Utilization ofBRCA1/2 genetic testing in the clinical setting

Utilization of BRCA1/2 Genetic Testing in the ClinicalSettingReport from a Single Institution

Soo-Chin Lee, M.D.1

Barbara A. Bernhardt, M.S.2

Kathy J. Helzlsouer, M.D.3

1 Department of Oncology, Johns Hopkins MedicalInstitution, Department of Haematology/Oncology,National University Hospital, Singapore.

2 Genetics and Public Policy Studies, Johns Hop-kins Medical Institutions, Baltimore, Maryland.

3 Department of Epidemiology, Johns Hopkins Uni-versity, Bloomberg School of Public Health, Balti-more, Maryland.

Presented at the Annual American Society of Clin-ical Oncology Meeting, San Francisco, CA, May15–18, 2001.

Supported in part by the Ministry of Health, Sin-gapore, through the Human Manpower Develop-ment Program (HMDP) Fellowship program.

The authors thank all the patients who participatedin the Breast and Ovarian Surveillance Service forproviding their personal and family history infor-mation to make our database possible. They arealso grateful to Dr. Florence Houn, Karen A. John-son, Susan E. Appling, and Jennifer Bucholtz forproviding clinical services, Linda Thompson forproviding administrative support, and Alison Kleinfor designing the clinical database.

Address for reprints: Barbara A. Bernhardt, M.S.,Genetics and Public Policy Studies, Johns HopkinsMedical Institutions, 550 N. Broadway, Suite 511,Baltimore, MD 21205; Fax: (410) 955-0241;E-mail: [email protected]

Received September 17, 2001; revision receivedNovember 20, 2001; accepted November 26,2001.

BACKGROUND. Clinical testing for BRCA1/2 has been available since 1996. Interest

in testing in the research and hypothetical situations has been consistently high,

but there have been limited reports on its clinical utilization.

METHODS. This is a retrospective study of BRCA1/2 test utilization by high-risk

patients who were seen at the Johns Hopkins Breast and Ovarian Surveillance

Service.

RESULTS. Between February 1996 and December 1999, 258 families who had at

least a 10% chance of carrying a BRCA1/2 mutation were offered genetic testing. Of

these, 26 families seen between February 1996 and October 1996 had access to free

testing. Overall, 68 of 258 (26%) underwent genetic testing. Educational level,

number of children or daughters, breast carcinoma screening behavior, smoking

and drinking behavior, perceived risk of breast carcinoma, and family history was

not associated with test utilization. Eligibility for free testing, prior history of breast

or ovarian carcinoma, Ashkenazi Jewish versus non-Ashkenazi Jewish heritage,

genetic risk category, and age category were associated with test utilization, and in

multivariate analysis, the first three remained statistically significant factors asso-

ciated with genetic testing. Only 26% of the 50 patients who did not have access to

free testing sought insurance reimbursement, of which greater than 50% (7 of 13)

had a prior diagnosis of breast or ovarian carcinoma.

CONCLUSIONS. The actual utilization of BRCA1/2 genetic testing in a clinical setting

is lower than in the research and hypothetical settings. Potential obstacles include

cost, fear of insurance discrimination, and need to involve an affected family

member in the testing process. Cancer 2002;94:1876 – 85.

© 2002 American Cancer Society.

DOI 10.1002/cncr.10420

KEYWORDS: BRCA1, BRCA2, genetic testing, hereditary breast carcinoma, hereditarybreast and ovarian carcinoma.

Breast carcinoma is the most common female malignancy in theUnited States, with an age-standardized incidence of 103 per

100,000.1 An estimated 5–15% of breast carcinoma is hereditary andcaused by single gene mutations,2 such as the BRCA1/2 genes.3–5 TheBRCA1/2 genes account for approximately 30% of breast carcinoma–only families6 and 50% of breast and ovarian carcinoma families.6 TheAmerican Society of Clinical Oncology recommends extensive discus-sion of the potential benefits, risks, and limitations before BRCA1/2genetic testing, as identification of mutation carriers has a presumedbut not established medical benefit.7 In practice, medical consider-ation of genetic testing is warranted when the patient’s estimated riskof being a mutation carrier is at least 10%.7

1876

© 2002 American Cancer Society

Before the widespread availability of clinicalBRCA1/2 testing, several studies reported a high levelof interest in cancer susceptibility testing among phy-sicians and patients in hypothetical8 –16 and researchsituations.2,17 The motivations governing genetic test-ing uptake in these study situations are likely to bedifferent from that in clinical practice, and there iscurrently limited literature on the actual uptake ofBRCA1/2 testing in the clinic.18 We report one of thefirst large clinical series on the rate and pattern ofBRCA1/2 genetic test utilization and examined the uti-lization of genetic testing and associated factorsamong high-risk women.

