C. EXECUTIVE SUMMARY

The recent characterization of two genes associated with susceptibility to breast and ovarian cancer makes it technically possible to identify a subset of individuals with an increased risk of developing such malignancies. However, the clinical utility of DNA-based susceptibility testing has not yet been fully determined. These Guidelines have been formulated to assist the health care professional in identifying individuals at increased heritable risk for breast and ovarian cancer and to address their needs and concerns.

RISK ASSESSMENT

The provider should determine which individuals among those in his/her practice are at "increased genetic risk" by eliciting an appropriate personal and family history on all patients. The health care provider is not expected to calculate an exact quantitative risk, but rather to ascertain whether the patient is in an increased risk category. This qualitative risk should be derived from a complete personal and family cancer history, including three generations on both maternal and paternal sides of the family (see Sample Cancer Family History Questionnaire). The assignment to a risk category is based on the number of first degree relatives (including parents, siblings, and children) and second degree relatives (including grandparents, grandchildren, aunts and uncles, half-siblings and nieces and nephews) with breast, ovarian, or other relevant cancers such as prostate and colon, ages at diagnosis in affected family members, and other factors such as ethnic background. For example, it should be noted whether the patient is of Ashkenazi (Eastern or Central European) Jewish descent.

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"Clues which increase the likelihood that a cancer-susceptibility mutation is present in a family include:"

Detecting a mutation is unlikely if the family has fewer than three affected close (first- and/or second-degree) relatives on the same side of the family unless special features are present. These special features (justifying exception to the requirement for three affected relatives) include:

• a family member has been identified with a detectable mutation
• early age at breast cancer diagnosis (especially before 45 years) in the patient or any close (first- and/or second-degree) relative**
• one or more cases of ovarian cancer at any age, in addition to one or more individuals on the same side of the family with breast cancer at any age
• multiple primary or bilateral breast cancers in one individual
• breast cancer in a male first- or second-degree relative
• Ashkenazi Jewish descent with a family history of one or more cases of breast or ovarian cancer at any age.

**Early age of onset in a patient has been associated with an increased likelihood of detecting a mutation. In some situations it may be appropriate to offer testing to an unaffected individual with a close relative with early age of onset. For instance, testing may be appropriately offered to an unaffected woman whose first-degree relative, diagnosed before age 45, is now deceased or refuses testing.

The health care provider must make sure that each female patient is up to date, according to American Cancer Society surveillance recommendations for all women (see Table I) prior to assigning her risk status. If not, a clinical examination needs to be performed and a mammogram obtained, if age appropriate.

Risk assessment may be a complex process. Many patients, when asked about family history of cancer, will have a single distant relative with a diagnosis of late-onset breast cancer. Such individuals do not fall into an increased risk category as defined here. They should be reassured that their risk is not significantly different than the general population risk and provided with a review of standard recommended surveillance measures (see Table I) depending on their age. Given the associated risks, burdens and limitations, genetic testing is not indicated where increased risk has not been demonstrated. However, factors such as level of patient concern and clinical judgement may influence the decision as to whether more comprehensive genetic counseling is indicated and the possibility of genetic testing considered.

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"Three family pedigrees where BRCA1 and BRCA2 may be segregating are included. (Sample Pedigrees A, B, + C)"

The focus of the health care provider is to utilize the personal and family cancer history information to delineate individuals at increased risk. Admittedly, those at increased risk do not constitute a clearly discrete category, but rather lie toward one end of a continuous distribution, so that it may be difficult to demarcate an exact cut off or testing threshold. Some patients may appear to approach the level of the increased risk group; others may appear to have a risk only slightly higher than the general population risk. An example of the former would be a woman with two relatives (on the same side of her family) with breast cancer diagnosed in their 50’s. An example of the latter is a woman who, by chance, has only very few female relatives, one of whom has breast cancer. In such instances, more thorough risk assessment, appropriate counseling, and a full elaboration of the benefits and burdens of testing should be helpful.

At present, it is not recommended that the health care provider initiate discussion of the testing option with unaffected Ashkenazi Jewish individuals unless additional factors are uncovered in the family or personal history (i.e., one or more relatives with breast and/or ovarian cancer). For that matter, it is not currently recommended that widespread screening of any subpopulation be initiated. However, some patients with a high level of anxiety or with concerns generated by ethnic background only (e.g., Ashkenazi Jewish patients with negative family histories) may benefit from a balanced discussion of the likelihood that they carry a BRCA1 or BRCA2 mutation and of the complex issues regarding testing and interventions.

