Brustkrebs: genet. Erkrankung

Transkript

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2 Brustkrebs: genet. Erkrankung Bert Vogelstein (*1949) Johns-Hopkins-University,The revolution in cancer research can be summed up in a single sentence: Cancer is, in essence, a genetic disease.

3 Multiple Hit Theory Akkumulation von Mutationen Proto-Onkogene - Onkogene 6 Bereiche Wachstumsfaktoren, -rezeptoren G-Proteine Proteinkinasen nukl. Transkriptionsfaktoren tumorspez. Chromosomenaberrationen virale Onkogene (HPV, HTLV, RSV)

4 Multiple Hit Theory

5 Gene Syndrome Anomalies BRCA1 BRCA2 TP53 Hereditary breast and ovarian cancer Hereditary breast and ovarian cancer Li-Fraumeni Breast (female), ovarian, fallopian tube, testis Breast (female + male), ovarian, fallopian tube, pancreas Breast cancer, soft tissue and bone sarcomas, leukemia, brain, adrenocortical, choroid plexus, lung PTEN Cowden/PTEN hamartoma macrocephaly, breast, endometrial, nonmedullary thyroid, colon, renal cell CDH1 STK11 MMR genes (MSH2, MLH1, MSH6, PMS2) Hereditary diffuse gastric cancer Peutz-Jeghers Lynch (HNPCC) Lobular breast cancer, diffuse gastric cancer Hamartomatous gastrointestinal tract polyps; mucocutaneous pigmentation; breast, small bowel, stomach, colorectal, pancreas, lung, endometrium and ovary; sex cord tumor Colon, endometrial, ovarian, stomach

6 Eigene Daten

7 Eigene Daten

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9 BRCA - OC BRCA1 (~70%) andere Gene (~8%) HNPCC (~2%) BRCA2 (~20%)

10 Häufigkeit von BRCA-Mutationen

11 Erbgang von BRCA-Mutationen

12 Risiko

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14 BRCA - OC Gesamtpopulation Ontario: BRCA1: 0.32%; BRCA2: 0.69% n=1171 OC; unselected: 13.2% BRCA1: OC, fbc, Hoden BRCA2: OC, f+mbc, PAN Risiko abhängig von Mutationsposition innerh. d. Gens

15 BRCA - OC n=1421; CAN; unselected BRCA1: 8%; BRCA2: 5% 10-Jahres-Überlebensdaten Fazit: initiale Chemosensitivität kein Überlebensvorteil

16 BRCA - OC

17 Genes & OC n=209; OC; unselected; US 15%; BRCA1 n=20; BRCA2 n=12 keine BRCA-Mutationen in Boderline-Tumoren keine BRCA-Mutationen in muzinösen OCs 63% der BRCA+ OCs serös

18 Genes & OC non-brca, non-familial OC n=360; US; unselected RAD51D: 0.8% fam. Belastung: n=449; RAD51D: 0% Fazit: RAD51D = 1% non-familial OC

19 Genes & OC n=360 24% germline loss-of-function mutation 13 Tumorsuppressorgene BRCA1, BRCA2, CHEK2, RAD51D, BARD1, BRIP1, MRE11A, MSH6, NBN, PALB2, RAD50, RAD51C, TP53 Alter: a höchste Frequenz

20 Somat. Mut. n=235; US; unselected Frequenz in OC-Gewebe: n=44 (19%) BRCA1 n=31; BRCA2 n=13 von 28 Frauen germline DNA 9/21 BRCA1- u. 2/7 BRCA2- Mutationen somatisch Fazit: 40% BRCA1, 30% BRCA2 somatische Mutationen

21 BRCA - Mechanismus Turner et al. Nature Reviews Cancer 2004

22 BRCA - Mechanismus Banerjee, S. et al. (2010) Making the best of PARP inhibitors in ovarian cancer Nat. Rev. Clin. Oncol.

23 BRCA - Mechanismus Polyak and Garber, Nature Medicine. 2011

24 Screening vs. Prävention Hochrisikopatientin Früherkennung=Screening Vorsorge=Prävention Ziel: Senkung der Mortalität Ziel: Senkung der Inzidenz

25 Prävention: Adnexektomie

26 Prävention

27 Prävention: Adnexektomie

28 Ergebnisse

29 Ergebnisse

30 Prävention: Adnexektomie

31 Ergebnisse

32 Prävention: Adnexektomie

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34 Morbidität: Adnexektomie

35 Morbidität: Adnexektomie ASCO 2014: Women With BRCA Mutations Report Significant Side Effects Following Risk-Reducing Salpingo-Oophorectomy The majority of patients who had risk-reducing salpingooophorectomy reported suboptimal scores in sexual function, sleep, menopausal symptoms, and stress. 73% of patients reported sexual dysfunction, such as the absence of satisfaction and presence of pain; 61% had problems sleeping; 57% had symptoms of menopause such as hot flashes and vaginal dryness; and 56% had elevated levels of stress. Hormone replacement therapy did help mitigate symptoms, particularly in women with no cancer history who underwent oophorectomy prior to age 50.

36 HRT nach rradnexektomie?

37 Synchrone Hysterektomie? PRO Tamoxifen Therapie Hormonersatztherapie Blutungen, Myome, etc CONTRA Höhere Morbidität Längerer Spitalsaufenthalt Komplexerer Eingriff, Organverlust

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39 Wer macht das?

40 Wer macht das?

41 Wer macht das?

42 TAM & BRCA Analyse NSABP-P1 n=288 getestet; 19 (7%) BRCA 1/2 BRCA1: RR 1.67 ( ) BRCA2: RR 0.38 ( ) Fazit: TAM verhindert BRCA2-, nicht jedoch BRCA1-abhängige BC King et al. JAMA 2001

43 Gewichtabnahme Alternative?

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