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Abstract

Two breast cancer susceptibility genes have been identified, BRCA1 and BRCA2, which when inherited in altered form, confer a substantially increased risk of breast and ovarian cancer. Genetic testing for mutations in the BRCA1 and BRCA2 genes is available to adult men and women at increased risk of carrying such a mutation based on their personal and/or family history of breast and/or ovarian cancer. Testing has profound implications not only for the individual being tested but for their entire family. It is therefore important that the psychosocial and ethical issues are explored through genetic counseling to ensure individuals make informed decisions about testing. Genetic testing may impact on psychological wellbeing, decisions regarding cancer risk management, childbearing and the wider family. Individuals who test positive for a mutation may face ethical dilemmas regarding childbearing and when and how to inform relatives of the genetic information. Female carriers will also face complex and challenging decisions concerning cancer risk management.

Keywords

breast and ovarian cancer ethical issues genetic testing psychosocial impact

In the UK, approximately one in nine women develop breast cancer at some stage during their lifetime [101]. Most of these cancers occur sporadically and are most likely to be caused by a complex interaction between environmental, lifestyle and genetic risk factors. Age is the strongest risk factor, the risk increasing with age, and the majority of breast cancers occur in postmenopausal women.

A family history of breast cancer is a significant risk factor. The risk of breast cancer increases with the number of affected relatives and a younger age at diagnosis [101]. It is thought that clustering of breast cancer in families is mainly due to an inherited genetic susceptibility [1]. It has been estimated that 5–10% of breast cancer cases are caused by dominantly inherited mutations that confer a significantly increased risk of breast cancer [2,3]. So far, two highly penetrant susceptibility genes, BRCA1 and BRCA2, have been identified [4,5]. Mutations in either of these genes significantly increase the risk of breast and ovarian cancer, and moderately increase the risk of some other types of cancer. BRCA1 and BRCA2 mutations are rare but are the most important cause of breast cancer among high-risk families in which there are four or more cases of breast cancer among blood relatives [1,101]. BRCA1 and BRCA2 mutations do not account for all high-risk families so it is possible that other highly penetrant gene(s) remain to be identified. The majority of families with a history of breast cancer have fewer cases, and it has been suggested that many interacting susceptibility genes, each of small effect, may be responsible for the increased risk in these families. A mutation in a gene known as CHEK2 has been shown to be a low-penetrance mutation that increases the risk of breast cancer by approximately twofold in individuals who do not have a BRCA1 or BRCA2 mutation [6]. Other low-penetrant susceptibility genes remain to be identified.

Breast and ovarian cancer susceptibility is also associated with a number of rare hereditary cancer syndromes for which the susceptibility genes have been identified, including Li Fraumeni syndrome, Cowden syndrome, Peutz–Jegers syndrome and hereditary nonpolyposis colorectal cancer (HNPCC). However, mutations in the susceptibility genes for these cancer syndromes are rare causes of breast and ovarian cancer.

This review will focus on hereditary breast and ovarian cancer due to mutations in the BRCA1 and BRCA2 genes. Genetic testing to identify mutations in these genes has been available since the mid-1990s in the UK. This review will discuss the psychosocial and ethical issues relating to testing and the dilemmas faced by individuals undertaking this testing.

Hereditary breast & ovarian cancer due to mutations in BRCA1 & BRCA2 genes

Mutations in either the BRCA1 or BRCA2 genes are associated with bilateral and early onset breast cancer [101]. Families with a history of multiple cases of breast cancer, usually with some cases of early onset breast cancer or with breast and ovarian cancer, or with bilateral breast cancer, and/or cases of male breast cancer, are associated with an increased likelihood of a BRCA1 or BRCA2 mutation [101]. Women of Ashkenazi Jewish ancestry have a 5–10-times increased chance of having a BRCA1 or BRCA2 mutation compared with women with no Ashkenazi Jewish ancestry, due to the presence of three highly prevalent founder BRCA1 and BRCA2 mutations (one BRCA1 and two BRCA2 mutations) [101]. These three mutations together may account for approximately 25% of early onset breast cancer and 60% of early onset familial breast cancer among Ashkenazi Jewish women [7]. Probability models have been developed to estimate the chance of identifying a BRCA1 or BRCA2 mutation in an individual or family. A discussion of these models is beyond the scope of this paper, but a good review has been carried out by Sifri and colleagues [8].

Mutations in the BRCA1 and BRCA2 genes are inherited in an autosomal dominant manner such that a person with a mutation has a 50:50 chance of passing the mutation on to each of their children.

BRCA1 and BRCA2 gene mutations are highly penetrant in women, which means that a high proportion of females carrying a germ-line BRCA1 or BRCA2 gene mutation will develop breast and/or ovarian cancer. There is evidence to suggest that different mutations may be associated with different risks of cancer [1]. In addition, it is evident that disease penetrance of the same mutation varies between individuals, suggesting that it is likely that other genetic, environmental and lifestyle factors modify the penetrance of mutations [102]. The exact cancer risks associated with BRCA1 and BRCA2 mutations remain uncertain, but a range of cancer risks has been estimated from high-risk families and population-based studies [1]. The estimates from population-based studies generally tend to be lower than those from high-risk families. Based on estimates from both types of studies, female carriers of BRCA1 mutations have a 60–70% risk of developing breast cancer by the age of 70 years and up to a 40% risk of developing ovarian cancer by the age of 70 years [1]. Female carriers of BRCA2 mutations have a 45–85% risk of developing breast cancer by the age of 70 years and a 11–25% risk of developing ovarian cancer by the age of 70 years [1]. Female BRCA1 or BRCA2 mutation carriers have an increased risk of early onset breast cancer such that the risk of breast cancer by 40 years of age in BRCA1 mutation carriers is up to 20% and up to 10% in BRCA2 mutation carriers [1]. There is evidence that the risks of certain other cancers, such as pancreatic and fallopian tube cancer, are moderately increased in female carriers of BRCA1 or BRCA2 mutations [1]. The risk of breast cancer in male BRCA1 mutation carriers is not significantly increased over that in the general population, but male carriers of BRCA2 mutations have a 5–7% lifetime risk of breast cancer [9]. Male BRCA2 carriers have been shown to have a significantly increased risk of prostate cancer. Current evidence suggests that the risk of prostate cancer in male BRCA1 mutation carriers may only be slightly increased, if at all. This requires further investigation. There are smaller increases in risks of other cancers, such as pancreatic cancer, in male BRCA1 and BRCA2 mutation carriers [1].