METHODSThis is a retrospective study of the utilization ofBRCA1/2 clinical testing and the factors associatedwith genetic test utilization in a clinical population ofwomen at increased risk for hereditary breast andovarian carcinoma.

SubjectsThe study population comprised female patients whowere seen in the Breast and Ovarian Surveillance Ser-vice at Johns Hopkins Hospital as a new consultationbetween February 1, 1996 and December 31, 1999 (seeFig. 1). The data were analyzed in August 2000, allow-ing a minimal follow-up period of 8 months, becausepatients may take weeks to months after the counsel-ing session to make a genetic testing decision. Mostpatients were physician-referred and resided in theBaltimore–Washington area. Patients who had a per-sonal and/or family history of breast and/or ovariancarcinoma and whose families were estimated to haveat least 10% chance of carrying a BRCA1/2 mutation, towhom genetic counseling was provided and genetictesting discussed, were eligible for this study. Familiesthat had more than one member attend the clinic onseparate occasions were considered a single unit inour analysis, designating the person first seen as theproband. Patients whose families were estimated tohave less than 10% chance of carrying a BRCA1/2 mu-tation were excluded, even if genetic counseling mayhave been provided and genetic testing discussed,because testing would not be considered strongly asan option on clinical grounds because of low yield.Patients who had been tested previously, or who had afamily member who had been tested before the pa-tient visiting our service, whether or not a BRCA1/2mutation was identified, were excluded. These latterindividuals formed a small minority of our study pop-ulation and were excluded from analysis because thehigher yield of genetic testing in this subgroup is po-tentially confounding. Only three male patients were

seen during the study period, and these were excludedto maintain the homogeneity of our study population.

Data CollectionData were obtained from review of the medicalrecords, and a previsit questionnaire was completedby each patient. Basic demographic information (age,ethnic group, marital status, years of education, num-ber of children and daughters), personal cancer his-tory, screening practices (breast self-examination,mammography), lifestyle behavior (smoking and alco-hol consumption), perceived lifetime risk of invasivebreast carcinoma, and a three-generation family can-cer history were obtained from the previsit question-naire. The estimated familial risk of carrying aBRCA1/2 mutation as assigned by the provider and ascommunicated to the patient during the visit was ob-tained from the patient’s written consultation note.Quantified risks were provided for some cases,whereas for others, descriptive terms were used toconvey the information. For the purpose of this study,we considered the family to be “low-risk” when theestimated chance of carrying a BRCA1/2 mutation inthe family was recorded to be between 10% and 20%.The family was considered “moderate-risk” and “high-risk” when the estimated risk was recorded to be be-tween 20% and 50% and greater than 50%, respec-tively. When descriptive terms were used, weconsidered the family to be low-risk when the consultnote reported that the family history is “mild,” “some-what suggestive,” “has some suspicion,” “has a smallrisk,” or is “mildly suggestive” of a BRCA1/2 mutation.When the consultation note used terms such as “con-sistent,” “concerning,” “likely,” “maybe,” “possible,”“suggestive,” “reasonable,” or “suspicious,” we con-sidered the family to be of moderate-risk. When theconsult note used terms such as “highly suggestive,”“high probability,” “high-risk,” “significant,” “stronglysuggestive,” or “strong possibility,” we considered thefamily to be high-risk.

Patients who were tested for mutations in theBRCA1/2 genes were identified from a master recordkept in the genetic counselor’s office (B.A.B.). Infor-mation regarding the timing of the test, person in thefamily who was initially tested, mode of payment, typeof test, and test results were collected.

