Uptake of BRCA1 Genetic Testing in Adult Sisters and Daughters of Known Mutation Carriers in Norway

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Journal of Genetic Counseling [jgc] ph217-jogc-470243 September 12, 2003 18:1 Style file version Nov 28th, 2002

Journal of Genetic Counseling, Vol. 12, No. 5, October 2003 (C© 2003)

Uptake of BRCA1 Genetic Testing in AdultSisters and Daughters of Known MutationCarriers in Norway

Trine Levin Bodd,1 Jon Reichelt,1 Ketil Heimdal, 1 and Pal Møller1,2

This study was undertaken to examine transmission of information to first-degreerelatives of BRCA1 mutation carriers and uptake of genetic testing. The intentionwas to consider revision of current legislation related to privacy if informationon life-saving health care was not disseminated to at-risk family members. TheNorwegian Radium Hospital provides clinical genetics services for families at highrisk for hereditary breast and ovarian cancer. Together with major hospitals na-tionwide we provide medical surveillance. Nearly all expenses are covered by theNational Health insurance. Because of the high number of families with foundermutations in BRCA1, we are in a unique position to gather information about thesegroups. Within a consecutive series, we identified 75 BRCA1 mutation carriers andregistered information transmission and uptake of genetic testing 6 months or moreafter the index mutation carriers had been informed about their mutation status.These 75 BRCA1 mutation carriers had 172 living first-degree relatives, aged18 years or older (84 females, 88 males). Forty-four out of 54 (81.5%) of femalesover 30 had opted for genetic testing. The testing rate among all relatives was 43%.At any age, 63% of the females underwent genetic testing compared with 24% ofthe males (p< 0.05). The overwhelming majority of adult females at risk opted forgenetic testing. Males with daughters more frequently than males without daugh-ters asked for testing. The findings give neither reason to reconsider legislation onprivacy, nor for us to consider more aggressive methods of contacting relatives.

KEY WORDS: BRCA1 testing; genetic counseling; predictive testing predictors; breast cancer;ovarian cancer.

1Section of Genetic Counseling, Department of Cancer Genetics, The Norwegian Radium Hospital,Oslo, Norway.

2Correspondence should be directed to P˚al Møller, MD, PhD, Section of Genetic Counsel-ing, Department of Cancer Genetics, The Norwegian Radium Hospital, N-0310 Oslo, Norway;e-mail: [email protected].

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1059-7700/03/1000-0405/1C© 2003 National Society of Genetic Counselors, Inc.

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406 Bodd, Reichelt, Heimdal, and Møller

INTRODUCTION

The discovery of the BRCA1 and BRCA2 genes (Mikiet al., 1994; Woosteret al., 1995) and the availability of testing for disease associated mutations havechanged the opportunities for many families with hereditary breast and ovariancancers. In these families we may now be able to confirm that the clustering ofcancers is indeed hereditary. Once a mutation is found in a family, healthy rela-tives have the opportunity to learn of their mutation status. However, the decisionwhether or not to undergo testing is not necessarily an easy one.

Before testing became available, some studies anticipated an overwhelminginterest in genetic testing for breast and ovarian cancer (Lermanet al., 1994, 1995;Presset al., 2001). Lermanet al. (1996) found that individuals in breast-ovariancancer families, in general, wanted genetic testing. They also found that femaleswere more interested than men were, as did Struewinget al.(1995), Julian-Reynieret al.(2000), and Fosteret al.(2002). Once genetic testing became available, actualparticipation proved, in general, lower than the anticipation. Reports on uptakeof genetic testing ranged from 43 to 80% (Bieseckeret al., 2000; Julian-Reynieret al., 2000; Lermanet al., 1996; Patenaude, 1996; Reicheltet al., 1999). However,because of different testing criteria employed in the different studies, the seriesmay not be easily compared.

