The Advancement of Hereditary Cancer Testing

Evaluating cancer family history based on single syndromes is too narrow and can lead to uncertainty

Approximately 5% to 10% of all cancers are hereditary

Hereditary Cancer Risk Assessment and Testing is essential to optimize patients' medical

management.

Patient management recommendations are vastly different for those with a gene

mutation associated with hereditary cancer risk:

• Use of risk-reducing surgeries or medications as well as screenings that would not

be recommended in the general population

• Initiating risk-reducing surgeries or medications or screenings at younger ages

• Conducting screenings more frequently

A comprehensive hereditary cancer risk assessment impacts medical decisions and may

reduce the occurrence of a first or subsequent primary cancer.

Introducing Myriad myRisk™ Hereditary Cancer Panel:

• A 25-gene panel for the identification of clinically significant mutations impacting

inherited risks for eight important cancers: breast, colorectal, ovarian, endometrial,

gastric, pancreatic, melanoma and prostate.

• Blends genetic test status AND personal/family cancer history into clinically

significant risk assessment and follow-up.

• Provides specific management recommendations for patients testing positive AND

negative based on guidelines of leading professional medical societies.

Are there other genetic factors causing her cancer?

What is this patient’s risk for a second cancer?

Does this patient need additional testing?

How do I manage this patient?

How do I advise this patient to talk to her family?

Her family:

Mother Grandmother

Ovarian caDx. 55 yo

Breast caDx. 45 yo

BRCA1 and BRCA2in 2012

Breast Cancer at age 39

?

? UNCERTAINTY

Mutations Identified inPatients with Breast Cancer1

Mutations Identified inPatients Suspicious for LS2

Mutations Identified inPatients with Ovarian Cancer3

Single SyndromeTesting*†

Myriad myRisk

moremutations

moremutations

moremutationsSaam J. et al, Evaluating the Personal and Family History Overlap Between Hereditary Cancer Syndromes. Presented at NCCN Annual Conference - March 2014

* BRCA1/2† Lynch Syndrome1 Prevalence of Gene Mutations Among Hereditary Breast and Ovarian Cancer Patients Using a 25-gene Panel, Nadine Tung et. al. Presented at ACMG - March 20142 Multi-gene Panel Testing in Patients Suspected to Have Lynch Syndrome, Matthew B. Yurgelun et. al. Presented at ASCO - June 20143 A Study of Ovarian Cancer Patients Tested With a 25-gene Panel of Hereditary Cancer Genes, Lucy R. Langer et. al. Presented at ASCO - June 2014

HBOC or Lynch Testing alone may miss important mutations for Hereditary Cancer

7%

30%

of HBOC patients meet criteria for Lynch

of Lynch patients meet criteria for HBOC

Myriad myRisk advances Hereditary Cancer Testing with comprehensive knowledge of

cancer risk and management

Emerging data confirms this dilemma across multiple patient presentations

In 1,781 Patients with Breast Cancer

In 1,260 Patients Suspicious for Lynch Syndrome (LS)

In 648 Patients with Ovarian Cancer

32% of pathogenic mutations identified with Myriad myRisk

were outside of BRCA1 and BRCA21

27% of pathogenic mutations identified with Myriad myRisk

were outside of the genes associated with Lynch Syndrome2

34% of pathogenic mutations identified with Myriad myRisk

were outside of BRCA1/2 and the genes associated with LS3

1. Prevalence of Gene Mutations Among Hereditary Breast and Ovarian Cancer Patients Using a 25-gene Panel. Nadine Tung et al. Presented at ACMG - March 2014

2. Multi-gene Panel Testing in Patients Suspected to Have Lynch Syndrome. Matthew B. Yurgelun et al. Presented at ASCO - June 2014

3. A study of Ovarian Cancer Patients Tested with a 25-gene Panel of Hereditary Cancer Genes. Lucy R. Langer et al. Presented at ASCO - June 2014