Genetic testing for mutations in the BRCA1 & BRCA2 genes

In the UK, genetic testing for mutations in the BRCA1 and BRCA2 genes is only offered to at-risk adults (where there is a strong family history of breast and/or ovarian cancer) and is usually undertaken by regional genetic centers. Based on guidelines developed by the UK Clinical Genetics Society, testing for BRCA1 and BRCA2 mutations in childhood is not recommended [10]. It is generally agreed among the clinical genetics community that children should not be tested for breast and ovarian cancer susceptibility as there is no significant risk of cancer in childhood in BRCA1 and BRCA2 mutation carriers, and therefore there is no medical benefit to be obtained from testing during childhood. From an ethical point of view, it is argued that childhood testing for adult-onset diseases is not appropriate since it removes the child's future autonomy and right ‘not to know’ and may result in the child being labeled, stigmatized or discriminated against [11]. Fundamentally, the child's best interests must be paramount when a decision is being made regarding genetic testing, which includes taking into account both the medical and psychosocial benefits.

Two different types of genetic tests are offered to at-risk adults; diagnostic tests are offered to affected individuals in families where the mutation is unknown, and predictive tests are offered to at-risk relatives once the disease-causing mutation has been identified within the family.

Diagnostic genetic testing

In the UK, based on current NICE guidelines [101], individuals who have had breast and/or ovarian cancer from families in which there is a 20% or greater chance of finding a BRCA1 or BRCA2 mutation, should be offered diagnostic genetic testing. Unaffected individuals from these high-risk families are not usually offered testing for a disease-causing mutation. This is because the test is likely to be more informative for affected individuals, since they are more likely to carry the mutation if one is present in the family. This means that some eligible families will not be able to have genetic testing, as they do not have any living or consenting relatives with breast and/or ovarian cancer. This can be very difficult for some families to accept. If the family has Ashkenazi Jewish ancestry and there are no living or consenting affected relatives, an unaffected individual can be tested for the three common founder mutations. In other countries, such as The Netherlands and the USA, individuals without a personal history of cancer who are members of a high-risk family where the mutation is unknown are offered testing. However, in this situation the mutation screen is more likely to be uninformative and the detection of a variant of unknown clinical significance is also more difficult to interpret.

The interpretation of the results from diagnostic testing is complicated, as the mutation screening methods currently used are not able to detect all potential mutations and since there are hundreds of variants in the BRCA1 and BRCA2 genes, many of which have not been proven to be disease causing [12]. The three possible outcomes from BRCA1 and BRCA2 diagnostic genetic testing are: a negative result, which is when a mutation is not detected; an inconclusive result, which is when a BRCA1 or BRCA2 gene variant of unknown clinical significance is detected; or a positive result, which is when a pathogenic (disease-causing) mutation is detected [102]. A negative result does not provide much information regarding the cause of the cancer in the individual or their family. It could mean that the individual has a BRCA1 or BRCA2 mutation that was not detected by the mutation screening method, that the individual has a mutation in another cancer susceptibility gene(s), or that the cancer is due to nongenetic risk factors. A person receiving a negative result is recommended to continue with a screening protocol based on the family history. An inconclusive result occurs when a BRCA1 or BRCA2 variant is identified but it is not known whether it is a cancer-predisposing variant or a common polymorphism. This may need to be followed up by tests on the tumor and/or tests on other members of the family to see whether the variant segregates with cancer in the family. This type of result does not exclude the possibility of a genetic susceptibility to cancer in the family and surveillance would be recommended based on the family history. A negative or inconclusive result in an affected person leaves them with no less uncertainty than they had before testing. It is important to prepare people for this possible outcome. A positive result in an affected individual suggests that their cancer was most likely due to an inherited BRCA1 or BRCA2 mutation. It means that they have an increased risk of contralateral breast cancer (second primary breast cancer) and an increased risk of primary ovarian cancer. Receiving a positive BRCA1 or BRCA2 mutation result at the time of diagnosis of breast cancer has been shown to influence treatment and surgical decisions [13,14]. A positive result has implications for the wider family, since it means that first-degree relatives have a 50% chance of being carriers of the mutation.

Predictive genetic testing

The identification of a pathogenic BRCA1 or BRCA2 gene mutation in an individual means that their adult relatives, either affected or unaffected, who are at risk of carrying the mutation, can be offered a predictive genetic test. The test is straightforward and involves examining for the presence or absence of the specific familial BRCA1 or BRCA2 mutation. A negative result from a predictive test means that the individual does not have the known familial mutation. Women with breast cancer in such families are sometimes found not to carry the familial mutation, which suggests that other genetic and/or environmental risk factors are responsible for causing their cancer. This result can be confusing for the individual and poses counseling difficulties with regard to future cancer risks and treatment. Women who test negative for the familial mutation are considered to be at population risk of developing breast cancer, although one recent study has suggested that these women may have a slightly increased residual risk [15]. Under current guidelines, unaffected women testing negative for a familial mutation are not offered any extra breast or ovarian screening. Women who receive a positive result from a predictive test have inherited the familial mutation and are at significantly increased risk of breast and ovarian cancer (see section for cancer risks associated with BRCA1 and BRCA2 mutations).

Informed consent & BRCA1 & BRCA2 genetic testing

Genetic counseling is considered an essential part of genetic testing for BRCA1 and BRCA2 mutations to ensure informed consent, which is fundamental to any genetic testing process [101]. The ethical principle of informed consent states that an individual must make a fully informed, autonomous decision regarding genetic testing that is free from coercion and reflects their beliefs and values [16]. In order for people to make this informed and autonomous decision, the pretest counseling consultation should involve an in-depth discussion of the advantages and disadvantages of genetic testing. This includes providing detailed information about the genetics of hereditary breast and ovarian cancer, the cancer risks associated with BRCA1 and BRCA2 mutations, the individual's risk of carrying a BRCA1 or BRCA2 gene mutation, the technical limitations of the mutation screen, the timescale of the test results, and the risks, benefits and limitations of the cancer risk-management options. The psychosocial and ethical issues should also be thoroughly explored, including the potential for psychological distress during the waiting period for the test result, the psychological impact of the test result, the impact of the genetic information on risk management and reproductive decisions, the impact of results on the family, the dissemination of the test result to family members, and the potential for insurance and employment discrimination [17].

