hereditary cancer risk assessment: indicators of...

Hereditary Cancer Risk Assessment:

Indicators of Hereditary and Familial Risk

Karen CopelandCertified Genetic CounselorDirector – International Medical AffairsMyriad Genetics GmbH

Impact of Hereditary Cancer

• Breast Cancer Incidence: ~5,400 / year• 1,300 deaths per year

• Ovarian Cancer Incidence: ~580 / year• 420 deaths per year

• BRCA1/BRCA2 mutations responsible for 5 - 10% of breast cancers• ~400 breast cancers due to BRCA mutations every year

• BRCA1/BRCA2 mutations responsible for 12 - 14% of ovarian cancers• ~60 ovarian cancers due to BRCA mutations every year

Breast and Ovarian Cancer in Switzerland

Bundesamt für Statistik 2005‐2009Coughlin. AM J Prev Med. 1999;16(2):91‐98.  Narod. Nat Rev Cancer. 2004;4(9):665‐76. 

Antoniou. Genet Epidemiol. 2000;18:173‐90.Anglian. Br J Cancer. 2000;83:1301‐8.

Introduction

• Physicians should view hereditary cancer risk

assessment as crucial component of evaluation of new

cancer patients

• Physicians should view the results of genetic testing

for hereditary cancer crucial for treatment and

managment decisions for appropriate patients

4

Key Features of Hereditary Breast / Ovarian Cancer Syndrome

• Prevalence• 1 in 300 – 1 in 500

• Primarily due to BRCA1/BRCA2 gene mutations• Cancer Risks

• Significant lifetime risks for breast and ovarian cancer• Early onset breast cancer• Increased risk for other cancers

• Highly Penetrant• Variable expression of age onset, tumor site and number of

primary tumors• Cancer risk depends on numerous variables, including age

and gender

• Hereditary risk for family members

Indicators for Hereditary Breast and Ovarian Cancer Syndrome

• Family History- A previously identified HBOC

mutation in the family- Breast Cancer diagnosed < 50y- Ovarian Cancer- Male breast cancer- Two primary breast cancers- Ashkenazi Jewish ancestry with an

HBOC-associated cancer*^- Three or more HBOC-associated

cancer at any age*^

*In the same individual and/or on the same side of the family^HBOC-associated cancers include breast (including DCIS), ovarian, pancreatic, and aggressive prostate cancer (Gleason score of ≥7) Assessment criteria based on medical society guidelines. For these individual medical society guidelines, go to www.myriadpro.com/references

• Age at Diagnosis- Breast Cancer diagnosed < 50y

• Pathology- Triple negative breast cancer

• Personal History- Ovarian cancer- Male breast cancer- Two primary breast cancers- Ashkenazi Jewish ancestry with an

HBOC-associated cancer*^- Breast cancer with 2 or more

relatives with an HBOC-associated cancer at any age*^

Case #1

• 50 year-old woman with Stage 1 ER-negative unilateral invasive breast cancer

• No family history of breast or ovarian cancer• Small maternal family and few female relatives in

paternal family history

• Are there indicators for hereditary cancer?• What guidelines does she meet?

NCCN Guidelines: Genetic / Familial High-Risk Assessment: Breast and Ovarian

• Personal history of breast cancer + >1 of following:• Dx age <45• Dx any age with >1 close relative with breast cancer <50 or >1 epithelial ovarian cancer at any age

• 2 breast primaries with 1st breast cancer dx <50y• Dx age <60y with triple negative breast cancer• Dx age <50 with a limited family history• Dx any age with >2 close relatives with breast cancer at any age

• Dx any age with >2 close relatives with pancreatic or aggressive prostate cancer at any age

• Close male relative with breast cancer• Ashkenazi Jewish ancestry

NCCN.org. Version 1.2013 Published 7 March 2013

Guidelines met:Personal diagnosis of breast cancer <50 years with a limited family structure

Case # 2

• 58 year-old woman with Stage 2 triple negative unilateral invasive breast cancer diagnosed at age 52 years

• Lumpectomy with adjuvant chemotherapy • Father with prostate cancer (Gleason 8) at age 63 years• Paternal grandfather with pancreatic cancer at age 79

• Are there indicators for hereditary cancer?• What guidelines does she meet?

Guidelines met: • Triple negative breast cancer <60y• Breast cancer diagnosed at any age with >2 close relatives with

pancreatic or aggressive prostate cancer at any age

NCCN Guidelines: Genetic / Familial High-Risk Assessment: Breast and Ovarian

• Personal history of breast cancer + >1 of following:• Dx age <45• Dx any age with >1 close relative with breast cancer <50 or >1 epithelial ovarian cancer at any age

• 2 breast primaries with 1st breast cancer dx <50y• Dx age <60y with triple negative breast cancer• Dx age <50 with a limited family history• Dx any age with >2 close relatives with breast cancer at any age

• Dx any age with >2 close relatives with pancreatic or aggressive prostate cancer at any age

• Close male relative with breast cancer• Ashkenazi Jewish ancestry

NCCN.org. Version 1.2013 Published 7 March 2013

Case # 3

• 55 year-old woman with Stage 2 ER/PR +, HER2 –diagnosed with unilateral invasive breast cancer

• Lumpectomy with adjuvant chemotherapy • Paternal aunt with breast cancer at age 49y

• Are there indicators for hereditary cancer?• What guidelines does she meet?

