Estimates are that as many as 10 percent of breast cancer cases are hereditary and are primarily the result of BRCA1 or BRCA2 gene mutations. In this issue of American Family Physician, Rosenthal and Puck¹ have skillfully reviewed the genetic risk of breast cancer. They state that “A family history remains the best tool for planning breast cancer surveillance.” DNA studies in search of cancer-causing gene mutations must be targeted toward families that merit such testing. However, the cancer family history, although potentially the most cost beneficial component of a patient's medical work-up, is notoriously neglected.^2,3

The lay press strives to keep patients fully informed about new gene discoveries and what impact these discoveries will have on them and their families. However, some media reports have overinterpreted the benefit of gene mutation testing for breast cancer susceptibility and have not fully addressed some of the drawbacks. In turn, some molecular genetic laboratories have made such testing appear to be the panacea for the control of breast cancer. For example, they may neglect to mandate a careful family history so that a hereditary breast cancer syndrome can be identified. Patients with hereditary syndrome should be offered genetic counseling in concert with DNA testing.

Any form of DNA testing, as is the case for all forms of diagnostic testing in medicine, has its limitations. Therefore, one must be aware of the potential for false-positive (rare) and false-negative (slightly more common) results. Samples may be mislabeled, technical problems in the assay may occur, neutral polymorphisms may be identified that have nothing to do with predisposing the patient to cancer, tests may be grossly misinterpreted,⁴ genetic counseling may not be available, and the screening and management benefit derived from recognition of the particular gene mutation may be highly exaggerated.

Genetic counseling should be provided to patients before testing and at the time of disclosure of test results. Patients should be made aware of the potential for experiencing fear, anxiety, apprehension, intrafamily strife, and insurance or employment discrimination.^5,6 The patient may not be sufficiently prepared to accept a positive (mutation present) or even negative (mutation absent) finding, with the latter result possibly leading to survivor guilt or ultimate disbelief in the results (i.e., “With so much cancer appearing in the family, how could I possibly be negative for the mutation?”).

In a study by Lerman and colleagues,⁷ stress symptoms that were related to breast-ovarian cancer at a baseline interview predicted the onset of depressive symptoms in family members who were invited for testing but declined: “Among persons who reported high baseline levels of stress, depression rates in decliners increased from 25 percent at baseline to 47 percent at one-month follow-up; depression rates in noncarriers decreased and in carriers showed no change (odds ratio for decliners versus noncarriers: 8.0; 95 percent confidence interval: 1.9 to 33.5). These significant differences in depression rates were still evident at the six-month follow-up evaluation.” It was concluded that in BRCA1/BRCA2–linked families, individuals showing high levels of cancer-related stress who ultimately declined genetic testing appeared to be at increased risk for depression. Even though they declined to be tested, these individuals may require monitoring for the potential occurrence of adverse psychologic effects.

When a cancer-causing mutation is identified, how do we use this information to benefit the patient? How can we determine that screening and preventive surgical management, or both, particularly prophylactic bilateral mastectomy or oophorectomy (in patients who have completed their families) in BRCA1/BRCA2 mutation carriers, will actually save lives? We believe that data collected from randomized case-control studies of large cohorts of hereditary breast-ovarian cancer patients will be helpful. However, gathering data of this type (namely case-control studies) would, in our opinion, be unethical, because we would never consider placing a patient in the control group knowing the potential benefit of prophylactic surgery.

What is needed is an open mind to the pros and cons of DNA testing, genetic counseling and its translation into medical practice by the basic science, genetic, practicing physician and ethics communities. Answers to the following questions⁸ will require extensive research to prepare physicians for the anticipated extraordinary molecular genetic advances of the next century. Progress in this area will certainly lead to these more complex questions:

• What surveillance and management strategies will improve the natural history of the syndrome?

• How can we best elucidate genetic or environmental interactions in patients with germ-line cancer-prone mutations so that we can modify penetrance and expressivity of the cancer-prone mutation?

• What are the future prospects for gene therapy?

• Has existing molecular genetic knowledge outpaced the physician's ability to effectively translate it into sound health care delivery for hereditary cancer syndromes?

• Are there enough sufficiently trained genetic counselors or physicians to meet the essential genetic counseling needs?

• Do physicians have the time available to them to meet this responsibility?

• How can potential penalties and liabilities of DNA testing (i.e., insurance and employment discrimination, intrafamily strife, fear and anxiety) be resolved?

• Is the physician at risk for medical malpractice if he or she failed to perform DNA testing, provide accurate genetic counseling, provide targeted surveillance and management, or to protect patients' confidentiality?

In their place on the front lines of medicine, family physicians will need to stay informed about both the pitfalls and the promises of genetic screening.