Public Health Aspects of Breast Cancer Gene Testing in Canada
Part 2: Selection for and Effects of Testing

J Mark Elwood

Abstract

Criteria set by clinical services for referral for counselling and genetic testing are variable and often arbitrary. Empirical data and computer models are available to estimate the probability of being a mutation carrier, based on family and personal history. Surveys show that high proportions of women at risk of cancer and of women in the general population are interested in being tested, but this may be based on inflated perceptions of personal risk and limitations in understanding of the tests used and their implications. A high proportion of women with a positive family history have a greatly overestimated perception of their own risk, and even expert counselling has little impact on this. This risk perception may produce psychological distress and may reduce participation in screening programs. Counselling, while improving understanding, may also have little impact on prior interest in being tested. Interest in being tested relates to a wish to assess the risk for children, and hazards include potential health insurance discrimination. Testing may result in a reduction of psychological disturbance in those shown to be non-carriers, with little change in those shown to be carriers, but unwillingness to be tested may be related to psychological distress. The impact of publicity concerning genetic testing on perceptions of risk and on psychological disturbance, and the subsequent impact of counselling and intervention, require further assessment.

Key words: attitude to health; breast neoplasms; decision making; genetic counselling; genetic screening; ovarian tumours; risk

Introduction

This is the second of three related papers; the methods are described in the first.^1,2 The use of genetic markers to identify families and individuals at high risk of breast cancer involves many scientific, ethical and economic issues.^3-5 It has been widely accepted that families with a history suggesting a BRCA1 or BRCA2 mutation should be tested within a research protocol and encouraged to participate in intervention and prevention trials.^6-8

Testing for genetic susceptibility has many limitations. Knowledge of carrier status could lead to psychosocial harm and altered family relationships. Genetic testing has limitations in sensitivity and specificity.⁹ A negative result may be due to the limitations of the test, and a positive result may be due to a variation in gene structure that is not related to disease risk. The existence of many relevant genes and mutations with variable risk implications, the difficulty in interpreting results in small families, problems in communicating the results well, the uncertainty of benefit from most management options, the costs of testing, counselling and follow-up and the possible impacts on insurance and employment all have to be considered.

Selection Criteria for Genetic Testing

Most clinics have defined criteria for genetic testing, which are based, explicitly or intuitively, on the prior probability of identifying a gene mutation.¹⁰ Thus, subjects who are in families that show multiple cancer cases, a young age at incidence or combinations of cancers, such as breast and ovarian cancers, are likely to be eligible. There are several estimates of the probability of finding a relevant mutation given a certain personal and family history.^9,11-14 Many authorities have suggested a 10% prior probability as a useful cut-off; for the BRCA genes this would mean testing families with two or more breast cancer cases under age 50 or two or more ovarian cancer cases under age 60; a threshold of 50% would include only families with at least four cases of breast cancer and one of ovarian cancer.¹⁵ These estimates relate to selecting for gene testing from an already selected group: those who have sought counselling and assessment on the basis of their family and personal history. The criteria for this first level of referral from the general population also require attention.

Computer Models of Prior Probabilities

Several models have been developed to estimate prior probabilities of carrying a BRCA gene, most of them using Bayes' theorem. The logic behind one well-described model will be given as an example. Berry et al.¹⁶ computed likelihood ratios for being a carrier of BRCA1 based on the observed family history. For a given family history H, the probability of being a gene carrier, P(M | H), is given by P(M | H) = LR / (LR + O), where LR is the likelihood ratio based on the family history and O is the prior odds against being a gene carrier.

Given the prevalence of the carrier state as 0.0012,¹⁷ O is (1- 0.0012) / 0.0012 = 832. The LR is taken from data on observed cancer risks with and without the gene. For a subject with breast cancer at age x, the LR is the ratio of the cumulative risk of breast cancer by age x in BRCA1 carriers to the risk in the general population. For an unaffected subject, the LR is the ratio of the probabilities of not being affected (1 - cumulative risk) in gene carriers and in the general population.

These ratios can be developed for a range of personal and family histories, and the probability of being a BRCA1 carrier can be calculated. If gene testing is done, the probabilities of carrying the gene are then estimated again, taking into account the sensitivity and specificity of the test. The model has been extended to include BRCA2 and is being used in a randomized trial to compare the use of the model's results with standard printed material in counselling.¹⁸

Other predictive models are available.¹⁹ These prior probabilities depend on data from multicase families; as noted in Part 1,¹ penetrance estimates based on representative series of cases from the population are considerably lower, and future models will need to allow for this.

