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Writing Genetic Testing Guidelines Complex Endeavor

Writing Genetic Testing Guidelines Complex Endeavor

FORT LAUDERDALE, Fla--Writing guidelines for cancer screening that include genetic testing--the next major guidelines initiative for the National Comprehensive Cancer Network (NCCN)--will be complex because "every cancer, every gene linked to a cancer, and every patient situation is going to present different kinds of problems," Henry Greely, JD, said at the NCCN's second annual conference.

Mr. Greely is a professor of law at Stanford University and is uniquely qualified to speak to this issue in his position as chair of the steering committee for Stanford's Center for Biomedical Ethics and codirector of Stanford's Program on Genomics, Ethics and Society.

Mr. Greely described seven areas in which genetic diseases and genetic testing can differ, and which must be taken into account when writing guidelines:

1. The nature of the genetic inheritance. Genetic diseases can be dominant (requiring only one bad copy of the gene to put a person at higher risk); recessive (requiring two bad copies); or several other types. "The nature of the genetic inheritance will affect the meaning of the patient's result for their children, parents, and siblings," Mr. Greely said.

2. The relationship between the genetic defect and the disease. The key issue here is penetrance, ie, what percentage of people with a given genetic variation are actually going to get the disease, he said, noting that penetrance of different diseases can vary widely.

For example, the lifetime likelihood of developing breast cancer in a woman with a BRCA1 or BRCA2 mutation is somewhere between 60% and 85%. "That represents an absolute rate, which must be compared to the lifetime risk in the population as a whole, the relative rate, which is about 9% to 12%," he said. In some diseases, the relative risk is fairly small but the absolute risk is great and vice versa.

In addition, some genetic diseases require defects in two or more different genes for the disease to develop, while in others a defect in any one of a number of genes can lead to an increase in risk.

3. The type of genetic testing available. There are at least three different ways of doing genetic tests. Linkage analysis requires samples from some affected family members, "and it's never entirely accurate because there is always the possibility of recombination within the relevant region of the chromosome."

For diseases in which the culprit gene has been identified and located, genetic tests may be used to look for a particular mutation that accounts for all or almost all of the disease, as with sickle cell anemia, or to look for many possible mutations, as with BRCA1, which may require total gene sequencing.

4. The severity of the disease and the interventions available. Some diseases are inevitably fatal, some are often fatal, and some lie in between. "A test for Huntington's disease means something different than a test for susceptibility to squamous cell skin cancer, because the conse-quences are so different. A test for breast cancer is somewhere in between," Mr. Greely said.

The consequences of testing also differ depending on the kinds of interventions available. Prophylactic and screening measures are available, for example, for patients at high risk of colon cancer, "but it's much harder to screen for, say, ovarian or pancreatic cancer," he noted.

5. The time in a person's life the testing is performed. Genetic testing can be done before conception by couples who want to know if they are carriers of specific genes, postconception but preimplantation by patients using in vitro fertilization, or prenatally via amniocentesis. Testing can be done in children or in adults presymptomatically or as diagnostic testing. "Although diagnostic genetic testing is not perhaps significant in cancer, it is turning out to be important in Alzheimer's disease," Mr. Greely said.

6. The costs of testing-financial and psychological. The financial costs will range from $100 to $200 for a simple single mutation probe, to several thousand dollars or more for more complicated linkage analysis or total gene sequencing. But patients also face social and psychological costs in dealing with their family, their potential insurability, and possible employment discrimination, and these will differ depending on the disease and the test result.

7. Patient differences. Patients from different cultures have different feelings about genetic testing and the cancers that underlie them. "A patient from a culture where cancer is never mentioned is likely to feel differently about genetic testing for breast cancer than a patient from a culture that deals with cancer in a more straightforward way," he said.

The patient's relationship with his or her family is likely to be affected by testing, whether the result is positive or negative. In either case, it may bring a family closer together or tear it apart. "The patient's relationship with his family will be an important consideration in testing," Mr. Greely said.

Finally, the patient's personality will make a difference. "Some people want to know and others don't," he said. "These are personality differences that you can't necessarily predict until you get down to the level of talking to individual patients."

Looking at the Process

Mr. Greely estimates that these seven areas of differences in genetic testing with their many permutations produce hundreds of thousands of different combinations of outcomes. "Since it is inconceivable that one could write 200,000 different practice guidelines or even 1,000 different practice guidelines," he said, the answer is to look at process rather than substance.

He outlined six aspects of the process of genetic testing for which guidelines should be written.

1. Counseling patients about medical issues. Patients need to understand something about the cancer for which their genetic risk is being tested and the genetics of the disease. "This is particularly important," he said, "since for most genetic tests for cancer risk, the medical answer won't be straightforward, but will fall into a gray zone where the patient's preferences and situation will play a larger-than-usual role in the medical decision making."

Strong Psychological Reactions

2. Counseling patients about nonmedical issues. Patients need to know before they get genetic testing that the results may, given our current health care system and laws, lead to discrimination in health insurance or employment.

They need to know that some people have very strong psychological reactions to test results, including severe depression and in some cases suicide; that family members often have mixed reactions to results; and that such reactions are not always predictable.

3. Updating of scientific and medical content. Because out knowledge of genetics is changing so rapidly, there needs to be an ongoing process to evaluate new data. Mr. Greely recommends ongoing panels to review the indications for genetic testing and intervention in specific diseases.

4. Competency standards for counselors. Currently, there are only about 1,500 genetic counselors in the United States, and most of these focus on prenatal diseases, not cancer. On the other hand, an oncologist who specializes in breast cancer isn't necessarily equipped to counsel patients about the genetics of the disease or the family dynamics of genetic testing.

"We need programs that train people to a level where they can give competent advice about the disease, the genetics, and the possible familial, psychological, and social reactions," he said.

5. Patient follow-up. Follow-up is crucial after genetic testing. In some cases, it involves medical interventions such as an increased screening schedule or a prophylactic regimen.

In all cases, there should be at least some follow-up with respect to the psychological and familial consequences of genetic testing.

6. Linking counseling to ongoing research. Guidelines should recommend that testing programs be linked to research, so that patients, both those who test positive and those who test negative, are followed to see how the information affects their lives and their outcomes in terms of developing cancer.

"Only with this kind of database," Mr. Greely said, "drawn from a broader spectrum than the very high risk families that are the subjects of gene discovery studies, will we learn what genetic testing means to individual patients."

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