Those patients identified as high-risk by the health care provider must be presented comprehensive information concerning the benefits, burdens and limitations of each of the available options, including DNA-based mutation detection or heightened surveillance without genetic testing. Moreover, it may be essential to provide a more exact risk figure to facilitate the patient’s decision-making process. In such instances, consultation with or referral to a specialist with expertise in cancer genetics, clinical genetics or genetic counseling may be valuable.

Genetic testing is not considered appropriate for individuals under 18 years of age, since there is no recommended preventive intervention in childhood for those known to have BRCA1 or BRCA2 mutations, and breast and ovarian cancer rarely manifest in this age group.

EDUCATION AND GENETIC COUNSELING

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"Components of the Genetic Counseling Process"

An individual who is identified to be at increased risk and wants to consider genetic testing may benefit from consultation with an expert in cancer genetic counseling. The consideration of mutation testing should be discussed in the context of a multistep process illustrated in the accompanying Algorithm. Additional information about the personal and family history should be elicited, if needed. Because individuals are often not fully informed about cancer diagnoses in the family, it is important to document, where possible, primary site, age at diagnosis and other information through retrieval of appropriate medical records. Based on all available information, the practitioner should assign an approximate risk (average vs. increased) for the patient to have a breast/ovarian cancer-predisposing gene mutation.

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"Common Misconceptions"

The patient should be encouraged to consider how her or his behavior would change depending on the test result. However, making such decisions in the abstract may not always be predictive of actual behavior when confronted with test results. The patient must be educated as to the potential benefits and burdens of genetic testing in order to make an informed decision about whether or not DNA-based mutation testing would be appropriate for her or him. Mutation testing can confer both benefits and burdens.

Benefits can be conferred whether the test reveals a mutation or not.

Burdens can also be conferred by a positive, negative, or uncertain test result. These are expensive tests which may or may not be covered by third party payers.

Because of the complexity of the material covered in the pre-test education component, it is unlikely that many individuals can process the information and make a decision about whether or not to proceed with testing during the same visit. Accordingly, it is recommended that testing be deferred to a second or subsequent visit. Pre-test education and time to review the written materials should be provided.

INTERVENTION LIMITATIONS

At the present time, there is limited information about the natural history associated with individual mutations in these genes and about the effectiveness of preventive and early detection measures in mutation carriers. Therefore, the health care professional should avoid recommending genetic testing, but rather should offer education and counseling to enable the patient to balance the personally applicable benefits and burdens.

A fundamental issue is that none of the early detection or prevention strategies for breast/ovarian cancer are entirely satisfactory. Mammography certainly has been shown to reduce morbidity and mortality in women over the age of 50. Prophylactic mastectomy and oophorectomy may reduce the likelihood of a primary or secondary cancer in high-risk women, but they do not eliminate the risk entirely (see Appendices II and VIII). Because individuals with BRCA1 and BRCA2 mutations have been identified only recently, insufficient experience has been accrued to date to definitively resolve these issues. Benefits of chemoprevention in "high-risk" women are evident, but it is not yet known how effective these techniques will be in BRCA1 and BRCA2 mutation carriers. Patients must understand the limitations of our current knowledge as a prerequisite to any decision making regarding whether or not to be tested.

Patients considering mutation testing must understand that a positive result does not mean that cancer is certain to develop. Furthermore, a negative test result does not mean that cancer will not develop. Those in whom a mutation is detected are not guaranteed significant improvement in prevention, detection, treatment, or survival.

In light of the potential for the psychological and social burdens discussed above, patients considering susceptibility testing for breast and ovarian cancer predisposition must be informed about these issues. Patients must be made aware of concerns regarding confidentiality, insurance and employment discrimination, and personal and familial stigmatization, should their test result prove positive. Current legislative efforts do not yet offer complete protection against such abuses. Accordingly, confidentiality of medical test results can not be completely guaranteed, and patients should be made aware of this (see Appendix XIV).

