familial gynaecological cancers a/prof andreas obermair gynaecological oncologist rbwh, greenslopes...
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Familial Gynaecological Cancers
A/Prof Andreas Obermair
Gynaecological OncologistRBWH, 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%
• 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)
• 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
• 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
• 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 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%)
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
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
• 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 1992-1998
• 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 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
• Menopause – lipid profile– 2x 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
• 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
• ? 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) 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
• 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 IsraelBut small study & wide confidence limits• Modan et al. N.Eng.J.Med. 345(2001)
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
• 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
www.obermair.info07 3830 5824