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

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