Erfelijke borstkanker. Medicamenteuze primaire preventie: MBC symposium P. Neven (GNC, MBC-UZ Leuven)

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1 Erfelijke borstkanker Medicamenteuze primaire preventie: MBC symposium P. Neven (GNC, MBC-UZ Leuven)

2 Oestrogenen (E)/ Progestagenen(P)/ Erfelijke Borstkanker E/P~ BRCA-2 en CHEK2 (meestal ER-pos) BRCA-1 ~ ER-neg (mogelijk *ER-pos in vroeg stadium) -Vrouw > Man; jonger -E2 + P hoger -Vroege partus; multipariteit verhoogt kans en jongere leeftijd -Borstvoeding >6m verlaagt kans BRCA-1 > BRCA-2 -Intense sport verlaat tumoren (verhoogt SHBG) -BSO : Borstkankersterfte bij BRCA-1 is lager (vnl ER-neg) *ER transcriptional repression in mbrca-1 *ER-beta Huzardski et al. Polish Group in BCRT 2015 Metcalfe, Lynch, Foulkes et al. (12 centres Canada/ US) JAMA Oncol 2016 ER-neg BrCa: HR (BSO) BCSS 0.44 (95 % CI ; p = 0.02)

3 itt secundaire preventie Hormonale therapie Contraceptie: Hoger/Lager? SERM of Aromatase-remmer? Effect van RRSO +/-HT? Andere Pathways Klinische studies

4 OAC-pil & borstkanker : Geen RCT 2007 OAC-Pil & erfelijke borstkanker* Data from Collaborating Groups EMBRACE, GENEPSO, GEO-HEDON, IBCCS Ooit gebruik : HR % CI, Langer gebruik & voor 1 ste zwangerschap HR 1.49 (95% CI ) mbrca (95% CI ) mbrca-2 Past use = Current use Geen data voor andere dan mbrca1/2* *Geen éénduidigheid (conflicting results) owv: Controle groep: Niet altijd getest op mutatie/ Geen correctie preventieve HLK/ Geen correctie lft 1ste kind, BV,.

5 2014: OAC-pil & borstkanker bij mbrca-1 Data 72 centra (13 landen) -(RRSO, OvCa,< 1925) Missing info OAC-use n= 3276 breast cancer n= 4800 no breast cancer n= 2492 matched CC (years of birth) Mutatieonderzoek OAC increases risk OAC start < 20yrs Early onser BrCa <40yrs X OAC-pil ~ BRCA-2

decreases the risk of breast cancer in BRCA1 mutation carriers with

6 Borstkanker Baarmoederhalskanker Leverkanker Endometriumkanker Eierstokkanker Colo-rectale kanker Late age at first live birth decreases the risk of breast cancer in BRCA1 mutation carriers with women aged >30 years vs <30 years (HR = 0.65; 95% CI =0.42 to 0.99). J Natl Cancer Inst 2014;106

7 SERM of Aromatase Remmers? Effect op CL-borst Effect puur chemopreventie Effect van RRSO RRSO + HT Klinische studies Lancet 2000;356: Tamoxifen and risk of CL- breast cancer in BRCA1 and BRCA2 mutation carriers: A case-control study. Hereditary Breast Cancer Clinical Study Group. BRCA1 mutations (OR 0.38, 95% CI ) BRCA2 mutations (OR 0.63, 95% CI )

8 JCO 2013: Tamoxifen lowers risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers Table 3. Association Between Tamoxifen Use After First BC and CBC ASCO 2015: Aromatase inhibitors lower risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. 3 cohorten BRCA BRCA CBC Variable No. Person-Years No. %/Person-Year HR 95% CI P BRCA1 mutation carriers Combined data Took tamoxifen for first BC No 1,200 9, Yes 383 3, * 0.27 to 0.55 <.001 Prospective data only Took tamoxifen for first BC No 481 1, Yes to BRCA2 mutation carriers Combined data Took tamoxifen for first BC No 427 3, Yes 454 3, * 0.22 to 0.50 <.001 Prospective data only Took tamoxifen for first BC No Yes to Abbreviations: BC, breast cancer; CBC, contralateral breast cancer; HR, hazard ratio * Adjusted for age at diagnosis (continuous), year of diagnosis (continuous), bilateral prophylactic oophorectomy (time varying), and country of residence (categorical, as per Table 1). Adjusted for age at diagnosis (continuous) and country (categorical: Australia, Canada, France, United States, United Kingdom, other). CBC

9 JCO 2013: Tamoxifen lowers risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers 44% ER-known 24% BRCA-1 Tam Tam ~ Much Older ASCO 2015: Aromatase inhibitors lower risk of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers: YES but abstr only; NW Data are uninformative Chemopreventie trials?