Interest in Genetic Testing in Various Groups

Relatives of Cancer Patients

In a US telephone survey of women who were unaffected first-degree relatives of patients with breast or ovarian cancer,²⁰ 75% stated that they would "definitely want to be tested" and 20% said they would "probably want to be tested" after being given information about the BRCA1 gene. Interest in testing was positively related to perceived risk. Women did not understand that a negative test did not exclude the possibility of being at high risk, despite having been informed that only 5% of all breast and ovarian cancers are linked to the BRCA1 gene. These authors commented on barriers to adequate informed consent: most individuals overestimate their personal risk of severe events such as cancer occurrence, have difficulty making a decision based on probability and may be unable to process the information they receive because of stress and anxiety.

In a similar study of 105 women aged 30S75 who were unaffected first-degree relatives of patients with breast or ovarian cancer, de Silva et al.²¹ showed that 91% wanted to be tested. The most common reason given was to assess their children's risk. Most women expected that a positive test result would give them increased anxiety, depression and a reduced quality of life, and 72% felt that a negative result would not prevent anxiety. Another survey of 238 women with a first-degree relative with breast or ovarian cancer concentrated on consent issues: only 57% thought that written consent was necessary before results were given to the immediate family, but most (87%) thought that written consent was needed before results were given to insurers or employers.²² Lerman et al.²³ summarized the situation, concluding that over 90% of women with a family history of breast or ovarian cancer want to be tested, but that this interest is linked to a "grossly overestimated sense of personal risk, heightened breast cancer anxiety, and misunderstanding of the benefits, limitations, and risks of genetic testing."

General Population

Tambor et al.²⁴ surveyed 473 women over age 50 in a health maintenance organization in the US in 1994/95, using a telephone interview; the response rate was 53%. In all, 10% of these women had a mother or sister with breast cancer, 51% had heard of the breast cancer gene and 69% were interested in being tested, an interest that was greater in women who were younger, white, more educated, more affluent and supportive of mammography. However, there was no exploration of what benefits were assumed to come from the test, and what actions would result. Some older studies using general population samples have also shown levels of interest of over 80% in testing for genetic susceptibility to breast²⁵ or colon cancer.^26,27

Relation Between Interest in Testing and Participation

A high level of interest in testing does not, of course, mean an equivalent demand in actuality. In a study noted earlier,²³ 50% of first-degree relatives of breast cancer patients gave blood samples for testing, whereas over 80% had given affirmative answers to questions on wanting to be tested. Past experience with Huntington's disease (a more complex situation, as there is no preventive action that can be taken) showed that over 60% of relatives expressed interest in testing, compared with less than 15% who later underwent testing.²⁸

Risk Perception and the Effects of Counselling and Gene Testing

Risk Perception

Understanding personal risk is a complex area, and major problems arise when individuals need to make important decisions based on their understanding of risk. For example, it has been pointed out that a woman who is told that she has a 1 in 4 risk of developing breast cancer may consider herself to be at lesser risk if her sister had been given that diagnosis, believing her sister to be the unlucky one.²⁹ Most testing centres stress the need for prior information on the limitations as well as potential benefits of testing and the need for adequate informed consent. The content and organization of consent forms vary greatly.³⁰

There have been several excellent studies carried out in the US, including randomized trials, which relate to the evaluation of very intensive one-on-one counselling by experts (reviewed later). Studies are also needed on less intensive and less direct methods of providing information, for example by mail or telephone or through family physicians. There is little information on whether the concerns of anxious subjects who do not meet the criteria for referral are adequately dealt with. The socio-behavioural issues involved in genetic counselling and genetic testing have been reviewed in a Canadian context,³¹ and a report on communicating risk with regard to familial cancer has been produced in British Columbia.³²

Women's perceptions of their risk of breast cancer may vary considerably from the reality. In the United States, a study of 145 women aged 40S50 with no personal history of breast cancer compared respondents' estimate of their 10-year risk of breast cancer with that calculated from the predictive model developed by Gail et al.³³ The respondents overestimated their risk of death from breast cancer by more than 20 times and greatly overestimated the reduction conferred by screening.³⁴ In another study of women identified as first-degree relatives of breast cancer patients, over three quarters of women aged under 30 thought they were likely to develop breast cancer, and one third of women at all ages had breast cancer worries that impaired their daily functioning. Although half of the women aged 35S39 had undergone mammography within the previous year, psychological distress was associated with a reduction in the use of mammography and with both infrequent and excessive use of breast self-examination.³⁵

