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Brca1/Brca2 and Beyond BRCA1/BRCA2 AND BEYOND ESMO – Hereditary Cancer Genetics 26-27 April Lugano Name Dr Marc Tischkowitz MD PhD Reader in Medical Genetics, Department of Medical Genetics Honorary Consultant, East Anglian Medical Genetics Service DISCLOSURE OF INTEREST I have no conflicts to declare OVERVIEW BRCA1/2 – prospective risk estimates Who should be tested, Who should test, and how should they do it? PALB2 update Panel testing – panacea or pandora’s box? Incorporating low-risk alleles for accuracy in BC TYPICAL REFERRALS TO A CANCER GENETICS CLINIC TYPICAL REFERRALS TO A CANCER GENETICS CLINIC Other Rare syndromes Colorectal Breast/ovary Relatives Cancer patients Moderate risk High risk Direct gene testing feasible GERMLINE (INHERITED) CANCER PREDISPOSITION Cancer Genetics 2 types of gene test: Diagnostic – finding the gene change in someone who is affected with cancer. Oncologist, Gyn specialist, Breast specialist Predictive/Presymptomatic – Testing for a known family mutation in a healthy individual (= risk stratification) Medical Geneticists, Genetic Counsellor Breast Cancer Predisposition Genes 1st Wave 1990s CDH1 BRCA1 TP53 10 BRCA2 STK1 2nd Wave late 90s/mid 2000s PALB2 PTEN NBBC Genes Relative Risk Relative CHEK2 ATM 2007-present Risk SNPs 1 0.000001 0.00001 0.0001 0.001 0.01 0.1 1 Allele frequency Doug Easton, Peter Devilee, 2014 DECIDING WHO WE OFFER TESTING TO Risks models (“10% guideline”) ◆ Manchester, IBIS, BOADICEA, BRCAPRO ◆ Each has pros and cons Criteria Ethnicity Clinical judgment Pathology Will it affect management? A “TYPICAL” BRCA1/2 FAMILY…… LIFETIME CANCER RISKS KUCHENBAECKERKUCHENBAECKER,, 2017 BREAST OVARIAN • Prospective cohort – 6,036 BRCA1, 3,820 BRCA2 females • 5,046 unaffected • 4,810 with breast and/or ovarian cancer or both • Recruited in 1997-2011 LIFETIME CANCER RISKS KUCHENBAECKER, 2017 General Cancer BRCA1 BRCA2 population 50-85% 50-85% BC 11% 65-79% 61-77% 20-50% 10-30% OC 1.4% 36-53% 11-25% 2nd BC n/a 35-45% 20-33% (20y risk) Pancreatic 3% 3% 6% Prostate 13% 13% 26% LIFETIME CANCER RISKS KUCHENBAECKER, 2017 Family history & mutation position – important variables in risk assessment. RISK ASSESSMENT ✓ Manchester (Mutation Probability) ✓ BRCAPRO ( Mutation Probability) James et al JCO 2006 ✓ Tyrer-Cuzick ( Breast Risk and Probability) ✓ BOADICEA (Risk and Probability) ◆Non-BRCA1/2: ◆ PTEN mutation probability calculator Fischer et al J Med Genet. 2013 Jun;50(6):360-7 Factor Gail Claus BRCAPRO IBIS Current Extended BOADICEA BOADICEAh Family history YES YES YES YES YES YES (descriptive) BRCA1/2 NO NO YES YES YES YES Common low-risk NOb NO NO NO YESc YES alleles Intermediate risk NO NO NO NO NO YES mutations (CHEK2, PALB2, ATM etc) Residual non- NO NO NO Dominant YES YES BRCA1/2 familial aggregation BRCA1/2- NO NO YESe NO YES YES pathology associations BRCA1/2 risk NO NO NO NO YES YES modification Variants of NO NO NO NO NO YES uncertain significance Predicting ER- NO NO NO NO NO YES specific risks Mammographic NO NO NO NO NO YES Density (MD) Hormonal, YES NO NO YES NO YES Lifestyle, Same Reproductive effect on BRCA1/2 Other cancers NO NO YES NO YES YES (non-BC or OvC) Predicting second NO