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Practice Guidelinesin Oncology v.1.2007

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NCCN Clinical Practice Guidelines in Oncology

Genetic/Familial

High-Risk Assessment:Breast and Ovarian

V.1.2007

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Version 1.2007, 03/22/07 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.

NCCN Practice Guidelines

in Oncology v.1.2007

Guidelines Index

Genetics Table of Contents

MS, References

NCCN Genetic/Familial High-Risk Assessment: Panel Members

Genetic/Familial High-RiskAssessment: Breast and Ovarian

Mary B. Daly, MD, PhD/ChairFox Chase Cancer Center

Jennifer E. Axilbund, MS, CGCThe Sidney Kimmel Comprehensive

Cancer Center at Johns Hopkins

Eileen Bryant, PhD

Fred Hutchinson Cancer ResearchCenter/Seattle Cancer Care Alliance

Saundra Buys, MDHuntsman Cancer Institute at the

University of Utah

Consultant

Charis Eng, MD, PhD

Laura J. Esserman, MDUCSF Comprehensive Cancer Center

Carolyn D. Farrell, MS, CNP, CGCRoswell Park Cancer Institute

Raymond U. Osarogiagbon, MDSt. Jude Childrens Research

Hospital/University of Tennessee Cancer

Institute

Boris Pasche, MD, PhDRobert H. Lurie Comprehensive Cancer

Center of Northwestern University

Gwen Reiser, MS, CGCUNMC Eppley Cancer Center at The

Nebraska Medical Center

H. Lee Moffitt Cancer Center & Research

Institute at the University of South Florida

City of Hope Cancer Center

Kenneth Offit, MDMemorial Sloan-Kettering Cancer Center

Rebecca Sutphen, MD

Jeffrey N. Weitzel, MD

James M. Ford, MDStanford Comprehensive Cancer

Center

Susan Friedman, DVMFORCE-Facing Our Risk of Cancer

Empowered

Judy E. Garber, MD, MPHDana-Farber/Brigham and Womens

Cancer Center | Massachusetts

General Hospital Cancer Center

Wendy Kohlmann, MS, CGCHuntsman Cancer Institute at the

University of Utah

P. Kelly Marcom, MDDuke Comprehensive Cancer Center

Lisle M. Nabell, MDUniversity of Alabama at Birmingham

Comprehensive Cancer Center

*

Medical Oncology

Cancer Genetics

Internal Medicine

Hematology/Hematology Oncology

Surgery/Surgical Oncology

Gastroenterology Pediatric Oncology

Patient Advocacy

*Writing committee Member

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This manuscript is being

updated to correspond

with the newly updated

algorithm.

Summary of Guidelines Updates

Table of Contents

NCCN Genetic/Familial High-Risk Assessment: Panel Members

Breast and/or Ovarian Genetic Assessment (BR/OV-1)

Hereditary Breast and/or Ovarian Cancer (HBOC-1)

HBOC Management (HBOC-A)

Li-Fraumeni Syndrome (LIFR-1)

Li-Fraumeni Management (LIFR-A)

Cowden Syndrome (COWD-1)

Cowden Syndrome Management (COWD-A)

Guidelines Index

Print the Genetic/Familial High-Risk Assessment: Breast and Ovarian

Guideline

These guidelines are a statement of consensus of the authors regarding their views of currently accepted approaches to treatment. Any clinicianseeking to apply or consult these guidelines is expected to use independent medical judgment in the context of individual clinical circumstances todetermine any patient's care or treatment. The National Comprehensive Cancer Network makes no representations nor warranties of any kindwhatsoever regarding their content, use, or application and disclaims any responsibility for their application or use in any way. These guidelines arecopyrighted by National Comprehensive Cancer Network. All rights reserved. These guidelines and the illustrations herein may not be reproduced inany form without the express written permission of NCCN. 2007.


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Manuscript

References

Clinical Trials:

Categories of Consensus:NCCN

Thebelieves that the best managementfor any cancer patient is in a clinicaltrial. Participation in clinical trials isespecially encouraged.

To find clinical trials online at NCCNmember institutions,

All recommendations are Category2A unless otherwise specified.