244 mutations

157 mutations

104 mutations

27% Other

34% Other

32% Other

68%BRCA1/2

73%LS genes

60%BRCA1/2

6%LS

165

7943

114 62

42

104

157

244

The clinical dilemma

Genetic Overlap

Multiple genes can increase the risk of

a single cancer

Multiple cancers can be associated

with a single gene

Breast

Pancreatic

OvarianEndometrial

ProstateGastric

ColorectalMelanoma

TP53

BRCA1/2

BRIP1

PTENSTK11

PALB2

ATMBARD1

CDH1

CHEK2TP53

NBNRAD51C

BREAST

Clinical research validated this dilemma

A significant number of patients meet criteria for multiple syndromes

Patient Information

• 44-year-old

• G2 P2

• Childbearing complete

Visit Type

• Abnormal Uterine Bleeding

Recommended Management

• Common recommendations

may include:

- Oral contraceptives

- Mirena® IUD

- Hysteroscopic removal of

fibroids or polyp

- Ablation

enetic Laboratories, Inc. | 320 Wakara Way, Salt Lake City, Utah 84108 | PH: 800-469-7423 FX: 801-584-3615

CONFIDENTIAL

Name: Patient Name DOB: Jan 12, 1970 Accession #: 00001144-BLD Report Date: Jun 30, 2014

myRisk Management Tool Associated with:

myRisk Management Tool: Page 3 of 5

WHAT MANAGEMENT FOR CANCER RISKS SHOULD BE CONSIDERED?Clinical management guidelines are based on this patient’s personal and family history and genetic test results. Unless otherwise stated, management guidelines included below are limited to those issued by the National Comprehensive Cancer Network (NCCN). See the reference listed for more details. If management for a specific cancer (e.g., breast) is available due to multiple causes (e.g., a mutation and a family history, or multiple mutations in different genes), only the most aggressive management is shown. Guidelines related to the patient’s long-term care for cancer prevention are included. Guidelines for the treatment of an existing cancer are not included. Any discussion of medical management options is for general informational purposes only and does not constitute a recommendation. While genetic testing and medical society guidelines provide important and useful information, medical management decisions should be made in consultation between each patient and his or her healthcare provider.

PROCEDURE AGE TO BEGINFREQUENCY

(Unless otherwise indicated by findings)

RELATED TO

FEMALE BREAST

Breast awareness- Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness 1

18 years NA BRCA1

Clinical breast exam 1 25 years Every 6 to 12 months BRCA1

Mammography and Breast MRI 1 25 years, or individualized based on earliest diagnosis in family

Annually BRCA1

Consider options for breast cancer chemoprevention (i.e., tamoxifen) 1 Individualized NA BRCA1

Consider risk-reducing mastectomy 1 Individualized NA BRCA1

OVARIAN

Consider options for ovarian cancer chemoprevention (i.e., oral contraceptives) 1 Individualized NA BRCA1

Bilateral salpingo-oophorectomy 1

35 to 40 years, after completion of childbearing, or individualized based

on the earliest diagnosis in the familyNA BRCA1

Consider transvaginal ultrasound and CA-125 measurement 1

30 years, or individualized based on earliest diagnosis in the family

Every 6 months BRCA1

PANCREATIC

Currently there are no specific medical management guidelines for pancreatic cancer risk

NA NA BRCA1

Daly M, et al. NCCN Clinical Practice Guidelines in Oncology ® : Genetic/Familial High-Risk Assessment: Breast and Ovarian. V 3.2013. June 10. http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf .

anagement:

Patient Name

iskisk MMananageement

MMAANAAGGEMMENT NT FOR nagement guidelines are bnt guidelines included bested for more details. If may history, or multiple mutayys long-term care for cance

of mef dical management opting and medical society gtion between each patient

DURRE

BRB EEAASTT

wareness- Women should basts and promptly report cre provider. Periodic, consirrtion (BSE) may facilitate br

reast exam 1

graphy and Breast MRI 1

options for breast cancer oxifen) 1

risk-reducing mastectomy

NN

options for ovarian cancecontraceptives) 1

salpingo-oophorectomy 1

transvaginal ultrasound ament 1

EEAATIICC

y there are no specific medes for pancreatic cancer ris

M, et al. NCCN Clinical Practice Ghttp://www.nccn.org/pro

CONFIDENTIALCONFIDENTIAL

GENE MUTATION

BRCA1 c.68_69del (p.Glu23Valfs*17)

THIS GENETIC TEST RESULT IS ASSOCIATED WITH THE FOLLOWING CANCER RISKS:

