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For the benefit of all.

Margaret W, now forty-one, has had regular mammograms since she was in her mid-thirties, when she discovered a small lump in her left breast. Although the lump proved to be a benign cyst, on the basis of her family history her physician had strongly recommended that she continue routine annual mammograms. Two of her mother's three sisters had been treated for breast cancer (one at age 45, the other at 48) and her maternal grandmother was diagnosed with breast cancer at age sixty-seven. The grandmother's sister had died of ovarian cancer at fifty-three. Cancer has now appeared in Margaret's own generation: not long ago her thirty-seven-year-old cousin Emily underwent a bilateral total mastectomy for infiltrating adenocarcinoma.

Emily's oncologist, aware of the family's history would like to refer her - and her relatives - to a geneticist colleague studying inherited susceptibility to breast and ovarian cancer. There is evidence, the oncologist told Emily, that about one in 200 women have inherited such susceptibility. The colleague he would like her to see is studying BRCA1, a newly identified gene associated with both breast and ovarian cancer. While researchers haven't yet isolated the precise sequence of BRCA1 (and so can't screen for it directly), he noted, linkage analysis in extended families with unusual cancer histories can reveal familial markers associated with, the gene.

Since Dr. Ayers, the geneticist, is willing to provide families with information about any markers such analysis uncovers, in participating in die research Emily, Margaret, and their relatives could not only provide data that might someday help other women avoid breast cancer, but could benefit directly themselves in being able to plan their care more thoughtfully with their physicians.

Her cousin came to Margaret to talk over the idea of participating in linkage studies. It would involve all members of their extended family in one way or another, and Margaret isn't sure they would want to or should take part. On die other hand, joining the research and being counseled about their individual risks might mean better health for each of them - Margaret is especially concerned about what the family history suggests for her two daughters, aged twenty and seventeen. In talking together Margaret and Emily realize they don't know all the questions they should ask to make a wise decision. What does being "genetically susceptible" to breast cancer really mean? What other implications might taking part in this research hold for them and their families? Who will give them the best counsel in making a decision?

This case foretells an imminent shift of emphasis in medical genetics. In marked contrast to the traditional focus of genetic counseling n providing diagnosis and reproductive risks for rare genetic conditions, the identification of genes associated with susceptibility to common disorders, such as breast cancer, will propel this specialty into the area of preventive health care.

But due to the significance of factors other than genetics in disease etiology, genetic susceptibility information - in the form of genes or DNA sequences associated with common diseases - will be inherently limited in predictive value. Individuals who are carriers of a genetic susceptibility trait might never experience the condition with which the trait has been associated.

While there may seem to be little appreciable difference, testing for genetic susceptibility is unlike testing for other types of susceptibility. An important difference is that instead of measuring the end result of combined environmental and/or genetic factors at a particular moment in time, such as with cholesterol testing, only genetic material, immutable and unchangeable over time, is assessed. Unlike cholesterol tests, which generate a course of action (such as diet and exercise recommendations or drug therapies), genetic information itself is resistant to human intervention. Moreover, as in all genetic tests, detecting a purely genetic feature generates information about other individuals who are identifiable by virtue of their biological connection to the test recipient.

The significance of these characteristics to those administering and those receiving tests is still not known. In deciding whether and how to provide genetic susceptibility testing, we need to learn how individuals and their families appreciate, understand, and value genetic susceptibility information.

For example, how is self-concept influenced by knowledge about genes or DNA markers? Does genetic susceptibility testing have a more profound effect on perceived health than other forms of susceptibility testing? It is possible that being identified as genetically susceptible may reassure some individuals, explaining familial disease patterns long perceived but never fully understood or clearly diagnosed. Conversely, being labelled genetically susceptible may give rise to feelings of vulnerability and inferiority. Perhaps some will be relieved to know that they have not inherited a particular genetic susceptibility. Yet reliance on a genetic test revealing a lack of susceptibility to a particular disorder may lead to unwarranted optimism regarding health status. In this case, the high incidence of breast cancer in the general population underlines die importance of regular breast exams and age-related screening for all women, regardless of the presence or absence of BRCA1. Margaret, Emily, and members of their families will have to consider these issues for themselves.

The value of genetic susceptibility information lies in the related implications for disease treatment and/or prevention. Dr. Ayers may feel compelled to offer test results to participants, given their family histories, in the thought that the results may influence the actions, decisions, and possibly the health of study participants. Women identified as carriers of BRCA1 might alter their breast exam or screening schedules, choose to participate in tamoxifen trials, or opt for prophylactic surgery, although the choices and actions of women identified as carriers and the effectiveness of these options in reducing mortality have yet to be determined.

In considering clinical use of genetic susceptibility tests, we must also examine their potential harms. Genetic information is interesting in this respect, since physical harms associated with tests to determine carrier status are very limited, similar to those for any blood draw. The potential harms in genetic testing reside at a different level and encompass harms generated through societal knowledge of genetic constitution. Such potential for harm is of concern in the use of all genetic tests but may be especially troubling in relation to susceptibility to common diseases like cancer. If Margaret, Emily, and family members choose to participate in Dr. Ayers's study and subsequently receive their BRCA1 test results, what are the implications for their health insurance? Will insurers view such genetic testing as beneficial, leading to preventive health care actions that may ultimately decrease their overall costs? Or will they view individuals with genetic susceptibilities as liabilities and exclude them from coverage? Will individuals found not to carry BRCA1 now be able to obtain previously denied insurance? These are also issues that Emily, Margaret, and other study participants must consider.

