Radiation Oncology Interface with Genetics

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Radiation Oncology Interface with
Genetics Genomic Health Care

• Carolyn D. Farrell, MS, CNP, CGC
• Director, Clinical Genetics Service, RPCI
• RWJF Executive Nurse Fellow Alumnus

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Public Perception of Genetics Risk
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Genetic Testingfrequently the focus, but only
part of the picture

• Who is You?
• Test for What?
• Cancer?
• Risk?
• When?
• Why?
• Genetics gt just testing applies to all

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Extent of Genetics Genomics in Oncology Then,
Now Future

• In the Beginning
• Genetic (Inherited) Risk 5-10 of cancers
• Identifying persons at risk
• Genetic Testing limited to a few cancer genetic
  syndromes
• With Advances in Genetics Knowledge
• Somatic (non-inherited) genetic factors of the
  tumor associated with differences in cancer risk
• Underlying Other genetic factors impact
  treatment, success or risk
• Insurance, Economic, Legal, Ethical, Practical
  Issues
• Impact Evolution of Human Genome Project
• Pharmacogenetics omics
• Personalized Medicine
• Increasing Applications re all above
• Expectation of Knowledge Integration by all
  Health Care Providers

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Genetic Consultation, Evaluation Counseling
Process Putting Risk
Assessment in Perspective

• Data Information Collection
• Individual health hx growth, development,
  reproductive, medical
• Family Hx (pedigree)
• Cultural, racial and religious background
• Psychosocial issues and needs
• Methods
• Screening questionnaire Interview
• Consult appointment Review/Clarify above
  Observation Physical evaluation
• Assess Risk per above, current genetics
  knowledge, advances
• Process
• Communicate assessment, including Differential
  Diagnosis/es
• Discuss risks, options recommendations decide
  on plan
• Further Eval, Exam and/or Testing? Approval
  processes, Consent, ELSI, etc
• Outcome Interpretation significance to patient
  family Follow-up

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CASE

• Woman in for 2nd radiation treatment after
  lumpectomy for diagnosis of breast cancer
• What information do you want to know?
• Why?
• What impact, if any, will genetics make?

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Distinguishing High Risk versus Increased
Risk versus Genetic Risk

• Methods/Tools to Identify, Quantify /or Manage
  Risk benefits limitations
• Professional background/experience
• Screening questionnaire/tool
• Mendelian inheritance Pedigree analysis
  (e.g.,Penetrance Bayesian)
• Models to calculate risk e.g., for breast cancer
  (e.g., Gail Claus)
• Expressing Risk Relative Attributive Absolute
  etc
• Likelihood of Detecting a Gene Mutation e.g.,
  software programs (e.g., BRCA PRO), lab data
• Family History evaluation for risk features
• Genetic testing (e.g., BRCA) or markers of risk
  (e.g., Her2 neu)
• Research participation eligibility criteria
• Combination

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How to Identify Persons at Possible Risk the
RED FLAGS

• Age (early) at diagnosis (even if singular
  affected)
• Bilateral (or multiple primary) tumors
• Rare cancers, or cancer in person not associated
  with risk factor
• Constellation of tumors consistent w/
  known/suspected cancer syndrome (e.g., breast
  ovary colon endometrial)
• Cancer in 2 or more close relatives (maternal or
  paternal)
• Evidence of autosomal dominant transmission
• High or Moderate risk by risk assessment tool
• Scheuner et al Farrell CD, et al Sifri R, et
  al, CA Cancer J Clin 2004, 54 309-26

Consider genetic evaluation for hereditary cancer
syndrome
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High Risk for Cancer
Practice Guidelines

• NCCN Clinical Practice Guidelines e.g.,
• Genetic/Familial High Risk Assessment Breast
  Ovarian
• Colorectal Cancer Screening
• http//www.nccn.org/professionals/physician_gls/f_
  guidelines.asp
• Professional Society e.g., Amer Gastroenterolog
  Asso
• B Levin, et al. Screening Surveillance for
  Early Detection of Colorectal Cancer
  Adenomatous Polyps, 2008 A Joint Guideline from
  ACS, US Multi-Society Task Force on CRC, and Am
  Coll Radiol
• (http//www.gastro.org/user-assets/Documents/02_Cl
  inical_ Practice/medical_position_statments/crc_ea
  rly_detection_mps.pdf)
• ACOG Guidelines (accepted for publication
  12/2008)
• Focus on Female Cancers Hereditary Breast
  Ovarian
• Guidelines not absolutes