HIGH RISK: Female Breast, Ovarian

ELEVATED RISK: Pancreatic

RECEIVING HEALTHCARE PROVIDER

Physician Name, MD Myriad Healthcare Partners 320 Wakara Way Salt Lake City, UT 84108

SPECIMEN

Specimen Type: Buccal Draw Date: Jun 8, 2014 Accession Date: Jun 9, 2014 Report Date: Jun 30, 2014

PATIENT

Name: Patient Name Date of Birth: Jan 12, 1970 Patient ID: 1144 Gender: Female Accession #: 00001144-BLD Requisition #: 000000ORDERING PHYSICIAN: Physician Name, MD

GENETIC TEST RESULTS SUMMARY INFORMATION

PERSONAL / FAMILY HISTORY SUMMARY AND MANAGEMENT INFORMATION

MODIFIED MEDICAL MANAGEMENT MAY BE APPROPRIATE

RESULT: POSITIVE—CLINICALLY SIGNIFICANT MUTATION IDENTIFIED

Note: “CLINICALLY SIGNIFICANT,” as defined in this report, is a genetic change that is associated with the potential to alter medical intervention.

ADDITIONAL FINDINGS: NO VARIANT(S) OF UNCERTAIN SIGNIFICANCE (VUS) IDENTIFIED

FAMILY MEMBER

CANCER / CLINICAL DIAGNOSIS

AGE AT DIAGNOSIS

Patient None

Mother Breast 45

Maternal Aunt Breast 55

This information was provided by a qualified healthcare provider on the test request form and was not verified by Myriad.

Integrated BRAC Analysis ® with Myriad myRisk ™ Hereditary Cancer

myRisk Management Tool

ies, Inc. | 320 Wakara Way,y Salt Lake City, yy Utah 84108 | PH: 800-469-7423 FX: 801-584-3615 myRisk Management Tool:TT Page 3 of 5enetiic c LLaaborator

anagement:

PROCEDURE AGE TO BEGINFREQUENCY

(Unless otherwise indicated by findings)

RELATED TO

FEMALE BREAST

Breast awareness- Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness 1

18 years NA BRCA1

Clinical breast exam 1 25 years Every 6 to 12 months BRCA1

Mammography and Breast MRI 1 25 years, or individualized based on earliest diagnosis in family

Annually BRCA1

Consider options for breast cancer chemoprevention (i.e., tamoxifen) 1 Individualized NA BRCA1

Consider risk-reducing mastectomy 1 Individualized NA BRCA1

Advancing your Hereditary Cancer Testing approach The solution to the clinical dilemma

Myriad myRisk report provides significant information and clear direction

78% of patients with positive genetic result had management changes

based on information gained from the Myriad myRisk Management Tool1

25% of patients with negative genetic result had management changes

based on information gained from the Myriad myRisk Management Tool1

Evaluate patients' family histories† and identify patients for increased risk of hereditary

cancer....

Breast Cancer at age 39

Provides medical management

published in societal guidelines.... and test appropriate patients with Myriad myRisk to determine their optimal medical

management

An individual with a personal or family history of any one of the following‡.

Myriad myRisk evaluates 25 genes associated with 8 cancer sites Gene Selection Criteria

** Presence of tumor infiltrating lymphocytes, Crohn’s-like lymphocytic reaction, mucinous/signet-ring differentiation, or medullary growth pattern. * Adenomatous type‡ Assessment criteria based on medical society guidelines. For these individual society guidelines go to http://www.myriadgenetics.eu/healthcare-professional-treating-

diseases/professional-practice-guidelines/† Family member include first-, second-, and third- degree blood relatives on both your mother and your father’s sides. Certain ancestries may have greater risk for

hereditary cancer syndromes (e.g. Ashkenazi Jewish ancestry)

1. Langer et al, 25-gene Panel Testing and Integrated Risk Management Tool Impacts Medical Management in Hereditary Cancer Syndrome Evaluation, ASCO 2014

1. Langer et al, 25-gene Panel Testing and Integrated Risk Management Tool Impacts Medical Management in Hereditary Cancer Syndrome Evaluation, ASCO 2014.