See

NCCN

click here:nccn.org/clinical_trials/physician.html

NCCNCategories of Consensus
http://contents.pdf/http://contents.pdf/http://print/http://print/http://help.pdf/http://help.pdf/http://www.nccn.org/clinical_trials/physician.htmlhttp://www.nccn.org/clinical_trials/physician.htmlhttp://www.nccn.org/clinical_trials/physician.htmlhttp://www.nccn.org/clinical_trials/physician.htmlhttp://contents.pdf/http://help.pdf/http://contents.pdf/http://print/


4/30Version 1.2007, 03/22/07 2007 National Comprehensive Cancer Network, Inc. All rights reserved. These guidelines and this illustration may not be reproduced in any form without the express written permission of NCCN.



Guidelines Index


MS, References

Summary of the Guidelines updates

Genetic/Familial High-Risk Assessment

Hereditary Breast and Ovarian Cancer:

)

:

HBOC Criteria( ):Entire page revised.

HBOC Follow-up( ):Footnote gandk were modified.

HBOC Management( ):Links to the

and the are new to the page.A new section entitled isk to Relatives .

Also for( and( )

Footnotes a and b were modified( ).

Detailed Family History: History of chemoprevention and/or risk

reducing surgery was added( ).

R was added to the page

BR/OV-1

BR/OV-1

NCCN Guidelines for Detection, Prevention, & RiskReduction of Cancer

HBOC-1

HBOC-2

HBOC-ANCCN Prostate Cancer Early Detection Guidelines

LIFR-A COWD-A

UPDATES

Summary of the major changes in the 2007 version of the Genetic/Familial High-Risk Assessment: Breast and Ovarian Cancer

guidelines from the 1.2006 version include:

Li-Fraumeni Syndrome

Cowden Syndrome

:

Footnotes b, c, and d were modified ( ).

Other Cancer Risks( ):Bullet 1 modified to include why screening is recommended

for cancer survivors with LFS.Bullet 3 now states that annual comprehensive exam

includes careful skin and neurologic examinations.New bullet added to Consider colonoscopy every 2-5 y.

Footnote 2 was modified( ).

:

Mucocutaneous lesions: Mucosal lesions was removed( .

Clarified wording of Operational Diagnosis for pathognomonic

criterion for an individual( ).

Footnotes b and c were modified( ).

Cowden Syndrome Management ( ):Bullet under Risk to relatives modified.Footnote 1is new to the page.Footnote 2 was modified.

LIFR-2

LIFR-A

LIFR-A

COWD-1

COWD-1

COWD-2

COWD-A

)

Note: All recommendations are category 2A unless otherwise indicated.

Clinical Trials: NCCN believes that the best management of any cancer patient is in a clinical trial. Participation in clinical trials is especially encouraged.

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Offer research andindividualizedrecommendationsaccording to personaland family history

Breast screening as

perNCCN Breast CancerScreening andDiagnosis Guidelines

HBOC Management(see HBOC-A)

HBOC Management(see HBOC-A)

SCREENING

RECOMMENDATION



gh

i

j

k

l

If Ashkenazi Jewish descent, in addition to the specific familial mutation, test for all three founder mutations.Genetic testing may not be pursued due to a lack of availability, logistic/financial reasons, or personal decision not to pursue testing.

If more than one affected, consider: youngest age at diagnosis, bilateral disease, multiple primaries, ovarian cancer, most closely related to theproband/patient/consultand.

BRCA1/BRCA2 testing: If patient is of Ashkenazi Jewish descent, test three common mutations first. Then, if negative, consider full sequence testingbased on assessment of individual and family history. If patient is non-Ashkenazi Jewish, full sequence test.

Testing of unaffected family members when no affected member is available should be considered. Significant limitations of interpreting test resultsshould be discussed.

Consider other efforts to define functional impact of variant. Testing for variant of unknown significance should not be used for clinical purposes and is

not recommended for unaffected relatives at risk (except for research purposes).