In another US study, 75% of women with a first-degree relative affected believed that their risk of breast cancer was "higher or much higher" than the risk among other women, while the other 25% believed that their risk was the same or lower. Heightened awareness of breast cancer risk was associated with a higher educational level.³⁶ In a study evaluating breast cancer risk counselling for high-risk women, the women most likely to participate were those aged 40S49, those who had greater levels of education, those who were married and those who perceived their risk as high and were worried about it. The factors influencing participation differed between women with higher and lower levels of education, and the authors suggested that recruitment strategies need to be tailored to the women's educational levels.³⁷

In a US study of 672 twin sisters of women with breast cancer diagnoses³⁸ (mean age 63 years), 35% thought their risk of getting breast cancer some time in their life was the same as among other women, 10% thought it was less, 51% thought it was somewhat or much higher and 4% thought it was "almost inevitable."

Effects of Counselling on Risk Perception and Behaviour

Studies have shown that women with family members affected by breast cancer who show increased levels of anxiety are less likely to participate in screening, both in the US and the UK.^29,35,39 One study reported that 27% of such women had a level of psychological distress consistent with the need for counselling.⁴⁰ The same authors⁴¹ found that barriers to screening included lack of knowledge, erroneous beliefs about breast cancer and, most important, anxiety and emotional stress. They recommended counselling designed to deal with such barriers, and reported positive results in reducing perception of risk and increasing adherence to screening recommendations in a small pilot study; a randomized trial is planned.

Lerman et al.⁴² performed a randomized trial of psychological counselling in high-risk breast cancer patients (Table 1). This study involved 200 women aged 35 and older with a history of breast cancer in a first-degree relative. At recruitment, around 65% of subjects greatly overestimated their own breast cancer risk. Women were randomly assigned to participate in either a general health counselling program (the comparison group) or a specific program involving a 1.5-hour counselling session with a trained nurse educator, which dealt with the provision of individualized risks according to the Gail et al. model,³³ stressed the uncertainty of these risk data and provided both absolute and relative risks. The results showed a technically significant improvement in risk comprehension due primarily to a move of women in the counselled group from overestimation to accurate estimation; however, the counselling made no substantial impact on the two thirds of all women who greatly overestimated their risk at the beginning of the study. Thus, this study shows that, among women with a family history of breast cancer, the majority have a greatly exaggerated estimate of their own risk, and this is not substantially modified even by a thorough and detailed counselling session by a trained educator.

A somewhat different result has been reported from the United Kingdom⁴³ in a study of women referred to a family history clinic. The questions are posed in terms of lifetime risk expressed as odds, whereas it would be more appropriate to present risks related to the current age of the individuals. The results suggest that, whereas a quarter of women substantially underestimated their risk initially, a quarter substantially overestimated it, and that the counselling system used at the clinic improved personal risk assessment when re-evaluated at a one-year follow-up.

Most of the published work relates to counselling by experts and in centres of excellence. Expert counsellors cannot be available for all subjects who seek advice. The attitudes of women at risk, physicians and nurse practitioners to different information and consent issues vary considerably.⁴⁴ A survey of 98 high-risk women showed that more preferred pre-test information to be given by a genetic counsellor than by an oncologist, with the opposite result for post-test counselling.⁴⁵ The appropriate role of others, such as family physicians, who may be able to deal with many more subjects, needs to be further explored. The effectiveness of their counselling, ways in which it could be optimized and the development of effective support materials are all important topics. Approaches to these issues include group therapy⁴⁶ and interactive computer programs.⁴⁷ The issues of exchange of information within families are complex. In a Minnesota study of 544 high-risk breast cancer families,⁴⁸ nearly all first-degree relatives of probands knew of the positive family history before notification, but only 74% of second-degree relatives and 46% of third-degree or more distant relatives knew about it. Small proportions of subjects had concerns about confidentiality issues or about participating in a family genetic study.

Effects of Counselling on Choice of Genetic Testing

Lerman et al.²³ conducted a randomized trial among 400 women who had a first-degree relative with breast or ovarian cancer, to compare the effects of an educational approach with an educational/counselling approach on the women's decision to use genetic testing. Both interventions were substantial and personal: the educational approach involved a 45S60-minute individual session, and the educational/counselling approach used a 75S90-minute session with a trained oncology nurse or a genetic counsellor supervisor. Both interventions increased knowledge, and the counselling approach improved understanding of the limitations and the risks of testing; but neither affected the choice itself: 52% of subjects provided a blood sample for testing, a proportion that was similar to intent before intervention and not affected by either intervention. These participants were at generally low risk: 80% had only one first-degree relative with breast cancer. The main objective of this study was to use counselling to produce a more balanced view of the risks and limitations of genetic testing and so to reduce the demand for testing. In this objective, the counselling failed. The authors concluded that the counselling process may only reinforce and validate the subjects' prior intentions, as has been noted in other contexts, such as bone marrow transplantation. In this study, a blood sample was more likely to be provided for testing the stronger the family history was, but there was no effect of strength of family history on the results of counselling. The effects of counselling were reduced among African-Americans.