To date, the information available on the reasons for and against testing hasmostly been gathered through patient contact, surveys, interviews, and specialinvitations. In many studies where surveys are being used, the concern for childrenseems to be one of the major reasons for testing (Fosteret al., 2002; Lodderet al.,1999). Here we describe our experience with uptake of BRCA1 mutation testingin Norway. A few founder mutations in BRCA1 account for a large proportion ofhereditary breast and ovarian cancer in Norway (M¨oller et al., 2001a). We countedthe observed uptake of genetic testing in families with a demonstrated BRCA1mutation. The target groups for our health service were women over the age of30 and men with adult daughters. Our goals were (1) to learn what proportionof adult individuals at 50% a-priori risk of carrying a known mutation in theirfamily proceeded with genetic tests, (2) to learn whether information such as age,sex, and parental status predicted whether someone opted for genetic testing, and(3) to evaluate how these results compare to other hereditary cancer syndromes.The outcome from this study is to be used to help inform legislation and policyregarding medical health privacy. Our intention was to request revision of currentlegislation if ascertainment of at-risk individuals was not complete.

MATERIALS AND METHODS

At our genetic clinic at the Radium Hospital in Oslo, Norway, we provide com-plete clinical services to families with suspected and confirmed risk of hereditary

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Uptake of BRCA1 Testing in Norway 407

breast and ovarian cancers. The genetic clinic was established based on family his-tory alone as a tool for risk estimation (Møller, 1993). When the genes BRCA1 andBRCA2 were identified, it was demonstrated that the majority of Norwegian BRCAmutation carriers had one out of four BRCA1 founder mutations (Mølleret al.,2001a,b). We developed high capacity testing for these mutations and screenedaffected members in all families who contacted us requesting mutational testing.In this way we had identified 27 families (December 31, 1998) with mutations andoffered genetic testing to 232 members of these families (Reicheltet al., 1999).The patients described in this study were recruited from these families. The in-troduction of predictive genetic testing in these families, changed the health offerfrom surveillance of sisters and daughters to affecteds to targeted health care formutation carriers.

The genetic work up of the families included backwards and lateral expan-sion of the families as far as possible, confirmation based on informed consent(from each living relative and from descendants to the dead ones) of all relevantdiagnoses in all families (obtained from the treating hospital or the Cancer registryof Norway). All information was kept in one computerized medical file. The com-puter systems in addition to filing and retrieving of information, included graphicaldisplay of family structures and links to digital maps capable of relating each kin-dred to geographical origin. The activity has been conducted the last decade by astaff including two to four medical geneticists, four genetic counselors, and foursecretaries together with researchers. We conduct more than 1000 genetic coun-seling sessions for inherited cancer each year. The activity described in this reportis the outcome of health service alone, and includes no element of pure researchactivity. The government pays for health care including genetic testing in Norway.Besides a small fee paid by the patient, the government also covers travel expensesfor genetic counseling. Medical surveillance and treatment are given at their lo-cal hospitals. We receive reports from each examination. In this manner, we havemedical records including complete family history of all previous diseases and allprospectively observed events in all our at-risk patients.

Study Population

As of December 31, 1998, 232 relatives to mutation carriers had been offeredgenetic testing. Seventy-five of them turned out to be BRCA1 mutation carriersand were selected as index persons for this study. They belonged to 22 separatefamilies. The demographics of the index persons are summarized in Table I. Themethod and primary results are in Figure 1 and Table II. There were occasionswhere two index persons belonged to the same sibship, but each individual wasonly counted once. As of June 2001, these 75 individuals had 278 first-degreerelatives (FDR) with a 50% a-priori risk of being mutation carriers, after exclusionof the parents and half-sibs on the side determined or believed not to have the

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Table I. Index Person: Age and Sex Distribution

−30 years 31–40 years 41–50 years 51–60 years 60+ years Total

# Females 2 8 20 19 9 58# Males 1 4 4 4 4 17

Total 3 12 24 23 13 75

mutation. After excluding those under the age of 18 and those deceased, therewere 172 subjects left (84 females and 88 males). Information was then gathered,recorded, and evaluated for each of these relatives. This included whether they hadcontacted us, and if so, if they had requested genetic testing. Other informationcollected included their age and their parental status.

