Cancer Risk AssessmentThe Why and How for Affected and

Unaffected Patients

Kevin S. Hughes, MD, FACSFounder: Hughes RiskApps.LLC

Co-Director, Avon Comprehensive Breast Evaluation Center

Massachusetts General Hospital

Associate Professor of Surgery

Harvard Medical School

Medical Director

Bermuda Cancer Genetics and Risk Assessment Clinic

KsHughes@HughesRiskApps.Com

Why evaluate risk

Not identifying high risk individuals will lead to unnecessary morbidity and death

Cancer Risk

Breast 50-87% 50-87%

Ovary 40-60% 10-20%

Breast 6%

F

e

m

a

l

e

M

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e

BRCA1 BRCA2

Hereditary vs Sporadic CancerKnudson’s 2 hit hypothesis

HEREDITARY CANCER

SPORADIC CANCER

18 years of BRCA testing

Female Carriers in the US ~560,000 to 720,000

Carriers found ~70,000, mostly affected

95% of unaffected carriers remain unaware and mismanaged

More genes to test for: Breast

• 1781 HBOC patients

• 25-Gene Panel (MyRisk)

– 13.5% had a mutation

• 9.3% in BRCA 1 or 2

• 4.2% in at least one other gene

More genes to test for: Breast

Tung et al ACMG2014

More genes to test for: Ovary

More genes to test for: Ovary• 360 women

• Ovarian

• Primary peritoneal

• Fallopian tube cancer

• 21 gene panel (12 found)

• 24% had a mutation

– 18% BRCA 1/2

– 6% another gene

• 30% carriers had no family history

• 35% of patients were > 60 y.o.

University of Washington Walsh et al 2011

Significance and Management by mutation

Prevalence and Penetrance for breast cancer genes

http://www.ambrygen.com/sites/default/files/pdfs/canc

er%20forms/BreastNext_WhitePaper_100412.pdf

If you think you can’t keep up with all this…

Don’t worry!

No one else can either!

The human brain is approaching its limit

Yet we continue to practice memory based medicine

Crane, Raymond, The Permanente Journal 7:62, 2003

Yoo et al. BMC Bioinformatics 2007 8(Suppl 9):S4

Knowledge is growing exponentially

Articles published on Breast Cancer Genetics

4335 articles in 2012

Disorders with genetic tests available

GeneTests 2014

Clinical Decision Support (CDS) •Apply Models/Guidelines to patient data

•Identify best course of action

•Results displayed as intuitive Visualizations

BRCAPRO Mutation Risk 25%

BRCAPRO Mutation Risk 25%

Consider Genetic Testing

Opposing viewpoints defined in the 1950’s

• Artificial Intelligence (AI)

– The computer would replace humans

• Intelligence amplification (IA)

– Computers have strengths and weaknesses

– Humans have strengths and weaknesses

– Humans working with computers are:

“Better...stronger...faster”

“We have the technology”

Mechanical Amplification

• Human 3 miles/hour

• Human plus bike 20 miles/hour

• Human plus car 60 miles/hour

Intelligence Amplification• Human

– Talk to patient, gather data

– Draw pedigree and eyeball

– Counsel

• Human plus computer

– Human Talk to patient, gather data

– Computer Run risk models/guidelines

– Computer Draw pedigree, visualizations

– Human Synthesize, counsel patient

High Risk Program

• Identify women at high risk• Breast imaging, Primary Care, Oncology, OB/GYN

• High Risk Clinic/System• Manage women needing

– Genetic testing

– More intensive screening

– Chemoprevention

• Risk of mutation

– BRCA testing

• Risk of developing breast cancer

– MRI

– Chemoprevention

– Personalized screening

ID High Risk

Hereditary

Hormonal

Pathologic

Risk Factors

Hereditary

Hormonal

Pathologic

Risk FactorsBreast cancer

Age diagnosed

Ovarian Cancer

Age diagnosed

Male breast cancer

Age diagnosed

Degree relative

Age all relatives

Genetic testing

Height

BMI

Parous vs nulliparous

Age first live birth

Age menarche

Age menopause

HRT years used

HRT intended use years

Combined vs estrogenNumber of biopsies

Atypical hyperplasia

LCIS

Tumor markers

ID High Risk

Eyeball

Models

Guidelines

ID High Risk

Eyeball

Models

Guidelines

Age

Vital Status Cancer statusAge diagnosis

Ethnicity/ReligionGenetic testing

Risk Factors

Eyeball

Eyeball

Multiple relatives affected

Young age at diagnosis

Multiple primary cancers

Unusual Cancer

Male breast cancer

ID High Risk

Eyeball the pedigree

Models

Guidelines

Guidelines by Examples

USPSTF for BRCA testing 2013

USPTF Ann Intern Med 2013

Guidelines by Tools

• If positive by any of the following tools

– Ontario Family History Assessment Tool

– Manchester Scoring System

– Referral Screening Tool

– Pedigree Assessment Tool

– FHS-7

Guidelines by Models

33

Women

MostHighest

risk

Current Breast Cancer Screening Guidelines:

• American Cancer Society (ACS)

• National Comprehensive Cancer Network (NCCN)

>20%

risk of

breast

cancer(Tyrer Cuzick,

BRCAPRO,

Claus)

Guidelines by Models

ID High Risk

Eyeball the pedigree

Models

Guidelines

Hereditary

Hormonal

Myriad

Pathologic

Claus

Gail

BRCAPRO

Tyrer Cuzick

Hereditary

Hormonal

Risk MutationMyriadGenetic Testing

Pathologic

Risk Mutation & Risk Breast Ca

Risk Breast CaClausChemoprevention

MRI

Personalized screening

GailChemoprevention

Personalized screening

BRCAPROGenetic Testing

Chemoprevention

MRI

Personalized

screening

Tyrer CuzickGenetic Testing

Chemoprevention

MRI

Personalized

screening

George Edward Pelham Box 1919 –2013)

British mathematician/Professor of Statistics at the University of Wisconsin

All models are wrong

George Edward Pelham Box 1919 –2013)

British mathematician/Professor of Statistics at the University of Wisconsin

All models are wrong, but some are useful

Hereditary• Breast cancer

• Age diagnosed

• Ovarian Cancer

• Age diagnosed

• Male breast cancer

• Age diagnosed

• Degree relative

• Age all relatives

• Genetic testingHormonal• Height

• BMI

• Parous vs nulliparous

• Age first live birth

• Age menarche

• Age menopause

• HRT years used

• HRT intended use years

• Combined vs estrogen

Pathologic• Number of biopsies

• Atypical hyperplasia

• LCIS

• Tumor markersBRCAPRO

BRCAPRO: Bayes-Mendel Model

Woman Vs. Machine

148 pedigrees

BRCAPRO Vs NPs and GCs

Woman Vs. Machine

You cannot have a highly trained NP or GC see every

patient

You can run risk models on every patient

Genetic Consultation

Patient Referral

Patient enters data

Risk Calculations

MRI

Options to find high risk

Clinical Decision

Support

Quick and easy risk calculations

Hughes RiskApps Express

Thru

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