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What if Possible Genetic/Inherited Risk was
Raised at Initial Diagnosis? Would it Change
Anything?
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Hereditary Breast Cancer
Multifactorial 20
PTEN, P53 LKB1/STK11 lt5
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Risks/Features Associated with BRCA Gene Mutations

• BRCA1 risks
• Br ca 56-87
• Ov ca 16-44
• Asso w/ Triple negative tumors

• BRCA2 risks
• Br ca 56-87
• Ov ca 16-27
• Melanoma
• Pancreas

• Both BRCA1 BRCA2
• 2nd primary cancer
• Prostate cancer
• Colon cancer
• Early onset, BRCA negative consider FA testing?

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Genetic Testing identify suspected
syndrome/gene
Not available
Begin genetic testing with affected individual
No Mutation Identified
Mutation Identified
Indeterminate result (VUS)
Testing unaffected at risk limited, e.g.,
population at risk

• NEGetiology unknown
• Testing not practical for relatives at risk
  usually manage as increased risk
• Offer Pt DNA banking
• Future genetic testing?
• Re-evaluate annually

• POS for mutationetiology of ca
• Risk for asso cancer/s see HR guidelines
  med surg managemt assess personal
  considerations
• Testing for mutation appropriate option for
  at-risk relatives and/or high risk screening and
  med/surg management

Re-evaulate??
appropriate gene!
Also see NCCN Guidelines
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Genetic Testing Chromosomes, DNA and
Genes
Gene
Nucleus
Cell
Chromosomes
DNA bases
Protein
Adapted from Understanding Gene Testing, NIH, 1995
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Breast Cancer Information Core
BRCA1 BRCA2 Mutations
All Examples of Population Specific
Del exons 13 or 22
6k dup exon 13
Del exons 8 or 9
5382insC Prevalence 0.2
185delAG Prevalence 1
997del5
6174delT Prevalence 1.3
African American - mutations are unique
British Dutch Icelandic Ashkenazi Jewish
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Genetic Risk vis-à-vis Testing -- What to Know

• Clinical vs Investigational vs Research
• Diagnosis vs Susceptibility vs Screening
  Germline vs Somatic
• Type chromosomal DNA linkage (markers)
  biochemical
• Method DNA sequencing RNA ASO protein trunc
  MSI etc
• Results sensitivity specificity interpretation
  (VUS?)

• Laboratory certified? Permit for clinical
  testing? http//www.health.state.ny.us/press/relea
  ses/2001/genetics.htm
• Informed consent potential results benefits,
  risks, limits
• Practical cost insurance coverage affected
  deceased etc
• Alternatives e.g., DNA banking
• Resource http//www.genetests.org/

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Inherited Risk for Cancer?

• Hereditary Cancer Syndrome?
• Which? What cancer risk/s? Extent of risk?
• Offer genetic test? For what? For whom?
• Rationale? Criteria??

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Prevalence () of Deleterious Mutations in BRCA1
and BRCA2
No Br Ca lt 50 or Ov Ca in anyone 2.8 6.8/
2.9 12.8 8.8 39.1/ 17.6
Br Ca lt 50 in 1 rela no Ov Ca 4.5 5.3/
15.8 21.8 23.1 53.9/ 26.1
Ov Ca any age 1 rela no Br Ca 5.6 16.9/
6.4 20.0 21.1 66.0/ 30.3
Ov Ca gt1 rela no Br Ca lt50 9.6 27.3/
12.2 40.0 33.2 70.8/ 46.2
Br Ca lt50 Ov Ca any age 12.2 39.2/
15.9 61.9 46.5 79.0/ 60.0
Br Ca lt50 in gt1 rela no Ov Ca 8.7 30.1/
11.4 41.9 42.3 67.2/ 46.2
Pt. HX No Br Ca lt50 or Ov Ca Br Ca
lt50/gt50 Male Br Ca Ov Ca any age Br Ca lt50/gt50
Ov Ca any age
Myriad Genetics, Inc, Spr/2006 total
gt37,000 N lt20
_at_lt50
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Genetic Testing Interpreting Results

