Hereditary Cancer Risk Assessment: Indicators of Hereditary and Familial Risk

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Hereditary Cancer Risk Assessment:

Indicators of Hereditary and Familial Risk

Karen Copeland

Certified Genetic Counselor

Director – International Medical Affairs Myriad Genetics GmbH

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• 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 2005‐2009 Coughlin. 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.

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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

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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

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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*^

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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?

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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

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Guidelines met:

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

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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?

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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

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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

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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?

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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

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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?

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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

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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

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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

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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

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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 familiären

Geschichte an Krebserkrankungen für eine genetische Beratung und zur Evaluation einer BRCA1/BRCA2 Gen Testung zuzuweisen:

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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

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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

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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

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• 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

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Differential Diagnosis

Other cancers Syndromes

Breast 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, mucocutaneous lesions

• 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 

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Evaluating Cancer Family History Based on

Single Syndromes is Too Narrow

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Evaluating Cancer Family History Based on

Single Syndromes Can Lead to Uncertainty

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Clinical Rationale for Panel Approach

• Family history presentations are often complex

• Phenotype does not always reflect genotype

• Emerging data demonstrates that the current

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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

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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

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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

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Profile of myRisk Hereditary Cancer Panel

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

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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.

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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

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References

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