Breast cancer genetics and who we should be screening · (Non AJ pop 25/407 = 6%) Genes tested increased from 2 to 25. Yield has increased by 0.4% (30 to 32) “The clinical significance

Breast cancer genetics and who we should be screening

Marc Tischkowitz PhD FRCP

Reader/Consultant in Medical Genetics,

Department of Medical Genetics

Honorary Consultant, East Anglian Medical Genetics Service

[email protected] [email protected]

mailto:[email protected]

Overview

• BRCA1/2 – prospective risk estimates

• RABT - Rapid Access Breast Testing

• Panel testing – panacea or pandora’s box?

• PALB2 update

• What about SNPs?

• Guidelines – where to find them

I have no conflicts of interest to declare

Typical Referrals to a Cancer Genetics Clinic

Colorectal

Rare syndromes

Breast/ovary

Other

Relatives

Breast Cancer patients

High riskDirect gene testing feasible

Moderate risk

Universal access to BRCA1/2 testing

Norwich

Cambridge

King’s LynnPeterborough

HuntingdonBury St Edmunds

Ipswich

Saffron Walden

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

Germline (inherited) Cancer Predisposition

1

10

0.000001 0.00001 0.0001 0.001 0.01 0.1 1

Rela

tive

Risk

Allele frequency

BRCA1

BRCA2TP53

PALB2

CHEK2ATM

CDH1

STK1

PTEN NBBC Genes

Risk SNPs

Doug Easton, Peter Devilee, 2014

1st Wave 1990s

2007-present

2nd Wave late 90s/mid 2000s

Breast Cancer Predisposition Genes

Pitfalls When Assessing Pedigrees

CA Ovary 42

?CA Breast 32

CA Ovary 55 Road Traffic Accident 28 CA Breast 72

CA Breast 49 CA breast 55

1

2 3 5

6

4

Prophylactic mastectomy

Prophylactic

mastectomy

6

5

1

4

2

3

CA Breast 72

CA Ovary 42

CA breast 55

CA Breast 49

Road Traffic Accident 28

CA Ovary 55

?CA Breast 32


Inability to confirm diagnosis

Prophylactic

mastectomy

6

5

1

4

2

3

CA Breast 72

CA Ovary 42

CA breast 55

CA Breast 49


CA Ovary 55

?CA Breast 32


Premature death in a gene carrier

Prophylactic

mastectomy

6

5

1

4

2

3

CA Breast 72

CA Ovary 42

CA breast 55

CA Breast 49


CA Ovary 55

?CA Breast 32


Non-penetrance

Prophylactic

mastectomy

6

5

1

4

2

3

CA Breast 72

CA Ovary 42

CA breast 55

CA Breast 49


CA Ovary 55

?CA Breast 32


Male transmission of a condition affecting mainly women

Prophylactic

mastectomy

6

5

1

4

2

3

CA Breast 72

CA Ovary 42

CA breast 55

CA Breast 49


CA Ovary 55

?CA Breast 32


Prophylactic surgery in gene carriers

Prophylactic

mastectomy

6

5

1

4

2

3

CA Breast 72

CA Ovary 42

CA breast 55

CA Breast 49


CA Ovary 55

?CA Breast 32


Founder effects in ethnic groups

Non-paternity Adoption Family conflicts/estrangement

Small families

Prophylactic

mastectomy

6

5

1

4

2

3

CA Breast 72

CA Ovary 42

CA breast 55

CA Breast 49


CA Ovary 55

?CA Breast 32

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 risksKuchenbaecker, 2017

• 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

BREAST OVARIAN


Cancer General population BRCA1 BRCA2

BC 11%50-85%65-79%

50-85%61-77%

OC 1.4%20-50%36-53%

10-30%11-25%

2nd BC (20y risk)

n/a 35-45% 20-33%

Pancreatic 3% 3% 6%

Prostate 13% 13% 26%


Family history & mutation position – important variables in risk assessment.