Description of Service ProvidedThe Breast and Ovarian Surveillance Service at JohnsHopkins Hospital was established in 1989 and isstaffed by two attending physicians, two genetic coun-selors, and two nurse practitioners. An attending phy-sician, who conducted the consultation with a geneticcounselor and/or a nurse practitioner, saw each pa-

Clinical Genetic Testing for BRCA1/Lee et al. 1877

tient. The patient’s family history was reviewed, andthe patient given a risk estimate of the family carryinga BRCA1/2 mutation. Whenever possible, the patient’sreported family history of cancer was verified throughpathology reports. The Couch model,19 first publishedin 1997, was used to quantify the risk when deemedappropriate, because this was one of the most com-prehensive models available during the study period.Because the Couch model provided risk estimates per-taining only to BRCA1, the number was doubled em-pirically to give patients an approximate estimate oftheir family’s probability of carrying a BRCA1 orBRCA2 mutation. In some patients, the risk estimatewas not quantified because the Couch model had notyet been published, because it was not appropriate toapply the Couch model, because the risk was difficultto quantify because of incomplete or uncertain familyhistory, or because of provider preference. In thesecases, clinical judgment was used to estimate the risk,and a descriptive term was used to convey the infor-mation to the patient and accordingly recorded in theconsultation note.

During the genetic counseling session, informa-tion regarding the mode of inheritance of the BRCA1/2genes and the associated cancer risks were discussed.Nondirective counseling was provided in all cases,because BRCA1/2 testing has not been established toresult in definitive medical benefits. Patients were in-formed that the lifetime risk of breast and ovariancarcinoma in BRCA1/2 mutation carriers is 50 – 85%and 15– 45%, respectively.20,21 The benefits (improvedcancer risk assessment, relief from uncertainty andanxiety about cancer risk, useful information for fam-ily members, lifestyle decision making, empower-ment, etc.), risks (psychologic distress, loss of privacy,discrimination by employers and insurers, change infamily dynamics, false sense of security, etc.), andlimitations (not all mutations are detectable, uncer-tain significance of some mutations, negative resultnot informative unless a mutation has been identifiedin the family, results indicate probability and not cer-tainty of developing cancer, unproven efficacy of mostinterventions, etc.) of genetic testing were discussed.Patients also were given screening recommendationsbased on their family history, as well as informationon the surveillance options for breast and ovariancarcinoma for BRCA1/2 mutation carriers as recom-mended by the Task Force convened by the CancerGenetics Studies Consortium.22 Preventive options(tamoxifen chemoprevention,23–25 prophylactic mas-tectomy,26,27 and oophorectomy27,28) were discussedas appropriate.

In general, patients were offered full sequencingof BRCA1/2 including all the coding exons and splice-

site junctions. Beginning in 1997, patients of Ash-kenazi Jewish heritage were offered the option of ascreening test for the three common founder muta-tions, 185delAG and 5382insC in BRCA1 and 6174delTin BRCA2. Patients of Ashkenazi Jewish heritage wereinformed that these three mutations account for mostidentifiable BRCA1/2 mutations in their ethnicgroup.29 All patients who undertook genetic testingsigned an informed consent form. Testing was per-formed at Myriad Genetics Laboratories (Salt LakeCity, UT). The cost of the Ashkenazi screening panelwas $300 –350, whereas that of full gene sequencingwas $2400. Patients could opt to pay for the test out-of-pocket or seek insurance reimbursement. Patientswho were seen from February 1, 1996 to October 31,1996 and who fulfilled the following criteria had accessto free testing through the beta-testing phase offeredby Myriad Genetics Laboratories: 1) an individual withbreast cancer diagnosed before age 50, and who has afirst-degree relative with breast carcinoma diagnosedbefore 50, or a first-degree relative with ovarian carci-noma diagnosed at any age; 2) an individual withovarian carcinoma diagnosed at any age, and who hasa first-degree relative with breast carcinoma diag-nosed before 50, or a first-degree relative with ovariancarcinoma diagnosed at any age. At the patient’s re-quest, information regarding the genetic test and re-sults could be kept in a shadow chart separate fromthe patient’s medical records.