MULTIPLEA combination of cancers on the same side of the family

YOUNG Any 1 of the following cancers at age 50 or younger

RAREAny 1 of these rare presentations at any age

• 2 or more: breast / ovarian / prostate / pancreatic cancer• 2 or more: colorectal / endometrial / ovarian / gastric / pancreatic

/ other cancers (i.e., ureter/renal pelvis, biliary tract, small bowel, brain, sebaceous adenomas)

• 2 or more: melanoma / pancreatic cancer

• Breast Cancer• Colorectal Cancer• Endometrial Cancer

• Ovarian Cancer • Breast: male breast cancer or triple negative breast cancer• Colorectal cancer with abnormal MSI/IHC, MSI associated histology**• Endometrial cancer with abnormal MSI/IHC• 10 or more gastrointestinal polyps*

Genes Breast Gastric Prostate OtherOvarian Colorectal PancreaticMelanomaEndometrial

BRCA1, BRCA2

STK11

TP53

CHEK2

MUTYH

CDH1

BARD1

APC, BMPR1A, SMAD4

PTEN

NBN

CDKN2A, CDK4

PALB2, ATM

BRIP1, RAD51C

RAD51D

MLH1, MSH2, MSH6, PMS2, EPCAM

Patient Information

• 44-year-old

• G2 P2

• Childbearing complete

Visit Type

• Abnormal Uterine Bleeding

Recommended Management

• Common recommendations

may include:

- Oral contraceptives

- Mirena® IUD

- Hysteroscopic removal of

fibroids or polyp

- Ablation

CONFIDENTIALCONFIDENTIAL

Integrated BRAC Analysis ® with Myriad myRisk ™ Hereditary Cancer

myRisk Management Tool

FAMILY MEMBER

CANCER / CLINICAL DIAGNOSIS

AGE AT DIAGNOSIS

Patient None

Mother Breast 45

Maternal Aunt Breast 55

This information was provided by a qualified healthcare provider on the test request form and was not verified by Myriad.

RECEIVING HEALTHCARE PROVIDER

Physician Name, MD Myriad Healthcare Partners 320 Wakara Way Salt Lake City, UT 84108

SPECIMEN

Specimen Type: Buccal Draw Date: Jun 8, 2014 Accession Date: Jun 9, 2014 Report Date: Jun 30, 2014

PATIENT

Name: Patient Name Date of Birth: Jan 12, 1978 Patient ID: 1144 Gender: Female Accession #: 00001144-BLD Requisition #: 000000ORDERING PHYSICIAN: Physician Name, MD

GENETIC TEST RESULTS SUMMARY INFORMATION

PERSONAL / FAMILY HISTORY SUMMARY AND MANAGEMENT INFORMATION

RESULT: NEGATIVE / NO CLINICALLY SIGNIFICANT MUTATION IDENTIFIEDNote: “CLINICALLY SIGNIFICANT,” as defined in this report, is a genetic change that is associated with the potential to alter medical intervention.

ADDITIONAL FINDINGS: NO VARIANT(S) OF UNCERTAIN SIGNIFICANCE (VUS) IDENTIFIED

MODIFIED MEDICAL MANAGEMENT MAY BE APPROPRIATE

No clinically significant mutations were identified in this patient. However, based on personal/family history, the patient’s cancer risks may still be increased over the general population. Clinical management should be based upon personal and family history.

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© 2014 M yriad Genetic Laboratories Inc | 320 Wakara Way Salt Lake City Utah 84108 | PH: 800 469 7423 FX: 801 584 3615

CONFIDENTIAL

Name: Patient Name DOB: Jan 12, 1978 Accession #: 00001144-BLD Report Date: Jun 30, 2014

myRisk Management Tool Associated with:

myRisk Management Tool: Page 1 of 2

WHAT MANAGEMENT FOR CANCER RISKS SHOULD BE CONSIDERED?Clinical management guidelines are based on this patient’s personal and family history and genetic test results, when appropriate. Unless otherwise stated, management guidelines included below are limited to those issued by the National Comprehensive Cancer Networ k (NCCN). See the reference listed for more details. If management for a specific cancer (e.g., breast) is available due to multip le causes (e.g., a mutation and a family history, or multiple mutations in different genes), only the most aggressive management is shown. Only guidelines for the patient’s long-term care related to cancer prevention are included. No information is provided related to treatment of a previous or existing cancer or polyps. Any discussion of medical management options is for general informational purposes only and does not constitute a recommendation. While genetic testing and medical society guidelines provide important and useful information, medical management decisions should be made in consultation between each patient and his or her healthcare provider.

