Familial Ovarian Cancer

Diane Stirling

Ovarian cancer in the UK

• 5th highest incidence of ovarian cancer.• 4th most common cancer in women• Risk of developing ovarian cancer

up to age 64 - 0.9%up to age 74 - 1.5%

• 5000 women are diagnosed each year & 4000 deaths (East of Scotland has approximately 180 cases per year)

• 12.1% increase in prevalence from 1989-1998

Five year survival ratesEurope 33%United Kingdom 25%Scotland 27.8%

Borders 29%Lothian 27.8%Fife 20.3%

Accounts Commission for Scotland “Fighting the silent killer” 1998.

The Silent Killer

• Vague or non-specific symptoms– abdominal discomfort– swelling (tumour mass or ascites)– menstrual irregularities– gastro-intestinal symptoms

Pathology

• 90% epithelial origin

• Borderline tumours ( low malignant potential tumours)

• Non epithelial ovarian cancers include– germ cell tumours– sex cord tumours

Staging (FIGO 1986)• Stage 1 - LIMITED TO OVARIES

1A - One ovary, capsule intact

1B - Two ovaries, capsule intact

1C - One or both ovaries with ruptured capsule/surface tumour or positive cytology

• Stage 2 PELVIC EXTENSION

2A Uterus or tubes

2B Other tissues

2C Ruptures tumour, surface tumour, positive cytology

• Stage 3 ABDOMINAL OR NODAL METASTASIS3A Microscopic seeding of abdo - peritoneal surfaces

3B Abdo - peritoneal implants 2cms or less, -ve nodes

3C Adbo - peritoneal implants 2cm or more and or +ve nodes

• Stage 4 DISTANT METASTASIS (includes pleural effusion with +ve cytology,parenchymal liver metastasis )

Staging and Treatment

• Establishing the stage of the disease accurately requires extensive surgical exploration

• Treatment - surgical removal of as much tumour as possible followed by adjuvant chemotherapy

• Stage 1 disease - surgery alone

Prognosis

• 5 year survival rate in UK - 30%

• Improved prognosis reported in Stage 1 disease with a 5 year survival rate varying between 72% - 81%– ? Scope for outcomes to be improved by

increasing the number of early detected cancers

• Improved prognosis if surgery carried out by a specialist in gynaecological cancers

Risk Factors

Family history is the strongest known risk factor

• Population risk 1%

• One relative with ovarian cancer 3%• Two relatives with ovarian cancer 15%• Three or more relatives between 30-40%

Protective Factors– Use of OCP (over 5 years) reduces risk of ovarian

cancer by up to 50%– Pregnancy– Breast feeding

• HypothesisThe suppression of ovulation confers protection from ovarian

cancer• trauma and healing of ovarian epithelium predisposes malignant

change• high levels of circulating gonadotrophins induces malignant change

Hereditary ovarian cancer

• 5-10% of ovarian cancer is thought to be hereditary

• At least 3 distinct clinical patterns :* Breast / ovarian - BRCA 1 and BRCA 2* Colon / rectum / endometrial / stomach / ovarian

(HNPCC spectrum) - Mismatch Repair Genes* Ovarian specific

Ovarian Specific

• May not be a clinical entity but may be one end of a spectrum of involvement of ovarian cancer in the other clinical syndromes

• Also the possibility that other more common predisposing genes of weaker effect exist which rarely give rise to multiple case families

BRCA1 (17q 21) gene carriers

Ovarian Cancer Risk

by Age 40 0.6%50 22%60 30%

70 63%(Easton et al 1995)

BRCA 2 (13q 12-13) gene carrier

Ovarian Cancer Risk

By Age 40 0.0%

50 0.4%

60 7.4%

70 27% (Ford et al 1998)

HNPCC

Ovarian cancer risk

9%

for HNPCC gene carriers (Vasen et al 1995)

Genotype/ Phenotype Correlation

• Mutations in terminus end of BRCA1 are associated with greater risk of ovarian cancer

• BRCA2 mutations clustered in a region in EXON 11 are more likely to cause ovarian cancer

(Gayther et al 1997)

Age at onset of hereditary ovarian cancer

• More likely to be older that breast cancer onset in families

• Where there is a family history present the average age at diagnosis is 52.4yrs

• Compared to the general population average age at onset is 59yrs

(Lynch et al 1991)

Genetic Couselling - Aims

• To identify individuals at increased risk of hereditary cancer

• To offer interventions and screening to individuals fulfilling moderate and high risk criteria

• To offer genetic testing to individuals fulfilling high risk criteria

• To offer support and information

Scottish Cancer Genetics Sub -Group Guidelines

• Published March 2001

• Uses family history to assess individuals risk of ovarian cancer

• Assessed as – High, Medium or Low Risk– Moderate Risk - 3/4 times population risk

High Risk Criteria

• An individual in a family with BRCA1, BCRA2, hMLH1, hMSH2 or other predisposing gene

• An untested 1st Degree relative of a gene carrier• 1st degree relative with breast and ovarian cancer

At least one case of ovarian cancer in each category

Moderate Risk Criteria

• 2 or more 1st or 2nd degree relatives with ovarian cancer (OvCa)

• 2 or more 1st or 2nd degree relatives with OvCa at any age or BrCa under 50yrs

• 1 OvCa and 2 BrCa diagnosed less than 60yrs on same side of the family in 1st or 2nd degree relatives or 2nd degree via a male

• 2 1st or 2nd degree relatives with CRC and an endometrial Ca and one with OvCa

• 1 affected relative with OvCa and HNPCC family history

At least one case of ovarian cancer in each category

Low Risk Criteria

Anyone not fulfilling moderate or high risk criteria

• information on mode of inheritance• risk• offer reassurance• advice regarding healthy lifestyle• option of a consultation with Community