Psychological impact of genetic testing for BRCA1 & BRCA2 mutations

Ethically, it is important to ensure that the benefits of genetic testing for BRCA1 and BRCA2 mutations outweigh any potential harm, such as psychological morbidity. Genetic testing can be psychologically demanding due to the complexity and uncertainty of the information and the potential impact on future health status for the individual and their family. Women and their partners may experience increased anxiety and distress during the waiting period for test results. The results from one study suggest that a longer time frame for results may be associated with increased anxiety [18]. This is an important issue to discuss during pretest counseling. The timescale for results varies between centers, with some taking up to 1 year. The psychological consequences of predictive genetic testing have been widely investigated (see Table 1 for a summary of the studies). Two systematic reviews of the studies assessing the short-term psychological impact of predictive testing conclude that overall, there appear to be no adverse psychological outcomes in individuals who undergo predictive genetic testing [18,19]. The majority of studies found that the level of distress, anxiety or depression in most carriers was not significantly increased after disclosure of their positive result. These studies suggest that noncarriers experience psychological benefits after disclosure of results, such as significant relief [18,19]. Although these studies are reassuring, the results are limited since they have only assessed the short-term psychological impact of genetic testing. A large study involving nine UK genetic centers assessed the psychological outcomes in men and women during the first year after predictive testing [20]. In this study, many female carriers, in particular younger carriers (<50 years), experienced increased levels of cancer-related worry and distress during the first month post-testing, which returned to pretest baseline levels by 12 months. This study suggests that female carriers, especially younger carriers, do not benefit psychologically from genetic testing. In this study, noncarriers experienced an immediate decrease in cancer-related worry compared with pretest baseline levels, which was sustained throughout the 12 months post-testing. Noncarriers therefore appeared to benefit psychologically from testing, which is consistent with findings from other studies [18,19]. Male carriers and noncarriers did not experience increased mental health problems following genetic testing. A small qualitative study of Australian women who had undergone predictive testing (time range from 1 month to 5 years) found that most initially experienced a short-lived negative emotional response, such as distress and guilt, to both positive and negative results [21]. In contrast to the UK multicenter study [20], most female carriers in this study reported both physical and emotional advantages following the initial negative response, suggesting that they benefited psychologically from knowing their carrier status. However, the results from this study may not be representative of women in other countries. Results from a prospective study in Scandinavia also suggest that both carriers and noncarriers benefit psychologically from testing [22]. This study reported decreased levels of anxiety up to 1 year following predictive testing in both carriers and noncarriers. Some studies have identified factors that may make women more vulnerable to short- and long-term adverse psychological outcomes after disclosure of a positive mutation result. These include younger age (<50 years) at testing [20], trait anxiety [23], first to be tested in the family [24], the only carrier among siblings [24], having lost a relative to breast and/or ovarian cancer, poor communication within the family and higher perception of cancer risk [25]. Women who may be more vulnerable to negative psychological outcomes after testing may need extra psychological support during pretest counseling and after testing. Family factors, such as carrier status of siblings, have also been shown to influence the levels of distress in male carriers and noncarriers after disclosure of test results [26]. In conclusion, data emerging from these studies seem to suggest that predictive genetic testing for BRCA1 and BRCA2 gene mutations does not have a long-term negative psychological impact on male or female carriers or noncarriers, but it remains controversial whether carriers gain any psychological benefits from testing.

Table 1.

Summary of studies investigating the psychological impact of genetic testing for BRCA1 and BRCA2 mutations.

Study	Findings	Conclusions	Ref.
Review of 15 papers assessing the short-term psychological impact of predictive testing for Huntington's disease, hereditary breast and ovarian cancer, familial adenomatous polyposis and spinocerebellar ataxia	No increased distress in carriers or noncarriers at any time 12 months post-result disclosurePretest emotional state predictive of post-test distress not test result	Predictive genetic testing does not appear to have an adverse psychological impact	[18]
Review of four prospective studies investigating psychological outcomes of genetic testing for BRCA1 and BRCA2 in high-risk women. Studies conducted between 1997 and 2002 in the USA, Europe and Australia	No significant increases in depression or anxiety in carriers post-disclosure of test resultCarriers experienced significant reductions in distress and relief	No adverse psychological outcomes after genetic testing for carriers and noncarriersNoncarriers benefit psychologically from testingWomen who undergo testing but decline result may be at increased risk of adverse psychological outcomes	[19]
Assessed psychological outcome in adults undergoing predictive genetic testing for BRCA1 and BRCA2 from nine UK genetic centers from 1996–2000. Self-report questionnaires were completed at baseline and 1, 4 and 12 months post-disclosure of test result	Some carriers, especially younger women (<50 years), experienced increased levels of cancer-related worry at 1 month post-result disclosure, which returned to pretest baseline levels Female noncarriers experienced significant reductions in cancer-related worry and general mental health post-testing	Carriers, particularly younger women, do not appear to benefit psychologically from testing Younger women (<50 years) carriers are the most vulnerable and experience increased psychological distress in the short term post-result disclosure Genetic testing had no adverse impact on general mental health in men	[20]
Interviewed 47 unaffected women who had undergone genetic testing for BRCA1 and BRCA2 and received results between 1 month and 5 years ago	Many carriers and noncarriers reported a high level of emotional turmoil such as shock, distress, guilt and relief in the short term post-result disclosureMany carriers and noncarriers reported long-term physical and emotional advantages to testing	Carriers and noncarriers may experience emotional turmoil initially but appear to benefit psychologically in the long term from genetic testing	[21]
Assessed anxiety and depression among unaffected women during the first year following predictive testing for BRCA1 and BRCA2 and colon cancer genes	Both carriers and noncarriers experienced decreased levels of anxiety at 1 year post-testingLevels of depression increased slightly in noncarriers Levels of depression decreased in carriers	Predictive genetic testing for cancer susceptibility genes does not appear to cause adverse psychological consequences in individuals who receive pre- and post-test counseling and support	[22]

Studies investigating the psychological impact of diagnostic genetic testing in women with breast and/or ovarian cancer suggest that testing may potentially cause negative psychological reactions in those who are found to be carriers [27 –29]. The psychological impact of testing around the time of breast cancer diagnosis requires further investigation. There is concern that genetic testing at this time may be overwhelming and provoke increased stress [30].

Anticipated reaction to results

It is important to explore an individuals' anticipated emotional response to the different possible test results during pretest counseling, as it is hoped this will help with psychological adjustment to the information provided by the test result. Exploring how a person may respond to the results may also help them decide whether or not it is the right time for them to have the test.

It is important to explore coping strategies for dealing with genetic risk and uncertainty surrounding risk status [103]. Although a positive mutation result provides more definitive information regarding breast and ovarian cancer risks, uncertainty remains concerning when, or even if, a carrier will develop cancer. Often, one of the motivations for testing is to relieve uncertainty, so it is important that individuals understand that there is an element of uncertainty with all possible results. A negative result from predictive testing in an unaffected individual provides the most relief from uncertainty. However, there is controversy over the risk of breast cancer for individuals with a negative predictive test result. It is important to help people think through how they may cope with the uncertainty associated with negative or inconclusive results from diagnostic testing, since these results do not provide any new information about their cancer risk status. The complexity and uncertainty of the information may provoke confusion, frustration and anxiety [31,103]. An individuals' ability to understand and cope with this information may be mainly determined by psychological processes [26]. A person's motivation for testing may influence how they cope with a negative or inconclusive result. For example, women with cancer who undergo a diagnostic test in order to provide genetic information for future generations, which is often the case, may feel frustrated and guilty about a negative or inconclusive result.

It is important to explore how people may feel about the impact of the result on the whole family. Both carriers and noncarriers may experience feelings of guilt and regret after disclosure of test results. It has been shown that many male and female carriers feel guilty about the possibility of passing the BRCA1 or BRCA2 mutation on to their children, especially their daughters [32].

