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1、Breast Cancer Risk Assessment and Genetic Testing,Susan W.Caro,RNC,MSN,APNGDirector,Family Cancer Risk ServiceVanderbilt-Ingram Cancer Center,Objectives:,1.Appreciate the complex and emerging information about the impact of genetics on breast cancer risk.2.Identify resources available for assessing
2、genetic risk.3.Articulate when risk counseling and assessment is recommended.4.Know the TN resources for genetic risk assessment.,In 1990,the National Institutes of Health and the Dept.of Energy launched the Human Genome Project,an international effort to map,sequence,and characterize the human geno
3、me.Working draft completed in June 2000,published in Science and Nature in February 2001.,Why?,Hereditary cancer syndromes are being more clearly defined with increasingly clear recommendations for management.Clinical genetics tests for hereditary cancer syndromes are available and in some markets a
4、re being marketed directly to the consumer.Recognizing hereditary cancer syndromes provides the opportunity to identify those at significantly increased risk and offer options to identify cancers earlier or prevent cancer in these individuals.Potential for medico-legal implications of not recognizin
5、g hereditary cancer syndromes.,Lynch HT,Paulson JD,Severen M,et al.Failure to Diagnose Hereditary Colorectal Cancer and Its Medicolegal Implications.Dis.Colon Rectum January 1999;42:31-35.,Hereditary Cancer Burden in Tennessee?,Breast Cancer 3,720 new diagnoses 920 deathsColorectal Cancer 3,290 new
6、diagnoses 1130 deaths If 10%hereditary cancer 372 new cases of hereditary breast cancer(392 CRC)this year.Could some of these have been foreseen,even prevented?,*Excludes carcinoma in situ(CIS,non-invasive cancer)of any site except urinary bladder.Does not include basal and squamous cell skin cancer
7、s(of which there are 1.3 million per year).,American Cancer Society,2008,Prevention(medical),In medicine,prevention is any activity which reduces the burden of mortality or morbidity from disease.This takes place at primary,secondary and tertiary prevention levels.Primary prevention avoids the devel
8、opment of a disease.Most population-based health promotion activities are primary preventive measures.Secondary prevention activities are aimed at early disease detection,thereby increasing opportunities for interventions to prevent progression of the disease and emergence of symptoms.Tertiary preve
9、ntion reduces the negative impact of an already established disease by restoring function and reducing disease-related complications.Wikipedia,All cancer is genetic,not all cancer is hereditary.,Breast Cancer Genes Found,BRCA1(for BReast CAncer gene 1)was described in 1990 on chromosome 17,isolated
10、in 1994BRCA2 was isolated on chromosome 13 in late 1994BRCA3?,The Development of Hereditary Cancer,1 damaged gene1 normal gene,2 normal genes,2 damaged genes,In hereditary cancer,one damaged gene is inherited.,1 damaged gene1 normal gene,2 damaged genes,2006 Myriad Genetic Laboratories,Inc.,Myriad G
11、enetics,Inc.,American Society of Clinical Oncology Guidelines for Genetic Testing,Personal or family history features suggestive of hereditary cancer riskTest can be adequately interpretedTest result will aid in diagnosis or influence medical management of the patient and/or family,J Clin Oncol 2003
12、;21:2397-406,Cancer Syndromes,Hereditary Breast Cancer SyndromesBRCA1,BRCA2,Cowden,CHEK2,Li-FraumeniHereditary Colorectal Cancer SyndromesHNPCCFAPEndocrine Syndromes VHL,MEN1,MEN2,FMTCOther Li Fraumeni,Peutz-JeghersDNA Banking,Ask out loud,Ask the question:Do you have a family history of cancer?Clar
