GENETIC TESTINGVolume 2, Number 4, 1998Mary Ann Liebert, Inc.
Genetic Testing for Breast-Ovarian Cancer Susceptibility:A Regional Trial
STARLENE LOADER,1 JEFFREY C. LEVENKRON,2 and PETER T. ROWLEY1
To evaluate receptivity to testing for a genetic susceptibility to breast-ovarian cancer, information is neededon the response when the offer is open to all qualifying women in a given region. To qualify in this trial, awoman who had not had breast or ovarian cancer had to have at least two first-degree relatives or one first-and one second-degree relative with breast and/or ovarian cancer, whereas a woman who had had breast orovarian cancer had to have at least one first-degree relative with breast or ovarian cancer and a first- or sec-ond-degree relative without cancer willing to be tested. Of 140 women qualifying and interested enough to re-turn questionnaires requesting baseline information, 111 were referred by their physician and 29 were iden-tified from a regional tumor registry. Of these 140, 112 came for pretest education and 98 of these chose tobe tested. Thus, the acceptance rate was 70% for all those returning baseline questionnaires, but 88% forthose interested enough to come for pretest education. The most common reasons for accepting testing wereto take extra precautions if a mutation were found (42.9%) and to determine if offspring were at risk (24.5%).The most common reasons for declining were anxiety and absence of specific interventions. Factors predict-ing who chose testing were years of education (p < 0.005) and family closeness (p < 0.02). Fourteen deleteri-ous BRCA1 or BRCA2 mutations were found in 13 of the 87 families actually tested. If the criteria for test-ing had been three or more affected family members rather than two or more, the number of families testedwould have been reduced by 46%, but the number of families found to have a deleterious mutation wouldhave been reduced by only 9%.
The isolation of the breast-ovarian cancer susceptibil-ity genes BRCA1 (Miki et al., 1994) and BRCA2 (Woosteret al, 1995) and the characterization of mutations in these genesin affected families have made it possible to identify women athigh risk for these types of cancers. Widespread public concernabout these types of cancers, especially about breast cancer,means that large numbers of women may seek testing from theirphysicians even though the impact of such testing has yet to befully evaluated.
For BRCA1, located on chromosome 17q21 (Hall et al.,1990), over 500 different mutations have been reported (BreastCancer Information Core Steering Committee, 1998). Reportsbased on families with large numbers of affected individualssuggest that a woman with a BRCA1 mutation has an 87%chance (confidence interval 72-95%) of developing breast can-
cer and a 44% chance (confidence interval 28-56%) of devel-oping ovarian cancer by age 70 (Ford et al., 1994). However,penetrance may be lower in families with fewer affected mem-bers or in certain subpopulations (Easton, 1997), e.g., a reported56% risk of breast cancer and 16% risk of ovarian cancer byage 70 in persons of Ashkenazi Jewish descent (Struewing etal, 1997). BRCA2 is located on chromosome 13ql2-13(Wooster et al, 1994). Over 280 different BRCA2 mutationshave been reported (Breast Cancer Information Core SteeringCommittee, 1998). A BRCA2 mutation confers a high risk ofbreast cancer, similar to a BRCA1 mutation, but a lower riskof ovarian cancer than a BRCA1 mutation (Wooster et al,1995). About 2.5% of Ashkenazi Jews have a BRCA1 orBRCA2 mutation (Easton, 1997). This increase is due chieflyto three specific mutations, two in BRCA1 (185delAG and5382insC) and one in BRCA2 (6174delT).
Interest in mutation detection is high among affected fami-
1 Department of Medicine, Division of Genetics, and the 2Department of Psychiatry, University of Rochester School of Medicine, Rochester,NY 14642.
306 LOADER ET AL.
lies (Lerman et al, 1994, 1995) and even in the general public(Andrykowski et al, 1997). Previously, we have assessed in-terest in testing for genetic susceptibility to breast and ovariancancer in Rochester among 498 women visiting their privateobstetrician-gynecologist for any reason and 484 women hav-ing routine mammography in a busy radiologie practice (Cha-liki et al, 1995). These women were unselected for a personalor family history of breast or ovarian cancer. Yet over 90% ineach group said they would want such testing, if free, and 56%provided their name, address, and telephone number for notifi-cation when testing became available.