People who have tested negative may experience ‘survivor’ guilt, where they feel guilty about their relief when other family members have been found to be carriers. Some carriers and noncarriers may feel regret about decisions they made in the past [103]. Another area to explore is how people may cope with the responsibility of informing other family members about their test result, since this can be distressing. It is also important to explore how they may deal with family members' reactions to the information.

It may be helpful to explain that an individual may initially experience negative emotional responses, such as guilt, regret and an increase in cancer-related worry following disclosure of either a positive or a negative result, and that these responses are likely to be short-lived.

Impact of test result on life decisions: cancer risk management & reproductive choices

One of the major benefits of genetic testing for BRCA1 and BRCA2 mutations is to provide women with more definitive information about their cancer risks in order for them to make more informed decisions regarding risk-management options and other life decisions, such as future childbearing. During pretest counseling it is therefore important to explore how the test result may influence these decisions.

Cancer risk management

An individual's perception of their risk and understanding of the result has been shown to influence decisions concerning risk management [31]. It is therefore important to ensure that an individual understands their cancer risks and the implications of the result for themselves and their families so that informed choices can be made [20].

A woman receiving a negative result from a predictive test is believed to be at the population risk for breast and ovarian cancer, and will therefore not be offered any extra screening. These women are eligible to join the National Breast Screening program at 50 years of age. It is important to explore how a woman may feel about discontinuing extra screening, and to ensure that she does not misunderstand the meaning of a negative result. Negative or inconclusive results from diagnostic testing may be misinterpreted due to the complexity of the information and this may lead to inappropriate medical management, not only for the individual, but for their entire family [32].

Women who are found to be BRCA1 or BRCA2 mutation carriers face challenging decisions regarding cancer risk management. Currently, the options available to female carriers are either strategies to detect cancers at an early stage, such as regular screening of the breasts and ovaries and breast self-examination, or preventative measures such as breast and/or ovarian prophylactic surgery, chemoprevention and lifestyle modification. Each of these options has limitations and risks [33].

Currently, there is no breast cancer screening program available for male carriers of BRCA1 and BRCA2 mutations, since they do not have enough breast tissue, and they are therefore encouraged to examine their own breasts. A multicenter study (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening for prostate cancer in BRCA1 and BRCA2 carriers [IMPACT]) has just been initiated to investigate the effectiveness of prostate cancer screening by the prostate-specific antigen (PSA) test for detecting early cancers in mutation carriers [34]. Male carriers of BRCA1 and BRCA2 mutations are eligible to join this study.

Strategies aimed at early cancer detection Breast screening

Current recommendations in the UK are for BRCA1 and BRCA2 mutation carriers to undergo annual breast screening by X-ray mammography [101]. The age at which breast screening is commenced in mutation carriers is usually individualized according to breast density, but it is not usually started before the age of 30 years in the UK. Guidelines for women at moderately increased risk are that screening should commence at 40 years of age due to the reduced sensitivity of mammography at a younger age. The aim of cancer screening programs is to detect cancers at an early stage in order to influence prognosis and increase the chance of survival. However, the efficacy of X-ray mammography in BRCA1 and BRCA2 mutation carriers is questionable. There is evidence that the sensitivity of mammography is decreased in carriers, particularly BRCA1 mutation carriers, compared with noncarrier controls [33,35 –37]. The reduced sensitivity may be partly due to BRCA1 and BRCA2 mutation carriers being more likely to develop breast cancer at a young age when the breast tissue is denser, which makes the interpretation of mammograms less reliable. In addition, BRCA1 mutation carriers, in particular, are more likely to develop high-grade, rapidly developing cancers, which are harder to detect at an early stage [38]. Several studies have demonstrated that magnetic resonance imaging (MRI) of the breast is more sensitive for cancer detection than mammography [33,35 –37,39]. The findings from the MRI for Breast cancer Study (MARIBS) in the UK indicate that MRI in combination with mammography would be the most effective screening method for BRCA1 and BRCA2 mutation carriers and other high-risk women [36]. However, in the UK, MRI is not yet available as a screening option from the National Health Service, although NICE is currently reviewing the evidence in order to advise whether or not MRI should be introduced for BRCA1 and BRCA2 carriers and other high-risk women. MRI is already available to BRCA mutation carriers in the USA and The Netherlands [40,41].

Ovarian screening

Current recommendations in the UK are that ovarian screening by transvaginal ultrasound (TVU) and cancer antigen (CA)-125 measurement should only be available to BRCA mutation carriers as part of a research study, as the efficacy of this screening strategy remains in doubt [101]. Annual ovarian screening has been found to be ineffective at detecting ovarian cancer at an early stage in high-risk women and has not been proven to reduce mortality [33,42]. However, more frequent screening, such as every 6 months, may be more effective and this is currently being investigated. In the USA and elsewhere, ovarian screening is available to female carriers not wishing or yet ready to have an oophorectomy, from 30–35 years of age onwards [43]. In the UK, a prospective, multicenter familial ovarian cancer screening study (UK-Familial Ovarian Cancer Screening Study [UK-FOCSS]) is currently underway to assess the sensitivity of TVU and serum CA-125 levels and to develop an optimal ovarian screening protocol in high-risk women [44].

Psychosocial implications of screening

As well as understanding the limitations of the current breast and ovarian screening strategies, it is essential that female carriers consider the psychosocial implications of screening so that they can make informed decisions regarding management. Clearly, the lack of effective screening protocols may bring an emotional burden on BRCA mutation carriers. An important issue to consider is that screening will not be available during pregnancy and breastfeeding, which may induce anxiety during this period [45]. Reassuringly, evidence from studies investigating the psychological impact of breast screening suggests that it does not have a negative psychological impact among high-risk women and BRCA mutation carriers. The Dutch MRI SCreening (MRISC) study has assessed the psychological impact of annual imaging by both MRI and mammography among high-risk women and BRCA mutation carriers [46,47]. This study concluded that breast screening does not adversely impact on generic health-related quality of life (QoL) in the short term [47] and does not cause psychological distress over time [46]. This study confirmed previous findings that subgroups of women, such as younger women (<40 years) and excessive breast self-examiners, have higher levels of breast cancer and general distress during screening. The findings of a systematic review of seven studies investigating the psychological consequences of screening in high-risk women suggest that mammographic screening does not induce high levels of anxiety among this group [48].

The level of participation and long-term compliance with regular screening among BRCA1 and BRCA2 mutation carriers is an important issue, since the overall aim of testing is to reduce morbidity and mortality from breast and ovarian cancer through the uptake of risk-management programs. However, this issue has not been widely investigated. A UK multicenter study reported changes in screening behavior in the expected direction, with significantly more carriers undertaking screening than noncarriers, who showed a reduction in risk management post-testing [20]. In this study, 92% of carriers compared with 30% of noncarriers had undergone mammography by 12 months after predictive genetic testing [20]. Of note, uptake of screening did not appear to reduce cancer-related worry at 1 year after testing.