13、ify-maternal AND paternal family historyAsk the question again more specifically:Does anyone in your family have a history of breast,ovarian,colon cancer,colon polyps,or other cancers?Ask the question again at follow up visits,as family histories change over time.,FCRS,Listen when your patients voic
14、e a concern:,In many health care encounters today,we are focused on the problem at hand and it is difficult to go beyond this.Not suggesting that every health care provider have an expert knowledge of the complex issues surrounding all of the hereditary cancer syndromes-rather that continual exposur
15、e to this information will prompt recognition and referral for more thorough evaluation of the family.A significant number of our patients seek consultation independently.Their health care providers do not always recognize the significance of family history.,Refer,Refer for comprehensive risk assess
16、ment and consideration of genetic testing.Genetic testing is only one aspect of this.There is a great deal to be learned from gathering and documenting the family history and the educational component of the counseling process.Many patients are concerned as a result of things they have read or been
17、told about insurance discrimination.This is addressed in the counseling session(before any decision for genetic testing is made).,Family Cancer Risk Consultation,Should include:Education about cancer risk in familiesCancer/genetic risk assessmentDiscussion of possible risks and benefits of genetic t
18、estingPsychological support,guidance about medical options,and referral for medical or surgical means of early detection or prevention of cancer,Offit,1998,p.3,Comprehensive Risk Assessment/Consultation,Assess patients view of their risk,experience with cancer in the familyReview what is known and n
19、ot known about cancer riskMedical history,current surveillance activityReview family history and draw pedigreeDocument cancers in history(medical record and pathology review)Provide risk assessment-Risks associated with hereditary cancer syndromes under consideration,risks if no recognizable syndrom
20、eEducation-Cancers,risks factors,surveillance,basic genetics,cancer geneticsTesting?Benefits,limitations,risks,costs,insurance,processRecommendations for surveillance or possible preventive measures,discuss implications to others in family.Interpretation of test results,including psychological,socia
21、l,and family implications of test results,Management Options/Counseling,Review options for increased screening or measures to decrease risk Discuss efficacy(or lack of efficacy/or lack of data to support efficacy)of surveillance,prophylactic/risk reducing,or chemopreventive measuresIncreasing unders
22、tanding of utility and consequences of surveillance and intervention options a moving target.,ASCO,How Much Breast and Ovarian Cancer Is Hereditary?,SporadicFamily clustersHereditary,Ovarian Cancer,Breast Cancer,5%10%,5%10%,15%20%,Breast and ovarian cancers,Breast Cancer Families,Breast and Ovarian
23、Cancer Families,King,Rowell,Love,1993;Ford,Easton,Stratton,et al,1998,Contribution of BRCA1/2 to hereditary breast/ovarian cancer families:,BRCA Mutations and Ashkenazi Jews,185delAG mutation noted in 1%of 850 samples of Ashkenazi Jewish individuals unselected for family history of cancer(studied st
24、ored samples from Tay-Sachs research)Carrier rate 3 X that expected in general populationMay account for 16%of breast and 39%of ovarian cancer in AJ women 502 other“founder mutations”,Male Breast Cancer and BRCA2,Studies of BRCA2 in population-and clinic-based series of male breast cancer patients f
25、rom the United States and Europe have found carrier frequencies of BRCA2 mutations of 4%-40%The percentage of male breast cancer cases that are associated with a BRCA2 mutation varies depending on the population.Figures from various studies(some small):4%in U.S.;21%in Sweden;40%in Iceland.One study