The existing information about test receptivity is limited byreliance chiefly on members of single families or small num-bers of families previously recruited for cancer genetic researchwho therefore may not be representative of at-risk families inthe general population (see Discussion). Our study was de-signed to provide more generalizable information and differsfrom previous studies in several ways. First, individuals offeredtesting were not part of families previously identified to havea mutation. Rather, genetic counseling and testing were opento everyone in the county who met the cancer family historycriteria. Second, most individuals coming to inquire about test-ing first learned about it from their own physician, not from aresearch team. Third, to be tested, an individual had to recruita relative willing to be tested. Fourth, all participants expectedto learn their results. Fifth, women who presented themselveswere asked to decide whether or not to be tested on the basisof whether, following detailed pretest education, they expectedthat benefits would outweigh burdens in their own case, andnot in order to help research.
PATIENTS AND METHODS
Population studiedTwo populations were studied. One consisted of patients re-
ferred by their physician because of a family history of breastcancer. Because most of these patients had not had breast can-cer themselves, a second population, women with a family his-tory of breast cancer who had had breast cancer themselves,was obtained from our regional tumor registry.
To identify the first population, we informed area providersabout the clinical trial at a regular conference of the obstetrics-gynecology staff of each of the five hospitals having such a ser-vice in Monroe County (containing Rochester). Physicianknowledge and attitudes about testing for a genetic suscepti-bility to breast and ovarian cancer as assessed on those occa-sions have been previously reported (Rowley and Loader,1996). All other physicians in the county were invited to par-ticipate via an article in the county medical society newsletter.To be eligible for testing, a woman who had not had breast orovarian cancer, an "at-risk" woman, had to have at least tworelatives with breast or ovarian cancer on the same side of herfamily; one of these had to be a first-degree and the other afirst- or second-degree relative, one of whom had to be living.
The second population was drawn from all women diagnosedin 1994 with breast cancer at or below age 50 in Monroe County(n = 213) using the Rochester Regional Tumor Registry. Physi-cians of record reported that six had died and did not give uspermission to contact 37 others. We wrote to the remaining 170
women to inform them of the offer of genetic testing and to in-vite them to contact us if they had a qualifying family history.To qualify, we required a first-degree relative with breast orovarian cancer and an at risk first or second-degree relative sothat these families would be similar to the two-affected-mem-ber families ascertained through physician referral.
Pretest educationWhen a woman from an affected family telephoned us to in-
quire about testing, it was determined whether her family metthe criteria stated above. If it did, the woman was sent a set ofquestionnaires, including a cancer family history questionnaire,the Breast Cancer Worry Scale (Lerman et al, 1994), the MillerBehavioral Style Scale (Miller, 1987), the Brief Cope (Carveretal, 1989), the Beck Depression Inventory (Beck et al, 1979),the Life Orientation Test (Scheier et al, 1994), and the Rand36-Item Health Survey 1.0 (SF-36) (Hays etal, 1993). The pur-pose of the Beck Depression Inventory was to exclude from of-fering DNA testing any seriously depressed person, but nonewere detected. Also included was a questionnaire assessingbreast cancer knowledge, attitudes, and surveillance practices.The attitude questions included perceptions about seriousness,susceptibility, curability, and surveillance effectiveness andwere similar in design to those used in previous genetic screen-ing studies of ours (Rowley et al, 1991), and involved ratingusing a Likert scale. As soon as the completed questionnaireswere returned and reviewed, an appointment was made.
At the first visit, a detailed family history of all types of can-cer was obtained to detect any variant cancer syndrome (e.g.,Li-Fraumeni); none were detected. The patient was given anexplanation of genetic susceptibility for breast and ovarian can-cer and of the significance of mutation detection. Both poten-tial benefits and potential risks and limitations of testing (listedin the Discussion) were enumerated so that she could make adecision for herself; in other words, we merely offered testing,rather than recommending it. It was explained that a negativeresult in an at-risk person had limited value unless an affectedrelative had been shown to have a mutation, because the mu-tation responsible for multiple cases in the family might be onenot detected by current methods or might be in a gene not an-alyzed. For this reason an affected family member had to beshown to have a mutation before an at-risk member was tested.The first visit usually required about 90 min.