Preventative measures

Prophylactic surgery

Prophylactic bilateral mastectomy (removal of healthy breasts) and prophylactic bilateral salpingo–oophorectomy (removal of healthy fallopian tubes and ovaries) are the most effective ways of reducing breast and ovarian cancer risk. Bilateral prophylactic mastectomy reduces the risk of breast cancer in BRCA1 and BRCA2 mutation carriers by up to approximately 90% [49]. Premenopausal prophylactic salpingo–oophorectomy (which can be performed laparoscopically as day surgery) reduces the risk of ovarian cancer by 85–95% and the risk of breast cancer by approximately 50% in carriers [50]. It also reduces the risk of further contalateral and ipsilateral breast cancers in carriers who have had a primary breast cancer [51]. A small study has demonstrated that BRCA1 and BRCA2 carriers who developed breast cancer after a bilateral oophorectomy were more likely to have smaller, lower-grade tumors, which are associated with a better prognosis, compared with carriers who had not had an oophorectomy [52]. Women who have undergone bilateral salpingo–oophorectomy remain at risk of primary peritoneal cancer.

Issues impacting on decision making around prophylactic surgery

Despite the effectiveness of prophylactic surgery, it is a radical option. The uncertainty around cancer risks, the different surgical options, the surgical risks and the psychosocial implications of surgery make the decision to opt for these procedures very complex. Female carriers considering surgery are faced with making a decision to remove their healthy breasts and/or ovaries irreversibly, based on a probability, rather than a certainty, of developing cancer. In addition, it is difficult to give confident individualized cancer risks, although it is evident that the disease penetrance of mutations is variable [102]. As with any procedure, there are surgical risks and complications associated with prophylactic mastectomy and oophorectomy, and these need to be taken into consideration. There is a 0.5–1% risk of significant complications such as infection, hemorrhage and bowel or bladder damage with oophorectomy [44].

There are a number of different surgical options both for a mastectomy and an oophorectomy, each with different pros and cons, which further complicates the decision-making process. In the UK, female mutation carriers considering prophylactic mastectomy and/or oophorectomy have the opportunity to discuss each procedure and the potential risks and complications with the relevant surgeon, including plastic surgeons, as appropriate [101]. The breast surgeon would discuss the advantages and disadvantages of a total bilateral mastectomy with or without breast reconstruction or subcutaneous mastectomy and the types of breast reconstruction. It is important to consider that there may be substantial waiting lists for breast reconstruction and this may influence surgical decisions.

The different surgical options for an oophorectomy include a bilateral salpingo–oophorectomy or an abdominal hysterectomy with bilateral salpingo–oophorectomy. Surgery in premenopausal carriers will induce a premature menopause, which may cause various physical effects, such as hot flushes and sexual dysfunction. These symptoms can be alleviated by hormone replacement therapy (HRT). Premenopausal carriers will therefore need to consider the risks and benefits of HRT use and the impact of surgical decisions on HRT options. Although there has been concern regarding the safety of HRT use in BRCA1 and BRCA2 carriers with respect to breast cancer risks, evidence from a recent study suggests that at least short-term use of HRT in BRCA1 and BRCA2 carriers after a premenopausal oophorectomy does not alter the reduction in breast cancer risk conferred by this surgery [53]. It remains controversial whether the benefits of having a hysterectomy at the same time as an oophorectomy outweigh the disadvantage of the slightly higher morbidity associated with this procedure. Carriers who are contemplating this surgery are faced with making a complex decision regarding the type of surgical procedure while balancing the pros and cons of different HRT options [54].

These issues would be discussed with the gynecologist. The timing of prophylactic surgery is obviously a crucial factor in the decision-making process, particularly when considering prophylactic oophorectomy. For women contemplating an oophorectomy, childbearing decisions are of obvious importance and women will wish to complete their family before having the procedure. The risk of ovarian cancer in carriers tends to be in women over the age of 40 years, which makes it easier to defer surgery until this time. In BRCA2 carriers, surgery can reasonably be left until close to the menopause. However, the increasing tendency for women to delay starting their families may complicate these decisions.

Psychosocial impact of prophylactic surgery

A major consideration with prophylactic surgery is the potential psychosocial impact on a woman's feelings of femininity, body image, sexual and physical attractiveness, self-esteem and intimate relationships. Interestingly, most studies to date have found that the majority of women who had undergone prophylactic mastectomy or ooophorectomy showed either no change or a decrease in cancer-related worry and psychosocial morbidity, such as body image and sexuality problems postsurgery [55 –62]. Most of these studies have also demonstrated that the majority of women were satisfied with their decision to have surgery. However, a multicenter study in the UK found that the levels of cancer-related worry and avoidant or intrusive thoughts were not reduced 12 months after surgery in BRCA1 and BRCA2 mutation carriers [20]. Negative feelings about sexual attractiveness, sexual relationships and body image have been reported after testing in carriers in a small number of studies [25,57]. All of these studies have been small and therefore the results need to be interpreted with caution. Further studies are needed to assess the long-term impact of prophylactic surgery on psychosocial issues, levels of distress and cancer-related worry.

In many genetic centers in the UK, mutation carriers have the opportunity to explore their motivations for surgery, the psychosocial issues, the potential emotional impact on them and their family, and the impact on their future QoL as a result of undertaking such surgery, with a psychologist.

Uptake of prophylactic surgery

Balancing the significant reduction in breast and ovarian cancer risk against the potential psychosocial impact, physical effects and surgical risks is a challenging process.

The uptake of prophylactic surgery among BRCA1 and BRCA2 carriers and high-risk women varies between countries and hospitals and is thus influenced by social, cultural, ethnic and religious background, and the opinion of advisors and close relatives [20,62,63]. The uptake may also be influenced by psychological factors such as level of cancer-related worry, experience of cancer in the family [26] and timing of testing, for instance at the time of diagnosis [13,14]. One study has reported higher rates of contralateral mastectomy among women who find out that they are BRCA1 or BRCA2 mutation carriers at the time of diagnosis of a primary unilateral breast cancer compared with women with the same diagnosis who subsequently became aware of their mutation status [64]. In a study across nine UK genetic centers, 28% of carriers underwent prophylactic bilateral mastectomy and 31% underwent oophorectomy within 12 months of predictive testing [20].