26、showed that among men with breast cancer and a first-degree relative(e.g.,mother or sister)with breast cancer approximately 11%were carriers of a BRCA2 mutation.For male BRCA2 alteration carriers:Estimated cumulative risk of male breast cancer is 6%by age 70 Age of onset not as early as female breas
27、t cancer in BRCA2 carriersBRCA1 may account for more cases of male breast cancer than initially estimated.(Couch et al.1996,Thorlacius et al.1996,Friedman et al.1997,Csokay et al.1999),Cumulative Risk of Breast and Ovarian Cancer in BRCA1 and BRCA2 Mutation Carriers,From Rebbeck,T;J Clin Oncol 18:10
28、0s-103s 2000,Risks of Breast Cancer with BRCA1 or BRCA2 Mutation,Easton DF,Ford D,Bishop T,and the Breast Cancer Linkage Consortium,1995.Am J Hum Gen 56:265-271.Easton DF,et al.,and the Breast Cancer Linkage Consortium,1999.JNCI 91:1310-1319.Ford D,Easton DF,Stratton M,Narod S,et al.,1998,Am J Hum G
29、enetics 62:676-689.Struewing JP,Harge P,Wacholder W,et al.NEJM,1997.336(20):1401-1408.Ford D,Easton DG,Bishop T,Narod S,1994.Lancet 343:692-695.,Contralateral Breast Cancer Risk BRCA1/2 Mutation Carriers,The hope is that increased surveillance and/or interventions may identify cancers early or reduc
30、e the risk of cancers.Risk assessment may also identify those not at increased risk.,Recognition:the first step in management of familial cancer risk,Cancer Clusters,Cancer can happen in a family just by chance Cancer can cluster in families because of shared environmental exposures(diet,lifestyle,“
31、environment”,work related exposures)Cancers may be due to inheritance of a single genetic alteration that poses very high risk of cancerCancers may be due to inheritance of less penetrant genetic alterations,Sporadic/Familial/Hereditary,Sporadic cancers Age appropriateCommon cancers,Familial CancerO
32、ccurring in or affecting more members of a family than would be expected by chance”Generally,two or more family members with the same type of cancer,age appropriate,Hereditary Cancer-Multiple affected family membersSeveral cases of the same type of cancer or cancers known to be part of an hereditary
33、 cancer syndrome(e.g.breast&ovarian,colon&endometrial,sarcoma&breast).Younger than expected ages of onset-such as breast 40,colon 50Rare cancers in the family such as males with breast cancerIndividuals with multiple primary cancers or multifocal or bilateral cancersFamily history consistent with ge
34、neration to generation transmission,Tools for risk assessment:,Breast cancer risk assessment models-Claus,Gail,BRCAPRO,Frank/Myriad modelsModels for other cancers from the literatureComputer/Internet resourcesGene tests,OMIM,NCI website Ongoing education,Models used to calculate breast cancer risks,
35、Claus Model-Age specific risk estimates for breast cancer,considers maternal and paternal history,age at onset,first and second degree relatives(excludes some relatives).Gail Model-Estimates the chance that a woman of specific age would develop breast cancer,includes age at menarche,childbirth,#of p
36、rior biopsies,and first degree relatives.Excludes paternal relatives,non-first degree relatives.Adapted to consider atypical hyperplasias.Tyrer-Cusick Model(2004)Uses personal risk factors for breast cancer,and likelihood of BRCA gene mutation and a low penetrance gene to assess breast cancer risk.,
37、Claus EB,Risch N,Thompson WD,1990;1991;1994;Gail MH,Brinton LA,Byar EP,et al,1989;Tyrer J,Duffy SW,Cuzick J.Stat Med 2004;23:1111-1130,FCRS,Models used to calculate likelihood of BRCA1 or BRCA2 mutation:,BRCAPRO-computer model,uses pedigree to calculate risk based on several different models.Frank o