Manchester (Mutation Probability)

BRCAPRO ( Mutation Probability)

Tyrer-Cuzick ( Breast Risk and Probability)

BOADICEA (Risk and Probability)

Non-BRCA1/2:

PTEN mutation probability calculator

James et al JCO 2006

Fischer et al J Med Genet. 2013 Jun;50(6):360-7

Risk Assessment

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

Two stage design

Primary outcome measure

Exploratory outcomes measure

Stage 1(n=50) Safety of adding Olaparib

Stage 2 (n=444 including patients in stage 1)

pCR Relapse-free survivalDisease specific survivalOverall survivalTime to secondary cancer

KEY ELIGIBILITY CRITERIA

RANDOMISATION 1:1StratificationAge: 10mm).TNBC or germline BRCA1/2 mutation positive with any hormone status.

Randomised, open label, phase III trial

Genetics-ledLabour intensive

Time Consuming, SlowCritically dependent on Counselling Resources

Tried and TestedNationally established

Will miss some mutations

Oncology-ledStreamlined

UniversalFast

Can it work across multiple Hospitals in a region

Will miss some families

Genetics-coordinatedStreamlined

Close working between Genetics and Oncology

UniversalFast

Red

uctio

n in

Can

cer R

isk

(%)

0

20

40

60

80

100

Tamoxifen MastectomyOophorectomy

(pre-menopausal) Birth control pill

>95% ~90%

~50% up to 56%~50%

Options to reduce risks in HBOC

Panels vs Exomes vs Genomes

Whole exome sequencing

Whole genome sequencing

• Panel = 10s to 100s genes• Exome = 22,000 genes and

flanking intronic sequence85% of disease causing mutations occur in coding sequence

• Genome = intron and exon

panel

Lindor 2017

Gene-panel sequencing and the prediction of breast-cancer risk.

Easton DF et al N Engl J Med. 2015 Jun 4;372(23):2243-57

BRCA1, BRCA2TP53, CDH1, PTEN, STK11, and NF1 (pleiotropic tumor syndromes)PALB2

Hereditary Breast Cancer Panels – Current Status

Easton 2015 UK CGG 2018 PanelApp Invitae 2019 Myriad 2019 GeneHealth UK 2019Ambry 2019

Publication Publication NHS/GEL Commercial Commercial Commercial CommercialBRCA1BRCA2PALB2TP53PTEN

STK11NF1

CDH1ATM

CHEK2BARD1BRIP1NBN

RAD50RAD51C ?RAD51D ?MRE11AMUTYH

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%):

18 BRCA1 1 MSH6

12 BRCA2 1 PMS2

10 CHEK2 (8 were 1100delC) 1 RAD51C

4 ATM 1 RAD51D

4 BRIP1*

1 PALB2

1 PTEN

1 NBN


Sequential Series of Patients With Breast Cancer Tung et al, 2016 “The clinical significance of mutations in moderate-risk

breast cancer genes such as CHEK2, ATM, and NBN is still being evaluated”

Using moderate risk genes in predictive testing

55 mutations identified in 52 women (10.7%):

18 BRCA1 1 MSH6

12 BRCA2 1 PMS2


4 ATM 1 RAD51D

4 BRIP1*

1 PALB2

1 PTEN

1 NBN

single centre (Dana Faber)


Sequential Series of Patients With Breast Cancer Tung et al, 2016 “The clinical significance of mutations in moderate-risk

breast cancer genes such as CHEK2, ATM, and NBN is still being evaluated”

4 BRIP1

2006 2016

55 mutations identified in 52 women (10.7%):

18 BRCA1 1 MSH6

12 BRCA2 1 PMS2


4 ATM 1 RAD51D

4 BRIP1*

1 PALB2

1 PTEN

1 NBN


Sequential Series of Patients With Breast Cancer Tung et al, 2016

True yield for actionable genes = 32/458 = 7%(Non AJ pop 25/407 = 6%)

Genes tested increased from 2 to 25Yield has increased by 0.4% (30 to 32)

“The clinical significance of mutations in moderate-risk breast cancer genes such as CHEK2, ATM, and NBN is still being evaluated”

