Women at Increased Risk
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• Tamoxifen for women > 35 years
Reduction of invasive BrCA, DCIS, and LN
1a A
• Raloxifen for postmenopausal women
Reduction of invasive BrCa only
1b A +*
+*
• Aromatase inhibitors for postmenopausal women 5 D +/Exemestane
1b A +
Chemopreventive regimes should only be offered after individual and
comprehensive counseling. The net benefit strongly depends on risk
status, age and pre-existing risk factors for side effects.
*Risk situation as defined in NSABP P1-trial (1.66% in 5 years)
Risk Reduction for Ipsi- and
Contralateral Breast Cancer
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Rationale: Women with breast cancer have an
increased risk for a second primary
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
Tamoxifen*
1a
A
+

Aromatase inhibitors*
1a
A
+

Suppression of ovarian function*
+ Tamoxifen
1b
B
+
*Only proven for ER/PgR-positive primary sporadic BrCa