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Familial Gynaecological Cancers. A/Prof Andreas Obermair Gynaecological Oncologist RBWH, Greenslopes Private Hospital www.obermair.info. Major Known Mutations. BRCA1 BRCA2 Mismatch Repair Genes Other undiscovered. Hereditary Ovarian Cancer. BRCA1 life-time risk 16-54\%

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familial gynaecological cancers

Familial Gynaecological Cancers

A/Prof Andreas Obermair

Gynaecological Oncologist

RBWH, Greenslopes Private Hospital

www.obermair.info

major known mutations
Major Known Mutations
  • BRCA1
  • BRCA2
  • Mismatch Repair Genes
  • Other undiscovered
hereditary ovarian cancer
Hereditary Ovarian Cancer
  • BRCA1 life-time risk 16-54%
  • BRCA2 life-time risk 10-25%
    • Risks vary depending on the population being studied
  • ~10% of cancer due to these genes
  • ? Primary Peritoneal Cancer, Fallopian Tube Cancer
hnpcc lynch syndrome type ii
HNPCC(Lynch Syndrome Type II)
  • Microsatillite DNA sequences which are prone to mutation during replication
  • HNPCC & endometrial cancer
  • Rare: Urological tumours
  • MSH2 & MLH1 genes most commonly implicated
hpncc mismatch repair genes
HPNCC/mismatch repair genes
  • Most have colon cancer penetrance of 30-70%
  • Endometrial Ca 42%
    • Annual Uterine sampling &Transvaginal Ultrasound
    • Hysterectomy at time of colectomy
cancer gene testing in qld
Cancer Gene Testing in Qld
  • Qld Clinical Genetics Service established in 1995
  • Funding for 50 tests per year
    • Uses software to estimate individuals with a risk >15%
    • May not detect all predisposing mutations
  • Requires a blood sample from an affected living relative
hereditary ovarian cancer1
Hereditary Ovarian Cancer
  • 4 Cohort studies (2 retrospective, 2 prospective)
  • 1 family history only, 3 BRCA mutations
  • All 4 studies found protective effect of surgery
  • Variability in patient populations & patient methodology
slide8
Rebbeck et al. The Prevention and Observation of Surgical end points Study Group. Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. N.Eng.J.Med. 346(2002),pp.1616-1622
  • Retrospective cohort of 259 women with BSO and 292 no BSO (matched control group)
  • BSO group – 6 cases of stage 1 ovarian ca
    • 2 cases of peritoneal ca found 3.8&8.6 yrs later
  • No BSO –58 ovarian ca (8.8yrs median follow-up)
    • Only 6 stage 1(11%)
slide9
Kauff et al. Risk reducing salpingo-oophorectomy in women with BRCA1 or BRCA2 mutation. N.Eng.J.Med.346(2002),pp 1609-1615
  • Prospective
  • 98 BSO vs. 72 who chose not to have BSO
  • 2 groups similar age & other risk factors
    • Mean follow-up 25.4 months
  • BSO – 1 peritoneal Ca (16.3 months)
  • No BSO –4 ovarian Ca
    • 8 breast Ca, 1 peritoneal Ca
slide10
Piver et al. Familial Ovarian Cancer.A report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry 1981-1991. Cancer 71(1993) pp582-588
  • 324 women (familial ovarian cancer registry) with family history of 2 or more 1st or 2nd degree relatives with ovarian Ca
  • All patients had prophylactic BSO
  • 6 women primary peritoneal Ca (1.9%)
  • Residual risk of Primary Peritoneal Cancer
summary prophylactic surgery
Summary Prophylactic Surgery
  • Risk of ovarian cancer reduced by > 95%
    • Most patients found at stage 1 (prognosis  )
  • Risk of breast cancer reduced by 50%
  • Risk of occult cancer found at surgery 14 to 18%
  • Residual risk of primary peritoneal cancer < 2%
risks of surgery
Risks of surgery
  • Risks of laparotomy ~ 17%
  • Risks of laparoscopy ~ 4%
elit et al prophylactic oophorectomy in ontario fam cancer 1 2001 pp 143 148
Elit et al . Prophylactic oophorectomy in Ontario.Fam. Cancer 1 (2001),pp. 143-148
  • Ontario Hospital based study 41 institutions prophylactic BSO from 1992-1998
  • 274 pts (141 co-existent gynae problems)
  • 15.7% complications –bleeding, infection, damage to organs - most laparotomy
slide14
Krauf et al. Risk reducing salpingo-oophorectomy in women with BRCA1 or BRCA2 mutations. N.Eng.J.Med.346(2002),pp. 1609-1615
  • 98 BSO - complications 4
  • 1 re-operation for small bowel obstruction
  • Increasing trend to laparoscopy with risk of complications 0.22-4.0%
long term adverse effects
Long-term adverse effects
  • Menopause
    • lipid profile
    • 2x CAD
    • Osteoporosis
    • Higher rate of decreased libido & sexual satisfaction
  • Role of HRT
surgical options
Surgical Options
  • Minimum of BSO
    • Occult ovarian or fallopian tube Ca
    • Fallopian tube and Infundibulo-Pelvic Ligament need to be removed completely.
    • Age? Uncommon in women < 35 years
  • Peritoneal lavage for cytology
    • 35 women, 3 + cytology
      • 1occult fallopian tube Ca, 1 fallopian ACIS
      • 1 no histological evidence of Ca
        • Coglan et al. Gynecol Oncol. 85(2002), pp.397-403
role of hysterectomy
Role of Hysterectomy
  • ? Increased risk of endometrial Ca
  • Hysterectomy guarantees complete resection of fallopian tube
  • HRT simplified