Lifestyle modification

It remains unclear whether known risk factors for sporadic breast cancer such as parity, breastfeeding, age at menopause, oral contraceptive (OC) use, alcohol consumption and body mass index modify the breast cancer risk in BRCA1 and BRCA2 mutation carriers [1,101]. The effects of some of these risk factors in BRCA1 and BRCA2 carriers have been investigated in small studies, and therefore any associations need to be confirmed. For some risk factors, such as OC use, conflicting associations have been reported [65,66]. One study showed a potential increased risk of breast cancer in BRCA1 carriers under the age of 40 years who used OCs [65]. Another study found no evidence to suggest that OC use increases the risk of early onset breast cancer in BRCA1 and BRCA2 carriers, and suggested that OC use may reduce the risk of breast cancer for BRCA1 carriers [66]. These conflicting results may make it difficult for BRCA carriers to make a decision about taking OCs. In addition, BRCA carriers will need to balance this against the evidence that OC use reduces the risk of ovarian cancer in BRCA1 and BRCA2 carriers by 50% if taken for 5 years [67]. In the UK, the NICE guidelines recommend that OCs should not be taken primarily to reduce the risk of ovarian cancer [101].

There is evidence that breastfeeding for up to 1 year or more reduces the risk of breast cancer in BRCA1 mutation carriers, but not BRCA2 mutation carriers [68]. Using this information may raise anxiety, since BRCA carriers will be faced with balancing the benefits of breastfeeding against the problems with obtaining breast cancer screening while breastfeeding.

Until the modifying effects of these risk factors are established, specific changes in lifestyle are not recommended apart from encouraging generally healthy living such as exercise and healthy eating.

Chemoprevention

Tamoxifen, which is a nonsteroidal antiestrogen that targets the estrogen receptor (ER) in the breast, is an established treatment for sporadic ER-positive breast cancers in the general population. There is evidence that tamoxifen may decrease the risk of contralateral breast cancer in affected BRCA1 and BRCA2 mutation carriers by up to 50% [69]. Prophylactic use of tamoxifen from the age of 35 years has been shown to reduce the incidence of breast cancer among healthy BRCA2 mutation carriers, but not healthy BRCA1 mutation carriers [70]. In the UK, tamoxifen is not licensed for prophylactic use in unaffected women [101]. In other countries, it is offered as a chemoprevention option among high-risk women. There is evidence that tamoxifen is associated with an increased risk of endometrial cancer and venous thromboembolic events [33]. Other drugs, such as selenium, are currently being investigated for chemoprevention in BRCA carriers [33].

Reproductive choices

Male and female BRCA1 and BRCA2 mutation carriers may be faced with difficult decisions regarding future childbearing. Carriers have a 50% chance of passing the mutation on to each of their children. The options available to carriers who decide that they do not want to pass on the mutation are: to remain childless; possibly to adopt children; to try for gamete donation or to go for a natural pregnancy with or without prenatal diagnosis (PND). Another option is pre-implantation genetic diagnosis (PGD); however, this is not yet available in the UK, but is under consideration for public debate.

PND for BRCA1 and BRCA2 mutations involves testing fetal tissue (DNA) collected either by chorionic villus sampling or amniocentesis for the known BRCA1 and BRCA2 mutation. If the fetus has inherited the BRCA mutation, the option of pregnancy termination is available. Although PND for BRCA1 and BRCA2 mutations is technically and legally possible, it raises ethical dilemmas for couples considering this option. Mutations in BRCA1 and BRCA2 confer an increased risk of cancer in adulthood and, therefore, people with BRCA mutations can live healthily for many years and some will never be affected, due to the incomplete penetrance of mutations. The cancers are also amenable to preventative and treatment options that are likely to improve over the years. The demand for PND by BRCA1 and BRCA2 carriers in the UK is unknown, but from anecdotal reports from different genetic centers, it appears to be low. It is important to support couples through this complex decision-making process.

PGD, which involves genetically testing embryos before implantation, is an alternative to PND. Ethical concerns have been raised regarding the use of PGD for hereditary breast and ovarian cancer and it is currently a matter of debate [11]. PGD involves using in vitro fertilization to produce embryos that are then screened for a specific disease-causing mutations at the eight-cell stage, and only embryos (usually up to two) that do not have the mutation are replaced into the woman's womb. Centers that offer PGD in the UK are regulated by the Human Fertilization and Embryology Authority (HFEA), which adheres to the Human Fertilization and Embryology Act (1990) [104]. A license from the HFEA is required for each genetic disease for which PGD will be offered. The HFEA have developed an ethical framework for considering new applications and granting licenses. So far, approximately 50 different genetic conditions have been licensed. Heritable breast and ovarian cancer is different from the other conditions already licensed, as it has a lower disease penetrance, a later onset of disease and preventative measures, and successful treatments are available. The HFEA launched a discussion paper in November 2005 to assess the views of the public on PGD for BRCA1 and BRCA2 mutations [104]. A team at University College (London, UK) has also sent a questionnaire to female BRCA1 and BRCA2 mutation carriers to find out their views concerning the possible option of PGD [71]. Experts within the field have argued that PGD for BRCA1 and BRCA2 gene mutations will give individuals the opportunity to end the increased cancer burden in their family for future generations. PGD for BRCA1 and BRCA2 has been offered in other European countries and the USA [11,71]. The decision of whether or not to license PGD for BRCA1 and BRCA2 mutations is likely to be made by the HFEA in 2006.

Communication of results to family members

Genetic testing for BRCA1 and BRCA2 has profound implications not only for the client but for the entire family whose cancer risks may be altered by the result. Once a BRCA mutation has been identified in a family member, at-risk relatives have the opportunity to determine their carrier status through genetic testing. This enables at-risk relatives to gain a better understanding of their cancer risks and make informed decisions regarding cancer risk management and reproduction. However, the process of communicating relevant genetic information to the wider family is ethically complex, and with whom the responsibility for this lies is a matter of a debate.

Ethically, the extended family have a ‘right to know’ about significant genetic information that may affect their future health. However, the relatives' right to privacy and their right ‘not to know’ unsolicited genetic information needs to be respected. In general, health professionals do not directly contact their clients' at-risk relatives unless they have already requested genetic counseling, due to the importance of maintaining the confidentiality between them and their client and their client's right to privacy, which are core ethical principles that underpin genetic testing [11,72]. The individual undergoing testing has therefore been given the moral responsibility for disseminating genetic test results to their relatives. However, from an ethical point of view the family member may not be the most appropriate person, since the relatives' right to make an autonomous decision regarding how to use the information may be compromised as they feel pressurized by the family member to undergo genetic testing. Once a genetic test result is given, clients are encouraged to share the result with their relatives, particularly if a mutation has been identified, since this will enable at-risk relatives to undergo predictive testing. It is clear from studies, however, that being the ‘messenger’ can be a burden and that communication within families is a complex and problematic process that is not always effective [21,28,72 –77]. Several studies have demonstrated that the majority of female and male participants have informed their first-degree relatives (parents, siblings and children) of their test results, irrespective of the nature of the result [62,73,75,76]. However, it has been demonstrated that individuals who are found to be mutation carriers are more likely to inform their relatives than those with a negative or inconclusive result [73 –75]. Dissemination of information to second- and third-degree relatives (e.g., aunts, uncles, cousins and grandchildren) has been shown to occur less often and to be more difficult [62,73,77]. The main barrier to informing more distant relatives was found to be a lack of a close relationship and/or not being in contact with a relative [72,74]. These studies have revealed that there are many personal and family factors that influence the pattern and extent of disclosure of test results to family members. These include the client's understanding and perception of the risk, their distress and sense of burden of being a ‘messenger’, their fear of giving bad news and upsetting a relative, their carrier status, the gender of the client and the relative, the client's coping mechanism, the client's perceived support from relatives, their motive for being tested, their degree of closeness to relatives, and difficult relationships and family conflict [21,28,72 –77]. During pretest counseling, it is important to thoroughly explore family relationships, the communication patterns among relatives and the potential impact of test results on family members, in order to try to identify any potential barriers to communication [17].