Since there is no general agreement within the medical genetic community concerning the most appropriate mode by which to offer testing for genetic susceptibilities, we are left to wonder how Dr. Ayers informs participants of their results. Is there a "standard" testing and counseling protocol? How was it devised? What does it look like? Why did Dr. Ayers decide routinely to offer BRCA1 linkage results to study participants?

The possibility of widespread genetic testing for susceptibilities raises challenging questions about which tests to provide and to whom, the criteria by which such decisions are made, and ultimately, how to offer such tests and services efficiently. Since the identification of genetic sequences conferring susceptibility to breast cancer and other common disorders will have the potential to affect large numbers of people, will likely lead to calls for large-scale population testing or screening, and may significantly affect people's lives, it is important that we begin to discuss and address these issues before we import susceptibility testing into the clinic.

Breast cancer may occur sporadically, in small family clusters, or, as in this case, in strong hereditary patterns. Although only 5 to 10 percent of breast cancer is due to inheritance of a dominant susceptibility gene, if such a gene were in the family, individuals might have as high as 50 percent risk of inheriting it and significant chance of eventually developing a tumor if they did carry the gene.

Although relatively new and as yet little standardized, cancer risk assessment and counseling are being implemented at a number of levels. Screening involves identifying families with greater than average risk. Asking the right questions is crucial. One must include at least ovarian, colon, prostatic, and uterine as well as breast cancer, extend the history to three generations, and include paternal as well as maternal history. Screening should be incorporated at every level of medical care, not just in diagnostic work-ups for cancer.

Brief counseling of women with positive family histories should include documentation of all cancers, basic breast cancer information, supportive and/or grief counseling regarding family losses and current health concerns, and referrals for specialty consultations as necessary. This can be incorporated into routine health care in a variety of settings.

Comprehensive cancer risk counseling is indicated especially where, as for Margaret and Emily, a more strongly hereditary case is suspected. Comprehensive counseling offered in a context of multidisciplinary teams extends the scope of assessment, counseling, and recommendations for intervention. In these settings, counseling usually includes such activities as diagnosis of hereditary syndromes, risk assessment and notification, expanded psychosocial, nutritional, and medical counseling, enrollment in registries, and liaisons with research studies and DNA repositories.

Facilitating decisionmaking begins with understanding the person's motivation for change. Why is this person now seeking information about hereditary aspects of breast cancer? Is a relative newly diagnosed or having a recurrence? Has the woman recently had a health scare such as breast pain or a lump? Is she nearing the age when her mother was diagnosed or some other significant anniversary? What does the individual hope to get out of the process of risk assessment and counseling?

In the present case the motivation for testing seems to be generated more by Emily's oncologist than by the family itself. The oncologist obviously has become well informed about current developments in breast cancer genetics, appreciates how rare it is to see a family with five affected individuals over three generations, and has gone beyond brief counseling into the realm of comprehensive risk counseling. In suggesting that Emily, Margaret, and their family now participate in BRCA1 research studies, he is operating from the assumption that more genetic knowledge is better, a view shared by many health professionals. However, we have little systematically collected research documenting public attitudes to genetic knowledge about cancer and genetic testing for cancer susceptibility.

In genetic linkage studies it is necessary to secure the cooperation of multiple family members. For example, for Margaret to obtain any information, Emily and other affected relatives must be tested first. Since several are deceased, next of kin must be approached for permission to obtain DNA samples from paraffin blocks of tumor specimens of affected relatives. This may not be easy if losses are fresh or emotionally festering.

Presumably, Dr. Ayers is providing the family and primary physician with copies of the informed consent form approved as part of his research protocol. Informed consent should include more than just clear statements about risks and benefits of knowing one's genetic mutation carrier status. Strategies for obtaining and shipping specimens, the time frame for analysis, and methods of informing participants of results should be worked out prior to testing so that all family members know what to expect. In cases where family members live in different regions of the country, genetic counseling networks can collaborate in providing information to different branches of the family.

Informed consent may encompass consideration of alternatives as well. Emily might decide she doesn't want to participate in genetic linkage studies now but might bank some of her DNA to be available for future studies when technology has evolved further.

Informed consent also includes explaining the context of medical research in contrast to clinical service. Whereas the responsibility in the clinical setting is to help the person or family seeking assistance with minimal harm done, the primary responsibility of medical research may be to develop knowledge that accurately reflects biological and social realities. This may or may not eventually be useful for helping society as a whole, a particular subset of society with specific medical needs, or selected individuals.

Individuals sometimes demonstrate powerful altruistic drives to do whatever may help prevent repetition of the painful consequences of breast cancer they have experienced in their families. They can be vulnerable to exploitation or inadvertent harm by overzealous or misdirected research, clinical, or commercial interests. Clinicians and risk counselors therefore have a special responsibility to these families to be sensitive gatekeepers of the introduction of new technologies. A balanced position is neither paternalistically protective nor oversells potential benefits of participation in counseling or research.

As counselors and researchers we can create opportunities for public dialogue about the broader meaning of genetic endowments, be they susceptibilities, giftedness, enhancements, or protection against disease. Testing for genetic susceptibility to diseases like cancer can have a place in the clinic, if it is carefully restricted to high-risk patients like Margaret and Emily and accompanied by sensitive and comprehensive pre- and post-test counseling and long-term follow-up to learn the consequences of receiving such information.
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Title Annotation:includes commentary; concerns about participation in research study of genetic markers for breast and ovarian cancer
Author:Durfy, Sharon J.; Peters, June A.
Publication:The Hastings Center Report
Date:Sep 1, 1993
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