The patient was not asked to make a decision about testingon this first visit, but rather was given an explanatory brochureand a detailed consent/decline form to take home. She was toldthat, if she decided to be tested, she should return with the ap-propriate relative. The appropriate relative for an at-risk womanwas a relative who had had breast or ovarian cancer. If the in-dex patient had had breast or ovarian cancer, we requested thatshe return with a relative who had not had cancer, not becauseit was medically necessary, but because we wished to compareat-risk women who learned about testing from their physicianwith at-risk women who learned about testing from a relativewith breast or ovarian cancer.
BRCA1 and BRCA2 testingWhen the index patient returned with the appropriate rela-
tive, any additional questions were answered, informed consentdocumented, and blood drawn on both persons. Mutation de-
BREAST-OVARIAN CANCER SUSCEPTIBILITY TESTING 307
tection for the affected patients was performed by Myriad Ge-netic Laboratories, Inc. (Salt Lake City, UT) by sequencing theentire coding region of BRCA1 and adjacent intronic regionsas previously described (Shattuck-Eidens et al., 1997). Samplesfrom most patients were analyzed independently by OncorMed(Gaithersburg, MD) employing initial screening by antisenseoligonucleotide hybridization for common mutations and byprotein truncation assays for mutations in exon 11 ; these werefollowed by sequence analysis only if an abnormality was de-tected by one of the two screening tests.
Before results from all the BRCA1 tests had been reported,Myriad Genetics permitted us to offer BRCA2 testing to amember of the 26 families who had submitted samples most re-cently, and whose affected member had tested negative for aBRCA1 mutation. Of these 26 offers, 21 families accepted. Oneindividual each from three other families, who tested negativefor a BRCA1 mutation but were not offered free BRCA2 test-ing, paid for such testing. Thus, of 87 families tested for aBRCA1 mutation, some member of 24 families was also testedfor a BRCA2 mutation. Myriad used the same method to de-tect BRCA2 mutations as for BRCA1 mutations.
Communication of resultsBefore blood was drawn, it was explained that results were com-
municated only in person to the index patient and relative together,thus necessitating a third visit. For women found to have a muta-tion, the recommendations for management made by the CancerStudies Consortium (Burke et al, 1997) were communicated.
Human subjectsThis project was approved by the Research Subjects Review
Board of the University of Rochester. No charge was made forpretest education, DNA testing, or post-test counseling.
Characteristics of index patientsAmong the women who contacted us to inquire about test-
ing, 140 women ("index patients") met the family history cri-teria and returned questionnaires providing baseline informa-tion. Of these 140 women, 41 women had a personal history ofbreast or ovarian cancer ("affected") and 99 had not ("at risk").These 41 women with a personal history of breast or ovariancancer included 29 patients identified from the Tumor Registry.Of the 140, 111 had families with breast cancer without ovar-ian cancer and 29 had a family history of both breast and ovar-ian cancer. The number of persons with breast or ovarian can-cer per family ranged from two to eleven, but most families(89%) had only two to four such persons. The mean age was44.3 years. The mean number of years of education was 14.9.The proportion married was 74.3%. The proportion employedwas 61.4%. Racial composition was three African-Americans,one Hispanic, and 136 non-Hispanic Caucasians. Nine persons(6.4%) were of Ashkenazi Jewish descent.
Decision about testingOf these 140 index patients qualifying for testing, 112 came
for the first visit to receive pretest education, but 28 did not.
After these 112 index patients had received pretest education,98 chose testing and 14 chose no testing. The acceptance ratewas thus 70% (98/140) for the whole group qualifying for test-ing, but 88% (98/112) for those interested enough to come forpretest education.
The most common reasons given for choosing testing wereto take extra precautions if a mutation were found (42.9%) andto determine if their offspring were at risk (24.5%). Reasonsfor testing less commonly given were to obtain reassurance orto comply with the recommendation of physician or a relative.
To those 28 who had qualified for testing, but had never re-turned the set of questionnaires mailed to them, we sent a sec-ond set including a question about their reason for decliningtesting and offered a small payment for completion. Of the 42who did not desire testing (including both the 28 who did notcome for pretest education and 14 who chose no testing aftereducation), 17 provided a reason. Seven were concerned abouttheir emotional reaction to a positive result, five would notchange their surveillance even if their result were positive, threefound that the intended relative was unwilling or had died inthe interim, and two were worried about the effect of a posi-tive result on their insurability.