The invitations to the relatives to contact us were given verbally to the indexpersons at the time of the genetic counseling session. Some of the relatives hadalready contacted us and were under surveillance and were informed that theynow had the option of predictive testing. The media (TV, newspapers) were alsointerested in our study and repeatedly ran stories on the project. We did not directlywrite or phone any of the relatives. Relatives were enrolled in the study throughthree different mechanisms (1) direct referral by their doctor, (2) direct contact bythe relative to us, and (3) accompany a relative to a genetic counseling session. Wedid not accept telephone referrals because of the need to document how each single

Fig. 1. Flowchart demonstrating study design and numbers in groups.

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Table II. Uptake of Genetic Testing Categorized According to Sex and Age

18–29 years 30–49 years 50+ years

Females# 30 34 20Tested (%) 9 (30) 28 (82) 16 (80)

Males# 22 37 29Tested (%) 3 (14) 9 (24) 9 (31)

patient was recruited, to avoid misunderstandings, and our inability to properlyanswer telephone calls when occupied in counseling sessions.

Genetic Counseling and Recruitment of Relatives

Genetic counseling and written informed consent were obtained according tonational legislation mandatory prior to genetic testing. Penetrance and expressionof breast and ovarian cancer associated with the Norwegian mutations have previ-ously been reported (for last update, see Heimdalet al., in press). The breast cancerrisk starts at 30 years of age. Ovarian cancer risk starts at 35–40 years. Cumulativerisk for breast or ovarian cancer is 1.2% at age 30 years, 38% at age 50 years,and 70% at age 70 years. Thus, we were able to share very specific penetranceand expression information with our patients. Male mutation carriers were notconsidered to be at significant elevated risk of cancer and did not receive any med-ical surveillance. We follow the recommendations of the Biomed 2 DemonstrationProgramme on Inherited Breast Cancer (M¨oller et al., 1999) with regard to screen-ing and prophylactic surgery. This group has collected results from many cancerclinics in Europe and has concluded that females with BRCA1 mutations havesubstantial risk of ovarian cancer and may consider prophylactic oophorectomy atthe end of childbearing age. To address the breast cancer risk that these womenface, we offered annual mammography and clinical examinations from the age of30. We did not automatically bring up the subject of prophylactic mastectomy. Weare not engaged in any chemoprevention trials. At the time, magnetic resonanceimaging for the early detection of breast cancer was not an option.

It is included in our standard routines to ask each new patient to fill out aform regarding their closest relatives, including their names, date of birth, cancerdiagnosis, year of diagnosis and hospital of treatment, and, if applicable, date ofdeath. This was to document each individual’s place in the family and to confirmthe family history. All cancers reported were, whenever possible, confirmed frommedical files or the Cancer Registry of Norway. The information form gave usinformation about the subjects’ ages, the age, number, and sex of their children.In this way, not only all index patients but all the FDR who contacted us also,

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gave complete information on all their FDR. Those relatives who contacted usand completed a genetic counseling session were then separated into two groups“acceptors” and “decliners” according to whether or not they proceeded withtesting. The “decliners” also included those who chose to defer testing till a latertime.

We had permission from the government to waive confidentiality in order toobtain as complete as possible clinical picture of these families. This permissionwas given as separate funding for this study by the Department of Health wasprovided following a debate in Parliament on whether or not legal restriction onviolating privacy rules should be removed in order to help insure that all mem-bers of identified at-risk families have access to genetic testing. This permissionwas obtained from the Regional ethical committee. However, we chosenot toemploy the option of violation of privacy rules. The rationale behind this strictinterpretation of privacy applied in our general activity, is the assumption thatthe long time effect of being known to respect privacy of sensitive informationwill more than outweigh the putative increased short-time compliance associatedwith other behavior patterns. Therefore, we adhered to our standard procedure ofnever asking the index person’s permission to address relatives directly. Becausewe had in the usual way obtained information on all FDR to index persons welacked complete information on children (numbers and sex) of nonattending malerelatives. However, because we had positive confirmation through their relativesthat all nonattenders were informed and had chose not to participate, they weregrouped as decliners.

One female did not return the family information form. There were 76 indi-viduals among the 172 FDR who had not contacted us. They were mostly males(n = 57). They have by “default” not been tested. Each subject who proceededwith testing was given a minimum of one pretest consultation and one posttestdisclosure session.