• Positive deleterious mutation identified
  risk for syndrome-related cancer/s
• Variant of Uncertain Significance
• Nature of mutation e.g., point intron where in
  gene conserved region
• Segregate with disease?
• Other existing deleterious mutation?
• Associated with specific population?
• Negative no mutation identified
• Is it True Negative? (Nature limitations of
  gene testing)
• Result/s make sense?
• Consider other testing clinical and/or research
• Unexpected Result
• Testing automatically done with order for other
  gene test (e.g., MYH with APC)
• Test result/s has significance beyond intended
  (e.g., APOE3 UGT1A1)
• Strategies
• Be Prepared to inform/advise patient before AND
  after testing
• Know be able to deal with possible outcomes
• Consult with genetics professional

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BRCA Gene Mutations Endometrial Cancer Risk

• Study 857 women w/ BRCA1 or 2 gene mutation
• Studied until ovary or endometrial cancer, death,
  or end of study average 3.3 year follow-up
• 6 diagnosed with endometrial cancer (1.13
  expected)
• 4 used Tamoxifen in past
• Among 226 who used Tamoxifen RR endometrial
  ca11.6
• Conclusion Main contributor to increased risk
  for endometrial cancer in BRCA mutation carriers
  was Tamoxifen use for previous breast cancer
• Beiner ME, et al. Gynecol Oncol 2007 104(1)7-10
• Study Ovarian Cancer in young women w/
  endometrial cancer
• 102 women (24-45yo) 26 had co-existing
  epithelial ovarian cancer
• Conclusion Importance to eval adnexa
• Thiffault IH. Brit J Ca 2004 90(2)483-91
• NOTE Importance to consider genetic risk

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Family HistoryIS a Valuable Risk Assessment Tool

• Cost effective available
• Evolving record update
• Developing maintaining patient-provider
  relationship (including cultural perspectives,
  personal/family values)
• Ability to recognize persons at increased risk
• Stratify those at possible/suspected genetic risk
• Genetic testing not available or indicated for
  most
• NCHPEG guidelines for all practitioners
• Core Competencies
• http//www.nchpeg.org/core/Corecomps2005.pdf
• Core Principles http//www.nchpeg.org/core/core
  principles.pdf

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• Genetic Risk Assessment (Initial)
• BRCA 12 testing was negative in 2-2
• Genetic Risk Assessment REVISED
• HNPCC Amsterdam criteria modified criteria
• Implications of BRCA1/2 testing results

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Cancer Risks in HNPCC
100
80
with cancer
Colorectal 78

• (gt25 by 50 80 by 70)

60
Endometrial 43
40

• (20 by 50 60 by 70)

Stomach 19 (13)
20
Biliary tract 18 (2)
Urinary tract 10 (4)

Ovarian 9 (12)
0
20
40
60
80
0

• Small intestine brain

• Lancaster JM, et al. Gynecol Oncol 2007,107
  (2)159-62
• Aarnio M et al. Int J Cancer 64430, 1995
• Gastroenterology 19961101020-7
• Int J Cancer 199981214-8

Age (years)
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Genetic Testing Complex Issues Genetic
Heterogeneity
Chr 2
Chr 3
MSH6
MLH1
MSH2
PMS2
PMS1
Chr 7

• HNPCC associated with germline mutations in 5
  different genes
• Clinical testing not available for all genes
• Genotype-Phenotype correlations??
• Nuances of HNPCC genes protein products e.g.,
  heterodimers

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Genetic High Risk vis-à-vis Criteria for Dx
versus Criteria for Testing or Screening

• HNPCC Amsterdam
• 3 relatives w/ CRC
• 2 generations
• 1 dx before age 50
• 1 is 1st degree relative of the other 2

• Bethesda for testing of tumor
• Dx of CRC lt50
• Family history of 2 close relatives w/ HNPCC
  associated cancer
• MSI value per colon tumors

• Modified Amsterdam
• As above but incl other HNPCC asso cancers
  (endometrial, GI not ovary)