HBOCcriteriamet

DeleteriousfamilialBRCA1/BRCA2mutation known

Familial

mutationunknown

BRCA1/BRCA2

FAMILYSTATUS

HBOC FOLLOW-UP

Risk assessment

and counseling:

Psychosocialassessmentand supportRisk counselingEducationDiscussion ofgenetic testingInformed

consent

Hereditary Breast and/orOvarian Cancer

Negative for familialBRCA1/BRCA2mutation

BRCA1/BRCA2 testingnot performedh

PoBRCA1/BRCA2mutation

sitive for familial

Family membertested and mutationfound

Family member nottested or tested andno mutation found

h

Variant of unknownsignificance found(uninformative)l

TEST OUTCOME

ConsiderBRCA1/BRCA2testing forspecific familialmutationg

Consider testingaffected familymember withhighest likelihoodofmutation

BRCA1/BRCA2i,j,k

HBOC-2

GENETIC TESTING
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Criterianot met

Criteriamet Follow-up (see LIFR-2)

Cancers associated with Li-Fraumeni syndrome include but are not limited to:

Premenopausal breast cancerBone and soft tissue sarcomasAcute leukemiaBrain tumorAdrenocortical carcinomaUnusually early onset of other adenocarcinomas, or other childhood cancers

aAdapted from: Varley JM, Evans DGR, Birch JM: Li-Fraumeni syndromeA molecular and clinical

review. . ; 1-14, by permission of Nature Publishing Group.Br J Cancer 1997 76(1),

LI-FRAUMENI CRITERIAa

Classic Li-Fraumeni Syndrome Criteria:

Member of kindred with a known TP53 mutationCombination of an individual diagnosed < age 45 y with a sarcoma, andhaving a first-degree relative diagnosed < age 45 y with cancer and anadditional first- or second-degree relative in the same lineage withcancer diagnosed < age 45 y, or a sarcoma at any age

Li-Fraumeni-Like Syndrome Criteria

An individual with:

A childhood tumor or

A first- or second-degree relative with a typical Li-Fraumeni Syndrometumor at any age, and another first- or second-degree relative withcancer diagnosed < the age of 60

sarcoma, brain tumor, or adrenocortical carcinoma diagnosed < age 45

AND

Individualized recommendationsaccording to personal andfamily history

FOLLOW-UP

LIFR-1
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Risk assessmentand counseling:

Psychosocialassessment andsupportRisk counselingEducationDiscussion of

genetic testingInformed consent


DeleteriousfamilialTP53mutation

known

FamilialTP53mutationunknown

b

c

d

e

Youngest age at diagnosis, bilateral disease, multiple primaries, sarcoma at age < 45 yr.

Testing of unaffected family members when no affected member is available may be considered. Significant limitations of interpreting test resultsshould be discussed.

Genetic testing may not be pursued due to a lack of availability, logistic/financial reasons, or personal decision not to pursue testing.

Consider other efforts to define functional significance of mutations. Testing for variant of unknown significance should not be used for clinical

purposes and is not recommended for unaffected relatives at risk (except for research purposes).

FAMILYSTATUS

LI-FRAUMENIFOLLOW-UP

Li-Fraumenicriteria met

TEST OUTCOME SCREENING

RECOMMENDATION

Consider TP53testing forspecific familialmutation

Positive for familialTP53 mutation

Negative for familialTP53 mutation

TP53 testing notperformed d

Li-FraumeniManagement(see LIFR-A)

Consider testingaffected familymember withhighest likelihoodof TP53 mutationb,c

Offer research andindividualizedrecommendationsaccording to personaland family history

Breast screeningas perNCCN BreastCancer Screening andDiagnosis Guidelines

Li-Fraumeni

Management(see LIFR-A)

LIFR-2

GENETIC TESTING

Family member

tested and mutationfound


d

Variant of unknown

significance found(uninformative)e

G id li I d
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LI-FRAUMENI MANAGEMENT


BREAST CANCER RISK

Training and education in breast self-exam and regular

monthly BSE starting at age 18 y

Semiannual clinical breast exam starting at age 20-25 y,or 5-10 y before the earliest known breast cancer in thefamily (whichever is earlier)

Annual mammogram and breast MRI screening startingat age 20-25 y, or individualized based on earliest age ofonset in family

Discuss options for risk-reducing mastectomy on case-by-case basis and counsel regarding degree ofprotection, degree of cancer risk, and reconstructionoptions

Discuss option to participate in investigational breastimaging when available (eg, novel imaging technologiesand more frequent screening intervals)

