4. RECOMMENDED PROTOCOL

The process recommended below applies both to the person who has already had breast or ovarian cancer and to the person who has not, but who is at increased risk based on a positive family history (see Algorithm).

a. Risk factor identification. Since males as well as females can transmit a mutation, a family history must be obtained for both maternal and paternal lineages. The complete family history (at least three generations) should include all types of cancer, to permit recognition of the less common cancer syndromes (e.g., Li-Fraumeni). Age at diagnosis should be recorded to identify individuals with an early age of onset. Since many women with a positive family history overestimate their risk, the patient may benefit from a pedigree-derived estimate of the genetic risk of developing breast cancer (Hoskins et al 1995). Other methods, such as those of Claus (Claus et al 1994) and Gail (Gail et al 1989) include environmental and other variables which may influence the total risk (see Table IV). These factors have been found to influence to varying degrees the relative risk for breast cancer, but in general to a lesser degree than the presence of a BRCA1 or BRCA2 mutation. The Claus method takes into account the increased risk due to the occurrence of breast cancer in first and second degree relatives. The Gail method takes into account the increased risk due to a young age at menarche (<12 years), nulliparity or first full-term pregnancy after age 30, late age of menopause (>50 years), history of breast biopsy, and the occurrence of breast cancer in a mother or sister. In contrast to models involving multiple factors, the family history itself may suggest that the family's cancer susceptibility may be due to a single copy of a mutant gene. Lifetime risks are influenced by current age; for example, since half the breast cancers due to a BRCA1 mutation occur by the age of 47, a 47 year old woman with an identified mutation, who has not had breast cancer, has a risk of developing it that is substantially lower than the overall lifetime risk would have been if she were identified at a younger age (See Appendix III).

Click here to view
Table IV
Some Other Risk Factors For Breast Cancer

b. Criteria for offering testing. Genetic testing in the absence of a personal or family history of breast or ovarian cancer is not recommended at this time because of the low probability of detecting a mutation and the considerable economic as well as psychological costs involved. Detecting a mutation is unlikely if the family has fewer than three affected close (first and/or second degree) relatives unless special features (detailed in the next paragraph) are present. Of course, such a criterion will result in missing some individuals with mutations (Langston et al 1996); for example, a series of male-to-male transmissions can account for an individual who has a mutation, yet a negative family history.

Offering testing with fewer than three closely related affected individuals may be useful in the case of any of the following: early age at diagnosis of breast cancer (less than 45 years), one or more cases of ovarian cancer and at least one relative on the same side of the family with breast cancer (at any age), multiple primary breast cancers in one individual, and breast cancer in a male. In certain populations (e.g., Ashkenazi Jewish individuals), the carrier frequencies of specific mutations are increased compared to the general population. Because of this, genetic testing of individuals with fewer than three affected relatives may be considered if appropriate education is provided, and an informed choice is made.

Click here to view
Components of the Genetic Counseling Process

Wide-spread screening of specific populations or subpopulations is not endorsed at this time. Population-based screening should not be considered until (1) the penetrance (likelihood of overt disease being manifest) of the vast majority of specific mutations is determined, (2) the efficacy of medical interventions following mutation detection is established, (3) adequate technical and professional resources for genetic testing and counseling are in place, and (4) the risks of employer and/or insurance discrimination have been minimized.

Once a mutation has been detected in a family, close adult relatives of the tested person fulfill the risk requirement for testing.

Click here to view
Definition of Genetic Counseling

c. Genetic counseling. The professional(s) providing pre- and post-test genetic counseling must be aware of the intense nature of this activity, the time required and the principles associated with this practice (see definition below). Genetic counseling must be part of a therapeutic relationship that recognizes the specific psychological, ethnocultural and medical needs of the individual and family. The first encounter with an individual or family must include an articulation of the patient's or family's questions, concerns and expectations regarding the risk assessment and genetic testing process and the relevant implications.

Click here to view
Common Misconceptions:

d. Pre-test education. It is implicit in these Guidelines that to offer testing is to take responsibility (whether oneself or through appropriate referral) for adequate pre-test education, the process of informed choice, and post-test counseling. Before testing an unaffected family member, an affected family member, if available, should be tested. If a positive result is not obtained in an affected family member, a negative result in an unaffected family member may be falsely reassuring.

Pre-test education should include the following points:

• Genetic susceptibility testing does not detect cancer itself, but only an increased risk of developing cancer;
• A positive result does not mean that cancer is certain to develop;
• A positive result does not guarantee improved prevention, detection, treatment, or survival;
• A negative test result does not mean cancer will not develop;
• A negative test result does not eliminate the possibility of a mutation in the gene analyzed because testing has imperfect sensitivity;
• Unlike early detection measures (e.g., mammography), testing for a mutation in a given gene does not have to be done more than once (unless technology improves); and
• Benefits and burdens are associated with these tests.

