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 Reduction in Cancer Risk (%) TOOPTIONS RISKSIN HBOC REDUCE 100 40 20 80 60 0 Tamoxifen ~50% Mastectomy >95% (pre Oophorectomy ~50% - menopausal) ~90% Birth control pill up to 56% Ovarian cancer B r e a s t c a n c e r 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?

Cancer risk: 50% by 30y 90% by 60y What is a breast cancer gene?

• 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?

ATM c.5228C>T CGG/UKGTN CANCER PANELS WORKSHOP

◆ Issue: inconsistency of genes included in panels at different centres

◆ Aim: to reach consensus for panels of cancer genes with clinical utility for testing

◆ Participants:

◆ 21 Cancer Leads of UK Genetics Services (or deputies)

◆ 3 Clinical Scientists

◆ 4 Genetic Counsellors

◆ 6 UKGTN

◆ 4 CGG Steering Group BREAST CANCER: MAJORITY AGREEMENT

BRCA1 BRCA2 100% 100% 100% 100% 80% 80%

60% 60%

40% 40%

20% 20% 0% 0% 0% 0% 0% 0% 0% 0% 0% 0% Strongly Disagree Neither Agree Strongly Strongly Disagree Neither Agree Strongly disagree agree nor agree disagree agree nor agree disagree disagree PALB2 PTEN 100% 100%

80% 80%

72% 60% 60%

52% 40% 40% 40% 20% 20% 20% 0% 4% 4% 0% 4% 4% 0% 0% Strongly Disagree Neither Agree Strongly Strongly Disagree Neither Agree Strongly disagree agree nor agree disagree agree nor agree disagree disagree BREAST CANCER: MAJORITY AGREEMENT

STK11 TP53 100% 100%

80% 80%

60% 60% 64%

40% 40% 40% 40% 20% 20% 28% 0% 12% 8% 4% 0% 4% 0% 0% Strongly Disagree Neither Agree Strongly Strongly Disagree Neither Agree Strongly disagree agree nor agree disagree agree nor agree disagree disagree BREAST CANCER: TBD ATM BARD1 100% 100%

80% 80%

60% 60%

40% 44% 40% 44% 20% 36% 20% 20% 20% 0% 16% 0% 0% 12% 8% Strongly Disagree Neither Agree Strongly 0% disagree agree nor agree Strongly Disagree Neither agree Agree Strongly disagree disagree nor disagree agree BRIP1 CDH1 100% 100%

80% 80%

60% 60% 64%

40% 40%

32% 32% 20% 20% 20% 0% 12% 16% 8% 0% 16% 0% 0% Strongly Disagree Neither Agree Strongly Strongly Disagree Neither Agree Strongly disagree agree nor agree disagree agree nor agree disagree disagree BREAST CANCER: TBD

CHEK2 NBN 100% 100%

80% 80%

60% 60%

40% 40% 44% 40% 36% 20% 20% 24% 20% 0% 16% 0% 12% 8% 0% 0% Strongly Disagree Neither Agree Strongly Strongly Disagree Neither Agree Strongly disagree agree nor agree disagree agree nor agree disagree disagree Exclude TBD Include ATM BARD1 BRCA1 BRCA2 BRIP1 CDH1 CHEK2 NBN PALB2 PTEN STK11 TP53

Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer Tung et al, 2016

448 patients,

2010-12,

single centre (Dana Faber)

69.8% acceptance

61% of bloods taken within 90 days of diagnosis

(94% taken within one year)

25 Gene panel Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer Tung et al, 2016

55 mutations identified in 52/448 women (10.7%): “The clinical significance of mutations in moderate-risk breast cancer genes such as CHEK2, ATM, and NBN is still being 18 BRCA1 1 MSH6 evaluated” 12 BRCA2 1 PMS2

10 CHEK2 (8 were 1100delC) 1 RAD51C

4 ATM 1 RAD51D

4 BRIP1*

1 PALB2

1 PTEN

1 NBN Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer Tung et al, 2016

55 mutations identified in 52 women (10.7%): “The clinical significance of mutations in 18 BRCA1 1 MSH6 moderate-risk breast cancer genes such as CHEK2, ATM, and NBN is still being 12 BRCA2 1 PMS2 evaluated”

10 CHEK2 (8 were 1100delC) 1 RAD51C

4 ATM 1 RAD51D

44 BRIP1BRIP1* 1 PALB2

1 PTEN

1 NBN

single centre (Dana Faber) Frequency of Germline Mutations in 25 Cancer Susceptibility Genes in a Sequential Series of Patients With Breast Cancer Tung et al, 2016

“The clinical significance of mutations in moderate-risk breast cancer genes such as 55 mutations identified in 52 women (10.7%): CHEK2, ATM, and NBN is still being evaluated” 18 BRCA1 1 MSH6

12 BRCA2 1 PMS2 4 BRIP1 10 CHEK2 (8 were 1100delC) 1 RAD51C

4 ATM 1 RAD51D

4 BRIP1* True yield for actionable genes = 32/458 = 7% (Non AJ pop 25/407 = 6%) 1 PALB2 Genes tested increased from 2 to 25 1 PTEN Yield has increased by 0.4% (30 to 32) 1 NBN 162 VUS (33.2% of women)! (currently around 5% for BRCA1/2 alone) Hereditary Breast Cancer Panels – Current Status

GeneHealth UK Easton 2015 UK CGG 2018 PanelApp Invitae 2019 Myriad 2019 Ambry 2019 2019 Publication Publication NHS/GEL Commercial Commercial Commercial Commercial BRCA1 BRCA2 PALB2 TP53 PTEN STK11 NF1 CDH1 ATM CHEK2 BARD1 BRIP1 NBN RAD50 RAD51C ? RAD51D ? MRE11A MUTYH Hereditary Diffuse Gastric Cancer – CDH1

• HDGC is characterized by a susceptibility for diffuse gastric cancer

• thickening of the stomach wall (linitis plastica) without forming a distinct mass.

• Lifetime risk of gastric cancer by age 80 years is approximately 50-80%

• Women also have a 40% risk for lobular breast cancer.

• Risks for other cancers are unclear

www.nostomachforcancer.org CDH1 c.892G>A p.Ala298Thr CDH1 c.892G>A p.Ala298Thr

“it abrogates cell-cell adhesion and induces increased ability of cells to invade a matrix in vitro” Joana Figueiredo & Raquel Serruca IMPATIMUP, Porto Advantages of testing for other BC genes

Significant genetic heterogeneity: difficult to predict which gene may be mutated on the basis of phenotype or family history.

These unclear phenotypes may lead to answers we would not think of.

Able to give answers (?) Disadvantages for other BC genes

• Many genes on panels have not been well studied by international consortia. Unclear management.

• Testing negative in a mutation positive family may not justify a relaxation of surveillance.

• The magnitude of risk associated with a positive result may not warrant certain options (preventive surgery) beyond that justified by family history alone

• Backdoor to test for clinically unproven genes?

This is all germline - what about somatic? Therapeutic targets? Other Ovarian Cancer predisposition genes – RAD51C/RAD51D

RAD51C RAD51D Mutations in unselected 10/3112 0.32% 11/3112 0.35% OC controls 2/2769 0.07% 1/2769 0.04% More likely to Odds Ratio 5.2 (1.1-24) 12 (1.5-90) - be serous Risk by 50 1.3% (0.3-6%) 3% (0.4-21%) - have a +FHx Risk by 70 5.2% (1.1-22%) 12% (1.5-60%) BRIP1 and Ovarian Cancer predisposition

Cancer Panels Workshop 8/5/17