Patients were informed that the first person to betested in the family should ideally be a member af-fected with breast or ovarian carcinoma. Patients whowere unaffected and who did not have an availableaffected family member to participate in testing butwho desired testing were not denied it, although theywere informed that the information that was derivedin such a situation could be limited.

Data AnalysisThe demographic characteristics, cancer history,screening and lifestyle behavior, perceived breast car-cinoma risk, family history, family risk category, andaccess to free testing, were analyzed to determine ifany of these factors were associated with genetic test-ing uptake. Two-sided Pearson chi-square test wascomputed for univariate analysis. Factors were in-cluded in multiple logistic regression analysis if theywere associated with test uptake on univariate analy-sis with P value of 0.1 or less. All statistical analysis wasconducted using the SPSS statistical software (SPSSInc., Chicago, IL).

1878 CANCER March 15, 2002 / Volume 94 / Number 6

RESULTSA total of 443 unrelated new patients were seen inconsultation at the Breast and Ovarian SurveillanceService, Johns Hopkins Hospital during the study pe-riod. Of these, 258 patients (58%) were eligible andwere included in our study. The remaining 185 pa-tients were not included for reasons as detailed in Fig. 1.

The median time from the patient’s first consul-tation with the service to the time of data collectionand analysis for the 258 patients eligible for the studywas 25 months (range, 8 –55 months).

Demographics, Medical History, Screening and LifestyleBehavior, and Perceived Breast Carcinoma RiskMost of the patients were white, married, had com-pleted at least 4 years of college and had children.Thirty percent of the patient population was of Ash-kenazi Jewish heritage. Thirty percent had a previousdiagnosis of breast and/or ovarian carcinoma, 57%practiced regular self-breast examination at least ev-ery month, and 86% reported having had at least 1mammogram. Most did not smoke and had three orfewer alcoholic drinks per week. Of the patients whohad no history of breast or ovarian carcinoma andwho projected their risk of invasive breast carcinoma,86% perceived their lifetime risk to be greater than25% (Table 1).

Family History and Risk CategoryThree-quarters of patients were from breast carci-noma– only families, approximately one-quarter were

from breast and ovarian carcinoma families, and 4%were from ovarian carcinoma families. Slightly greaterthan half the patients had 3 or more family memberswith breast carcinoma, and 74% had at least one first-degree relative with breast carcinoma. Slightly greaterthan half the patients were from moderate- or high-risk families.

Details of Genetic TestingA total of 68 patients (26%) elected to undergo testing,whereas the remaining 190 patients declined testingor expressed interest at the time of the consult but hadnot been tested at the time of the analysis. The pro-portion of patients undergoing genetic testing duringeach year of the 4-year study period was 20 of 48 (42%)in 1996, 11 of 56 (20%) in 1997, 13 of 54 (24%) in 1998,and 24 of 100 (24%) in 1999 (P � 0.057). Of note, 18 of20 patients who were tested in 1996 had access to freetesting (Table 2).

Thirty-three of 68 individuals who were testedwere patients with cancer, 12 of 68 were affected rel-atives who were tested at the request of our cancerfree patients, and 23 of 68 were unaffected patientswho proceeded with testing without first testing anaffected family member. Slightly greater than half thepatients underwent full gene sequencing. Almost halfthe patients were tested on the same day of the con-sult and 96% within 1 year of the consult. Eighteen of68 patients had free testing. Of the remaining 50 pa-tients who had to bear the cost of the test, 0 of 28 whohad the Ashkenazi Jewish screening panel and 13 of 22

FIGURE 1. Patients seen in the Breast

and Ovarian Surveillance, Johns Hopkins

University, during the study period.


TABLE 1Demographic Characteristics, Medical and Cancer History, Screening and Lifestyle Behavior of Study Cohort and Proportion of Patients Testedin Each Subcategory

Characteristics (n � 258)aNo. of patients ineach subcategory

Percentage tested in eachsubcategory (%) P valueb

Age (yrs)� 40 92 23 0.0840–49 95 2550–59 53 26� 60 18 53

Ashkenazi JewishYes 77 41 � 0.001No 134 18

Marital statusSingle 3 31 0.50Married 214 25Divorced 0 0Widowed 13 39

Years of education12–15 67 22 0.7216 65 28� 16 98 26

Has children?Yes 183 28 0.40No 62 22

Has daughter?Yes 124 29 0.30No 121 23

Personal history of breast or ovarian carcinomaYes 77 43 � 0.001No 181 19

Breast self-examination practiceNever 13 21 0.87Less than monthly 65 26Monthly 106 22More than monthly 41 28

