Familial Gynaecological Cancers A Prof Andreas Obermair Gynaecological Oncologist

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

Major Known Mutations • • BRCA 1 BRCA 2 Mismatch Repair Genes Other undiscovered

Hereditary Ovarian Cancer • BRCA 1 life-time risk 16 -54% • BRCA 2 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) • Microsatillite DNA sequences which are prone to mutation during replication • HNPCC & endometrial cancer • Rare: Urological tumours • MSH 2 & MLH 1 genes most commonly implicated

HPNCC/mismatch repair genes • Most have colon cancer penetrance of 3070% • Endometrial Ca 42% – Annual Uterine sampling &Transvaginal Ultrasound – Hysterectomy at time of colectomy

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 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

Rebbeck et al. The Prevention and Observation of Surgical end points Study Group. Prophylactic oophorectomy in carriers of BRCA 1 or BRCA 2 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. 8 yrs median follow-up) – Only 6 stage 1(11%)

Kauff et al. Risk reducing salpingo-oophorectomy in women with BRCA 1 or BRCA 2 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

Piver et al. Familial Ovarian Cancer. A report of 658 families from the Gilda Radner Familial Ovarian Cancer Registry 1981 -1991. Cancer 71(1993) pp 582 -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

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 laparotomy ~ 17% • Risks of laparoscopy ~ 4%

Elit et al. Prophylactic oophorectomy in Ontario. Fam. Cancer 1 (2001), pp. 143 -148 • Ontario Hospital based study 41 institutions prophylactic BSO from 19921998 • 274 pts (141 co-existent gynae problems) • 15. 7% complications –bleeding, infection, damage to organs - most laparotomy

Krauf et al. Risk reducing salpingo-oophorectomy in women with BRCA 1 or BRCA 2 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 • Menopause – lipid profile – 2 x CAD – Osteoporosis – Higher rate of decreased libido & sexual satisfaction • Role of HRT

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 • 1 occult 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 • ? Increased risk of endometrial Ca • Hysterectomy guarantees complete resection of fallopian tube • HRT simplified But increased morbidity

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) pp 1475 -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 • Oral contraceptives - Controversies – 60% reduction in Ovarian Cancer if used for >6 yrs • 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 • Associated with decreased incidence in general population (? reason) • BRCA 1 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 BRCA 1/2 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 • 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 • 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

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