Transcript Familial Ovarian Cancer

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 rates
Europe
United Kingdom
Scotland
33%
25%
27.8%
Borders
Lothian
Fife
29%
27.8%
20.3%
Accounts Commission for Scotland “Fighting the silent killer” 1998.
The Silent Killer
• Vague or non-specific symptoms
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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
2C
Other tissues
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 )
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
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Population risk
One relative with ovarian cancer
Two relatives with ovarian cancer
Three or more relatives between
1%
3%
15%
30-40%
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
Hereditary ovarian cancer
• 5-10% of ovarian cancer is thought to be
hereditary
• At least 3 distinct clinical patterns :
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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
50
60
70
0.6%
22%
30%
63%
(Easton et al 1995)
BRCA 2 (13q 12-13) gene carrier
Ovarian Cancer Risk
By Age
40
50
60
70
0.0%
0.4%
7.4%
27%
(Ford et al 1998)
HNPCC
Ovarian cancer risk
9%
for HNPCC gene carriers
(Vasen et al 1995)
Genotype/ Phenotype Correlation
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Mutations in terminus end of BRCA1 are
associated with greater risk of ovarian cancer
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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
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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 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%
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 investigations
unproven
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
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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 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
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