Ever had a mammogramYes 222 24 0.53No 23 30

Smoking historyNever smoker 219 23 0.33Ever smoker 13 28

Alcohol consumption (drinks/wk)Never 70 30 0.60� 1 80 231–3 49 20� 3 46 26

Perceived life-time risk of invasive breast carcinoma(n � 118) (%)

� 25 17 18 0.1526–50 46 2651–75 22 23� 75 33 6

Family historyBreast carcinoma–only family 187 25 0.69Breast and ovarian carcinoma family 61 31Ovarian carcinoma family 10 22

No. of relatives with breast carcinoma0 10 20 0.931–2 107 273–5 110 27� 5 31 23

(continued)


(59%) who had full sequencing sought insurance re-imbursement, of which 7 had a prior diagnosis ofbreast or ovarian carcinoma.

Results of Genetic TestingApproximately one-third of the patients tested had aBRCA1/2 mutation identified. Among the patients whounderwent full gene sequencing, 20% had a variant ofuncertain significance. No deleterious mutations wereidentified in any of the 11 patients from low-risk fam-ilies, whereas 32% and 67% patients from moderate-and high-risk families, respectively, were found tocarry a deleterious mutation (P � 0.016). Fifty-eightpercent of patients from breast and ovarian carcinomafamilies carried a BRCA1/2 mutation, compared withonly 21% of patients from breast carcinoma– only fam-ilies (P � 0.014; Table 3).

Factors Associated with Genetic Testing UptakeAccess to free testing, prior diagnosis of breast orovarian carcinoma, and Ashkenazi Jewish heritagewere the only factors associated with genetic testingon both univariate and multivariate analysis. Age andgenetic risk category also were evaluated in multivar-iate analysis but were not significant.

DISCUSSIONThe BRCA1/2 genes were cloned in 1994 and 1995,respectively, and testing has been available commer-

TABLE 2Details of BRCA1/2 Testing (n � 68 Patients Tested)

Characteristic Percentage

Type of testScreening panel 41Full gene sequencing 59

Who tested?Cancer-affected family member (cancer freeproband) 18a

Patient seeking consult 82 (n � 56)Prior breast or ovarian carcinoma 59 (33 of 56)No prior breast or ovarian carcinoma 41 (23 of 56)

Time interval between consultation and genetic testingSame day 431–30 days 2831–90 days 791–180 days 107–12 mos 7� 12 mos 4

Mode of payment (screening panel, n � 28)Free 0Self-pay 100Insurance 0

Mode of payment (full sequencing, n � 40)Free 45Self-pay 23b

Insurance 33c

a Mother, four; sister, five; aunt, two; cousin, one.b Three of nine had prior diagnosis of breast/ovarian carcinoma.c Seven of 13 had prior diagnosis of breast/ovarian carcinoma.

TABLE 1 (continued)Demographic Characteristics, Medical and Cancer History, Screening and Lifestyle Behavior of Study Cohort and Proportion of Patients Testedin Each Subcategory

Characteristics (n � 258)aNo. of patients ineach subcategory

Percentage tested in eachsubcategory (%) P valueb

No. of first-degree relatives with breast carcinoma0 67 24 0.711 126 282 36 193 8 38� 3 3 0

No. of first-degree relatives with ovarian carcinoma0 204 25 0.821 18 282 0 0

Genetic risk categoryLow-riskc 75 15 0.05Moderate-riskc 118 32High-riskc 34 27Not categorized 31 31

Access to free testingYes 26 69 �0.001No 232 22

a Numbers do not always add up to 258 because of missing variables.b Two-sided Pearson chi-square test.c 80%, 25%, and 38% of low-, moderate-, and high-risk categories had a quantitative estimate.


cially since the end of 1996. Before the availability ofclinical testing, various studies in breast carcinomapatients,14 healthy family members of breast or ovar-ian carcinoma patients,8–12 and the general popula-tion13–16 have reported high level of interest in BRCA1/2genetic testing, ranging from 69% to 96%.8,9,11–14,16,30,31

