Ethical and clinical aspects of BRCA 1 / 2 mutations testing in children and adolescents
Tomas Jose Silber
In 1995, two professional medical societies concluded genetic studies in minors should not be done unless those studies contribute to diagnosis of a treatable disease. The American Academy of Pediatrics reached the same conclusion in 2001, and reiterated it in 2013. However, a new phenomenon is currently emerging: many young women with positive BRCA mothers are requesting the test, and positions have softened with the recognition that some exceptions can be justified. One such case is presented and discussed. The value of testing minors for the mutation will be considered in light of the value to BRCA positive parents and the professionals they see, perhaps eventually providing a more solid basis to the current majority recommendations, or leading to their modification.
Hereditary genetic mutations predisposing to breast cancer were identified by the end of the 20th century.  Females with a BRCA 1/ 2 mutation have a 37% to 85% risk of developing breast cancer and a 15% to 41% lifetime risk for developing ovarian cancer.  BRCA 1/ 2 mutations occur only in 10% of women with breast or ovarian cancer.  Hence, the vast majority of women with a family history of breast cancer will not have such mutations. Nevertheless, it is only natural for these women to be concerned about the possibility of having a hereditary predisposition to breast cancer.
Those women who are eventually found to have the BRCA 1 or BRCA 2 mutation, if they have children, daughters in particular, may subsequently develop a growing concern about whether or not their children too are carriers of the mutation. Like their BRCA 1/ 2 positive parent, both sons and daughters with the mutation have a 50% chance of transmitting it to their own offspring. Eventually, girls with the mutation may have to consider the possibility of having prophylactic oophorectomy and mastectomies. The case for sons with BRCA 1/ 2 mutation is different, as prophylactic prostatectomy is not recommended and, while they are also at risk of breast cancer, breast palpation in males is easily accomplished.
Information about the consequences of learning about having a BRCA mutation in adult women reveals their ability to adapt to a painful reality. [4,5] A longitudinalstudy showed that adult women at risk clearly benefitfrom the test.  It is therefore important to let motherswith familial breast cancer know that they could benefitsubstantially from genetic counseling, and share their concerns with the medical professional who knows them best. As time goes by, not unexpectedly, many mothers with BRCA 1/ 2 mutation will be getting restless and so distraught about their daughter’s future that they will reach the point of soliciting testing for the mutations on behalf of their minor daughters.
To illustrate the special ethical concerns involved in the testing for BRCA 1/ 2 mutation in adolescence, I will present a case from my practice of adolescent medicine that I will never forget:
Ruth, a sick-looking 50-year-old divorced teacher,brought her 16 year-old daughter to my office and stated: “I want you to keep seeing Jean when I’m not here anymore.” With that, I saw mother and daughter separately, which is my practice on a first visit. The poor woman then revealed to me that she had a BRCA 1 mutation, was diagnosed with metastatic breast cancer, and had little time left to live. She was now attuned to the task of dealing with the educational, medical, and financial needs of her only daughter. Within that context, she asked me what I thought about Jean, her 15-year-old daughter, getting the genetic test. I explained to her the reasons for not doing the testing, including: it has no practical or advisable application during adolescence; it would take away from her daughter the possibility of making a free and autonomous decision as an adult, condemning Jean to possess a knowledge perhaps she neither wanted nor for which she was prepared. I informed her that not only were these my thoughts, but that they were also the recommendations of most medical societies. After a thoughtful conversation Ruth nodded, and the visit ended with Jean’s physical and the application of her last HPV vaccine.
Two months later Ruth requested another office visit. Now Ruth was very weak, dyspneic, and exhausted. Again, she requested that Jean be tested. After she saw my reluctance, she became weepy and crestfallen. Following a moment of poignant silence, with the scarce strength she had left she passionately told me:
Dr Silber, I think all the time about everything we talked about–the test for Jean–and I have even talked about it with Jean’s estranged, alcoholic father. We decided together to talk with Jean about it. As a matter of fact, we talked a lot. Jean knows that I will soon die, and I keep thinking of the possibility that in some distant future, she may receive the bad news of having the BRCA 1 mutation like me—and that by then I will no longer be thereto console, guide, and support her. I worry all the time about how bad she would feel without me, and I beg you to order the study.
I then asked Jean to join us. She faced me and with a trembling voice, said, “Doctor, I know what my mother has been asking you. I also want to take the test.”
Before narrating my response to this poignant request and its aftermath, I will present a brief review of the issues involved in the predictive genetic testing of minors, familial communication about BRCA 1/ 2, what little is known about the response to learning about carrying the mutation in young adults, the closest comparable group to adolescents, and the recommendations from scientific groups and academic societies on the genetic testing of minors.
