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 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 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 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 NICE guidance 2004 / 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 More likely ER-, HER2- Less likely grade 1 -4 for HER 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 diagnosed under 55 BRCA testing 5 and 10 year risks of contralateral breast ca by age of first diagnosis 28% v 6% at y 19% v 4% at 40-44y 10% v 4% at 50-54y