Gynaecologist (further reassurance or current symptoms)

Moderate risk counselling

• Information on risk, mode of inheritance, genes, penetrance, other family members risks

• Screening - ovarian (breast)• Provide information on risk modifiers• Healthy lifestyle • Prophylactic surgery• Offer storage of DNA from affected relative

High Risk Counselling

• Same as moderate plus

• Offer genetic testing of an affected individual with the potential to offer presymptomatic testing to consultand and wider family

• Discussion of prophylactic mastectomy

Ovarian ScreeningOffered To Individuals Fulfilling Moderate And High Risk Criteria

• Research based programme (Edinburgh data + entry to UKCCCR trial)

• From age 35 or five years under youngest age of onset • Screening stops at age 65

• Annual trans-vaginal ultrasound of ovaries• Annual CA125 –serum tumour marker• In combination sensitivity 62-82%, specificity 63-92%

Ovarian Cancer Screening

• No screening modalities have been proven to be effective to date

• Varies cohort studies evaluating effectiveness • 3 RCT in progress (all postmenopausal women)

• St Bartholomhew’s Hospital - CA125 and u/s if raised

• European randomised trial of ovarian cancer screening (multicentre) - Trans vaginal u/s

• USA PLCO trial - Transvaginal u/s + CA125

Aim of Screening

To reduce mortality and morbidity from ovarian cancer by detecting it at an earlier stage when treatment may be more effective

Screening for Ovarian Cancer

• Advantages: may detect early ovarian cancer

• Disadvantages: false positive results (0.4 - 5 %)

recall rate 19.2% (Karlan et al 1993)unnecessary investigationsunproven

CA125

• Cancer antigen

• elevated levels have been reported in 61-96% of all clinically diagnosed epithelial ovarian cancers

• elevated levels also reported in• endometrial and pancreatic cancer

• benign gynaecological conditions (endometriosis, fibroids and PID

• levels of CA125 in healthy women vary with menopausal status

Familial Ovarian Cancer Screening Clinic

• Gynaecological data

• Genetic Information

• Prophylactic oophorectomy

• Discussion of advantages & disadvantages of screening

• First screen

• Arrangements for further screening– POSTAL SCREENING + option of FOCSC appointment

as needed

Psychological Status

Women attending FOCSC (Canada)

• Increased anxiety and depression levels

• 31% clinically depressed

• 16% anxious (SSAQ)

Almost all the women perceived the programme to be valuable

(Robinson et al 1996)

Diagnostic Surgery

• most women who are found not to have cancer are found to have benign ovarian or gynaecological condition

• potential benefits in this situation are unknown• risks are difficult to quantify but may be about 0.5 - 1%

including• death

• bowel or bladder damage

• infection or excessive bleeding

Pernet et al 1992

Qualatative study

10/15 women who had surgical intervention following false positive results

• Women were neither distressed or angry by their experience

• Comfort from the belief that surgery rendered them invulnerable to ovarian cancer

Wardle et al 1994

Same cohort as Pernet et al, more cautious results

• More serious adverse response to the combined trauma of a false +ve result and surgery.

• RECOMMENDATIONS – provision of a counselling service attached to screening service.

Prophylactic Oophorectomy

• First documentation was in the 1975.• Reduces but does not remove risk of ovarian

cancer (peritoneal)• Optimum age is 45• Women have to consider risks of surgery,

HRT, increase in osteoporosis and cardiac disease

Rozario et al 1997 (America)

Women with ovarian cancer diagnosis and recorded incidence of previous gynaecological surgery or abdominal surgery

• 270/404 cases had previously undergone abdominal surgery

• Depending on age of patient prophylactic

oophorectomy results in a 4% - 10.9% reduction in the incidence of ovarian cancer

• In order to prevent ovarian cancer in one woman, 200 to 500 healthy women would have oophorectomies

Sruewing et al 1995

Women with a family history of OvCaIncidence of peritoneal (ovarian) cancer following

prophylactic oophorectomy compared to incidence of ovarian cancer in women who have not opted for oophorectomy

• 13 fold excess of “ovarian cancer” in oophorectomy group compared to 24 fold increase in non-oophorectomy group ( in relation to pop risk)

• Preliminary data suggests oophorectomy gives a protective effect against both ovarian and breast cancer

Laparotomy vs Laparoscopy

• Benefit of laparotomy is the opportunity to carry out a thorough inspection of pelvic and abdominal cavities for early disease

• If previous abdominal or pelvic surgery laparoscopy may not be an option

• Benefits of laparoscopy - shorter recovery period, less major surgery

Use of HRT following PO

• In premenopausal women HRT recommended to reduce mortality from cardiovascular disease and osteoporosis

• Combined therapy with oestrogen and progesteron carries a higher BrCa risk than unopposed oestrogen BUT unoppossed oestrogen carries a substantial risk of endometrial cancer

• Therefore best option may be PO combined with hysterectomy and followed with low dose oestrogen

Use of HRT following PO cont

In older women (post menopausal)

• laparoscopic oophorectomy without HRT may be best option

• Most gynaecologists are reluctant to carry out oophorectomy below age 35

Summary

• 5-10% of all ovarian cancers are genetic

• Known genes– BRCA1 and BRCA 2 linked with breast cancer– MMR genes linked with HNPCC spectrum

• Up to 63% lifetime risk of ovarian cancer by age 70

• Options for individuals at increase risk include screening, prophylactic surgery and or gene testing