By Leila Jamal, ScM

Update 6.14.2013: Since this post was originally published a month ago, the Supreme Court has ruled in Association for Molecular Pathology v. Myriad Genetics, Inc. that genes, including BRCA 1 & 2, cannot be patented, ending Myriad Genetics’ monopoly on testing for breast and ovarian cancer caused by mutations of those genes, but leaving open questions about laboratory research and testing with synthetic DNA.

In an op-ed published in yesterday’s New York Times, actress Angelina Jolie publicly shared her experience of undergoing a bilateral mastectomy after learning she carries a mutation in the BRCA1 gene.   In a straightforward and measured tone, Ms. Jolie recounted the details of her genetic diagnosis and treatment while emphasizing the personal nature of her decision to undergo surgery.   At face value, Ms. Jolie’s circumstances do not mirror those of a “typical” person at increased risk of hereditary breast and ovarian cancer (HBOC).  A closer look at the complexity involved in BRCA1 and BRCA2-related cancer risk assessment suggests there may be no such person.  Beyond its value as an act of solidarity towards other women at risk for HBOC, Ms. Jolie’s decision to share her story may serve others by drawing attention to the many ethical and policy challenges facing the field of medical genomics today.

Women with cancer-predisposing mutations BRCA1 and BRCA2 are five times more likely to develop breast cancer over their lifetimes and are also at a substantially increased risk of developing ovarian cancer compared to members of the general population.  Considerable so-called “normal” sequence variation is also seen in the BRCA1 and BRCA2 genes of individuals who are not at increased risk of developing these cancers, posing a challenge to laboratories trying to determine which sequence changes in the genes are cancer predisposing and which are not.  While several common mutations in the BRCA1 and BRCA2 genes are more prevalent in certain ethnic groups, such as Ashkenazi Jews, hundreds of distinct cancer-predisposing mutations have been identified in these genes across all ethnic groups.

For individuals like Ms. Jolie who carry one of these mutations, it remains impossible to predict when in their lives they are most likely to develop cancer.  For reasons that are poorly understood, some mutation carriers will develop multiple primary tumors before they reach age 50, while other carriers of the same mutation may remain cancer-free into their 70s.  This means that even those with a clear genetic test result face alarming uncertainty when weighing their management and treatment options, which include elevated screening, chemoprevention, and prophylactic mastectomy and/or oophorectomy.  While pre-emptive surgeries can dramatically reduce a mutation carrier’s lifetime cancer risk, there is no consensus regarding the optimal timing of these drastic procedures or best practices for long-term follow-up afterwards.  This is concerning in light of findings from a recent study in which 31% of surveyed primary care providers claimed to offer BRCA1 and BRCA2 testing to adolescents “unconditionally,” despite practice recommendations that advise against doing so.

Mutation carriers must weigh the uncertain pros and cons of screening and treatment options in the face of a terrifyingly high, yet temporally imprecise, risk of developing cancer. This situation requires tradeoffs involving deep emotional reflections of the kind Ms. Jolie so bravely voiced in her op-ed.  When reading her story, it is important to remember that women (and men) undertake BRCA 1 and BRCA 2 testing at many different stages of their lives and under a variety of personal circumstances.  Numerous contextual factors drive individual decisions about when to be tested and what actions to take in light of any genetic result.  Whether or not one has a family history of cancer, is a parent, has intimate relationship(s), has health insurance, is financially secure, or is mentally healthy, the process that begins with a conversation about genetic testing can evolve into a meandering emotional journey in which rational assessments of risk and benefit play merely supporting roles.

Ms. Jolie rightly points out that the high cost (~$3,000) of BRCA1 and BRCA2 testing prohibits access for many women (and men) in the United States.  As the sole U.S. provider of this testing, Myriad Genetics Laboratories is presently the subject of legal scrutiny as questions over the constitutionality of its gene patents are being reviewed by the Supreme Court.  Yet test price inflation is only one potential hazard of Myriad’s monopoly on the BRCA1 and BRCA2 tests.  A broader concern is that assessing the clinical significance of genomic information requires widespread access to data about DNA sequence variants and clinical information about all the individuals who have been tested.

In an estimated 3% patients who undergo BRCA1 and BRCA2 testing, Myriad is unable to classify a patient’s specific BRCA1 or BRCA2 sequence variant as either ‘cancer-predisposing’ or ‘normal’.  For those without access to Myriad’s proprietary variant database, this proportion may be as high as 20%.   For individuals with a family history of breast or ovarian cancer, the decisional uncertainty following an ambiguous test result can be excruciating.

Since relatively little is known about the ‘normal’ range of BRCA1 and BRCA2 sequence variation in ethnic minorities, particularly African Americans (a knowledge deficit exacerbated by their lower rates of access to genetic testing), the burden of this uncertainty falls disproportionately on members of minority groups.  Irrespective of the Supreme Court ruling on the Myriad case, the data and algorithms used to calculate disease risk from human genomic data cannot remain in siloed proprietary databases if the fruits of genomic technologies are to be made fairly available to all.  While policies compelling commercial laboratories to share genetic variant data by making test reimbursement contingent on such behavior have been proposed, they have not gained sufficient traction in U.S. policy discussions about the future of genomic testing.

Ms. Jolie was motivated by compassion and altruism to share her story with the public.  Yet many women and men in similar situations are hesitant to disclose their genetic risk status, even to loved ones, for fear of discrimination if results fall into the wrong hands.   While the 2008 Genetic Information Non-Discrimination Act (GINA) prohibits employers and health insurance companies from using genetic test data to make employment and coverage-related decisions, the law does not apply to life or long-term care insurance.  Nor does it protect military service members or Indian Health Service beneficiaries. Few members of the general public are aware of GINA and there is little evidence that the rule has been effective in reducing the stigma associated with disclosing and sharing genetic information.

It is important to remember that the majority of breast and ovarian cancer, even hereditary forms, is attributable to genetic and environmental causes other than mutations in BRCA1 and BRCA2.  Genetic testing is not indicated in everyone with a family history of cancer, and careful family history assessment must precede genetic testing to minimize the risk of adverse outcomes of inappropriate testing, which include inaccurate medical recommendations and unnecessary healthcare spending.  Insurance coverage and eligibility criteria for genetic testing and counseling remain inconsistent and genetic counseling is not on the Centers for Medicaid and Medicare (CMS) list of covered healthcare services.  Despite this, financing and service delivery reforms to improve quality of and access to genetics services specifically are not among the goals of any healthcare innovations authorized under the 2010 Patient Protection and Affordable Care Act.  PPACA demonstration projects at the state level have the potential to correct this oversight.

Angelina Jolie deserves our compassion and respect for sharing her journey in the hope of helping others.  Those of us who work in bioethics and health policy should feel compelled by these sentiments to seek policy changes that will make meaningful and informed decisions like hers a plausible reality for all who must confront such difficult circumstances.

LJ photo

Leila Jamal is a genetic counselor at the Kennedy Krieger Institute and a doctoral candidate in Bioethics and Health Policy at the Johns Hopkins Berman Institute of Bioethics.

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One Response to “Genetic Risk for Hereditary Cancer”

  1. […] an insightful piece published in the Berman Institute Bioethics Bulletin, a publication of the Johns Hopkins Berman […]

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