Guidelines met: • Breast cancer diagnosed at any age with a close relative with breast

cancer diagnosed <50 year-old

Patient would have been missed if only a first-degree family history was taken

Case # 4

• 45-year-old healthy woman

• Mother diagnosed with ovarian cancer at age 59 years, deceased age 62

• Maternal grandmother with breast cancer at age 49 years, deceased age 65

• Maternal aunt with breast cancer at 55 years

• Are there indicators for hereditary cancer?• What guidelines does she meet?

NCCN Guidelines: Genetic / Familial High-Risk Assessment: Breast and Ovarian

• Family history only• 1st or 2nd degree relative meeting any of above criteria• 3rd degree relative with breast or ovarian cancer with >2 relatives with breast cancer (at least 1 <50 y) and/or ovarian cancer

• Clinical judgment should be used to determine if the patient has a reasonable likelihood of a mutation

• Testing unaffected individuals considered only when appropriate family member is unavailable for testing

• Significant limitations of interpreting test results for unaffected individuals should be discussed

NCCN.org. Version 1.2013 Published 7 March 2013

NCCN Guidelines: Genetic / Familial High-Risk Assessment: Breast and Ovarian

• Personal history of epithelial ovarian cancer

• Personal history of male breast cancer

• Personal history of pancreatic or aggressive prostate cancer at any age with >2 close relatives with breast, ovarian, pancreatic or aggressive prostate cancer at any age

NCCN.org. Version 1.2013 Published 7 March 2013

NCCN Guidelines: Genetic / Familial High-Risk Assessment: Breast and Ovarian

• Personal history of breast cancer + >1 of following:• Dx age <45• Dx any age with >1 close relative with breast cancer <50 or >1 epithelial ovarian cancer at any age

• 2 breast primaries with 1st breast cancer dx <50y• Dx age <60y with triple negative breast cancer• Dx age <50 with a limited family history• Dx any age with >2 close relatives with breast cancer at any age

• Dx any age with >2 close relatives with pancreatic or aggressive prostate cancer at any age

• Close male relative with breast cancer• Ashkenazi Jewish ancestry

NCCN.org. Version 1.2013 Published 7 March 2013

Societal Standards and Guidelines

• ACOG – American Congress of Obstetricians and Gynecologists• AGA – American Gastroenterological Association• ASBS – American Society of Breast Surgeons• ASCO – American Society of Clinical Oncologists• ASCRS – American Society of Colon and rectal Surgeons• ESMO - European Society of Medical Oncology• NCCN – National Comprehensive Cancer Network• NICE – National Institute of Health Care and Excellence• NSGC – National Society of Genetic Counselors• ONS – Oncology Nursing Society• SGO – Society of Gynecologic Oncologists• SSO – Society of Surgical Oncology• USPSTF – U.S. Preventive Services Task Force

Genetische Prädisposition Für Brust/Eierstockkrebs

•Schweizerische Zuweisungsrichtlinien Zur Genetischen Beratung Und Evaluation Eines BRCA1/BRCA2 Gen Tests •Diese Richtlinien wurden genehmigt von: • Der Schweizerischen Gesellschaft für Medizinische Onkologie • Der Schweizerischen Gesellschaft für Medizinische Genetik • Der Schweizerischen Gesellschaft für Senologie • Der Schweizerischen Gesellschaft für Gynäkologie und Geburtshilfe

Dieses erhöhte Risiko basiert auf bestimmten familiengeschichtlichen Mustern einschliesslich: • Brustkrebs im jungen Alter • Anzahl Brustkrebserkrankungen• Eierstockkrebs• Beidseitiger Brustkrebs• Ethnischer Ursprung: Zurzeit limitiert auf Personen mit Ashkenazi jüdischer

Herkunft

•... ist es sinnvoll Individuen mit der folgenden persönlichen oder familiärenGeschichte an Krebserkrankungen für eine genetische Beratung und zur Evaluation einer BRCA1/BRCA2 Gen Testung zuzuweisen:

www.pichert-genetik.ch .