But increased morbidity

benefits on breast cancer
Benefits on Breast Cancer
  • Prophylactic BSO protective for breast Ca
  • RR 0.47(95% CI 0.29-0.77)
  • HRT did not negate the reduction in breast Ca
      • Rebbeck et al Natl. Cancer Inst. 91(1999) pp1475-1479
  • Proportion Breast Ca free at 5 yr
    • 94% BSO group
    • 79% surveillance group(p=0.07)
      • Kauff et al N.Engl.J.Med. 346(2002),pp 1609-1615
alternative to oophorectomy
Alternative to oophorectomy
  • Oral contraceptives - Controversies
    • 60% reduction in Ovarian Cancer if used for >6yrs
      • Narod et al. N.Engl.J.Med.339(1998)
    • No reduction in study in Israel

But small study & wide confidence limits

      • Modan et al. N.Eng.J.Med. 345(2001)
tubal ligation
Tubal Ligation
  • Associated with decreased incidence in general population (?reason)
  • BRCA1 Tubal ligation in 232 assoc with odds ratio of 0.39 (95% confidence limits 0.22-0.70)
  • Tubal ligation & OCP 0.28 (95% confidence limits 0.15-0.52)
    • Narod et al. Lancet. 357(2001)pp.1467-1470
perceptions of women with brca1 2 mutations
Perceptions of women with BRCA1/2 Mutations
  • Psychological testing on those with surgery vs. observation,
  • Anxiety reduced with surgery,
  • 86% high level of satisfaction.

Tiller et al.: Gynecol Oncol 2002

discussion
Discussion
  • No randomized control trials of surgery vs. observation
  • Cohorts studies showed risk reduction
  • Complications are low (note impact of laparoscopic surgery)
  • Optimal procedure is not well defined
      • Fallopian tube ca
  • Role OCP & tubal ligation
conclusions
Conclusions
  • Women with family history should be assessed for genetic counseling & possible testing
  • Surgery - ovary + fall. tube MUST BE removed
  • Young women (< 35 years) >> ?role of OCP+/- tubal ligation
slide24
www.obermair.info

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