Familial Ovarian Cancer

1
Familial Ovarian Cancer

• Diane Stirling

2
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

3
Five year survival rates

• Europe 33
• United Kingdom 25
• Scotland 27.8
• Borders 29
• Lothian 27.8
• Fife 20.3
• Accounts Commission for Scotland Fighting the
  silent killer 1998.

4
The Silent Killer

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

5
Pathology

• 90 epithelial origin
• Borderline tumours ( low malignant potential
  tumours)
• Non epithelial ovarian cancers include
• germ cell tumours
• sex cord tumours

6
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 METASTASIS
• 3A 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 )

7
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

8
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

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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

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Protective Factors

• Use of OCP (over 5 years) reduces risk of ovarian
  cancer by up to 50
• Pregnancy
• Breast feeding
• Hypothesis
• The 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

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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

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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

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BRCA1 (17q 21) gene carriers

• Ovarian Cancer Risk
• by Age 40 0.6
• 50 22
• 60 30
• 70 63
• (Easton et al 1995)

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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)

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HNPCC

• Ovarian cancer risk
• 9
• for HNPCC gene carriers
• (Vasen et al 1995)

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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)

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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)

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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

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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

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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

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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

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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)

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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

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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

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Ovarian Screening

• Offered 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

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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 Bartholomhews 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

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Aim of Screening

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

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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 investigations
• unproven

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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

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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

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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)

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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

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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

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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.

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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

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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

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Sruewing et al 1995

• Women with a family history of OvCa
• Incidence 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

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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

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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

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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

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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