• NOTE Consider
• r/o FAP
• HNPCC screen MSI IHC

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Prophylactic Surgery HNPCC

• Study 315 women with germline mutations
  associated with Lynch syndrome
• Prophylactic surgery 61 hysterectomy 47 BSO
• Matched w/ 210 for analysis re endometrial cancer
  223 for analysis re ovarian cancer
• Followed until cancer or until last visit
• Results
• Prophylactic surgery cohort No GYN cancer
• Controls 69 (33) endometrial ca12 (5) ovarian
  ca
• Conclusion Prophylactic TAH w/ BSO effective
  cancer prevention strategy for Lynch syndrome
• Schmeler KM, et al. NEJM 2006 354(3)261-9

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Genetic High Risk vis-à-vis Clinical
Criteria for Syndrome Dx

• Issues
• Some associated cancers not incl in criteria,
  e.g., ovary in HNPCC
• 2/50 had HNPCC gene mutation
• 9/50 not tested would meet clinical criteria for
  dx
• South S, Vance H, Farrell C, et al. Consideration
  of hereditary non-polyposis colorectal cancer in
  BRCA mutation negative familial ovarian cancers.
  Cancer (accept for pub 8/08)
• Impact of small family size
• Issues Strategies
• Consider HNPCC screen versus testing gene/s
• Need for assessment for medical/surgical
  decisions
• Need related to family risk associated medical
  decisions
• Implications for other cancer risk e.g.,
  endometrial in HNPCC

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HNPCC Mutation Likelihood

• Prevalence Deleterious Mutations - MLH1 or MSH2
• Family hx (includes at least 1 first or second
  degree relative)
• No Affected Relatives gt1
  Relative Affected
• Patient Hx
• CRC lt50 7.2 27.5
  
• CRC gt50 4.4 14.1
• Endometrial Ca lt50 7.0 29.9
• Other HNPCC Cancer 3.6 14.3
• gt1 HNPCC Cancer 8.8 45.8
• estimate calculated according to PREMM model
  Myriads Nlt25
• Myriads Nlt50
• (HNPCC-related cancers include colorectal,
  endometrial, ovarian, gastric, ureter/ renal
  pelvis, brain, biliary tract, small bowel,
  pancreas, sebaceous adenoma/carcinoma
• Myriad data N 3410 (11/07)

• BRCA Pro another model

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Grappling with Gaps in Guidelines Issues
Strategies

• Lack required criteria Potential miss
  person/families at high risk
• Dont consider age criteria absolute check other
  personal family hx
• Isolated cases /or limited family history
• Dont ignore (e.g., 7 8 likelihood BRCA
  mutation in isolated breast ovarian cancer,
  respectively)
• Insufficient guideline for noted risk factor or
  medical management
• Consult with genetics and/or specialty expert
• When who to screen and how far to go
• Consider research participation (possibly get
  results, but)
• Genetic testing not medically necessary yet
  important to family?
• Offer/Consider DNA banking (with Genetics
  Clinical Lab)

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• What Cancer Risk Assessment Models to Use for 2.2
  ?
• Scheduled for surgery
• Genetic testing? If yes, for What? Why? When?
• What about relatives?

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Breast Cancer Associated with Different Genetic
Syndromes
Other Cancer/Traits prostate, male breast,
colon, pancreas?
Chr./Gene 17q21.1/ BRCA1 13q12-13/ BRCA2

• Syndrome
• Breast
• Breast/Ovary
• Li-Fraumeni
• Cowden

• Tumor
• breast
• (female) /or ovary
• breast
• breast

sarcomas, brain tumors, leukemia, adrenocortical
cancer hamartomas, thyr prob/ca, endometrial,
skin cancer, lipomas, macrocephaly
17p13/ p53 10q22-23/ PTEN
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Recognizing Hereditary Cancer Risk vis-à-vis
Cowden syndrome

• Characteristics
• Cancers breast thyroid (follicular)
  endometrial ovary colon
• Phenotype benign features
• fibrocystic breast disease fibroadenomas
• macrocephaly
• mucocutaneous lesions
• Lipomas fibromas GI hamartomas
• Penetrance (lifetime risk)
• breast cancer 25-50 (women) thyroid cancer
  3-10
• Incidence 1/200,000 underestimate ??
• PTEN gene

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Genetic High Risk Criteria for CLINICAL Research
Participation

• Cowden syndrome C Eng, Cleveland Clinic
• Evaluating Phenotypic features Gene mutations
  in persons suggestive of CS
• Issues Strategies
• Ability to get results?
• Need to confirm testing for clinical use
• Potential for use of results for risk assessment
  screening e.g., study
• Increased head circumference asso w/cancer
  genetic syndromes
• Trend gt 3SD diff between HC Height in
  persons w/ cancer
• Farrell CD, Nakashima K, Blaird-Wagner D, et
  al. Descriptive (Exploratory) Study of Benign
  Masses, Dermatologic Manifestations, and Head
  Circumference in Adults with and without Cancer.
  Abstract, ACMG Meeting, 3/06.

