BRCA Across Borders
What is a "Hereditary Risk of Breast Cancer?"
A Comparison of the Unites States, United Kingdom and France
by Ilana Löwy and Jean Paul Gaudillière

In 1990, the media reported a "race" to clone genes responsible for hereditary forms of breast cancer, then described controversies over the patenting of BRCA (for BReast CAncer) genes and the right to develop tests to detect their mutations. These debates, and polemics around the strategy of Myriad Genetics, a Utah-based startup company that secured exclusive patents for the use of BRCA 1 and 2 genes, became emblematic of
discussions about the "ownership" of human genomes. The story of BRCA genes is symbolic of new globalizing trends that followed the recognition of patents on parcels of our genome, and is highly revealing of new relationships between science, medicine, and the market.

Public debates often assume that the "hereditary risk of breast cancer" has a single, universal meaning: the display of a mutation in a BRCA gene. This text argues that this is not the case. The universality of molecular biology, and the marketing strategies of biotechnology companies aspiring to obtain global patents, may mask the existence of important differences in local uses of products and techniques. The BRCA gene is indeed identical everywhere, but "hereditary risk of breast cancer" is not. The diagnosis and the management of such a risk reflect differences in the organization of health care and health services — that is, in different economic, social and political choices.

Ownership of Tests

Hereditary cancer risk is managed differently in the United States, the United Kingdom, and France. One important difference is the ownership of BRCA tests. In the U.S., Myriad Genetics holds a broad patent for BRCA testing, and is the sole "owner" of all routine tests that identify whether or not a person carries a mutation in BRCA genes. Cancer genetics laboratories, which until 1997 provided BRCA tests — mainly, but not exclusively, research laboratories linked to major cancer treatment centers — were obliged to halt their activities.

Myriad's commercial strategy — complete monopoly on a test — is unusual. More frequently, biotechnology companies, which own patents on a gene, sell licenses permitting the involvement of this gene in research or testing. Myriad elected to keep exclusive ownership of BRCA testing because the owners wanted to recover investments in automatic sequencing machines. (Myriad’s tests use a single method: automatically sequencing the entire BRCA gene.) In addition, because diagnostic tests, unlike drugs, do not need FDA approval, they can be marketed rapidly.

BRCA tests offered by Myriad are considered reliable, as the laboratory is highly specialized and has excellent sequencing equipment. However, it offers only routine testing services. The machines can spot only the usual point mutations (the "one letter" inversion or deletion), and cannot detect atypical mutations, such as large deletions or segment inversions. The latter comprise, according to European experts, between 10% and 20% of all BRCA mutations.

The price of a complete, automatic gene sequencing is always the same; by contrast, partial sequencing is cheaper and more efficient, especially if there is a likelihood of a mutation. One starts by sequencing regions of the gene where mutations occur frequently. Then, if no mutation is found, other regions are sequenced until a mutation is discovered, or until the whole gene is analyzed. The cost of the operation is thus lower if a mutation is found rapidly: the most expensive results are the negative ones. In France and the United Kingdom, laboratories linked to state health systems test for BRCA mutations, using these partial gene sequencing techniques.

These searches for BRCA mutations start, as a rule, with someone diagnosed with cancer. If no such person can be found, laboratories are much more reluctant to perform the test, because it is possible that, even in a family with BRCA mutations, tested individuals will not inherit the family's mutation. Testing would be expensive and the result inconclusive. Hence the practice in Europe of involving several family members in the decision to undergo BRCA testing. By contrast, from Myriad's point of view all outcomes of tests are equally profitable, and there is no reason to prioritize people who have higher chances of testing positive. The decision to test is thus usually an individual one.

In France, BRCA tests are conducted in genetics laboratories affiliated with major cancer treatment centers — a relationship which also fosters collaboration with oncologists. These laboratories combine routine tests for mutations, the search for inversions and large-size deletions, other non-standard methods of investigation, and fundamental research. Laboratories test only for mutations which increase susceptibility to malignancies. They are not interested in susceptibility to other hereditary diseases. The French affirm that their routine tests for BRCA mutations are as efficient as those of Myriad Genetics.

In the U.K., laboratories which conduct research on hereditary predispositions to cancer are distinct from those which perform routine tests. Research laboratories are funded by cancer charities and the Medical Research Council (MRC). Some conduct clinical research, and have access to patients, but are not a part of National Health Service (NHS) networks. Some specialists complain about the quality of routine testing for BRCA mutations. These tests are conducted in NHS laboratories that perform tests for numerous hereditary disorders; the lack of specialization in NHS' genetics laboratories may decrease the efficacy of BRCA testing. Cancer geneticists in the U.K. adapt to the perceived inefficacy of routine BRCA tests by downplaying their importance. They continue to ground all decisions concerning medical supervision of “at risk” women in their family history.

European laboratories refuse to recognize the validity of Myriad's worldwide patents. In fall 2001, the Curie Institute in Paris initiated a lawsuit aimed at invalidating Myriad patents in the European Union. This legal action is supported by other French and European cancer genetics centers, and courts are now debating the issue. European centers claim that Myriad’s tests are of inferior quality, since they detect only point mutations; are too expensive; and hamper research by concentrating all testing in a single provider, and by making Myriad sole owner of “libraries of BRCA mutants.”

