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Familial Gynaecological Cancers A/Prof Andreas Obermair Gynaecological Oncologist RBWH, Greenslopes Private Hospital

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Presentation on theme: "Familial Gynaecological Cancers A/Prof Andreas Obermair Gynaecological Oncologist RBWH, Greenslopes Private Hospital"— Presentation transcript:

1 Familial Gynaecological Cancers A/Prof Andreas Obermair Gynaecological Oncologist RBWH, Greenslopes Private Hospital

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 1 st or 2 nd 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 ( > ?role of OCP+/- tubal ligation

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