ALTERNATIVES TO TESTING

Many patients found to be at increased risk will opt not to be tested. There are many alternatives including increased surveillance, participation in clinical research, and use of chemopreventative agents. Many experts recommend that women with a first degree relative or relatives with breast cancer start annual mammography at an age ten years younger than the earliest age of onset in the family. While this may be reasonable advice, there are no data to demonstrate or refute the effectiveness of this recommendation. Such methods would allow the patient to avoid some of the potential psychosocial burdens associated with genetic testing. Other alternatives might include delaying testing until a future time, or having samples banked for future DNA testing for the benefit of descendants.

The patient, once fully informed, is the only one who can weigh these alternatives and make a truly informed decision.

BRCA1 AND BRCA2 DNA TESTING

In cases where the primary care provider’s patient has not had breast or ovarian cancer herself, it is recommended that a closely related family member or members who have or have had breast or ovarian cancer be tested first following appropriate genetic counseling. The specific cancer-associated mutation in the family, if present, may thus be identified. This tactic will prevent the patient from being falsely reassured by a negative test result when the family mutation has not been determined.

At the session in which testing is to be carried out, it is imperative that written informed consent (required by NYS law) be obtained to document the education and counseling which has occurred and to confirm that the person is requesting testing, and recognizes the associated risks and limitations (see Appendix XIV). The patient should be allowed sufficient time to have all questions answered which have arisen in the interim. Regardless of results, these are expensive tests which may or may not be covered by third-party payers.

Clinicians should be aware that these are highly specialized molecular tests performed in only a small number of laboratories nationwide. They should only use those laboratories which meet institutional, state and federal standards. Clinical laboratory testing of New York State residents must be performed by appropriately licensed laboratories (see Appendix XIII). At the time that these Guidelines were developed, only six laboratories were approved to provide BRCA1 and/or BRCA2 testing to those residing in New York State. It is anticipated that the number of approved laboratories will increase in the future. Contact the Genetic Testing Quality Assurance Program at (518) 474-6796 for up-to-date information. Different laboratories may apply different methodologies for the detection of BRCA1 and BRCA2 mutations. As a result, depending on the method employed and the extent of the analysis, varying levels of sensitivity and specificity will be achieved. Such issues are important for the interpretation of test results. Moreover, substantial differences in cost are associated with different testing methods. In addition, clinicians must ascertain specifications of the selected laboratory for obtaining and shipping test samples.

POST-TEST EDUCATION

Patients who have been tested must be provided an explanation of test results after confirming that they still want that information and must be informed of any consequent revision of the risk management plan. It is strongly recommended that all patients be informed at the time of testing that all test results, whether positive, negative or uncertain, will only be disclosed in person at a subsequent visit.

The post-test counseling session allows the provider and patient to review the implications of the test results. Those found to have a deleterious mutation may need additional psychological support through various means including referral to a psychiatrist, other mental health worker and/or to a relevant voluntary health organization. Most critically, a strategic plan for early detection and/or preventive interventions should be thoroughly explored and initial decisions made. Discussion about education, counseling and (if desired) testing of at-risk adult relatives should be initiated as well. The patient should be assisted in the process of informing relatives by the provision of brochures, personal letters, etc. which can help the patient to convey such sensitive information to appropriate family members.

When a test result of uncertain significance is found, it is particularly critical that as many family members affected with relevant cancers as possible be approached for consideration of testing. This is not an infrequent finding with DNA sequencing-based mutation testing. In this way, the significance of the alteration, vis-a-vis carcinogenic potential, can sometimes be better estimated.

When a specific mutation is found in the family and the patient’s test result is negative, it is essential that the patient understand that the general population risks for breast and ovarian cancer still apply. If a familial mutation has not been identified, and the patient’s test result is negative, a hereditary cancer predisposition may still exist and an increased level of surveillance may be warranted based on family history and risk assessment.

At present there is limited information concerning the natural history associated with individual mutations in these genes and about the effectiveness of preventive and early detection measures in mutation carriers. Moreover, the psychological sequelae in individuals predisposed or susceptible to serious life-threatening disease is a relatively unexplored area in psychosocial research. Therefore, all patients identified to be at increased risk, whether choosing to be tested or not, should be encouraged to participate in clinical research studies over significant time intervals. Only in this way can the information garnered be incorporated into the improved care of future patients and families at risk.