02 2012e breast cancer risk and prevention
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breast ccTRANSCRIPT
Diagnosis and Treatment of Patients
with Primary and Metastatic Breast Cancer
© AGO e. V.in der DGGG e.V.
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Guidelines Breast
Version 2012.1
Breast Cancer Risk and
Prevention
© AGO e. V.in der DGGG e.V.
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Guidelines Breast
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Breast Cancer Risk and Prevention
Version 2003:
Kiechle / Schmutzler
Versions 2004–2011:
Albert / Blohmer / Fehm / Maass /
Schmutzler / Thomssen
Version 2012:
Schmutzler / Mundhenke
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Guidelines Breast
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Principles in Prevention
• 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
• Highest priority: „First, do no harm!“
(Primum nil nocere)
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Who Should be Tested for BRCA1/2
Mutations?
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
Oxford LoE: 2b GR: B AGO: ++
#Inclusion criteria of the German Consortium of Hereditary Breast and Ovarian Cancer
(GCHBOC) based on a mutation detection rate ≥10%
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Recruitment of the German Consortium for Hereditary
Breast and Ovarian Cancer (GC-HBOC)
0
2000
4000
6000
8000
10000
12000
14000
16000
18000
20000
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
Jahr
An
zah
l
Familien Studienpatienten
10.501
17.915
+ 1.289 families per year
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Guidelines Breast
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Gene Families Patients
Distinct
pathogenic
variants
Distinct
UCVs
BRCA1 1383 2456 310 160
BRCA2 636 1192 271 263
Negativ 5295 5295 - -
Total 7314
(28% pos.)
8943
Genetic Diagnostics within the GC-HBOC 8/2010
No. Families, Study Patients, Unclassified Variants
Acceptance Rate >90%
Relieved: 1402 persons
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Mutation Detection Rates
Based on 6215 Families from 1997–2010
Familial constellation Deleterious mutations %
>= 3 BrCa, 2 < 51 y 39.2
>= 3 BrCa 30.0
2 BrCa < 51 y 15.7
2 BrCa, 1 < 51 y 15.7
>= 1 BrCa and >= 1 OvCa 48.5
>= 2 OvCa 66.7
1 BrCa < 37 y 17.1
1 bil. BrCa, first < 51 y 39.0
>= 1 male BrCa and >= 1 female Br-
or OvCa
42.1
Legend: BrCa= breast cancer, OvCa= ovarian cancer;
female cancer if not speficied
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Guidelines Breast
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Other Risk Genes
RAD51C has been identified as a third high risk gene. However, due to the low
mutation detection rate, the predominent identification of mutations in
families with breast and ovarian cancer and insufficient data on genotype /
phenotype correlation genetic testing should only be performed within the
GC-HBOC
Based on the hypothesis that cancer susceptibility may also be transmitted by
a 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
Clinical genetic testing for RAD51C 2 B +/-
Clinical genetic testing for low risk variants 3b D --
Oxford / AGO
LoE / GR
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Guidelines Breast
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Nature Genetics April 18, 2010
• 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%)
Third High Risk Gene Identified within the
GC-HBOC
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Table 2: Summary of results for eleven SNPs selected for stage 3
that showed evidence of an association
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Collective of the German Consortium
GENE SNP All cases High risk (AB) Moderate risk
(C, D, G)
Easton et al.4
FGFR2 rs1219648 1.32 (1.21;1.44)
p = 2.39e-10+
1.43 (1.30;1.59)
p = 1.24e-12+
1.16 (1.03;1.32)
p = 1.89e-02
1.23 (1.23-1.30)*
TNRC9 rs3803662 1.33 (1.26;1.46)
p = 8.52e-10+
1.33 (1.19;1.48) p
= 1.54e-07+
1.30 (1.14;1.48) p
= 1.01e-04
1.20 (1.16-1.24)
LSP1 rs2271439 0.82 (0.72;0.95)
p = 5.49e-03
0.73 (0.61;0.87) p
= 5.23e-04
0.92 (0.78;1.09) p
= 3.41e-01
1.07 (1.09-1.18)*
2q35 rs1338704
2
0.87
(0.78;0.96) p =
8.34e-03
0.88 (0.77;1.00)
p = 5.39e-02
0.86 (0.76;0.98)
p = 2.31e-02
n. a.
