hereditary cancer risk assessment: indicators of...
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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