Familial gynaecological cancers
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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

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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


Familial gynaecological cancers

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%)


Familial gynaecological cancers

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


Familial gynaecological cancers

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


Familial gynaecological cancers

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


    Familial gynaecological cancers

    www.obermair.info

    07 3830 5824


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