An alert: there is a scientific fact about the interpretation of genetic screening that needs to be understood by both professionals and parents before addressing the issue of a BRCA 1/ 2 genetic studies during childhood or adolescence. While the intention of testing is to end uncertainty, sometimes that will not be possible to achieve because the test results can be indeterminate,with genetic variants not classified and of unknown prognosis. 
BRCA 1/ 2 genetic testing of minors
There is consensus that for adult women with a history of breast cancer in their family, the request for a genetic evaluation is reasonable and advisable, especially for high-risk groups such as Jews of Ashkenazi origin. This consensus does not extend to underage daughters. Genetic counseling is recommended for those adult patients because it can contribute to informed decision-making. Ideally, patients should be educated in advance regarding the potential benefits, risks, andlimitations of the genetic test. All this is stressful for any adult, and it does not require much imagination to intuit how difficult it would be for adolescents tointegrate the same information as they move from adolescence to adulthood.
Often the maternal concern about whether to request the study for a minor does not even reach the doctor: the existence of hereditary breast and ovarian cancers is known by most of the population, and many respond to the invitation to “take the test” promoted commercially. This tendency to bypass clinicians is certainly facilitated by the Internet. Moreover, the recent decision of the United States Supreme Court against allowing the patenting of genes will most likely lead to further decreasing the cost of the genetic studies, making BRCA 1/ 2 testing more and more accessible without a physician’s input.
Fortunately, many of the mothers who have the mutation still ask for a professional’s opinion about the BRCA 1/ 2 test for their teenage daughters, and even their young girls. The physician nevertheless now must also be proactive, and be prepared to anticipate the independent maternal explorations of the issue, as well as the questions that may arise.
What follows is a review of: a) studies of breast cancer-related communications between mothers and daughters, with emphasis on BRCA disclosure; b) the scant research of the consequences of learning about being a BRCA 1/ 2 mutation carrier in young adults; and c) information about the various medical societies position on testing minors for BRCA 1/ 2, expressing various viewpoints that can inform the medical practitioner. [9,10,11,12,13,14]
Both the sons and daughters of a father or mother with the mutation BRCA1 or BRCA2 have a 50% risk of having inherited the mutation, which raises the issue of when and how parents communicate their history to their offspring. To begin with, it is of interest to note that a component of the maternal motivation to get tested is often a concern about their daughters’ possible inheritance of a predisposition to cancer. [15,16] A few studies have examined various aspects of familial communication about the mutation. [17,18,19,20,21,22,23,24,25,26,27] Most parents thought it would be possible to transmit the information in a positive way. However there was also a degree of ambivalence, given that many doubted that it was appropriate to talk about it with their children. The researchers concluded that couples receiving information about hereditary cancers do not have sufficient support to help them communicate the genetic risk to their asymptomatic daughters, and that it would be useful to include such a service at the time of the genetic study.
The consequences of learning about having a BRCA 1/ 2 mutation in adolescence. As a clinician considering the appropriateness of testing adolescents, I think of the following theoretical consequences:
- As adolescents process information about carrying the mutation, they may begin early in life to have the disquieting experience of “The Sword of Damocles,” a debilitating anticipatory anxiety and uncertainty long before the danger of cancer becomes real.
- The emotional burden of knowing one is a carrier may perhaps be overwhelming for many, with effects on self-image around developing breasts and sexual powers damped by thoughts of potential surgery, mutilation, and death.
- The knowledge could affect self-esteem as they may view themselves as carrying a dark secret, or worse, of being defective.
Challenging this view is a proposal that if this information were provided to children, it would become a natural part of their identity without the upheaval that this would create in adolescence and later in life.
The truth is that there is not much evidence-based knowledge about the potential risks and/or benefitsof adolescent testing for BRCA 1/ 2. There are no studies of children and adolescents who undergo BRCA testing, but there are studies about adolescents who learn about the BRCA 1/ 2 mutations of their mothers. A prototypical study addressing specifically what happens to children who have a BRCA 1/ 2 mutation parent, is the multicenter study, Lessons in Epidemiology and Genetics of Adult Cancer in Youth (LEGACY) showing that already 38% of children 10 to 13 year-old girls thought that they were at risk for breast cancer and had a higher level of breast cancer specific distress than their peers. 
A medical note of caution: a cohort study suggests that exposure to mammography irradiation done before age 30 is associated with an increased risk of breast cancer.  Thus, the researchers recommended the use of magnetic resonance imaging (MRI) for young women with the BRCA1/BRCA2 mutation. This study awaits replication. In the meantime, the recommendations of the American Cancer Society on the use of MRI continue to stand.