NO NO NO YES YES cancer risks (CBC, OvC) Current testing guidelines for BRCA1/BRCA2 testing PLATINUM AND PARP INHIBITOR FOR NEO-ADJUVANT TREATMENT OF TRIPLE NEGATIVE (TNBC) AND/OR BRCA1/2 POSITIVE BREAST CANCER KEY ELIGIBILITY CRITERIA Randomised, open label, phase III trial 444 patients including 220 gBRCA (start Q3 -2015) RANDOMISATION 1:1 Stratification Inclusion criteria Age: <50 / ≥ 50 years Histologically confirmed invasive breast cancer Cancer type: TNBC / BRCA1 / BRCA2 Clinical stage T1-4 N0-2 (tumour or metastasic node diameter > 10mm). Clinical involvement of axillary nodes: no /yes Tumour size: , 50mm / ≥ 50 mm Inflammatory / Locally advanced disease: no / yes TNBC or germline BRCA1/2 mutation positive with any hormone status. Control Research Two stage design 4 cycles of 4 cycles of 3 weeks Primary outcome Exploratory outcomes 2 Paclitaxel 80mg/m on Day 1, 8 Paclitaxel on Day 1,8 &15 measure measure &15 every 3 weeks Carboplatin Day 1 Carboplatin AUC 5 Day 1 every Olaparib oral 150mg twice 3 weeks daily, D3- D14 Stage 1(n=50) Safety of adding Olaparib Stage 2 (n=444 pCR Relapse-free survival 4 cycles of 3 weekly anthracycline-based chemotherapy including Disease specific survival patients in Overall survival stage 1) Time to secondary cancer SURGERY +/- RADIOTHERAPY Long term follow-up Every 12 months for 10 years Genetics-led Labour intensive Oncology-led Time Consuming, Slow Streamlined Critically dependent on Counselling Universal Resources Fast Tried and Tested Can it work across multiple Nationally established Hospitals in a region Will miss some mutations Will miss some families Genetics-coordinated Streamlined Close working between Genetics and Oncology Universal Fast OPTIONS TO REDUCE RISKS IN HBOC Oophorectomy Tamoxifen Mastectomy (pre-menopausal) Birth control pill 0 20 Breast cancer 40 Ovarian cancer ~50% ~50% up to 56% 60 80 Reduction in Cancer (%) Risk Cancer in Reduction >95% ~90% 100 What is a breast cancer gene? Syndromic Risk HBC contribution Other cancers BRCA1 ✖ +++ +++ Ovary BRCA2 ✖ +++ +++ Ovary, Prostate, Pancreas PALB2 ✖ ++ ++ Pancreas TP53 ✖ ++++ + Brain, Sarcoma, Childhood PTEN ✔ +++ v rare Thyroid, Uterine STK11 ✔ ++ v rare Gastrointestinal NF1 ✔ + v rare Sarcomas CDH1 ✖ ++ v rare Diffuse gastric cancer ATM ✖ + + Pancreas CHEK2 ✖ + ++ >300 SNPs ✖ v small ++++ unknown What is a breast cancer gene? Syndromic Risk HBC contribution Other cancers BRCA1 ✖ +++ +++ Ovary BRCA2 ✖ +++ +++ Ovary, Prostate, Pancreas PALB2 ✖ ++ ++ Pancreas TP53 ✖ ++++ + Brain, Sarcoma, Childhood PTEN ✔ +++ v rare Thyroid, Uterine STK11 ✔ ++ v rare Gastrointestinal NF1 ✔ + v rare Sarcomas CDH1 ✖ ++ v rare Diffuse gastric cancer ATM ✖ + + Pancreas CHEK2 ✖ + ++ >300 SNPs ✖ v small ++++ unknown What is a breast cancer gene? Syndromic Risk HBC contribution Other cancers BRCA1 ✖ +++ +++ Ovary BRCA2 ✖ +++ +++ Ovary, Prostate, Pancreas PALB2 ✖ ++ ++ Pancreas TP53 ✖ ++++ + Brain, Sarcoma, Childhood PTEN ✔ +++ v rare Thyroid, Uterine STK11 ✔ ++ v rare Gastrointestinal NF1 ✔ + v rare Sarcomas CDH1 ✖ ++ v rare Diffuse gastric cancer ATM ✖ + + Pancreas CHEK2 ✖ + ++ >300 SNPs ✖ v small ++++ unknown What is a breast cancer gene? Syndromic Risk HBC contribution Other cancers BRCA1 ✖ +++ +++ Ovary