It is clear from these studies that nondisclosure of results to relatives is a common occurrence and it can be argued that this could cause serious harm. It is therefore important that a more effective approach for disseminating genetic information to the wider family is developed. This is a matter of debate within the field of clinical genetics. The role and responsibility of the geneticist in this process is controversial. Geneticists are faced with the ethical dilemma of respecting the confidentiality and privacy of their client and their duty to warn at-risk relatives of genetic information that may have significant medical and psychological consequences, while maintaining the relatives' right to privacy and autonomy. Developing an approach that balances the rights of all family members that are affected by a mutation result is challenging. To address this issue, it has been suggested that during counseling, clients should be helped to develop the skills and resources to communicate the information effectively to their family [72,78]. Alternatively, a team from Belgium has suggested that a more direct approach should be adopted by geneticists. They propose that a geneticist should ask a BRCA1 or BRCA2 mutation carrier for permission to send a letter to their at-risk relatives [77]. However, this may violate the relatives' right to privacy and ‘right not to know’. There is the potential that the unsolicited information may not be desirable and may have adverse psychological consequences. The South Australian Familial Cancer Service (Eastwood, Australia) has carried out such a study, whereby they obtained consent from the client to directly inform their at-risk relatives by letter that genetic testing was available [78] This group concluded that a proactive approach by genetic services to disseminating relevant genetic information to relatives who are not their clients can occur without violating the principles of privacy and autonomy [78]. Another approach that has been proposed is for a broad familial view to be adopted by geneticists, which would allow geneticists to inform the family. However, his approach is ethically problematic [79]. This issue remains unresolved.

Genetic discrimination

The potential of unfair discrimination against unaffected BRCA1 or BRCA2 mutation carriers in insurance applications or employment must be discussed during pretest counseling. Concerns over genetic discrimination may influence an individual's decision to undergo predictive testing. This is of much less concern to affected individuals, who will already be paying increased premiums.

In the UK, the Association of British Insurers (ABI) and the government have agreed a moratorium on the use of genetic test results by insurance companies until November 2011 [11,105]. The ABI has developed a code of practice which stipulates that insurers will not ask customers to undergo genetic testing or to disclose predictive genetic test results that become available after a policy has started or to disclose a family member's test result [105]. The moratorium applies to life-insurance policies of up to GB£500,000, critical-illness policies of up to GB£300,000 or income-protection policies of up to GB£30,000/annum [105]. This means that insurance companies cannot ask customers to disclose the results of predictive tests for policies up to these financial limits, and it is estimated that 97% of customers are within these limits [105]. For life-insurance, critical-illness and income-protection policies beyond these limits, insurers can use genetic test results, but only if the test has been approved by the UK Genetics And Insurance Committee (GAIC). To date, the GAIC has only approved the use of predictive genetic test results for Huntington's disease for underwriting life insurance policies of over GB£500,000. The ABI are planning to submit an application to GAIC by the end of 2006 for the use of BRCA1 and BRCA2 genetic test results for life-insurance and critical-illness cover over the set financial limits [105]. One of the roles of the GAIC is to monitor the insurance industry to ensure companies comply with the moratorium and the ABI code of practice.

It is important that clients understand the insurance issues surrounding testing and that they are aware of the uncertainty concerning the future of the moratorium and the ABI code of practice beyond 2011. The ABI code of practice may become part of UK legislation or the moratorium may be extended or abandoned. Given the moratorium, it is concerning that a recent study reported that 20% of female carriers experienced insurance discrimination in the first year after testing [20].

Conclusion

Genetic testing for BRCA1 and BRCA2 gene mutations raises many psychosocial and ethical issues. These, as well as the pros and cons of testing, should be explored during pretest genetic counseling to ensure an individual makes an informed and autonomous decision to be tested. The overall goal of genetic testing is to reduce morbidity and mortality through appropriate cancer risk management.

Genetic testing has the potential to cause psychological morbidity. However, studies so far suggest that predictive genetic testing for BRCA1 and BRCA2 mutations does not have a negative psychological impact in the long term. Various personal and family factors that may make a person more vulnerable to adverse psychological reactions after testing, including younger age at testing, level of emotional distress before testing, carrier status of other family members, and the order of testing in the family. Diagnostic genetic testing (i.e., testing individuals with breast and/or ovarian cancer for the presence of a BRCA mutation) may cause short- and long-term psychological morbidity.

Breast screening by X-ray mammography is less sensitive in younger female BRCA1 or BRCA2 mutation carriers than in women in the general population over the age of 50 years. Ovarian screening has not been proven to be effective at detecting cancers at an early enough stage to influence prognosis and is therefore only offered on a research basis. The only preventative options are prophylactic bilateral mastectomy, which reduces the risk of breast cancer by approximately 95%, and bilateral premenopausal oophorectomy, which reduces the risk of ovarian cancer by 90% and the risk of breast cancer by approximately 50%. Individuals contemplating surgery are faced with balancing the significant reduction in breast and ovarian cancer risks against the potential psychosocial impact of irreversibly removing healthy breasts and ovaries. In several studies, most carriers reported no change or a decrease in psychosocial morbidity after prophylactic surgery. However, in another study, cancer-related worry remained high after surgery.

Individuals who test positive for a BRCA1 or BRCA2 mutation may face ethical dilemmas regarding future childbearing. A carrier has a 50% chance of passing their mutation on to each of their children. PND is technically and legally possible. However, PND for an adult-onset condition with incomplete penetrance, which is amenable to treatment raises serious dilemmas, and uptake appears to be low. PGD is an alternative, although as it is not available as yet for BRCA1 or BRCA2 mutations in the UK, but is currently being considered for this application.

The impact of genetic testing on the whole family is a major consideration when undertaking testing, since after the disclosure of test results, individuals will be faced with the moral obligation of informing their relatives of the result. Some carriers may find being the ‘messenger’ a burden and distressing. Communication of test results to the family can be difficult and complicated, and there are many barriers to effective communication.