Genetische Prädisposition Für Brust/Eierstockkrebs

Identifikationskriterien USZ für ein hereditäres Krebssyndrom

Guideline Recommendation for Taking Family History

ACOG Committee Opinion, 478 (2011)• … recommended that all women

receive a family history evaluation as a screening tool for inherited risk. Family history information should be reviewed and updated regularly, especially when there are significant changes to family history…”

ASCO Expert Statement, 2014• New guidelines set forth by ASCO

recommend clinical oncologists document a detailed cancer family history of first- and second-degree relatives at a new patient’s visit including the age of diagnosis

Lu K, et al . J Clin Oncol. 2014;10;32(8):833-40.

Breast Cancer 37% Eisenbraun

Ovarian Cancer 100% NCCN

Colorectal Cancer 24% Kerber

Screening Mammography 6% Bellcross

Eisenbraun et al. Comm Oncol. 2010;7:75-81.NCCNv.4.2013 Genetic/Familial High-Risk Assessment: Breast and Ovarian. Accessed at www.nccn.org

Kerber RA, et al. Familial Cancer 2005;4:239-44.Bellcross CA et al. Genetics in Medicine. 2009;11:783-789.

Patients in Your Care Appropriate for Hereditary Cancer Testing

Standardization

What are the goals?• Screen / Evaluate

- Accurate personal/family history – every patient, annually- Consistent identification- Encompasses both Routine and Survivor Patients

• Diagnose- Informed Consent- Order test and personalize risk based on the result

• Treat- Result Disclosure- Surveillance, Surgical, and Chemoprevention options

• Manage- Customized medicl management plan- Family member impact

Practice Theory

• Cancer Family History Capture• 2 generation minimum with age of diagnosis

• Increasing Knowledge• Training Opportunities: ASCO, ASBS, ESMO

• Test with a comprehensive genetic panel• Utilize test result, guidelines and published data to

build short term and long term management plan

Moving Forward with Your Hereditary Cancer Protocol

Differential Diagnosis

Other cancers SyndromesBreast Cancer • Breast Cancer <35 • Li‐ Fraumeni (TP53)

Breast Cancer • Soft tissue or osteo‐sarcomas, adrenocorticol, colorectal, brain, leukemia

• Li‐ Fraumeni (TP53)

Breast Cancer • Macrocephaly, endometrial cancer, follicular thyroid cancer, GI hamartomas, mucocutaneouslesions

• Cowden syndrome (PTEN)

Breast Cancer • Lobular breast cancer• Diffuse gastric cancer

• Hereditary Diffuse Gastric Cancer (CDH1)

Breast Cancer • Mucocutaneous lesions, GI hamartomas, sex cord tumors, 

• Peutz‐Jeghers syndrome (STK11)

Breast Cancer • Breast Cancer• Pancreatic Cancer

• PALB2

Ovarian Cancer • Colorectal cancer• Endometrial cancer

• Lynch syndrome (MMR genes)

Evaluating Cancer Family History Based on Single Syndromes is Too Narrow

Evaluating Cancer Family History Based on Single Syndromes Can Lead to Uncertainty

A Negative Result Can Lead to Uncertainty

Clinical Rationale for Panel Approach

• Family history presentations are often complex

• Phenotype does not always reflect genotype

• Emerging data demonstrates that the current approach may miss pathogenic mutations

Many Genes Contribute to Hereditary Cancer

Multiple Genes Can Increase the Risk of a Single Cancer

Multiple Cancers Can be Associated with a Single Gene

Significant Syndromic Overlap

Patients that Meet Lynch Syndrome

Criteria

Patients that Meet HBOC Syndrome

Criteria• 7% of patients appropriate for HBOC testing also meet Lynch criteria

• 30% of patients appropriate for Lynch testing also meet HBOC criteria

Many patients have personal and family history associated with multiple syndromes

Saam, J. NCCN Annual Conference poster 2014

Patients that Meet Both

Criteria

With Myriad myRisk ~40-50% Relative Increase in Mutation Detection Over Current Approach

* BRCA1/2† Lynch Syndrome

Tung et al. Presented at ACMG March 2014; Yurgelun et al. Presented at ASCO June 2014; Langer et al. Presented at ASCO June 2014

Profile of myRisk Hereditary Cancer Panel

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

eight important cancers.

Indicators of Hereditary Cancer An individual with a personal or family history of any one of the following:

†Abnormal MSI/IHC or histology.‡Male breast cancer, triple negative breast cancer.**Other Lynch syndrome-associated cancers, 10 or more gastrointestinal adenomatous polyps.§HBOC syndrome-associated cancers include breast (including ductal carcinoma in situ [DCIS]), ovarian, pancreatic, and aggressive prostate cancers.^ Lynch syndrome-associated cancers include colon/rectal, uterine/endometrial, ovarian, stomach/gastric, kidney/urinary tract, biliary tract, small bowel, pancreas, brain, and sebaceous adenoma cancers.

Summary

• Cancer genetics is now a essential element in providing high quality comprehensive care in the gynecologic and oncology practice

• Every physician and nurse has a role to play in identifying these patients and their families with hereditary cancer risk assessment

• We can prevent many cancers that were destined to occur