It has also been proposed that those women diagnosedwith breast cancer at a very young age would benefitfrom a genetic study that should include BRCA1/ 2 and TP53, for the possibility of diagnosing the Li-Freemen syndrome. 
The consequences of learning about having a BRCA 1/ 2 mutation in young adults
A new phenomenon is currently emerging: many young women with positive BRCA mothers are requesting the test. [33,34,35,36,37,38,39] The lack of information on the outcome of disclosure to teenagers inclines towards studying the experience of these young adults. Although one cannot extrapolate their experience to that of a teenager, it may provide approximate information about what a mature adolescent’s response might be like. Here are some facts:
A study of women between the ages of 18 and 25, found that there are a variety of pathways that lead young women to the genetic counselor. The researchers noticed for instance that in many cases it was family pressure that had led them to the interview, raising the possibility of interference with autonomous decision-making. [/tooltip]
In a survey of women and men of reproductive age, with the mutation but without cancer, (n = 605), one third responded that when planning a pregnancy they would be willing to request a preimplantation genetic diagnosis, half were willing to undergo a prenatal diagnosis, yet only a little more than 10% would be willing to abort a fetus with the mutation. Most respondents thought the information about the possibility of a genetic preimplantation diagnosis, and of a prenatal study, should be compulsory information when the results of the genetic study are received.  This suggests that a portion of the population would consider doing the genetic study of their sons and daughters even before they were born.
To understand the experiences of young adults with the mutation, a qualitative investigation analyzed detailed interviews (n = 32) and found that some were already contemplating mastectomy before the age of 25 and all counted on the emotional support and financial assistance of their parents. 35 The researchers’ conclusions were that young adults had the ability to choose to take the test autonomously, to fully understand and act on the basis of genetic information, and to make autonomous decisions.
Another qualitative study of 18 to 39 year olds with the mutation (n = 44) showed that those who were not married were anxious about disclosure of their condition to a boyfriend, those who already had children saw as their priority to stay alive for them, and those who had no children expressed an urgent desire to have them.  Unfortunately, some of these women were already diagnosed with cancer (the youngest was 24 years old). The knowledgeof the mutation influenced their decision to have abilateral mastectomy. The researcher’s conclusion was that it is necessary for clinicians to be alert to the psychosocial dimension, especially as it relates to couple relationships and to reproduction.
Researchers at the National Cancer Institute also conducted an investigation to improve knowledge about the experience of women diagnosed with the mutation at an early age. They found that the relationship between risk perception and decision-making were strongly influenced by non-oncological components. This related to how they were fulfilling the tasks of young adulthood, such as differentiating from the family of origin, becoming a couple, and forming a family.The conclusion was that understanding of these underlying dynamics can help professionals provide appropriate counseling and support to the high-risk young women struggling to maintain a balance between the legitimate need to reduce risk and the desire to lead a normal life.
Other studies confirmed the wide range of young women’s concerns and interests. These include themes ranging from concerns regarding the use of contraceptives to the future use of preimplantation genetic studies. [38,39]
The conclusion of all researchers was that counseling by competent professionals can be helpful to provide women with information appropriate to their age and needs.
Recommendations on genetic testing of minors
Medical organizations have paid attention to this issue.The first to do so, in 1995, was the American Society of Human Genetics and the American College of Medical Genetics. Both categorically opposed genetic studies in minors unless such studies contributed to the diagnosis of a treatable disease that may occur before reaching the age of majority.  The American Academy of Pediatrics in 2001 reached the same conclusion.  In 2009, considerations were published from the European perspective.  More recently, in 2013, the American Academy of Pediatrics (AAP) and the American College of Medical Genetics and Genomics have published their recommendations regarding the ethics of genetic tests of minors and reiterated that they recommend testing only when this can be beneficial for children during their childhood or adolescence. This position was softened with the recognition that some exceptions to this rule can be justified. A strong dissenting view was developed in 2013 by the American College of Medical Genetics (ACMG), recommending instead to disclose incidental findings in clinical exome and genome sequencing.  In 2013, the ACGM Policy Statement was addressed in a technical report.
Considering everything reviewed so far, it should be noted that there are no studies of children and adolescents who were tested for the mutation, probably due to professional opposition to such testing. However, since many children, like my patient Jean, do get tested, it is desirable to pursue prospective studies of those adolescents that undergo genetic testing, despite the recommendations against this, and compare them to a control group that postpones the study until adulthood. The data obtained could be of great value to BRCA positive parents and the professionals they see, and eventually will either provide a more solid basis to the current majority recommendations, or in effect, lead to their modification. In the meantime, some reassuring data suggest that adolescents who receive genetic risk information suffer less damage than anticipated, have considerable resilience, and possess the ability to incorporate such risks into their self-concept and life plans. 