Since genetic testing for BRCA1/2 became available,there have been few published studies on the actualutilization of testing in clinical practice.18

Only one-quarter of patients who were eligible toconsider testing in our clinical population eventuallywere tested or arranged to have an affected familymember tested. Although we did not systematicallyrecontact our patients, we did see most in follow-up ormaintained telephone contact with them after theirconsultation. It therefore is unlikely that many weretested elsewhere without our knowledge. The uptakefor BRCA1/2 testing in the clinical situation thus islower than has been reported in previous hypotheticaland research situations. The only factors that wereassociated with genetic test utilization in our studywere access to free testing, personal history of breastor ovarian carcinoma, and Ashkenazi Jewish heritage.

Of note, many factors that have been reported previ-ously to be predictive of interest in genetic testing inhypothetical and research situations were not associ-ated with test utilization in our study. These includehigh educational level,10,12 health-seeking behavior,16

having children or daughters,2,8,32 healthy lifestyle,16

high perceived risk of developing cancer,9 and highpredicted genetic risks,18,32 all factors that were highlyrepresented in our study cohort. It is possible that thesignificance of these factors in the clinical situation isovershadowed by practical considerations such ascost, fear of insurance discrimination, or the recom-mendation to involve an affected relative in the testingprocess.

Approximately one-third of the entire patientpopulation tested was found to carry a BRCA1/2mutation. In keeping with what has been reportedby others,19,33 breast-ovarian cancer families weremore likely to carry deleterious BRCA1/2 mutationsthan breast carcinoma– only families in our series.We also found good correlation between the likeli-hood of finding a deleterious mutation and geneticrisk categories.

TABLE 3Results of BRCA1/2 Mutation Testing (n � 68)

Genetic test results No. of patients (%)

BRCA1 mutation 15 (22)BRCA2 mutation 7 (10)Variant of uncertain significance 8 (12)No mutation 38 (56)

Genetic test results by test type No. of patients (%)

Screening panel (n � 28)BRCA1 mutation 5 (18)BRCA2 mutation 2 (7)No mutation 21 (75)

Full gene sequencing (n � 40)BRCA1 mutation 10 (25)BRCA2 mutation 5 (13)Variant of uncertain significance 8 (20)No mutation 17 (43)

Genetic test results by family history Mutation Variant No mutation

Breast carcinoma–only families (n � 47) 10 (21) 6 (13) 31 (66)Breast and ovarian carcinoma families (n � 19) 11 (58) 2 (11) 6 (32)Ovarian carcinoma–only families (n � 2) 1 (50) 0 (0) 1 (50)

Genetic test results by genetic risk category Mutation Variant No mutation

Low-risk families (n � 11) 0 (0) 1 (9) 10 (91)Moderate-risk families (n � 38) 12 (32) 6 (16) 20 (53)High-risk families (n � 9) 6 (67) 1 (11) 2 (22)Not categorized (n � 10) 4 (40) 0 (0) 6 (60)


Potential Obstacles to BRCA1/2 TestingCost is likely to be one of the most important obstaclesto genetic testing. The current cost of BRCA1/2 testingranges from $300 to $2680 and is prohibitive for manyindividuals. Previous studies of patients’ response toprospective offers of genetic testing have found signif-icant reduction in interest when cost became a fac-tor.9,30 This would explain why nearly 70% of patientswho were eligible for free testing chose to be tested, asopposed to only 22% when patients had to bear thecost of the test. Although the greater estimated geneticrisk in the subgroup that had access to free testingmay have played a role in the higher test utilization,we do not believe this to be the main reason. We alsoreported significantly higher genetic test uptake amongAshkenazi Jewish patients, who could be screenedwith the less costly three-mutation panel, suggestingagain that cost is an important consideration.