1,2

3

OTHER CANCER RISKS

RISK TO RELATIVES

Address limitations of screening for many cancers

associated with Li-Fraumeni Syndrome: Because of the

remarkable risk of additional primary neoplasms,

screening may be considered for cancer survivors with

LFS and a good prognosis from their prior tumor(s)

Pediatricians should be apprised of the risk ofchildhood cancers in affected families

Annual comprehensive physical exam with high index

of suspicion for rare cancers and second malignancies

in cancer survivors: include careful skin and neurologic

examinations

Consider colonoscopy every 2-5 y

Advise about possible inherited cancer risk to relatives

and consideration of genetic consult and/or testing

Target surveillance based on individual family histories

Education regarding signs and symptoms of cancer

LIFR-A

1

2

3

The appropriateness of imaging scheduling is still under study.

Some centers are evaluating alternative imaging techniques as investigational tools.

High-quality breast MRI limitations include having: a need for a dedicated breast coil, the ability to perform biopsy under MRI guidance, experienced radiologists inbreast MRI, and regional availability.

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Cowden Syndrome

Criterianot met

Criteriamet Follow-up (see COWD-2)

COWDEN SYNDROME CRITERIAa

Operational diagnosis in anindividual, any singlepathognomonic criterion, but:

Mucocutaneous lesions alone if:there are six or more facialpapules, of which three or moremust be trichilemmoma, or

cutaneous facial papules and oralmucosal papillomatosis, ororal mucosal papillomatosis andacral keratoses, orpalmoplantar keratoses, six ormore

Two or more major criteriaorOne major and three minor criteria

orfour minor criteria

Operational diagnosis forindividuals in a family where onerelative is diagnostic for Cowdensyndrome. The individual must alsohave one or more of the following:

A pathognomonic criterionAny one major criteria with orwithout minor criteriaTwo minor criteriaHistory of Bannayan-Riley-Ruvalcaba syndrome

aAdapted from Eng C. Will the real Cowden syndrome please stand up: revised diagnostic

criteria. J Med Genet. ;37:828-830, with permission from the BMJ Publishing Group.2000

Individualizedrecommendationsaccording to personaland family history

COWD-1

Pathognomonic criteria:

Adult Lhermitte-Duclos disease (LDD)

(cerebellar tumors)

Mucocutaneous lesionsTrichilemmomas, facialAcral keratosesPapillomatous papules

Major criteria:

Minor criteria:

Breast cancerThyroid cancer, especially follicular thyroidcarcinomaMacrocephaly (megalocephaly) (ie, 97thpercentile)Endometrial cancer

Other thyroid lesions (eg, adenoma,multinodular goiter)Mental retardation (ie, IQ 75)GI hamartomasFibrocystic disease of the breastLipomasFibromas

GU tumors (especially renal cell carcinoma)GU structural manifestationsUterine fibroids

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Risk assessmentand counseling:

Psychosocialassessment andsupportRisk counselingEducationDiscussion ofgenetic testingInformed consent

FamilialPTENmutation

known

FamilialPTENmutationunknown

b

c

d

Testing of unaffected family members when no affected member is available may be considered. Significant limitations of interpreting testresults should be discussed.

Genetic testing may not be pursued due to a lack of availability, logistic/financial reasons, or personal decision not to pursue testing.

Consider other efforts to define functional significance of mutations. Testing for variant of unknown significance should not be used for clinical

purposes and is not recommended for unaffected relatives at risk (except for research purposes).

FAMILY

STATUS

COWDEN SYNDROME

FOLLOW-UP

Cowden Syndrome

Cowden

criteria

met

TEST OUTCOME SCREENING

RECOMMENDATION

Consider PTENtesting forspecific familial

mutation

Positivefor familialPTENmutation

Negativefor familialPTENmutation

PTENtesting notperformedc

Cowden SyndromeManagement(see COWD-A)

Consider testingaffected familymember withhighest likelihood

of PTEN mutation b

Offer research andindividualized

recommendationsaccording topersonal and familyhistory

Breast screening asperNCCN BreastCancer Screening andDiagnosis Guidelines

Cowden SyndromeManagement(see COWD-A)

COWD-2

GENETIC TESTING

Family membertested and mutationfound


c

Variant of unknownsignificance found(uninformative)d

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1

2The appropriateness of imaging scheduling is still under study.