I propose that while the recommendations against testing minors should stand until more is known, it is nevertheless possible to consider ethically permissible the genetic predictive study of minors under certain conditions. For instance, if the circumstances point to the decision being congruent with the “best interest of the child.”  This implies that parents could consider not only the medical aspect, but also the possible psychosocial benefits for both the girl and the family. This recognition of the possibility of extending the considerations beyond the medical indications recognizes the deference traditionally given to the parents to determine how they raise their children. 
The American Society for Human Genetics, contemplates this possibility, stating that when there are doubts about the benefit of the genetic study, itis acceptable under certain circumstances to do the study in adolescents with decision-making capacity. However, there needs to be an ethical justification as being “a substantial psychosocial benefit for the competent adolescent.”  Others also recommend taking into account the parental opinion and contribution to decision-making.  The opinion of pediatric ethicists about prospective genetic study of adolescents is divided, with the majority inclined to recommend the postponement until adulthood, but some clear dissent has been voiced.  Increasingly parents and providers of medical care for adolescents are contemplating the possibility that BRCA testing should be available to mature adolescents. [44,45,46]
It is possible that over time this debate will be a moot point, as the advancements of comprehensive genomic testing may make the current standards unsustainable.  There is also incongruence about telling asymptomatic children of the risk of adult onset disease in the family, but not testing for it.  Analytical reviews of the ethical arguments in the debate describe them as unpersuasive in the absence of evidence. [49,50]
Finally, it is important to remember to ask for the adolescent’s assent. Predictive genetic studies of adolescents who would not develop the disease during their adolescence fall within the category of elective procedures. Therefore, testing requires not only the permission of the parents but also the assent of the adolescent. If an adolescent is not interested in having a genetic study for a disease that will take decades to present, that decision should be accepted as definitive, and the genetic diagnostic testing should not proceed.
Mother, daughter, and I talked some more and concluded that in Jane’s case, the benefit of the potential counseling and maternal support was greater than the possible damage caused by a premature revelation of the risk of hereditary cancer. Jean proceeded to take the test, and it was negative for the BRCA mutations. Two weeks later, her mother died. The last time I saw Jean was during a break in her studies (genetics), when she came to see me for her first gynecological exam.
When she left she said, “Thanks for listening.”
Clinicians confronting a situation like the one I experienced with Jean need to balance their knowledge of the family with the recommendations of the professional associations, including the knowledge of their weakness and contradictions. This also requires one to stay attuned to the information generated by ongoing research. My own assessment is that we are condemned to think through our own decisions and recommendations. Here is what I offer:
- Today, there are numerous families with a member with hereditary cancer who obtains genetic studies for their adolescent daughters directly, without the interventionof a physician. Whenever clinicians first learnabout a parent with a BRCA mutation, they need to speak proactively about the subject of the children, focusing on the issue of whether, when and how to best manage the revelation. This includes the information that screening mammography in BRCA 1/2 needs to be started at age 25.
- In all cases, regardless of whether or not the genetic study of the young person is done, the psychosocial and familial aspect of the situation should be explored, and counseling provided, taking into account the processes of adolescent development.
- Professionals need to be aware that most academic and professional recommendations about predictive genetic tests for adolescents with possible late-onset diseases (after adolescence is completed), express opposition to such studies. Parents should also be told about the reasons for these recommendations: removing the child from the possibility of making an autonomous decision when reaching adulthood (foreclosed future), and the possibility of emotional harm for those adolescents who may not be prepared for such potentially devastating Information.
- However, any parental request for testing must be listened to carefully because there may indeed be situations that might actually justify an exception to the rule. Moreover, whenever the daughter is a mature adolescent and requests the genetic study, this should carry additional weight in favor of screening.
- Finally, if the teenager does not want to have the study that the parents request, she musthave the final word, and her decision must be complied with. Professionals should give their unequivocal support to an adolescent’s decision not to be tested in such situations.
Note: Genetic testing for breast cancer predisposition gene mutations has now expanded well beyond BRCA1 and BRCA 2. This was not addressed in this article, as it was not germane to the particular consultation described.
Tomas Jose Silber MD, MASS
Professor of Pediatrics, George Washington University Division of Adolescent Medicine
Medical Director, Donald Delaney Eating Disorders Program
Director, Pediatric Ethics Program
Research Subject Advocate
Children’s National Health System
111 Michigan Ave, NW, DC 20010
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