The study period was 30 months. It was, however, impossible to gain knowl-edge on exactly when the decliners had been informed—they had in general manyrelatives who had approached them repeatedly over time. The study period of30 months was chosen as it allowed that all relatives had had at least 6 months toconsider the offer of mutational testing. It is possible that some relatives may needmore time than given in this report to come forward for genetic testing. This pos-sibility may be the focus of an additional study in the future. All information waskept in the medical files together with the signed informed consent. No researchregister was established.

Mutation Analysis

All disease-causing mutations found in these 22 families were in the BRCA1gene. The mutations found were 1675delA (12 families), 1135insA (4 families),

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913delCT (1 family), 1569G-> T (1 family), 3166ins5 (1 family), 3297G-> T(1 family), 3726G-> T (1 family), 5194-2a>c (1 family). All mutation results arequality-controlled by a complete retest. Mutation analysis started in the family bystudying the sample from one affected female with either breast or ovarian cancer.

Statistics

The statistics programs, SPSS (version 9, SPSS Inc., Chicago) and Stat-exact4 were used for the analyses. Associations were sought for byχ2 or Fisher’s exacttest, as appropriate.

RESULTS

As of June 2001, the 75 index persons had 172 living at-risk FDR(84 females and 88 males), aged 18 or older, among whom 74 (43%) had chosento undergo genetic testing. Sixty-three percent of the females underwent genetictesting compared with 24% of the males (p < 0.05) (Table II). Nine out of 30(30%) of those females aged 18–29 chose testing, 28/34 (82.4%) in the age group30–49, and 16/20 aged 50+ opted for genetic testing (p < 0.05 for both oldergroups compared to the youngest). Among males, 14, 24, and 31%, respectivelyfor the three age groups, proceeded with testing (Table II). None of these agegroups were statistically different from each other (allp > 0.1).

Having children was not significantly associated with neither women normen’s decisions (p > 0.1) (Table III). However, there was a trend identified sug-gesting that males with daughters chose testing more frequently than men withoutdaughters. Fifteen out of 22 (68.2%) males with daughters had undergone test-ing, as compared with only 6/17 (35.3%) of those without daughters (p < 0.1,two-sided). No such trend was found for females (p > 0.1).

Those who had not been in contact with us were younger (p < 0.05) and morefrequently male than female (p < 0.05) compared to those participating. Seventy-six of the 172 eligible FDR had not contacted us at the end of the study period.

Table III. Distribution of Testing According to Sex and Parental Status

Variable Declined test Accepted test (%) Total

Females children Without 1 16 (94.1) 17With children 3 33 (91.7) 36

Males children Without 7 4 (36.4) 11With children 10 16 (61.5) 26

Females daughters Without 2 24 (92.3) 26With daughters 2 24 (92.3) 26

Males daughters Without 11 6 (35.3) 17With daughters 7 15 (68.2) 22

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In that group there were 57/76 (75%) males. Thirty-five out of the 76 (46.1%)were under the age of 30. As mentioned before, we decided not to use our givenoption of violating privacy to determine whether or not the males who were not incontact with us had daughters.

Uptake of Mutational Testing

Of the 96 FDR who had contacted us by June 1, 2001, 74 (77.1%) hadreceived test results. Fifty-three (71.6%) were females and 21 (28.4%) were males.Twenty-two (29.7%) were mutation carriers. Three female subjects were affectedwith breast or ovarian cancers. All of them were mutation carriers. Overall (indexpersons and subjects), there were 28 females affected with either breast or ovariancancer. The mean age of onset of breast cancer was 44 years (median 43.5, range29–58). Mean age of onset of ovarian cancer was 51.4 years (median 53.5, range35–72).

DISCUSSION

Our results show that 81.5% of at-risk women aged 30 or more opted forgenetic testing within the time studied. These results were obtained without anyspecific intervention for the purpose of this study. The subjects had to take an activerole in contacting us; we did not approach them. We have previously reportedthat 97% of at-risk females over the age of 25 contacted us within a given timeand the families confirmed that the remaining 3% had been informed about ourhealth services (Levinet al., 2001). We concluded that “non–contact” reflected theindividuals’ informed decision. The combined conclusion is that the informationof the availability of genetic services reached all FDR and that most at-risk femalesopted for testing within short time.