BRCA2 ✖ +++ +++ Ovary, Prostate, Pancreas PALB2 ✖ ++ ++ Pancreas TP53 ✖ ++++ + Brain, Sarcoma, Childhood PTEN ✔ +++ v rare Thyroid, Uterine STK11 ✔ ++ v rare Gastrointestinal NF1 ✔ + v rare Sarcomas CDH1 ✖ ++ v rare Diffuse gastric cancer ATM ✖ + + Pancreas CHEK2 ✖ + ++ >300 SNPs ✖ v small ++++ unknown Li Fraumeni Syndrome – TP53 Cancer risk: 50% by 30y 90% by 60y What is a breast cancer gene? Syndromic Risk HBC contribution Other cancers BRCA1 ✖ +++ +++ Ovary BRCA2 ✖ +++ +++ Ovary, Prostate, Pancreas PALB2 ✖ ++ ++ Pancreas TP53 ✖ ++++ + Brain, Sarcoma, Childhood PTEN ✔ +++ v rare Thyroid, Uterine STK11 ✔ ++ v rare Gastrointestinal NF1 ✔ + v rare Sarcomas CDH1 ✖ ++ v rare Diffuse gastric cancer ATM ✖ + + Pancreas CHEK2 ✖ + ++ >300 SNPs ✖ v small ++++ unknown PALB2 – current situation • Largest PALB2 penetrance estimation study to date • Multicentre, both selected and unselected BC • Women with PALB2 mutations are at “higher risk” of developing breast cancer • PALB2 mutations account for ~2.4% of breast cancer familial risk (assuming carrier frequency 0.08%). • Breast cancer risks modified by other genetic/familial factors INCLUDED IN THE ANALYSIS AFTER ASCERTAINMENT ADJUSTMENTS • Families were eligible for inclusion in the analysis if • ≥1 case(s) with a cancer of interest • have more information apart from the ascertainment part • 524 families ➢ 363 family-based ➢ 161 population-based # PALB2 1 2 3 4 5 6 7 9 10 mutations per family # families 288 120 74 18 10 6 3 3 2 PALB2 in gastric cancer PALB2 - SUMMARY • PALB2 mutations are associated with high BC risk • Associations with risks of ovarian, pancreatic and male breast cancer. • No evidence of increased risk for colon or prostate cancers • No overall increase in other cancer risk • ?gastric cancer • Manuscript submitted…. • www.palb2.org What is NOT a breast cancer gene? Three cautionary tales……..BRIP1, PPM1D, RECQL 2006 2016 FANCJ/BRIP1 and Ovarian Cancer predisposition • 30/3236 invasive EOC cases 0.9% Ramus et al 2015 • 3/3431 controls (0.09%) • 2000 unaffected high-risk women (UKFOCSS) (0.6%) • The average age at diagnosis 63.8 years vs 58 in noncarriers (58 years, P = .07). • All 30 BRIP1 mutations were serous, 25 were high-grade Nature, 2013 Ruark 18/6912 (0.25%) BC cases, 12/1121 (0.01%) OC cases, 1/5861 controls Akabari 20/1295 (0.15%) OC cases, 1/834 controls Mutations not found in relatives, no increased risk in relatives. 2015-16 “Chemotherapy exposure and age influence the accumulation of PPM1D-mutated PBMC clones. Care should be taken to control for chemotherapy exposure and age at blood draw when testing the association of somatic mosaic mutations in PBMCs with cancer risk.” 2015 2018 HBC genes or not? What is a breast cancer gene? Syndromic Risk HBC contribution Other cancers BRCA1 ✖ +++ +++ Ovary BRCA2 ✖ +++ +++ Ovary, Prostate, Pancreas PALB2 ✖ ++ ++ Pancreas TP53 ✖ ++++ + Brain, Sarcoma, Childhood PTEN ✔ +++ v rare Thyroid, Uterine STK11 ✔ ++ v rare Gastrointestinal NF1 ✔ + v rare Sarcomas CDH1 ✖ ++ v rare Diffuse gastric cancer ATM ✖ + + Pancreas CHEK2 ✖ + ++ >300 SNPs ✖ v small ++++ unknown ATM c.5228C>T CGG/UKGTN CANCER PANELS WORKSHOP ◆ Issue: inconsistency
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