High-quality breast MRI limitations include having: a need for a dedicated breast coil, the ability to

perform biopsy under MRI guidances experienced radiologists in breast MRI, and regional availability.Note: All recommendations are category 2A unless otherwise indicated.


Cowden Syndrome

COWDEN SYNDROME MANAGEMENT

WOMEN

Training and education in breast self-exam and

regular monthly BSE starting at age 18 y

Annual mammography and breast MRI screeningstarting at age 30-35 y or 5-10 y earlier thanearliest known breast cancer in the family(whichever is earlier)

Blind endometrial aspiration biopsies annuallyfor premenopausal women starting at age 35-40,or 5 y before earliest diagnosis of endometrialcancer in the family, and annual endometrialultrasound in postmenopausal women.

Discuss options for risk-reducing mastectomyon case-by-case basis and counsel regardingdegree of protection, extent of cancer risk, and

reconstruction options.

Semiannual clinical breast exam starting at age

25 y or 5-10 y earlier than earliest known breast

cancer in the family

1, 2

MEN AND WOMEN

Annual comprehensive physical exam starting atage 18 y or 5 y younger than the youngest age ofdiagnosis of a component cancer in the family(whichever is younger), with particular attention to

breast and thyroid exam

Annual urinalysis; consider annual urine cytologyand renal ultrasound, if family history of renalcancer

Baseline thyroid ultrasound at age 18 y, andconsider annually thereafter

Education regarding the signs and symptoms ofcancer

Consider annual dermatologic exam

RISK TO RELATIVES

Advise about possible inherited cancer risk to

relatives and consideration of genetic consultand/or testing

COWD-A
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NCCN in Oncology v.1.2007 MS, References

Manuscript

update inprogress

Disclosures for the NCCN Genetics/Familial High Risk ScreeningGuidelines Panel

At the beginning of each panel meeting to develop NCCNguidelines, panel members disclosed financial support they have

received in the form of research support, advisory committee

membership, or speakers' bureau participation.Members of the

panel indicated that they have received support from the following:

Abbott Laboratories, California Brea st Cancer Research Program,

Department of Defense, Komen Foundation, Myriad Genetics,

NCI/NIH, and V Foundation.

Some panel members do not accept any support from industry. The

panel did not regard any potential conflicts of interest as sufficient

reason to disallow participation in panel deliberations by anymember.

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Table 1:Genetic Test Results to Determine the

Presence of a Cancer-Predisposing Gene

Result Description

True-positive The person is a carrier of an alteration in

a known cancer-predisposing gene.

True-negative The person is not a carrier of a known

cancer-predisposing gene that has been

positively identified in another family

member.

Indeterminate The person is not a carrier of a known

cancer-predisposing gene, and the carrier

status of other family members is either

also negative or unknown.

Inconclusive The person is a carrier of an alteration in

a gene that currently has no knownsignificance.

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Manuscript

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Bilateral Prophylactic Oophorectomy in BRCA1 Mutation Carriers. J

Natl Cancer Inst 1999;91:1475-1479.

63. Hisada M, Garber JE, Fung CY et al. Multiple primary cancers infamilies with Li-Fraumeni syndrome. J Natl Cancer Inst 1998 Apr

15;90(8):606-11.

64. Dorval M, Patenaude AF, Schneider KA et al.Anticipated versus

actual emotional reactions to disclosure of results of genetic tests

for cancer susceptibility: findings from p53 and BRCA1 testing

programs. J Clin Oncol 2000 May;18(10):2135-42.

65. Warner E, Plewes DB, Hill KA et al. Surveillance of BRCA1 and

BRCA2 mutation carriers with magnetic resonance imaging,

ultrasound, mammography, and clinical breast examination. JAMA

2004;292(11):1317-25.

66. Eng C. Genetics of Cowden syndrome: Through the looking

glass of oncology. Int J Oncol 1998;12:701-710.

67. Eng C. Will the real Cowden syndrome please stand up: revised

diagnostic criteria. Journal of Medical Genetics 2000; 37(11):828-

830.

REF-4

Assessment: Breast and Ovarian

genetics screening

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