02 2012e breast cancer risk and prevention

Diagnosis and Treatment of Patients

with Primary and Metastatic Breast Cancer

© AGO e. V.in der DGGG e.V.

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in der DKG e.V.

Guidelines Breast

Version 2012.1

Breast Cancer Risk and

Prevention


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in der DKG e.V.

Guidelines Breast

Version 2012.1

www.ago-online.de

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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Guidelines Breast

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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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Guidelines Breast

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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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Guidelines Breast

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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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Guidelines Breast

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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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Guidelines Breast

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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



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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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Guidelines Breast

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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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Guidelines Breast

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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



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Guidelines Breast

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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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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

02 2012e breast cancer risk and prevention

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