APPENDIX VI: COMMUNICATING NEGATIVE RESULTS

Gladys Rosenthal, MS, CGC

Communication of negative results of BRCA1 and BRCA2 testing requires full interpretation and is dependent on the context in which the testing is done, i.e., affected vs. unaffected individual. Not finding a mutation is not synonymous with a negative result. Those offering testing should make it clear that it is not always possible to distinguish between a true negative and an inconclusive result. Psychological effects may need to be addressed.

Possible interpretations of not detecting a mutation according to testing context:

1. Affected Individual Tested

   1. Assuming full sequencing of both genes
      1. There is no family mutation.
      2. A mutation has been missed in the BRCA1 or BRCA2 gene due to limitations of technology.
      3. There is no mutation in the BRCA1 or BRCA2 gene. A mutation may be present in a still-to-be identified gene, e.g., BRCA3.

   2. Testing limited to specific mutation or panel of mutations, e.g., three mutation panel for individuals of Ashkenazi Jewish ancestry:
      1. There is no family mutation.
      2. A mutation other than the specific site(s) tested may be present in one of these genes.
      3. There is no BRCA1 or BRCA2 mutation, but a mutation may be present in a still-to-be identified gene, e.g., BRCA3.

2. Unaffected Individual Tested

   1. Mutation identified in an affected family member.

      1. Individual tested has not inherited the family mutation. Risk reverts to general population risk.

   2. Mutation not identified in an affected family member.
      1. There is no family mutation.
      2. A mutation in either gene was missed due to current limitations of technology.
      3. Individual tested does not have a mutation in the BRCA1 or BRCA2 gene. A mutation may be present in a still-to-be identified gene, e.g., BRCA3.

   3. Testing limited to a specific mutation or panel of mutations, e.g., heritage panel for individuals of Ashkenazi Jewish ancestry:
      1. There is no family mutation.
      2. A mutation other than the specific site(s) tested may be present in one of these genes.
      3. Individual tested does not have a mutation in the BRCA1 or BRCA2 gene. A mutation may be present in a still-to-be identified gene, e.g., BRCA3.

In summary, a negative result in an unaffected at-risk family member is definitive at this time only when a mutation has been identified in an affected relative.

Psychological Aspects of Testing Negative

There are scant data on psychological outcomes, particularly long term outcomes, associated with cancer susceptibility mutation testing.

The most extensive experience in predictive testing for adult onset disorders is that with Huntington disease (HD). Although many of the lessons learned in these studies can be transferred to inherited cancer risk counseling, difference in implications of neurological vs. malignant disease may generate different psychological sequelae. Difference in penetrance figures and options for risk reduction may influence psychological responses to knowledge of having a mutation. In a Canadian study,¹ participants in a testing program involving linkage results were prospectively followed. Distress, depression and well-being were measured prior to testing and at 7 days, 6 months and 12 months after results disclosure. At follow-up, those identified as low risk had consistently lower scores for distress than at baseline. About 10% of the low risk group, however, reported serious difficulty in coping with their new status, including the realization that they were facing an unplanned future. The authors cautioned against generalization since the sample was small.

In another HD study,² the impact of testing was assessed in groups considered to be at high and low risk following linkage analysis. Thirty-three percent (33%) of the low risk group reported disbelief in results for a month extending to years after testing, as opposed to 26% in the high-risk group. Low risk individuals reported relief at knowing that their children would be spared. Twenty-six percent (26%) of low risk persons reported feeling guilt and 16% reported that feelings of relief had not materialized.

Lynch et al studied a breast/ovarian cancer kindred consisting of 32 unaffected family members receiving results from linkage studies. The author found that 89% of low risk women and 62% of high-risk women felt relief immediately after results disclosure which appeared to persist over time. No figures were reported immediately after disclosure for depression but follow-up showed that 72% of high-risk and 12% of low risk individuals reported depression. No formal psychological measures or structured psychiatric interviews were conducted.

Lerman et al⁴ measured depression and functional impairment in individuals undergoing BRCA1 mutation testing. Mutation carriers showed no increase in depressive symptoms or functional impairment at one month following disclosure. Improvements in psychosocial functioning and functional impairment were significant for noncarriers. The authors concluded that further studies could aid in tailoring counseling to take into account potential effects of testing.

References:

1. Wiggins S, Whyte P, Huggins M, Adam S, Theilin J, Bloch M, Sheps S, Schechter M, Hydn M (1992). Psychological Consequences of Predictive Testing for Huntington Disease. New Eng J Med, 327:1401-1405.

2. Codori A, Brandt J (1994). Psychological Costs and Benefits of Predictive Testing for Huntington Disease. Am J Hum Genet, 54:174-184.

3. Lynch HT, Watson P, Conway T, Lynch JF, Slominski-Castor SM, Narod S, Feunteun J, Lenoir G (1993). DNA Screening for Breast/Ovarian Cancer Susceptibility Based on Linked Markers. Arch Intern Med, 153:1979-1987.

4. Lerman C, Narod S, Schulman K, Gomez-Caminero A, Bonney G, et al (1996). BRCA1 testing in families with hereditary breast/ovarian cancer. A prospective study of patient decision-making and outcomes. JAMA, 275:1885-1892.