6q22.33 rs6569479 1.17 (1.04;1.32)
p = 8.57e-03
1.15 (0.99;1.33)
p = 6.90e-02
1.19 (1.03;1.38)
p = 1.72e-02
n. a.
MAP3K1 rs726501 1.17 (0.99;1.38)
p = 6.11e-02
1.12 (0.91;1.37) p
= 3.01e-01
1.22 (1.00;1.50) p
= 4.92e-02
1.13 (1.10-1.16)
C17orf59 rs8531 0.81 (0.70;0.93)
p = 3.53e-03
0.87 (0.73;1.03) p
= 1.07e-01
0.76 (0.63;0.91) p
= 2.69e-03
n. a.
Hemminki et al. Int. J. Cancer 2010
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Requirements for the Introduction of New
Diagnostic or Predictive Genetic Testing
• 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
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Definition of Women at High Risk
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
Childhood cancer survivors after chest
irradiation in adolescence (e.g.
Hodgkin disease)
1a A ++
2b B ++
2a B ++
Oxford / AGO
LoE / GR
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Guidelines Breast
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Surveillance Program for Women at
High Risk*
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
For mortality reduction 5 D +
Oxford / AGO
LoE / GR
*Referral to specialized centres of the GC-HBOC is recommended
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Surgical Prevention for
Healthy BRCA1/2 Mutation Carriers
• Prophylactic bilateral salpingo-oophorectomy 2a B ++*(PBSO) around 40 years of age
reduces OvCa incidence and mortality
reduces BrCa incidence and mortality
reduces overall mortality
• Prophylactic bilateral mastectomy (PBM) 2a B +*
reduces BrCa incidence and mortality
PBSO is performed after completion of family planning;
PBM revealed a high incidence of premalignant lesions
Oxford / AGO
LoE / GR
*Study participation recommended
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Prophylactic Interventions for BRCA1/2
Mutation Carriers Affected by Breast Cancer
• Bilateral salpingo-oophorectomy (PBSO) 2b B +*
reduces OvCa incidence and mortality
reduces BrCa mortality
reduces overall mortality
(contradictory results for reduction of cl BrCa incidence)
• Bilateral mastectomy+ (PBM) 2b B +/-*
reduces cl BrCa incidence
• Tamoxifen (reduces cl BrCa incidence) 2b B +/-*
• Indication for PBM should consider age 2a B ++*
at onset of first breast cancer and the
affected gene
Oxford / AGO
LoE / GR
+ Overall prognosis has to be considered
*Study participation recommended
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Domchek et al. JAMA 2010
Table 3: Risk-reducing salpingo-oophorectomy and breast cancer risk
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Domchek et al. JAMA 2010
Table 4: Risk-reducing salpingo-oophorectomy and all-cause mortality
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Guidelines Breast
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Contralateral Breast Cancer Risk in
BRCA1 and BRCA2 Mutation Carriers
JCO, Published Ahead of Print on October 26, 2009 as
10.1200/JCO.2008.19.9430
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Cumulative Risk
Table 2: Cumulative risks and 95% CIs for contralateral breast cancer
depending on age at first breast cancer observed in relatives of index
patients
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Breast conserving therapy:
Adequate local tumor control (10 years observation) 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 B +/-*
PARP inhibitor in metastatic breast cancer 2b D +/-
Oxford / AGO
LoE / GR
Limited prospective cohort studies with short follow-up time
Therapy of BRCA1/2-associated Breast
Cancer+
+ Overall prognosis has to be considered
*Study participation recommended
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Medical Prevention for
Women at Increased Risk
• Tamoxifen for women > 35 years 1a A +*
Reduction of invasive BrCA, DCIS, and LN
• Raloxifen for postmenopausal women 1b A +*
Reduction of invasive BrCa only
• 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)
Oxford / AGO
LoE / GR
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Guidelines Breast
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Risk Reduction for Ipsi- and
Contralateral Breast Cancer
Tamoxifen* 1a A +
Aromatase inhibitors* 1a A +
Suppression of ovarian function*
+ Tamoxifen 1b B +
*Only proven for ER/PgR-positive primary sporadic BrCa
Oxford / AGO
LoE / GR
Rationale: Women with breast cancer have an
increased risk for a second primary