Comparison of index subjects accepting ordeclining testing
The 98 "acceptors" and the 42 "decliners" (see Fig. 1) amongthe index patients are compared in Table 1. The two groupswere significantly different in two characteristics. First, themean number of years of education was greater for acceptors(15.3 years) than for decliners (14.0 years, p < 0.005). Second,acceptors rated their families as closer than did decliners (p 2 >3 >4
FIG. 2. Relationship between the number of breast and ovar-ian cancers in a family that might be required for testing andthe number of families that would have been found to have adeleterious mutation in this study. For this purpose, the indexsubject is assumed unaffected. An affected first-degree relativeis required in each of the illustrated cases. Using two or morefirst- and second-degree affected relatives as the criterion foroffering testing, 13 families were detected to have mutationsamong 87 tested families. However, if three or more first- orsecond-degree relatives had been required, 12 families wouldhave been detected to have mutations among 47 families qual-ifying from the same set of families. Thus, the more stringentcriterion would have reduced the number of families tested by46%, while reducing the number of families found to have amutation by only 9%. If four or more affected relatives hadbeen required, only six of the families detected to have a mu-tation would have been identified.
Our study used a simple criterion for the offer of testing (i.e.,number of affected relatives). A more accurate estimate of thelikelihood of detecting a mutation can be obtained by consid-ering a large number of risk factors. Mathematical functions forestimating the likelihood of a BRCA1 or BRCA2 mutation havebeen proposed that take into account multiple factors affectingthe risk of having a mutation, including not only the number ofaffected relatives, but also age at diagnosis, bilaterality of breastcancer, occurrence of ovarian cancer, and Ashkenazi descent(Shattuck-Eidens et al., 1997; Frank et al., 1998). Perhaps asimportant a consideration as the likelihood of detecting a mu-tation is the practical significance of mutation detection. Con-sider two women with an identical a priori risk for having amutation based on the above risk factors. One is an elderlywoman who has no living relative, while the other is a youngwoman who has a large number of female relatives. With lim-ited resources, the latter woman may deserve a higher priorityfor testing.
312 LOADER ET AL.
Study limitationsThis study attempted to assess the characteristics of candi-
dates for testing in the setting resembling clinical service ratherthan research. However, certain limitations of the study in thisregard are here acknowledged. First, we do not know how manywomen who qualified for testing by family history were notidentified by their physician, were identified but not referred,or were referred but did not contact us. These uncertainties con-cerning physician-referred patients was one of our reasons foralso utilizing the tumor registry. In choosing to study patientsreferred by their own physicians, we incurred the liability ofhaving no denominator to use to calculate an acceptance rate,except for those who came for pretest education. Second, wetook the initiative of contacting some patients who had alreadyhad breast cancer because commercial laboratories are market-ing testing to oncologists and thus affected women are the in-dex patients in some families being tested on a service basiselsewhere. Our contacting and informing patients who have hadbreast cancer, although done with permission of the patient'sphysician, may have evoked a different response than a spon-taneous offer by the woman's own physician. Third, we re-quired that the first person in a family whose sample was ana-lyzed be an affected person. However this is not a requirementof all laboratories offering testing and, to this extent, our sam-ple may not be representative of candidates for testing wherethis requirement is not made. Fourth, since our sample size wassmall, some factors analyzed and found not to predict test ac-ceptance should be reassessed when a larger sample of similarsubjects is available. Fifth, we required completion of ques-tionnaires that would not be required in a service setting andthat may have discouraged some patients who would have oth-erwise participated. Finally, we offered testing and counselingservices free of charge because our intent was to evaluate whatinformation women want. For the present, the cost of testing islikely to limit testing severely, whether the payer is the patientor a third party. However, recent advances in technology arelikely to greatly reduce the cost of testing in the future.
We are following these patients found to have a deleteriousmutation or an alteration of uncertain significance and will laterreport on their understanding of their result, attitudes, and be-havior, including whether or not they told others their result,changed their surveillance, or chose prophylactic surgery.
We wish to thank participating families and providers, andespecially Myriad Genetics and OncorMed, for generously pro-viding mutation detection for this study without charge.
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Address reprint requests to:Dr. Peter T. Rowley
Division of Genetics, Box 641University of Rochester School of Medicine
601 Elmwood Avenue Room 5-6926Rochester, NY 14642
E-mail: peter_rowley@ URMC.Rochester.eduReceived for publication July 26, 1998; accepted November 9,1998.