38、r Myriad Model/Tables-use family history and personal history to estimate risk of mutation in BRCA1 or BRCA2.BOADICEA(Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm)University of Cambridge computer model to assess risk of BRCA1/2 mutation.,Euhus D,Berry D,Parmigian
39、i G,Iverson E,1998;Frank TS,Manley SA,Olopade OI,et al,1997,1998.Antoniou AC,Hardy R,Walker L,Evans DG,Shenton A,Eeles R,Shanley S,Pichert G,Izatt L,Rose S,Douglas F,Eccles D,Morrison PJ,Scott J,Zimmern RL,Easton DF,Pharoah PD.J Med Genet.2008 Jul;45(7):425-31.Epub 2008 Apr 15.,Characteristics of th
40、ose families appropriate for consideration for BRCA1 or BRCA2 testing(including patients personal history),several breast cancers or breast and ovarian cancertwo or more ovarian cancers in one familypresence of bilateral cancers of the breast or ovarycancers diagnosed at younger than expected agesmu
41、ltiple affected relatives,demonstrating an autosomal dominant pattern of inheritancepresence of individuals diagnosed with more than one cancer,e.g.breast and ovarianbreast and/or ovarian cancer and Ashkenazi(Eastern European)Jewish heritagemale breast cancer,Cindys Story,Cindy34 yo+BRCA2 mutation,R
42、enee65 yoOv dx 46Br dx 52,John66 yo,Caroline2 yo,John Jr.6 yo,RickColon dx 31D.33,James 5 yo,Katherine3 yo,Jason31 yo,Jane28 yo,BessieD.91Br Dx 91,Kate61 yo,X 3No CA,AliceD.50?stomach,Janice61 yo,?,Susan30 yo,FCRS,Cindys Risk Assessment,Gail ModelRace-CaucasianAge-34Age Menarche-13Age 1st live birth
43、-28#Mother,Sister,Daughter with Breast Cancer-1#previous biopsy-05 year risk=0.5%lifetime risk=19.2%,Claus ModelUsing Table of One First Degree RelativePredicted cumulative probability of breast cancer by age:39=.8%49=2.3%59=4.9%69=8.2%79=11%,Benichou J,Gail M,Mulvihill J.1996.JCO 14:103-10,Claus EB
44、,Risch N,Thompson WD,1994.CANCER 73:643-51.,FCRS,Hereditary Breast/Ovarian Cancer Syndrome,2,L br ca 42R br ca 55Oophorectomy(BSO)53+BRCA2,3,5,FCRS,3,75,3,70-80No cancer,30-50No cancer,+BRCA2Bil mastectomyBil Salingo-oophorectomy36,5,d.94 ht dz,Br ca 44Ov ca 52d.79,d.Br ca 42,-Risk Perception-Everyo
45、nes is Unique,Individuals view of“high risk”,“common”,“rare”,“unlikely”is colored by their experience and psychological make-up.Half-full vs.half-emptyExperience with statistics(“I will be the 1%who develops.”)Personal experience with cancer or cancer scares,caring for others with cancer(especially
46、if repeatedly or recently)Relationships and age influence reaction-parents cancer and child or adolescent vs.adult,siblings with cancer,friends with cancer.,Page DL,Caro SW,Dupont SD,1998.,Testing Process,Counsel/EducationGather pedigree and documentationTest affected individual for mutationIf famil
47、y+for mutation,then can test unaffected individualsIf+mutation in family,-mutation in individual,individual risk is close to population riskIf no identified mutation in family,risk is estimated based on history and empiric data,Outcome of process,Clarify risks of cancerIdentify individuals who may n
48、ot be aware of increased riskIdentify individuals who may not be at increased riskIdentify those appropriate for increased cancer surveillance,or measures to decrease risk(prophylactic surgery,chemoprevention),or those appropriate for research on surveillance or chemoprevention,Options for Women at
49、Risk,Increased SurveillanceRisk-reducing SurgeryMedical Intervention,FCRS,Increased Surveillance,Breast CancerClinical examination every 6 monthsMammogram yearly beginning age 25-35MRI(ACS 2007)Monthly BSEPrompt evaluation of abnormal findings,Ovarian CancerCa-125Pelvic color-doppler ultrasound ever
50、y 6-12 monthsPelvic examination every 6-12 months,ACS Recommendations for Breast MRI Screening as an Adjunct to Mammography 2007,Recommend Annual MRI Screening(Based on Evidence*)BRCA mutationFirst-degree relative of BRCA carrier,but untestedLifetime risk 2025%or greater,as defined by BRCAPRO or oth