10 BRCA1 mut. BRCA2 mut. Placebo TAM Risk Ratio (95% C.I.) BRCA WT All participants ( ) 0.38 ( ) 0.48 ( ) 0.52 ( ) No data from IBIS I neither data from NSABP-P2 or IBIS-II with AIs

11 Uitschakelen van eierstokken Effect van rrbso (sc gosereline*) RRSO + HT Klinische studies Relevantie van rrbso? <40j BRCA-1 <50j BRCA-2 *GISS-trial: von Minckwitz G. et al. Goserelin + Ibandronate+ Screening vs Screening Trial stopped following recruitement of 31/322 women. Cancer Epidemiol Biom 2011 *RAZOR-trial: Howell A. et al.(nct ): Raloxifene and Goserelin in Preventing Breast Cancer in women at high genetic risk for developing breast cancer: 2003 No data *TIZER-trial: No data

12 Geen RCT Matched case control studies & limited/variable FU (2/6yrs nobso/bso) 2009 meta-analysis Rebbeck et al. HR 0.21 (95%CI = ) risk of BRCA 1/2ovarian/fallopian tube cancer HR 0.49 (95%CI = ) risk of BRCA 1/2 breast cancer Optimal age of BSO more study needed Alle richtlijnen The potential benefits of RRBSO should be discussed with women. Management multidisciplinary team including genetics professional Timeline meestal: Profylactische mastectomie BSO Is er nut voor BSO Profylactische mastectomie? Misschien is bilaterale salpingectomie voldoende.

13 2015: Breast Cancer Risk After rrbso in Healthy BRCA1/2 Mutation Carriers: Revisiting the Evidence for Risk Reduction From: J Natl Cancer Inst The Author 2015.

14 HEBON analyse om zo veel mogelijk bias te voorkomen kon resultaten niet bevestigen bij gezonde BRCA1/2 mutatiedraagsters. -Gebruik makend van analyse door Rebbeck et al. -50% BrCa risk reduction. -- Previous studies showing 50% reduced BC risk is partly result from bias. Study BRCA1 BRCA2 BRCA1/2 Domchek et al. (2010), No. (%) (n = 970) (n = 597) (n = 1567) HEBON Cohort (n=589) (n = 233) (n = 822) Heemskerk-G et al. JNCI 2015 BSO 44j 6.8j 36/246 6/100 No BSO 33j 3.1j 39/343 8/133 BSO: no effect BSO: trend J Natl Cancer Inst. 2015;107(5)

15 Prospective study 5y FU in 3722 US/Can/Eur women mbrca1/2 Table 4. Bilateral oophorectomy and risk of breast cancer, stratified by BRCA mutation status and by age at diagnosis Variable Age-adjusted HR (95% CI) P Multivariable* HR (95% CI) P All women BRCA1 mutation carriers Oophorectomy No 1.00 (Referent) 1.00 (Referent) Yes 0.96 (0.73 to 1.26) (0.73 to 1.29).85 BRCA2 mutation carriers Oophorectomy No 1.00 (Referent) 1.00 (Referent) Yes 0.65 (0.37 to 1.16) (0.38 to 1.21).19 Breast cancer diagnosed prior to age 50 y BRCA1 mutation carriers Oophorectomy No 1.00 (Referent) 1.00 (Referent) Yes 0.79 (0.55 to 1.13) (0.58 to 1.21).34 BRCA2 mutation carriers Oophorectomy No 1.00 (Referent) 1.00 (Referent) Yes 0.18 (0.05 to 0.63) (0.05 to 0.61).006 BRCA-2: Yes it is preventive; BRCA-1: No, it is not preventive; 35-45yr: rrbso no effect

16 Hormonale substitutie na rrbso : Vermindert invaliderende gevolgen ervan Lange termijn gevolgen van premature of vroege menopause - Cognitie: Emoties; Geheugen; - Gemoedstoestand - Cardio-Vasculair - Bot - Sexuele Gezondheid - Risico op vroegere sterfte The use of hormone therapy has been shown to lessen some, although not all of these risks. Therefore, multiple medical societies recommend providing hormone therapy at least until the natural age of menopause. It is important to individualize hormone therapy for women with early estrogen deficiency Indien hysterectomie E-only Indien nog baarmoeder: E-P Eventueel rol voor tamoxifen

17 Andere pathways Levensstijl Reproductieve factoren Medicatie there is inconsistency in the epidemiologic literature on reproductive and lifestyle modifiers of BRCA1 and BRCA2 Klinische studies

18 Anti-Oestrogeen (LH-RH agonists +) AI (ApreS; LIBER- NCT ). Anti-progesterone RANKL-inhibitie Mifepristone Metformine Beta-HCG PARPP (-). ClinicalTrials.gov

RANK ligand as target for preventing BRCA-1 BrCa RANKL - RANK pathway is betrokken bij tumor inductie/progressive bij BRCA1 mutatie draagster. Progesterone activeert RANK+ cell.

19 RANK ligand as target for preventing BRCA-1 BrCa RANKL - RANK pathway is betrokken bij tumor inductie/progressive bij BRCA1 mutatie draagster. Progesterone activeert RANK+ cell. Cell of origin bij BRCA1-mutated tumors is RANK+ (ER/PR negative) cell die hypergevoelig is (via paracrine signalen) aan progesterone. Nolan E. RANK ligand: potential target for breast cancer prevention in BRCA1-mutation carriers. Nat Med 2016;22:

20 BRCA-P: Study Design

21 Besluit: Medicatie tegen Erfelijke Borstkankers Levensstijl? Chemopreventie Voor en nadelen van de OAC-pil Geen data voor LNG-IUD, POP Tamoxifen bij BRCA-2 rrbso + HT in BRCA-2 Trials: Denosumab trial bij BRCA-1; AI trials Effective chemo-preventive strategies are not yet available

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