Breast Cancer Risk and Prevention

Diagnosis and Treatment of Patients
with Primary and Metastatic Breast Cancer
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Breast Cancer Risk and
Prevention
Breast Cancer Risk and Prevention
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Guidelines Breast
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 Version 2003:
Kiechle / Schmutzler
 Versions 2004–2011:
Albert / Blohmer / Fehm / Maass /
Schmutzler / Thomssen
 Version 2012:
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Schmutzler / Mundhenke
Principles in Prevention
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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%
Recruitment of the German Consortium for Hereditary
Breast and Ovarian Cancer (GC-HBOC)
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20000
Guidelines Breast
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18000
Familien
Studienpatienten
16000
17.915
Anzahl
14000
12000
+ 1.289 families per year
10000
10.501
8000
6000
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4000
2000
0
1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011
Jahr
Genetic Diagnostics within the GC-HBOC 8/2010
No. Families, Study Patients, Unclassified Variants
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Gene
Families
Patients
Distinct
pathogenic
variants
BRCA1
1383
2456
310
160
BRCA2
636
1192
271
263
Negativ
5295
5295
-
-
Total
7314
(28% pos.)
8943
Acceptance Rate >90%
Relieved: 1402 persons
Distinct
UCVs
Mutation Detection Rates
Based on 6215 Families from 1997–2010
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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- 42.1
or OvCa
Legend: BrCa= breast cancer, OvCa= ovarian cancer;
female cancer if not speficied
Other Risk Genes
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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
Oxford / AGO
LoE / GR
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Clinical genetic testing for RAD51C
Clinical genetic testing for low risk variants
2
3b
B
D
+/--
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%)
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Table 2: Summary of results for eleven SNPs selected for stage 3
that showed evidence of an association
Collective of the German Consortium
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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)
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.
GENE
C17orf59
Hemminki et al. Int. J. Cancer 2010
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
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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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
++
www.ago-online.de

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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• 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)
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2a B +*
reduces BrCa incidence and mortality
PBSO is performed after completion of family planning;
PBM revealed a high incidence of premalignant lesions
*Study participation recommended
Prophylactic Interventions for BRCA1/2
Mutation Carriers Affected by Breast Cancer
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• Bilateral salpingo-oophorectomy (PBSO)
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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
+/-*
2b
B
+/-*
reduces cl BrCa incidence
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• Tamoxifen (reduces cl BrCa incidence)
• Indication for PBM should consider age
2a B ++*
at onset of first breast cancer and the
affected gene
+ Overall prognosis has to be considered
*Study participation recommended
Domchek et al. JAMA 2010
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Table 3: Risk-reducing salpingo-oophorectomy and breast cancer risk
Domchek et al. JAMA 2010
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Table 4: Risk-reducing salpingo-oophorectomy and all-cause mortality
Contralateral Breast Cancer Risk in
BRCA1 and BRCA2 Mutation Carriers
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 JCO, Published Ahead of Print on October 26, 2009 as
10.1200/JCO.2008.19.9430
Cumulative Risk
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Table 2: Cumulative risks and 95% CIs for contralateral breast cancer
depending on age at first breast cancer observed in relatives of index
patients
Therapy of BRCA1/2-associated Breast
Cancer+
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Limited prospective cohort studies with short follow-up time
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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
response
B
+
Platinum-based regimens
3
B
+/-*
2b
D
+/-
PARP inhibitor in metastatic breast cancer
+ Overall prognosis has to be considered
*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