Age was a significant determining factor for testing for the females. The twooldest age groups had a much higher uptake than the subjects under the age of30. Time will show whether the young females under the age of significant cancerrisk will choose genetic testing once they become older and need health services.Bieseckeret al. (2000) also found age to be an important predictor. Most otherreports studied did not look at the age distribution among their subjects.

There was a marked difference between our male and female subjects inchoosing genetic testing. Similar to other reports (Fosteret al., 2002; Julian-Reynieret al., 2000; Lermanet al., 1996), we observed a higher interest amongfemales than males for BRCA1 mutation testing. In contrast, gender was not animportant predictor in the study by Bieseckeret al.(2000). However, in that studytheir conclusion was based only upon those males actually participating; the maleswho did not respond on their invitation were not included.

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In this study only 23% of the total male population decided to learn theircarrier status. A possible trend was identified in those males choosing to be testedas we found that males with daughters may have a higher uptake of genetic testingthan those without daughters. Lodderet al. (2001) assessed males’ distress levelsduring genetic testing for hereditary breast and ovarian cancer mutations and foundthat males with daughters showed a higher degree of distress than those without.It is reasonable to conclude that males choose testing to help their daughters.DuDok de Witet al. (1996) suggested that males do not participate as readily asfemales in genetic testing for hereditary breast and ovarian cancers because (1) ofthe low risk of developing cancer for male mutation carriers and (2) they denythat this affects them. They saw that males tend to procrastinate testing. Thesefindings may suggest that males require additional time to establish contact andcontemplate their different options. It will be interesting to follow the males whohad not contacted us or had not chosen to have the mutation analysis to determine ifadditional time makes a difference regarding the decision to be tested. A long-termfollow-up study will allow us to address the additional questions such as: Will theycontact us/choose testing when they have children, when they have daughters orwill they wait until their children are adults, i.e., when their daughters start to haverisk? At that time, they may avoid the test all together and send their daughters fortesting instead. Our findings have led us to speculate that the males may advisetheir daughters to seek testing when they become adult, and are currently avoidingany unnecessary contact; thus, potentially avoiding stigmatization of their minordaughters.

Others have asked why women opt for genetic testing. Lermanet al. (1996)reported that their subjects, who were 67% females, answered that the most im-portant reason for testing was “to learn of my children’s risk.” Learning of theirchildren’s risk was also mentioned as one of the most important motivators forundergoing genetic testing by other studies, both in the Netherlands and in theUK (Fosteret al., 2002; Lodderet al., 1999). In our study we did not ask oursubjects questions about their motivation, but we did not see a difference in ge-netic testing rates for women with children (or daughters) as compared to thosewithout. We have above suggested that females need BRCA1 testing more thanmen do and that this may account for some of the differences in uptake. However,in Huntington disease, where the disease penetrance and expression are similarin both sexes, females still show a stronger interest in testing (Blochet al., 1989;Craufurdet al., 1989). It may be that males and females are, in general, different intheir genetic testing behavior. However, two studies looking at genetic testing forHNPCC (hereditary nonpolyposis colon cancer) did not show a gender difference(Aktan-Collanet al., 2000; Lermanet al., 1999). The latter was a large Finnishstudy, which did, however, comment that the largest group among thosenot par-ticipating in the study was men living alone whom had not previously participatedin any surveillance programs. The Finnish study looked at 446 individuals with

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a 50% risk of having a cancer predisposing gene. They found that 75% wantedgenetic testing. This is comparable to our results among our at-risk females, know-ing that in HNPCC, males and females have more similar cancer risks. Lermanet al.(1999) found a much lower participation rate (43%) in their study on genetictesting in HNPCC. It may be that the underlying factor is not gender, but rathercultural differences between the populations studied and methodological problemswhen comparing health care services with different acceptance/compliance in therespective populations.