Consequences of Gene Testing

In a further study, Lerman et al.⁴⁹ offered genetic counselling and BRCA1 testing to 279 members of 13 previously identified BRCA1 carrier families in the US and Canada. Overall, 43% participated fully and requested results; 31% declined any involvement in the study; and the rest (26%) took part in the interviews and counselling but did not want results. Of those given results, 46% were BRCA1 carriers. The desire to be tested increased with strength of family history, knowledge about the test and having health insurance; sex and education were not significant. The main reason for testing (92%) was to assess children's risk; 34% gave possible loss of health insurance as a major risk of testing. Between baseline and one month, those identified by testing as carriers showed no increase in psychological morbidity, assessed in terms of depression, role impairment or sexual impairment, whereas non-carriers showed significant decreases in all these. After testing, 17% of carriers planned prophylactic mastectomy and 33%, prophylactic oophorectomy. In an extension to the study with 327 male and female family members and six months' follow-up,⁵⁰ among those with high baseline levels of stress, depression rates fell in non-carriers, did not change in carriers, but increased in those who declined testing.

This study suggests that gene testing has psychological and quality-of-life benefits for those who test negative and no detriments for those who test positive. It was based on subjects who were already known to be members of multicase, BRCA1 carrier families, who would have had a very high prior level of knowledge and likely anxiety about their situation. Nine women tested had already had prophylactic mastectomy, and 15 had had prophylactic oophorectomy, of whom five and four, respectively, were carriers. The applicability of these results more widely is doubtful. Subjects with a much weaker family history or even those with a strong family history who have not been alerted and informed of the family situation may have a much lower prior level of anxiety, and therefore have less to gain and more to lose from the results of testing. It is important that studies like this are carried out in other contexts.

A four-year study of the behavioural and psychological effects of testing has been started in a large Utah kindred with BRCA1 carriers.⁵¹ Frequent screening for breast, ovarian and colon cancers is advised, and information is given on prophylactic surgery and involvement in prevention trials. Of the first 170 subjects counselled, 92% requested testing. Short-term results showed higher distress levels in carriers than non-carriers after testing, particularly in carriers with no personal cancer history.⁵²

In a study of members of high-risk families who received BRCA1 results,⁵³ 78 tested positive; of these, over one third reported sadness, anger or guilt, 35% considered prophylactic mastectomy and 76% prophylactic oophorectomy as options. Of 100 subjects who tested negative, 80% felt emotional relief. For all subjects, concerns about the risks to children and about surveillance and prevention were the main reasons for testing; 25% were concerned about discrimination in insurance.

Discussion

Different expert groups vary considerably in their criteria for genetic testing and for referral to expert counselling. There are few data on the potential numbers of subjects or families who would meet these different criteria. The different criteria used should be compared and monitored, along with data on outcome. Criteria for appropriate referral to different levels of service provision need to be developed and assessed; for example, referral processes from the community to family physicians have been little studied. There is a high level of interest in testing among the public, often not closely related to actual risk, and there is evidence from randomized trials that the desire for testing, once set, may be little changed by further information.

The literature reviewed here suggests that some women, perhaps a high proportion, who have an increased risk of breast cancer due to a family history will have a greatly exaggerated impression of their absolute risk, and randomized trials suggest that expert counselling may have little effect on these perceptions. The high perception of risk may result in substantial psychological disturbance, which may reduce participation in early diagnosis programs. This implies that publicity given to genetic factors conferring very high risks could have some detrimental effects, and reinforces the importance of evaluating the consequences of publicity and screening procedures. Good randomized trials are being carried out on the effects of expert counselling at leading referral centres, although there is little work on the effects of counselling by less intensive or skilled methods at the community or family physician level.

Acknowledgements

This paper is based on a report prepared initially for the Cancer Bureau, Laboratory Centre for Disease Control, Health Canada, under contract 502-8082 and project 502-0205.

Personal acknowledgments are noted in the first paper in this series of three.

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Author Reference
J Mark Elwood, Department of Preventive and Social Medicine, University of Otago, PO Box 913, Dunedin, New Zealand; Fax: 64-3-4797164;
E-mail: melwood@gandalf.otago.ac.nz

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