Fear of insurance discrimination often has beencited as a potential barrier to genetic testing.2,8,34 Mostof our patients were middle- to upper-class based oneducational attainment, and greater than 99% hadhealth insurance. Insurance plans increasingly pro-vided reimbursement for genetic testing over thecourse of our study period. In 1996, Maryland enacteda law prohibiting health insurers from using genetictest results to make coverage decisions or to modifyrates or terms of health insurance policies. Despitethis, many remain concerned about the potential neg-ative impact of genetic information on insurability,16,35

and many women in our series chose to pay out-of-pocket for confidentiality reasons. Of the patients whosought insurance reimbursement for the more costlyfull gene sequencing, greater than half (7 of 13) had aprior diagnosis of breast or ovarian carcinoma andwould have been less concerned about insurance dis-crimination based on the results of a genetic test.

Discrepancy between Hypothetical or Research Interestand Actual UtilizationWhat accounts for the discrepancy between actualclinical test utilization and reported interest in thehypothetical situation and research setting? Patientsseen in clinical settings often are given detailed infor-mation on hereditary breast and ovarian carcinomaand genetic testing. As such, these patients are betterinformed than those who were offered testing hypo-thetically. Although there may be genuine interest ingenetic testing, actual utilization of the test may below after the individual weighs the potential advan-tages against the disadvantages and limitations. Con-versely, uptake is high in the research setting despiteparticipants being fully informed of its disadvantages

and limitations. However, research participants do notbear the cost of the test, are relatively protectedagainst insurance discrimination, and are generallyhigher risk individuals, as opposed to a clinical popu-lation, which usually comprises of a mix of low-, mod-erate-, and high-risk families. Although genetic riskcategory did not have an impact on test utilization inour study, this nevertheless could have been a con-founding factor. Finally, individuals who have chosento participate in research are self-selected, highly mo-tivated, and often have altruistic desires to help sci-ence17 and thus are not representative of a clinicalpopulation.

Limitations of Our StudyThe genetic risk estimates provided to patients werenot based on a single model, nor were they deliveredto patients in a standardized manner. Of note, a sig-nificant proportion of patients were not given a quan-titative risk estimate for various reasons, and the as-signment of genetic risk categories for these patientsbecame somewhat arbitrary and subjective. The in-ability to categorically give a quantitative risk estimateto certain patients reflects the actual clinical situation.Furthermore, there are significant limitations to anysingle risk assessment model. The Couch model, forexample, does not take into account male breast car-cinoma, bilateral breast carcinoma, or cancers apartfrom breast and ovarian carcinoma that may be in-creased in BRCA1/2 mutation families. In addition, wehave empirically doubled the risk estimates derivedfrom the Couch model to provide an approximateestimate of each family’s probability of carrying aBRCA1/2 mutation. This may result in an overestimatebecause BRCA2 mutations are less prevalent thanBRCA1 mutations. Recently available models such asthe BRCAPRO may provide a more comprehensiveand objective risk estimate.36 A prospective study withsystematic documentation of genetic risk categorieswould have provided more valuable and relevant in-formation regarding how genetic risk categories mighthave an impact on genetic test utilization. Finally,clinical cancer genetics is a rapidly evolving field, notonly in terms of medical developments, but also in itssocial, ethical, and legal aspects. The passage of legis-lation to protect against genetic discrimination, in-creasing willingness of insurance companies to reim-burse for genetic testing, and emerging data on cancerpreventive measures26,37– 40 might have an impact ontesting uptake. Our experience in the first 6 months of2001 (not included in the analysis), however, has beenfairly concordant with what has been reported in thisstudy, with 33 of 107 (31%) of eligible probands un-dergoing testing (60% full sequencing, 40% screening


panel). Nonetheless, a follow-up study to evaluate po-tential changes in testing utilization with time wouldbe warranted.

CONCLUSIONSWe report a low utilization rate of genetic testing forBRCA1/2 mutations in a large clinical series. Potentialobstacles to testing include cost, fear of insurancediscrimination, and need to involve an affected familymember in the testing process. Factors that previouslyhave been reported to be important in hypotheticaland research situations, such as education level, re-productive status, involvement in screening, healthylifestyle, and high perceived risk of breast carcinoma,did not have an impact on test utilization in our study.Our study was, however, not a prospective one de-signed to look at motivators and barriers to genetictesting specifically. We thus lack the ability to examinethe relative importance of factors in any individualpatient’s decision making. Prospective studies exam-ining these factors are warranted.

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Utilization ofBRCA1/2 genetic testing in the clinical setting