162 VUS (33.2% of women)! (currently around 5% for BRCA1/2 alone)

4 BRIP1




STK11NF1

CDH1ATM

CHEK2BARD1BRIP1NBN


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




STK11NF1

CDH1ATM

CHEK2BARD1BRIP1NBN


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

# PALB2mutationsper family

1 2 3 4 5 6 7 9 10

# families 288 120 74 18 10 6 3 3 2

AGE-SPECIFIC ABSOLUTE RISKS

17% by age 50 (95% CI: 13-21%) 55% by age 80 (95% CI: 44-63%) For a woman born from 1950 to 1959

EXAMPLES

• Breast cancer absolute risk

OVARIAN CANCER AGE-SPECIFIC ABSOLUTE RISKS

AGE-SPECIFIC ABSOLUTE RISKS

CONCLUSIONS

• PALB2 mutations are associated with high BC risk• Associations with risks of ovarian, pancreatic and male breast

cancer.• No evidence of association with colon or other cancers

• Manuscript draft being finalised…• www.palb2.org

http://www.palb2.org

Advantages

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 (?)

Advantages of Panel testing

• Many genes on the 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

• Too much information we can’t yet handle/interpret.

• Are we finding red herrings?

Disadvantages of Panel testing

What about SNPs in Breast Cancer risk prediction?

Background

• BC 50-80%, OC (B1) 30-50% (B2) 10-20%

• RRM 6% uptake if risk 50%

• PRS score (Kuchenbaecker, 2017)

• B2 carriers OC risk:10th percentile of OC PRS= 6% vs 19% at 90th percentile

https://drive.google.com/open?id=1YZR8YlT451E2e6cv2AlyP9VLNYdcglp9

https://drive.google.com/open?id=1YZR8YlT451E2e6cv2AlyP9VLNYdcglp9

Strong FHxClear ascertainment

Targeted testing Genotype correlates with

PhenotypeHigh penetrance

Incidental Finding

Panels, Exomes, Tumour Sequencing

Weak/unknown correlation with phenotypeLower Penetrance?

Clinical implications less clear

The changing paradigm of diagnostic testing for germline mutations in cancer genetics

Breast cancer genetics and �who we should be screening OverviewTypical Referrals to a Cancer Genetics ClinicSlide Number 4Universal access to BRCA1/2 testingSlide Number 6Slide Number 7Pitfalls When Assessing PedigreesPitfalls When Assessing PedigreesPitfalls When Assessing PedigreesPitfalls When Assessing PedigreesPitfalls When Assessing PedigreesPitfalls When Assessing PedigreesPitfalls When Assessing PedigreesDeciding who we offer testing toSlide Number 16Lifetime cancer risks�Kuchenbaecker, 2017Lifetime cancer risks�Kuchenbaecker, 2017Lifetime cancer risks�Kuchenbaecker, 2017Risk AssessmentSlide Number 21Platinum and PARP inhibitor for Neo-adjuvant treatment of �Triple NEgative (TNBC) and/or BRCA1/2 positive breast cancerSlide Number 23Slide Number 24Options to reduce risks in HBOC Panels vs Exomes vs GenomesSlide Number 27Slide Number 28Slide Number 29Slide Number 30Slide Number 31Slide Number 32Slide Number 33Slide Number 34Slide Number 35Slide Number 36Hereditary Diffuse Gastric Cancer – CDH1Slide Number 38Slide Number 39Slide Number 40Slide Number 41Slide Number 42Slide Number 43Slide Number 44Slide Number 45Slide Number 46Slide Number 47Slide Number 48Slide Number 49What about SNPs in Breast Cancer risk prediction?Slide Number 51The changing paradigm of diagnostic testing for germline mutations in cancer geneticsSlide Number 53

Documents

Breast cancer genetics and who we should be screening · (Non AJ pop 25/407 = 6%) Genes tested increased from 2 to 25. Yield has increased by 0.4% (30 to 32) “The clinical significance