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Genetics Genomics expanding impact

• Gene Expression Profiling e.g., OncotypeDX
• Multi-gene assay, Genomic Health validated
• Expression panel 21 genes recurrence score
• Quantitative assessment of likelihood of distant
  recurrence
• Assesses benefit of chemotherapy
• Breast ca new dx, stage 1 or 2, node neg, ER
• Persons who will receive Tamoxifen

ASCO 07 abstracts NSABP study, Paik S et al,
NEJM, 2004351(27)
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Genetics Genomics Impact Practice, Risks
Expectations in Radiation Medicine

• Vis-à-vis Cancers
• E.g., Breast Brain Prostate
• Vis-à-vis Genetic Syndromes
• E.g., Ataxia telangectasia, breast cancer
  radiotherapy
• Vis-à-vis Characteristics of Tumor
• Breast cancer, BRCA mutations PARP inhibitors
• Losartan as treatment in specific genetic
  disorder/risks

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Genetics Prostate Cancer

• Increased risk associated with
• BRCA gene mutations, especially BRCA2 yet
  usually not early onset
• CHEK2 gene mutations
• Most prostate cancer gene testing is research
  only 1 clinical lab in US
• Influence on treatment?

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Pharmacogenetics/omics

• Implications for
• Identification of risk
• Individualized treatment
• Improved prognosis, prevention or cure!!
• Example drugs metabolized by major
  cytochrome (CYP)
  P450 drug metabolizing
  enzymes (CYP2D6, CYP2C9, CYP2C19) TPMT
• Potential Issues
• Research versus Clinical use
• Consent for testing needed?
• Misinterpretation, Misuse, or Fear to use
• Unforeseen risks Implic for pt/family? e.g.,
  UGT1A1, APOE
• Professional liability
• Insurance issues
• Pharmacogenetic Testing offered at
  Cincinnati Childrens Hospital
  http//www.cincinnatichildrens.org/svc/alpha/g
  /gps/drugs.htm

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Genetic Risk vis-à-vis Emerging Genomics
Environment Susceptibility Prevention

• Public Health Common Disorders
• Genes Environment Interaction
• Identify INCREASED RISK
• Prevention Perspective
• Early identification of Risk
• Individualized management, treatment,
  improved prognosis cure
• Research Technology
• Intervention Prevention
• Personalized medicine H.R. 6498
• http//thomas.loc.gov/home/gpoxmlc110/h6498_ih.xml

Multi-factorial 20-25
Sporadic
70
Inherited
10
40

• Ethical guidelines www.who.int/ncd/hgn/docline.ht
  m

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Consumer Marketing

• Public Interest Expectations
• Access Marketing
• Pros Cons
• ACMG Statement on Direct-to-
  Consumer Genetic Testing
• Tests for susceptibility are medical tests
• Provide only through qualified HCPs
• HCP responsible for ordering interpreting, and
  pre-test and post-test counseling
• Patient self-ordering genetic tests potentially
  harmful
• (Am Coll Med Genet Board of Directors Genetics
  in Medicine Jan/Feb, 2004)

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Legislation Policies Discrimination
Perception or Reality?

• Insurance Health
• Federal Medical/Health Health Insurance
  Portability Accountability Act (HIPAA) of 1996
  (enacted 7/97)
• cannot deny insurance, or charge higher rates
• States 48 w/ genetics legislation, BUT...
  definition genetic info content of med
  records differ
• http//www.ncsl.org/programs/health/genetics/
  charts.htm
• GINA H.R. 493 Genetic Information
  Non-Discrimination Act
• of 2008
• http//www.govtrack.us/congress/bill.xpd?bil
  lh110-493
• Employment Americans w/Disabilities Act
• Insurance Life -- no existing laws

