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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. 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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  1. Familial Gynaecological Cancers A/Prof Andreas Obermair Gynaecological Oncologist RBWH, Greenslopes Private Hospital www.obermair.info

  2. Major Known Mutations • BRCA1 • BRCA2 • Mismatch Repair Genes • Other undiscovered

  3. 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

  4. 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

  5. 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

  6. 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

  7. 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

  8. 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%)

  9. 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

  10. 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

  11. 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%

  12. Risks of surgery • Risks of laparotomy ~ 17% • Risks of laparoscopy ~ 4%

  13. 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

  14. 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%

  15. Long-term adverse effects • Menopause • lipid profile • 2x CAD • Osteoporosis • Higher rate of decreased libido & sexual satisfaction • Role of HRT

  16. 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

  17. Role of Hysterectomy • ? Increased risk of endometrial Ca • Hysterectomy guarantees complete resection of fallopian tube • HRT simplified But increased morbidity

  18. 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

  19. 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)

  20. 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

  21. 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

  22. 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

  23. 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

  24. www.obermair.info 07 3830 5824

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