To help the patient decide about testing, the three types of possible results should be explained and the patient asked how each would affect her or him. For example, would she/he change her surveillance behavior? If a mutation were detected, would she/he share her result with her physician, partner, children, or other relatives? Would she/he consider prophylactic surgery? Individuals who would not take any action regardless of the result should carefully consider whether the benefits of testing outweigh the burdens. Lerman et al (1997) compared two approaches to pre-test education for BRCA1 testing. The education-only approach provided factual information on the benefits, limitations, and risks of testing, whereas the counseling-education approach required the patient to consider the personal impact of a positive and of a negative test result. The latter approach increased perceptions of limitations and risks of testing and decreased perceptions of benefits, although it did not reduce the proportion requesting testing.

Measures for protecting the confidentiality of the test result should be discussed, but their fallibility should also be acknowledged. Patients choosing to be tested should be cautioned that submitting the bill to a third party for payment will document their having been tested and may adversely affect their insurability or premium rate. Patients should also be reminded to review their insurance agreement as to whether or not they must inform their insurance company about any medical test results.

Click here to view
Caveats in testing:

Comprehension of the information about testing may be improved by providing the patient with both written material intended for the lay person and the time to review the material at home before having to make a decision about testing.

In general, individuals under 18 years of age should not be offered testing since there is no intervention to be offered prior to that age (ASHG/ACMG report, l995; NSGC resolution, 1995). It is preferable for each individual to make a personal decision about testing after reaching the age of 18. In most cases, individuals with an impaired ability to comprehend the relevant information or to make a decision in their own interest are also inappropriate candidates for testing. Individuals undergoing severe stress may be more appropriately offered testing at another time. Caution in offering testing for breast and ovarian cancer genetic susceptibility has been urged also by the National Advisory Council for Human Genome Research (Statement, l994), the American Society of Human Genetics (Statement, l994), the American Society of Clinical Oncology (Statement, l996), the Committee on Genetics of the American College of Obstetricians and Gynecologists (Breast-Ovarian Cancer Screening, l996), and the Advisory Committee of the National Institutes of Health Office of Research on Women's Health (Pinn et al 1996).

e. Process of informed choice. The term "informed choice" rather than "informed consent" is used to emphasize that, for the present, the provider is viewed as offering testing, not recommending it. In deciding whether or not to be tested, patients may benefit from learning how much their estimated risk, based on their family history, may increase or decrease as a result of DNA testing. It should also be made clear that the patient may not receive any useful information from testing.

Testing should be voluntary and not the result of coercion by a third party. A person considering testing primarily to benefit a relative should be encouraged to sufficiently weigh the personal implications of the result before consenting to testing.

Signing of the informed choice document does not itself constitute the informed choice process, but rather is intended to confirm the occurrence of the appropriate communication process.

f. Testing. Testing should be performed only after completion of pre-test education and after formal execution of the informed choice (consent) document. Sufficient time must be given to allow patients to weigh the information. This process can generally not be completed in a single visit.

Before testing, the health care professional must assure that genetic testing will be performed in a manner consistent with state and federal laboratory regulations. For example, in New York State, specimens must be analyzed by a state certified genetics laboratory with a permit specific to the particular test. Separate permits are required for BRCA1 and BRCA2 analyses.

g. Communication of results and post-test counseling. Test results should be provided in person. There are three possible types of results, viz. (1) a deleterious mutation, (2) an alteration of uncertain significance, and (3) no detected alteration. Each requires careful explanation.

(1) Deleterious mutation. The finding of a deleterious mutation calls for (a) psychological support, (b) consideration of strategies for early detection or prevention, and (c) consideration of offering testing to relatives. Recommendations for early detection and means of prevention for individuals found to have a genetic susceptibility for breast and ovarian cancer have been recently formulated by the Cancer Studies Consortium of the Ethical, Legal, and Social Implications Branch of the National Human Genome Research Institute (see a modified version in Table V). These should be reviewed with all patients with mutation positive results with an awareness that new data will be forthcoming in the near future regarding the relative efficacy of various therapeutic modalities. Follow-up of patients found to have a deleterious mutation is also indicated to arrange appropriate referrals and to provide psychological support (See Appendix IV).

(2) Alteration of uncertain significance. In the case of an alteration of unknown significance, it is desirable to document whether all or most of the family members with breast or ovarian cancer share this alteration. If so, the alteration is more likely to represent a deleterious mutation. If they do not, reassurance is indicated.

(3) No detected alteration. If an affected relative has been found to have a deleterious mutation, but the patient does not, the patient can be told that she lacks the apparent cause of the increased familial incidence and that her risk is probably similar to that of the general population. Such women should be given appropriate background risk figures and provided reassurance and a review of surveillance measures appropriate for all adult women (see Table I). If no affected relative has been tested, she can be given only partial reassurance since she may have a mutation in a region of the gene not analyzed or in another gene (See Appendix VI).

Click here to view
Table I
American Cancer Society’s 1997 Guidelines

Click here to view
Table V
Options for Surveillance and Prevention for Carriers
of BRCA1 and BRCA2 Mutations