Notes for Personalized Management:

PROCEDURE AGE TO BEGINFREQUENCY

(Un less o therwise ind icated by f ind ings )

RELATED TO

FEMALE BREAST

Breast Awareness - Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness 1

Individualized NAPersonal /

Family History

Clinical breast exam 1 30 years Every 6 to 12 monthsPersonal /

Family History

Consider breast MRI in addition to mammography 1 30 years AnnuallyPersonal /

Family History

Consider risk reduction strategies 1 Individualized NAPersonal /

Family History

1. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 2.2013. July 3. Available at http://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf.

f 2

O

PROCEDURE AGE TO BEGINFREQUENCY

(Un less o therwise ind icated by f ind ings )

RELATED TO

FEMALE BREAST

Breast Awareness - Women should be familiar with their breasts and promptly report changes to their healthcare provider. Periodic, consistent breast self-examination (BSE) may facilitate breast awareness 1

Individualized NAPersonal /

Family History

Clinical breast exam 1 30 years Every 6 to 12 monthsPersonal /

Family History

Consider breast MRI in addition to mammography 1 30 years AnnuallyPersonal /

Family History

Consider risk reduction strategies 1 Individualized NAPersonal /

Family History

1. Bevers TB, et al. NCCN Clinical Practice Guidelines in Oncology®: Breast Cancer Screening and Diagnosis. V 2.2013. July 3. Available at http://www.nccn.org/professionals/physician_gls/pdf/breast_risk.pdf.

Confidence that the known genetic factors

have been evaluated.

Clear management based on personal/family

history.

POSITIVE - Clinically Significant Mutation Identified

NEGATIVE - No Clinically Significant Mutation Identified

Contribution to cancer of focus and

at least one of the following:

• An absolute cancer risk of ≥ 5%

• A 2 to 3-fold increase in cancer

risk over general population

• Existing society guidelines

around management or a change

in management is inferred based

on the level of risk

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Myriad, the Myriad logo, Myriad myRisk and the Myriad myRisk logo are either trademarks or registered trademarks of Myriad Genetics, Inc., in the United States and other jurisdictions.©2014, Myriad Genetics, GmbH. Not for distribution in USA.

Myriad Genetics GmbHLeutschenbachstrasse 958050 ZurichSwitzerland

www.myriadgenetics.eu

References:

1. Nadine Tung et al. Prevalence of Gene Mutations Among Hereditary Breast and Ovarian Cancer Patients Using a 25-gene Panel. Presented at ACMG - March 2014

2. Matthew B. Yurgelun, et al. Multi-gene Panel Testing in Patients Suspected to Have Lynch Syndrome. Presented at ASCO - June 20143. Lucy R. Langer A Study of Ovarian Cancer Patients Tested With a 25-gene Panel of Hereditary Cancer Genes, Presented at ASCO - June 2014 4. Roa, B., et al. Development of a Next Generation Sequencing Panel to Assess Hereditary Cancer Risk that Includes Clinical Diagnostic Analysis of the BRCA1

and BRCA2 Genes. Presented at ASHG - October 2013 5. Bowles K., et al. A Clinical History Weighting Algorithm Accurately Classifies BRCA1 and BRCA2 Variants. Presented at ASHG - October 2013. 6. Eggington J.M., et al. A Comprehensive Laboratory-based Program for Classification of Variants of Uncertain Significance in Hereditary Cancer Genes.

Clinical Genetics Nov. 2013. doi: 10.1111/cge.12315 [Epub ahead of print]

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Myriad myRisk

• 40-50% More Mutations Identified 1-3

• >99.92% Validated Analytical Sensitivity 4

• Medical Management Guidelines from NCCN and Others

• 14-21 Days Turn Around Time

From Myriad, your trusted advisor

• Global Leader in Hereditary Cancer Risk Assessment

• 20+ Years of Experience

• Over 1 Million Patients Tested

Powered by Myriad myVisionTM Variant Classification

• Lifetime Commitment for Accurate Variant Interpretations

• >$1 Million Invested in Developing Variant Classification Techniques and a Curated Database

Supported by 30+ Scientists

• >99% certainty for Variant Reclassification 5,6

A diagnostic test that detects gene mutations associated with eight major cancers.