Cancer Genetics
Issues
• Colorectal guidelines
– Awaiting publication of coloproctologists guidance
– SIGN / QIS update started
• Breast / ovarian
– Breast MRI
– Minor changes to guidelines?
• NF1
• Average age v absolute ages
• Incorporate pathology into testing criteria?
– Change to English guidance?
– Trials to report – UKFOCSS, FH01 etc
• Other conditions – gastric, renal etc.?
Breast cancer
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Breast MRI
NF1
English guidelines?
FH01 study results – confirm effectiveness,
reduce mortality
• Molecular testing
– Triple negative young women (<30)
– High grade serous ovarian cancer?
– BRCA3 results by Manchester score
– Double primary breast and ovary - audit
Proposals from last meeting
• Modify mutation testing to allow pathology
data to be used where available
• Test ovarian cancers with visceral metastases?,
or all high grade serous ovarian cancers
– Meeting of small group with Dr Gourlay
– Aberdeen d/w NSD funding additional testing
– Glasgow propose trainee project to assess yield
• Lower threshold if impacts management
(PARPi) – BRCA3 info
Ovarian BRCAness meeeting
• Should we test more women with ovarian
cancer?
– Visceral mets, young age, response to platinum,
prolonged survival
– High grade serous
– Literature – no ideal series. One publication suggests
23% of high grade serous have BRCA1 mutation but
ascertainment / possible founders etc not clarified.
– Agreed helpful to have further information in our
population group. ?test for 12 months and look at
data.
– Oncologists also interested in somatic mutations
– Not currently influencing treatment but will in future
Ovarian BRCAness meeeting
• Practicalities
– Need family history and pathology info
– Consent issues
– Suggest take blood at initial meeting, store until consent
sorted out.
– Joint leaflet for patients, standard request / consent form /
referral form. Refer if positive?
– ?additional capacity Aberdeen
• Numbers – 350 high grade serous / year?
• Oncology meeting in November
• Audit previous ovarian testing? (? Info to CG)
Ovarian BRCAness meeeting
• Technical issues
– ?tumour testing
– ? Rebiopsy to look for second mutations, mets etc
– ?other pretest would be useful? RT-PCR, antibody
stains etc??
Ovarian cancer in Glasgow
• Robots in molecular lab, improved turnaround
for BRCA2 dramatically.
• Previously reluctant to consider ovarian
samples, now willing to consider a trainee
project
• Store blood from ovarian cancer patients
• If high grade serous / FH / long survival etc,
refer to genetics to consider testing
UKFOCSS
• No longer recruiting
• Scans will end 2011
• No plans to arrange any ongoing screening,
will leave to gynaecologist
• UCL suggest baseline investigations at first
appointment, discuss surgery etc
BRCA3 results by Manchester score
• 618 results. Scores 4-65. 56 mutations (9%), 31
BRCA1, 25 BRCA2.
• 18 mutations in 446 with score <20. (4%). 3 with
ovarian FH, of 33 with ovarian history.
• 38 mutations in 172 with score >20. (22%)
• Score of 16+: 47 mutations in 290 (16%) [4%]
• Score of 18+: 44 mutations in 221 (19.9%) [8%]
Double Primary breast / ovary
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Breast / ovary double primaries
57 tested. 54 full results
17 BRCA1, 9 BRCA2, 6 VUS found. 46% pickup.
Manchester score over 20 – 66% pickup
(22/33)
• Manchester score <20 – 36% detection (4/11)
Triple negatives / young br ca
• Little data yet! 16 samples tested which say
triple neg on database. 7 BRCA1 mutations, 2
BRCA2, 2 VUS. (56%)
• Breast cancer under 30: 18 samples tested, 5
BRCA1, 2 BRCA2, 1 VUS BRCA2. (44%)
• Additional 4 <30 with p53: bilat breast ca
under 30, br ca 29 with affected M and MA, br
ca 29 with relative CACC, br ca 29 with
osteosarcoma.
FH01 study
• 6710 women under 50 at moderately increased
risk, control group from age trial and Dutch
series. FU 5 years, annual mammo.
• 136 breast cancers diagnosed, 77% screen
detected, 21% interval cancers. Tumours smaller,
less likely node positive, moe fabourable grade.
• Predicted mortality significantly lower. (Prevent
2.1 breast cancer deaths per 10,000 screens.)
IMPACT study
• Ready to recruit in Glasgow
• 4 men agreed to take part, 17 BRCA2 positive
and 12 BRCA2 negative eligible.
• Not yet approached BRCA1 men.
• Lower testing threshold?
• When management shown to be impacted
– Contralateral mastectomy
– PARP inhibitor trial results
England
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NICE guidance 2004 / 2006
1 under 40, 2 first degree relatives any age
Risk 1.7x population risk, 3% 10 year risk at 40
Now looking again at this, want to look at
survival benefit.
• Proposal to look at women with 4x risk, 18
monthly mammography from 40 to 73. No
screening for those at lesser degrees of risk.
Molecular testing
• Young women with triple negative tumours?
– Management impact?
– PARP inhibitor trials
– Contralateral mastectomy
– Recent paper looking at large series with breast cancer and
BRCA testing, by age and BRCA status
– Changed 10 year risk from 6% to 28%
• Incorporation of pathology data –
– Manchester score: simple to use
– BOADICEA: complicated to use
BRCA1
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More likely ER-, HER2Less likely grade 1
-4 for HER2+. +4 for grade 3 triple negative
Overall sensitivity and specificity increased
Suggest testing women <31 with triple
negative disease for BRCA1, no other groups
over 10% threshold without family history
Contralateral mastectomy
• Series of 705 bilateral cases and 1398 unilateral
controls, from cancer registry in US, cohort of
52000 diagnosed under 55
• BRCA testing
• 5 and 10 year risks of contralateral breast ca by
age of first diagnosis
• 28% v 6% at 25-29 y
• 19% v 4% at 40-44y
• 10% v 4% at 50-54y