Individuals need to consider the potential for genetic discrimination, in particular insurance discrimination. In the UK, a moratorium on the use of genetic test results by insurance companies has been agreed between the government and the ABI until 2011. Insurance discrimination should therefore not be a problem in the UK, although the issue will re-emerge in 2011 when the moratorium comes to an end.

Future perspective

Over the next 5–10 years, our understanding of hereditary breast and ovarian cancer due to BRCA1 and BRCA2 mutations will expand. Further research is needed to identify the modifying effects of other gene variants and lifestyle/environmental factors on the risk of breast and ovarian cancer in BRCA carriers, and to improve our understanding of the disease penetrance of different BRCA1 and BRCA2 mutations. With these advances it may be possible to provide individuals with more personalized cancer risks on which to base cancer risk-management decisions. Research should also improve options for cancer risk management. It is hoped MRI will replace mammography screening for BRCA mutation carriers, which will hopefully lead to a reduction in morbidity and mortality from these cancers. It is also possible that other preventative strategies, such as chemoprevention, will be discovered as an alternative to prophylactic surgery. Improved risk-management options may mean that female carriers are not faced with such complex and challenging decisions. Recently, a study of the effects of carboplatin in BRCA mutation carriers with metastatic disease has been initiated, and research into this and targeted cancer therapies may also allow drugs to be developed which are more effective for treating cancer in BRCA mutation carriers, predicated on the specific sensitivities of cells with these mutations.

The sensitivity of mutation screening methods will continue to improve with technological advances and more rapid methods of determining the clinical significance of gene variants may be developed, which will remove some of the uncertainty associated with diagnostic genetic testing.

Executive summary

Inherited susceptibility to breast & ovarian cancer

Only 5–10% of breast cancer cases are due to dominantly inherited mutations in highly penetrant genes; others are multifactorial.

BRCA1 mutation carriers: females have a 60–70% risk of breast cancer and up to 40% risk of ovarian cancer by the age of 70 years. The risk of breast cancer in male carriers is not significantly increased but they may have smaller increases in other cancers, such as pancreatic cancer.

BRCA2 mutation carriers: females have a 45–85% risk of breast cancer and a 11–25% risk of ovarian cancer by 70 years. Males have a 5–7% lifetime risk of breast cancer and a significantly increased risk of prostate cancers.

BRCA1 and BRCA2 mutations: carriers have a 50% chance of passing the mutation onto their children.

Diagnostic genetic testing for BRCA1 & BRCA2 mutations

Available to adults with breast and/or ovarian cancer and who have a 20% or greater chance of carrying a BRCA1 and/or BRCA2 gene mutation based on their personal and/or family history.

Predictive genetic testing for BRCA1 & BRCA2 mutations

Once a mutation has been identified in a family, at-risk adult family members can be offered carrier testing.

Implications of test results: diagnostic genetic testing

Negative result: no mutation identified

Inconclusive result: a variant of unknown clinical significance has been identified

Positive result: a pathogenic mutation has been identified.

Implications of test results: predictive genetic testing

Positive result: the individual has inherited the familial mutation and has an increased risk of breast and ovarian cancer.

Negative result: the individual has not inherited the familial mutation and their risk of breast and ovarian cancer may be the same or only slightly above that for the general population.

Informed consent & genetic counseling prior to genetic testing

The ethical principal of informed consent underpins any genetic testing process. Pretest genetic counseling, which should involve exploring the pros and cons of testing and the psychosocial and ethical issues, is essential to ensure informed consent.

Psychosocial & ethical issues relating to genetic testing

Genetic testing has profound implications not only for the individual being tested, but for their entire family.

Testing may provoke increased distress, increased cancer-related worry, depression, guilt, confusion, regret and frustration. Most studies have found that predictive testing does not cause adverse psychological outcomes. However, some carriers may experience increased psychological morbidity after predictive testing that is likely to be short lived. Noncarriers seem to benefit psychologically from testing. Diagnostic testing may also cause short- and long-term psychological morbidity.

Impact on cancer risk management

One of the main benefits of testing is to enable mutation carriers to make more informed decisions about cancer risk-management options. X-ray mammography has been shown to be less sensitive in BRCA carriers than in the general population, and ovarian screening has not been proven to be effective at detecting cancers at an early enough stage to influence prognosis. Prophylactic mastectomy and oophorectomy significantly reduce the risk of breast and ovarian cancer. Most studies suggest that prophylactic surgery does not cause adverse psychosocial outcomes, at least in the short term.

Impact on reproductive decisions

Testing may influence childbearing decisions. Prenatal diagnosis for BRCA1 or BRCA2 mutations is available. Preimplantation genetic diagnosis is an alternative. It is not yet available for BRCA1 and BRCA2 mutations in the UK, but may be in the future.

Impact on family

Genetic testing has implications for the whole family and the individual undertaking testing has the moral responsibility of informing their relatives of their test result. However, being the ‘messenger’ may be difficult and ineffective.

Impact of testing on genetic discrimination

Before undertaking genetic testing, it is important that individuals understand the potential for unfair discrimination based on their genetic status, in particular insurance discrimination. In the UK, a moratorium on the use of genetic test results by insurance companies has been agreed until 2011.

Public awareness regarding genetic testing for BRCA1 and BRCA2 genes is likely to grow. In parallel, the demand for PND for BRCA1 and BRCA2 mutations may also increase. It is possible that PGD for BRCA1 and BRCA2 mutations will be approved by the HFEA.

With these advancements in mutation screening techniques, improved understanding of cancer risks and improved management options, the psychosocial implications of testing may be lessened. However, the implications of testing for the family will always remain. There may be a shift in clinical genetic practice whereby it is acceptable for geneticists to contact relatives directly, but this approach needs to balance the confidentiality of the patient with the relatives ‘right to know’ or ‘right not to know’.

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Psychosocial and Ethical Issues Relating to Genetic Testing for BRCA1 and BRCA2 Breast Cancer Susceptibility Genes

Abstract

Keywords

Hereditary breast & ovarian cancer due to mutations in BRCA1 & BRCA2 genes

Genetic testing for mutations in the BRCA1 & BRCA2 genes

Diagnostic genetic testing

Predictive genetic testing

Informed consent & BRCA1 & BRCA2 genetic testing

Psychological impact of genetic testing for BRCA1 & BRCA2 mutations

Anticipated reaction to results

Impact of test result on life decisions: cancer risk management & reproductive choices

Cancer risk management

Strategies aimed at early cancer detection Breast screening

Ovarian screening

Psychosocial implications of screening

Preventative measures

Prophylactic surgery

Issues impacting on decision making around prophylactic surgery

Psychosocial impact of prophylactic surgery

Uptake of prophylactic surgery

Lifestyle modification

Chemoprevention

Reproductive choices

Communication of results to family members

Genetic discrimination

Conclusion

Future perspective

References