Effekte prophylaktischer Operationen bei BRCA1/2

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.’
Multiple Hit Theory
Akkumulation von Mutationen
  Proto-Onkogene - Onkogene
  6 Bereiche
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Wachstumsfaktoren, -rezeptoren
G-Proteine
Proteinkinasen
nukl. Transkriptionsfaktoren
tumorspez. Chromosomenaberrationen
virale Onkogene (HPV, HTLV, RSV)
Multiple Hit Theory
Gene
Syndrome
Anomalies
BRCA1
Hereditary breast and ovarian
cancer
Breast (female), ovarian, fallopian
tube, testis
BRCA2
Hereditary breast and ovarian
cancer
Breast (female + male), ovarian,
fallopian tube, pancreas
Li-Fraumeni
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
Hereditary diffuse gastric cancer
Lobular breast cancer, diffuse
gastric cancer
STK11
Peutz-Jeghers
Hamartomatous gastrointestinal
tract polyps; mucocutaneous
pigmentation; breast, small
bowel, stomach, colorectal,
pancreas, lung, endometrium
and ovary; sex cord tumor
MMR genes (MSH2, MLH1,
MSH6, PMS2)
Lynch (HNPCC)
Colon, endometrial, ovarian,
stomach
TP53
Eigene Daten
Eigene Daten
BRCA - OC
BRCA1 (~70%) andere Gene (~8%) HNPCC (~2%) BRCA2 (~20%) Häufigkeit von BRCA-Mutationen
Erbgang von BRCA-Mutationen
Risiko
BRCA - OC
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Gesamtpopulation Ontario:
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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
 
BRCA - OC
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n=1421; CAN; unselected
BRCA1: 8%; BRCA2: 5%
10-Jahres-Überlebensdaten
Fazit: initiale Chemosensitivität kein
Überlebensvorteil
BRCA - OC
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
 
Genes & OC
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non-BRCA, non-familial OC
n=360; US; unselected
RAD51D: 0.8%
fam. Belastung: n=449; RAD51D: 0%
Fazit: RAD51D = 1% non-familial OC
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: 40-60 a höchste Frequenz
Somat. Mut.
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n=235; US; unselected
Frequenz in OC-Gewebe: n=44 (19%)
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BRCA1 n=31; BRCA2 n=13
von 28 Frauen germline DNA
  9/21 BRCA1- u. 2/7 BRCA2Mutationen somatisch
 
Fazit: 40% BRCA1, 30% BRCA2
somatische Mutationen
BRCA - Mechanismus
Turner et al. Nature Reviews Cancer 2004
BRCA - Mechanismus
Banerjee, S. et al. (2010) Making the best of PARP inhibitors in ovarian cancer
Nat. Rev. Clin. Oncol.
BRCA - Mechanismus
Polyak and Garber, Nature Medicine. 2011
Screening vs. Prävention
Hochrisikopatientin
Früherkennung=Screening
Ziel: Senkung der
Mortalität
Vorsorge=Prävention
Ziel: Senkung der
Inzidenz
Prävention: Adnexektomie
Prävention
Prävention: Adnexektomie
Ergebnisse
Ergebnisse
Prävention: Adnexektomie
Ergebnisse
Prävention: Adnexektomie
Morbidität: Adnexektomie
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.
HRT nach rrAdnexektomie?
Synchrone Hysterektomie?
PRO
CONTRA
Tamoxifen Therapie
Höhere Morbidität
Hormonersatztherapie
Längerer Spitalsaufenthalt
Blutungen, Myome, etc
Komplexerer Eingriff,
Organverlust
Wer macht das?
Wer macht das?
Wer macht das?
TAM & BRCA
Analyse NSABP-P1
  n=288 getestet; 19 (7%) BRCA 1/2
  BRCA1: RR 1.67 (0.3-10.7)
  BRCA2: RR 0.38 (0.06-1.6)
  Fazit: TAM verhindert BRCA2-, nicht
jedoch BRCA1-abhängige BC
 
King et al. JAMA 2001
Gewichtabnahme – Alternative?