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Disclosure Confidentiality

• Electronic Medical/Health Record Registries
  Databases
• What information is important to include?
• Family history how? What?
• Sharing information legal, ethical, personal
  issues
• Who should have access?
• Who can enter or change information?
• What protections need to be in place
• Purposes Clinical management? Research?
  Personal?
• Results of carrier, pre-symptomatic
  susceptibility tests should be kept confidential
  from employers, insurers, schools gov agencies
  ...may be disclosed in accordance with laws
• http//h20247.www2.hp.com/publicsector/downloads/T
  echnology_Glaser_VB.pdf

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Practical Perspectives Genetic Risk and Cancer

• If genetic evaluation may impact medical or
  surgical management
• If genetic information may impact patient
  decision/s
• Use NCCN Guidelines as that not as absolute
• Keep in mind the 3 most common Breast GYN
  cancer genetic syndromes BRCA, HNPCC, CS
• Even singular affected may be at significant risk
  for cancer genetic syndrome/mutation
• Be alert for atypical or limited presentations
  e.g., small family
• Value critical nature of genetic assessment
  testing not just for patient, but relatives at
  risk
• Candidates for participation in clinical research
• Emerging applications of genetics prognosis,
  treatment, drugs, etc
• Call us if you need us x8400

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Screening Tools, Info Resources

• Surgeon Generals Family History Initiative
• www.hhs.gov/familyhistory/
• ASHG How to record your family history
• www.ashg.org
• Family hx concerns, resources, family tree
  symbols
• www.isong.org www.nsgc.org www.geneclinics.org
  www.geneticalliance.org
• AMA Prenatal, Pediatric Adult Screening
  Questionnaires
• www.ama-assn.org/ama/pub/category
• CDC Initiatives Public Health
• http//www.cdc.gov/genomics/activities/famhx.htm

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Evaluation of Family History Risk Assessment Tools

• Secretarys Advisory Council on Genetic Testing
  (SACGT) recommended 4 components be considered
• Analytic validity accuracy reliability to
  identify disease among those at risk --
  sensitivity, specificity
• Clinical validity ability to use family history
  of disease to stratify risk predict future
  disease
• sensitivity, specificity, pos neg predictive
  value
• Clinical utility impact, usefulness for person
  society
• Ethical, Legal, Social issues
• labelling patient disease,at risk costs
  interventions
• Yoon PW, et al, 2002, Genetics in Medicine
• Yoon PW, et al, Am J Prev Med,2003, 24(2)128-35

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Genomic Health Care the Future of Medicine

• Tailored Medical Management Treatment
• Individualized, disease genotype directed aka
  
  Personalized medicine H.R. 6498
• http//thomas.loc.gov/home/gpoxmlc110/h6498_ih.xml
  
• New approaches e.g., gene therapy
  immuno-therapy
• Genetics Public Health broaden focus to
  include
• Common Disorders combination of genetic
  environmental factors
• Identification of risk factors prevention of
  disease DNA on a chip
• Scientific advances, Public expectations
  Professional demands
• Testing early diagnosis, intervention, cure
  prevention anonymous
• Professional expertise provision of or referral
  for genetic services
• Allowing for future evolving genetic testing
  e.g., DNA banking
• Responsibility to relatives at risk?
• Evolving legislation professional standards

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Resources in Genetics a few

• RPCI Clinical Genetics Service 716 845-8400
  http//www.roswellpark.org/
• American College of Medical Genetics
  http//www.acmg.net/
• National Society of Genetic Counselors
  http//www.nsgc.org/
• International Society of Nurses in Genetics
  http//www.globalreferrals.com/
• National Human Genome Research Institute
  http//www.genome.gov/
• Secretarys Advisory Committee on Genetic Health
  Society http//www4.od.nih.gov/oba/sacghs.htm
• Online Mendelian Inheritance in Man
  http//www.ncbi.nlm.nih.gov/Omim/
• ASHG/ACMG Report Points to Consider Ethical,
  Legal, and Psychosocial Implications of Genetic
  Testing in Children and Adolescents, AJHG, 1995
• International Guidelines on Ethical Issues in
  Medical Genetics Services http//whqlibdoc.who
  .int/hq/1998/WHO_HGN_GL_ETH_98.1.pdf
• The Genetic Alliance (incl legislation policy)
  http//www.geneticalliance.org/
• Natl Coalition for Health Prof Educ in Genetics
  (competencies) http//www.nchpeg.org/