3. BENEFITS AND BURDENS OF MUTATION DETECTION

The commercial availability of a test does not assure its clinical utility. Indications for the use of a new test, like those for the use of a new drug, are best determined by clinical trials. Information on the impact of BRCA1 and BRCA2 testing on the testee is currently very limited (see Appendix IV). However, it is clear that both mutation detection and nondetection may confer both benefits and burdens on the individual.

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Potential benefits of a positive test result:

a. Benefits of DETECTING a mutation. Detecting a mutation can provide various benefits. An important benefit is the potential reduction in cancer morbidity and mortality. Such a reduction may be achievable by enhanced surveillance or by preventive measures in individuals with mutations. For breast cancer, surveillance strategies include breast self-examination, clinical examination by a health professional, and mammography at appropriate intervals. For women in the general population aged 50-69, annual mammography confers a 30% reduction in breast cancer mortality (Fletcher et al l993). Although a benefit for younger women in general has not been firmly established, it is encouraging that mammography appears to have a higher predictive value in women 40-49 years old with a first-degree relative with breast cancer than for women 50-59 years old with a negative family history (Kerlikowske et al 1993). Although the impact of mammography on the survival of women with BRCA1 or BRCA2 mutations is unknown, such women are generally advised to begin regular mammography between ages 25 and 35 (Burke et al 1997). For ovarian cancer, surveillance includes rectovaginal pelvic examination, serum CA-125 determination, and transvaginal ultrasonography at appropriate intervals (see Appendix VII). Unfortunately, these measures have not been shown to reduce ovarian cancer mortality in the general population (NIH Consensus Development Panel on Ovarian Cancer, 1995). In high-risk families, surveillance is of presumed, but not proven, benefit (Carlson et al 1994; see Appendix VII). Most recently, early evidence suggests that ovarian cancer risk may be significantly reduced in BRCA1/2 mutation carriers with sustained use of oral contraceptives (Narod et al 1998).

Strategies aimed at prevention may be surgical (e.g., prophylactic mastectomy; see Appendix II and/or prophylactic oophorectomy; see Appendix VIII) or chemical (e.g., tamoxifen prophylaxis; see Appendix I). Prophylactic mastectomy and prophylactic oophorectomy do not completely prevent cancer because they do not remove all cells of the target organ (Stefanek et al l995; Struewing et al l995c; Lopez et al l996). Chemoprevention in unaffected women is under active investigation. Recent evidence demonstrates a 45% decrease in breast cancer risk at short term follow-up for a high-risk group of women treated with tamoxifen (National Surgical Adjuvant Breast and Bowel Project Breast Cancer Prevention Trial P-01 - see summary on the National Cancer Institute homepage at http://www.nci.nih.gov). This study defined breast cancer risk using a modified Gail model (Gail 1989). Seventy percent of the women in the study had at least one first degree relative with breast cancer. However, the long-term efficacy of tamoxifen, and its influence on cancer prevention in carriers of mutations in BRCA1 and BRCA2 is as yet unknown. Potential benefits must be balanced against toxicity including menopausal symptoms in young women, and a risk, albeit small, of endometrial cancer and deep vein thrombosis. The findings of the NSABP Breast Cancer Prevention Trial highlight the importance of clinical trial research as an option for women at high risk for breast and ovarian cancer. Participation in prospective registries and randomized clinical trials should be encouraged and facilitated regardless of whether or not individuals choose to undergo genetic testing. One appropriate study in this setting is the NSABP P-02 breast cancer prevention trial comparing tamoxifen and raloxifene as chemopreventative agents for breast cancer, projected to open for accrual in early 1999.

Taken together, regarding morbidity and mortality reduction, the benefit of detecting a mutation may be greatest for a woman who is not already undergoing appropriate surveillance but who would be likely to begin appropriate surveillance or to choose prophylactic surgery if a mutation were detected. In future, another benefit of mutation detection may be the ability to tailor treatment regimens to patients with particular mutations.

Psychological benefits may also be important. Some may find the detection of a mutation valuable to resolve uncertainty about risk or to provide a needed explanation for one's personal or family history (Lerman et al 1996). An additional benefit is the opportunity to alert relatives to their possible risk. A frequently expressed reason to be tested is to determine whether children are at high risk although only adults are suitable candidates for testing (ASHG/ACMG 1995; NSGC 1995). Finally, some members of affected families are motivated to advance research and believe that knowing that they have a mutation allows them to make a contribution and/or benefit directly by participating in outcome or intervention studies.

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Potential burdens of a positive test result:

b. Burdens of DETECTING a mutation. Detection of a mutation may also confer burdens. These may include anxiety, intrusive thoughts, depression, lowered self-esteem, strained relationships with a partner, children, or other relatives, guilt about possible transmission to offspring, stigmatization, and discrimination by health or life insurers or by employers (Lerman 1994; Croyle et al 1997). There is even a risk that a young woman found to have a mutation may limit her life aspirations because of the expectation of succumbing to cancer. There is evidence that those requesting testing may represent a more psychologically vulnerable subgroup of those at risk (Lerman et al l994). Excessive anxiety about developing breast cancer can reduce adherence to recommendations for surveillance and impair the quality of life (Kash et al l992; Lerman et al l995).

Moreover, risks and costs of additional surveillance or prophylaxis may be incurred and may or may not be covered by third party payers. There is a concern that BRCA1 and/or BRCA2 mutation carriers may be more susceptible to even low levels of ionizing radiation such as those associated with routine mammography initiated at an earlier age (see Appendix V). This theoretical concern has not yet been studied. For these reasons, it is hoped that the use of X-ray related screening (mammography) in women at genetic risk can be replaced in the near future by methods employing non-ionizing radiation techniques such as ultrasound or magnetic resonance imaging.

It is unclear whether health insurers will cover the costs of counseling and testing for genetic susceptibility to cancer and, if a mutation is found, for increased surveillance or for prophylactic surgery. The perceived risk of discrimination by insurers is one of the most common reasons for declining testing (Lerman et al l996). Although legal protection against genetic discrimination is the intent of laws enacted or proposed in many jurisdictions, their efficacy is largely untested (Hudson et al l995; see Appendix XIV). While most legislation to date would prohibit companies from denying or dropping coverage for individuals carrying such genes (or to require genetic testing to determine eligibility), the possibility of premium adjustments or other loopholes (which may achieve the same result) are largely untested; in addition, there may be differences in protection between group and individual insurance policies.

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Potential benefits of a negative test result:

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Potential burdens of a negative test result:

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Potential burdens of an alteration of uncertain significance:

c. Consequences of NOT DETECTING a mutation.

Not detecting a mutation also may confer both benefits and burdens. Regarding benefits, if an affected relative has been shown to have a mutation, a negative result can provide reassurance that the testee's risk is similar to that of the general population and can result in the avoidance of unnecessary intensive surveillance or unnecessary prophylactic measures with their attendant risks and costs. It can also provide reassurance that no mutation of that gene has been transmitted to children.

Burdens of a negative result include survivor guilt (feeling undeserving of testing negative when other family members test positive) and the mistaken belief that the risk of breast or ovarian cancer is eliminated, resulting in neglect of recommended surveillance practices (Lerman 1994). Inappropriate reassurance is especially likely if no affected family member has been shown to have a mutation since the family may have a mutation in a gene not analyzed.

d. Burdens of detecting a variant of unknown significance. A significant fraction of abnormalities (as many as 30%) detected by DNA sequencing consist of missense mutations of unknown functional significance. Until their significance can be determined, the detected carrier may experience anxiety and frustration, but must continue intensive surveillance.