Breast Cancer Risk and Prevention

Transcription

1 Diagnosis and Treatment of Patients with Primary and Metastatic Breast Cancer Breast Cancer Risk and Prevention

2 Breast Cancer Risk and Prevention Version 2003: Kiechle / Schmutzler Versions : Albert / Blohmer / Fehm / Maass / Schmutzler / Thomssen Version 2012: Schmutzler / Mundhenke

3 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)

4 Who Should be Tested for BRCA1/2 Mutations? Oxford LoE: 2b 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%

5 Anzahl Recruitment of the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC) Familien Studienpatienten families per year Jahr

6 Genetic Diagnostics within the GC-HBOC 8/2010 No. Families, Study Patients, Unclassified Variants Gene Families Patients Distinct pathogenic variants Distinct UCVs BRCA BRCA Negativ Total 7314 (28% pos.) 8943 Acceptance Rate >90% Relieved: 1402 persons

7 Mutation Detection Rates Based on 6215 Families from Familial constellation Deleterious mutations % >= 3 BrCa, 2 < 51 y 39.2 >= 3 BrCa BrCa < 51 y BrCa, 1 < 51 y 15.7 >= 1 BrCa and >= 1 OvCa 48.5 >= 2 OvCa BrCa < 37 y bil. BrCa, first < 51 y 39.0 >= 1 male BrCa and >= 1 female Bror OvCa 42.1 Legend: BrCa= breast cancer, OvCa= ovarian cancer; female cancer if not speficied

8 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 Oxford / AGO LoE / GR Clinical genetic testing for RAD51C 2 B +/- Clinical genetic testing for low risk variants 3b D --

9 Third High Risk Gene Identified within the GC-HBOC Nature Genetics April 18, BRCA1/2 negative risk families: 670 breast only, 430 breast and ovarian cancer 6 deleterious mutations in BC/OC families only ( 1.5%)

10 Table 2: Summary of results for eleven SNPs selected for stage 3 that showed evidence of an association

11 Collective of the German Consortium GENE SNP All cases High risk (AB) Moderate risk (C, D, G) FGFR2 rs (1.21;1.44) p = 2.39e-10+ TNRC9 rs (1.26;1.46) p = 8.52e-10+ LSP1 rs (0.72;0.95) p = 5.49e-03 2q35 rs (0.78;0.96) p = 8.34e-03 6q22.33 rs (1.04;1.32) p = 8.57e-03 MAP3K1 rs (0.99;1.38) p = 6.11e-02 C17orf59 rs (0.70;0.93) p = 3.53e (1.30;1.59) p = 1.24e (1.19;1.48) p = 1.54e (0.61;0.87) p = 5.23e (0.77;1.00) p = 5.39e (0.99;1.33) p = 6.90e (0.91;1.37) p = 3.01e (0.73;1.03) p = 1.07e (1.03;1.32) p = 1.89e (1.14;1.48) p = 1.01e (0.78;1.09) p = 3.41e (0.76;0.98) p = 2.31e (1.03;1.38) p = 1.72e (1.00;1.50) p = 4.92e (0.63;0.91) p = 2.69e-03 Easton et al ( )* 1.20 ( ) 1.07 ( )* n. a. n. a ( ) n. a. Hemminki et al. Int. J. Cancer 2010

12 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

13 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) Oxford / AGO LoE / GR 1a A ++ 2b B ++ 2a B ++

14 Surveillance Program for Women at High Risk* Multimodal intensive surveillance program* Oxford / AGO LoE / GR 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 + *Referral to specialized centres of the GC-HBOC is recommended

15 Surgical Prevention for Healthy BRCA1/2 Mutation Carriers Oxford / AGO LoE / GR 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 *Study participation recommended

16 Prophylactic Interventions for BRCA1/2 Mutation Carriers Affected by Breast Cancer Oxford / AGO LoE / GR 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 + Overall prognosis has to be considered *Study participation recommended

17 Domchek et al. JAMA 2010 Table 3: Risk-reducing salpingo-oophorectomy and breast cancer risk

18 Domchek et al. JAMA 2010 Table 4: Risk-reducing salpingo-oophorectomy and all-cause mortality

19 Contralateral Breast Cancer Risk in BRCA1 and BRCA2 Mutation Carriers JCO, Published Ahead of Print on October 26, 2009 as /JCO

20 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

21 Therapy of BRCA1/2-associated Breast Cancer+ Limited prospective cohort studies with short follow-up time Breast conserving therapy: Oxford / AGO LoE / GR 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 +/- + Overall prognosis has to be considered *Study participation recommended

22 Medical Prevention for Women at Increased Risk Oxford / AGO LoE / GR 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)

23 Risk Reduction for Ipsi- and Contralateral Breast Cancer Rationale: Women with breast cancer have an increased risk for a second primary Oxford / AGO LoE / GR Tamoxifen* 1a A + Aromatase inhibitors* 1a A + Suppression of ovarian function* + Tamoxifen 1b B + *Only proven for ER/PgR-positive primary sporadic BrCa