It seems plausible that the reported discrepancies in genetic testing may reflectcomplex social and cultural differences. Study designs and settings are differentin Norway than, for example, in the USA (Bieseckeret al., 2000; Lermanet al.,1994, 1996). Genetic counseling, traveling, and genetic testing are mostly paidfor by the Norwegian government through the National Health Service. We havevery strict laws against genetic discrimination. As a result, economic concernsdo not usually prevent individuals from taking a genetic test. Norwegians are, ingeneral, confident in the Norwegian Health system and they believe that offersfrom hospitals and doctors are in the patients’ best interest. We do not breechtheir privacy in any way by contacting them, but we allow them to approach usfirst when they want to part-take in our services. This can give different resultsthan, for example, some of the studies where eligible subjects were contacted(Bieseckeret al., 2000; Lermanet al., 1996, 1999). Other European countries maybe more similar to Norway, both socially and economically. In addition, Norway’spopulation is more homogeneous than most other European countries. Most of theNorwegian families that participated in this study were old with well-establishedintrafamilial networks for communicating our offers of health care.

Practice Implications

The study was designed to address the question on whether or not informa-tion on health service reached the FDR to mutation carriers through our standardclinical practice. We found that information was disseminating and no support formodifying current privacy policy was found. A very high uptake of our health offerincluding genetic testing was documented in the targeted group adult women atrisk. Ameliorations of our routines to serve the target groups the best way possible,are the focus for our ongoing quality of life studies in kindreds at risk for inheritedcancers.

Because BRCA1 genetic testing of men is not an objective of it’s own, buta mean to reach their sisters and daughters, and because we decided to concludethe present report without obtaining full information of putative daughters to non-complying males, this report does not contain results to validate whether or notinformation to second degree female relatives through males are sufficiently ef-fective. This will be addressed in further studies.

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In sum, we will continue to inform the index patients that their relativesare welcomed to contact us without our making direct contact with relative. Wewill continue to focus on respecting their privacy. We will continue to make thecounseling sessions open discussions with each single patient, addressing what weactually know, what we do, why we do it, and results we have so far. In this waywe hope to maintain one of the highest compliances reported for activity like ours.

Future Directions

For the future, it would be interesting to evaluate whether the distance tothe nearest affected has an effect on uptake in genetic testing. We would predictthat the closer a subject is to an affected, either socially or biologically, the morelikely he or she would be to undergo testing. Social factors such as the familydynamics, communication styles, perception of their own risk would be expectedto be influenced by degree of contact with affected relatives.

Limitations to This Study

This material represents our first families. Although our activity by defi-nition was health service and not “research,” we were in media often denoted“researchers” and some families may have sought us to participate in “research.”This may have inadvertently led to some subjected being more enthusiastic andwilling to participate than others. Additionally, a general ascertainment bias mayexist in the study sample as families were initially ascertained because there weremultiple affected family members. Therefore, there is an increased awareness ofthe genetic risk as well as a bias towards wanting to participate in the research. Thehigh percent of test uptake may, therefore decrease with time and the relativelyhigh uptake among our target groups may not be representative of all Norwegianpopulations at risk.

The information regarding the number, ages, and genders of their nonattend-ing relatives is based upon the patients’ own accounts, and may theoretically bewrong. Our continuous work with the kindreds has verified that, in general, thegiven information is correct. Because we did not use our option of violating pri-vacy laws, we have no information on children to those who had not contacted us,unless their relatives provided the information.

CONCLUSION

In our patient population, women opt for testing when they need health ser-vices, and males when they have daughters who can benefit from test results. These

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empirical observations confirm that the families interpret the information given inaccordance with our intentions. Comparing our results with other reports, we arereluctant to claim our strategies alone leading to high compliance, variables asstudy design, as well as social and cultural factors in the population studied, maybe instrumental. We believe that uptake of genetic testing is neither static nor sta-ble, but will change both as our subjects grow older and develop and as our healthservices and knowledge improve, but also as our populations shift.

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Documents

Uptake of BRCA1 Genetic Testing in Adult Sisters and Daughters of Known Mutation Carriers in Norway