Uses of Tests

Another source of differences is the use of BRCA tests. In the U.S., the main concerns about tests were the patterns of their prescription, confidentiality, and reimbursement. Genetic counseling is not a precondition for BRCA testing in the U.S., as any doctor can prescribe it. In practice, only about three-quarters of U.S. women who undergo testing see either a genetic counselor or a cancer expert. Though Myriad Genetics has agreements with several HMOs to provide testing for their members, and other insurers increasingly reimburse testing costs, many women who elect to be tested pay out of pocket because of confidentiality concerns and fear of possible insurance discrimination. The pending Genetic Information Nondiscrimination Act makes such discrimination illegal in several states, but many consider its protections insufficient: laws can change, and insurers may increase pressure to access genetic data.

In the U.S., BRCA testees tend to be middle-class, health-conscious women who are free of malignancy but worry about their risk. Another category is women diagnosed with breast or ovarian cancer, who have a family history of the disease, and who are treated in a major teaching and research hospital that has genetic services — often, though not always, a privileged socio-economical category.

In France and the U.K., there are no major concerns about confidentiality or discrimination. Testing is impossible without the agreement of an accredited cancer genetics expert. French women are usually directed to such experts by their doctors, though some are self-referred. French experts are interested in reaching important segments of “at-risk” women, partly because they believe these women will benefit from knowledge of their genetic status, and partly because French testing and research are conducted in the same laboratories, an increased volume of routine tests also increases research opportunities. French cancer geneticists have made a consistent effort to educate gynecologists, oncologists, general practitioners, and the general public about hereditary forms of cancer. The costs of BRCA testing are not presented as problematic, nor have they influenced medical guidelines.

However, the French health care system has not attempted to reduce inequalities in access to genetic services. Poor women have lower chances than those from more privileged social strata to become aware of their hereditary risk of breast cancer and to receive professional advice about the management of such risk. Testing for BRCA in France remains the domain of middle-class women. The main exception is women referred by oncologists; they are a more representative sample of the general population, since in France the access to expert cancer treatment is relatively independent of socio-economic status.

The implementation of routine BRCA testing in the United Kingdom was driven by the double need to provide fair access and to keep costs under control. Their pyramidal, carefully balanced referral system places issues of hereditary breast cancer predispositions at the intersection of cancer and genetics, each of which has its own regional centers.

Because the capture area of a regional cancer center is smaller than that of a regional genetics center, several of the former are often affiliated with the latter. When BRCA tests became available, health administrators feared that medical genetics services would be overwhelmed by the demand. In order to avoid the rapid expansion of costly tests, regional health authorities pre-determined an acceptable volume of genetic tests, then established a selection system for delivering them. British experts established largely arbitrary definitions of hereditary breast cancer risk levels, taking into consideration population sizes and capture areas. They set a yield of a few hundred high risk families per capture area, a population that can be followed by that area’s single cancer genetics consultant. Only women in this category are offered access to BRCA tests and to intensive medical supervision.

However, NHS and cancer charities are concerned about fair access of all women, including the economically disadvantaged, to oncology and genetic services. General practitioners's are seen as the main gatekeepers of the system, and are responsible for ensuring fair access to experts in cancer genetics. Their efforts are not perfect: women from privileged backgrounds understand the system better and can more easily obtain services.

Ashkenazi Mutations

The majority of BRCA mutations are private — that is, specific to a single family. In some populations, there are also "public mutations" — the same mutation found in the majority of hereditary breast cancer cases in these populations. The best-known are ‘Ashkenazi mutations’, identified during the 1990s in Jews of Eastern European origin. Public mutations have also been found in other populations.

The existence of an identified mutation dramatically decreases the costs of genetic testing, from approximately $2400 per test to perhaps one-tenth of this sum. This has important consequences. Ashkenazi Jewish women can be more easily directed to genetic screening, or persuade doctors of its necessity — not only because BRCA mutations are relatively more frequent in the Jewish population, but because the test will be relatively inexpensive and rapid. In addition, information about Ashkenazi genes is widely diffused in the Jewish community; many Jewish women see themselves as being at risk, and wish to be tested. There is a good fit between the offer and the demand.

Testing of Ashkenazi mutations is popular in the U.S. It has much lower visibility in the United Kingdom, and is
totally invisible in France, where ethnicity is usually underplayed in medicine (with the sole exception of diseases clearly marked as prevalent in specific populations, such as thalassemia or sickle-cell anemia). Cancer is not perceived as an "ethnic" disease, and geneticists argue that while the prevalence of breast cancer varies in different populations, hereditary cancer reflects family history only. Moreover, while health systems in Europe
are interested in limiting the overall costs of BRCA testing, decisions made on the level of individual patients are cost-blind: a woman will not be referred for testing any more readily if she is of Ashkenazi origin.

Conclusion: Framing Breast Cancer Risk

There are few things as universal as the human genome and the techniques of molecular biology used to study it. But the "hereditary risk of breast cancer" is not a fixed entity, and is instead shaped by specific technical, professional, and administrative arrangements. The meaning of a mutation in BRCA genes cannot be disentangled from ideas about natural history of breast cancer, family histories, methods of hereditary risk calculation, mutation search techniques, access to tests, the medical division of labor, and variations in clinical management.

Debates on genetic tests are usually focused either on general issues, such as the patenting of human genes, or ethical dilemmas of testing for "late onset genetic disorders" and diseases for which there is no efficient prevention or cure — or, alternatively, on the psychological difficulties of people who consider undergoing genetic testing. Such debates rarely pay attention to the technical issues linked to the uses of genetic tests. Variation in medical practices, if mentioned at all, are frequently attributed to cultural differences — Latin versus Nordic, Catholic versus Protestant, Western versus non-Western. But often the most relevant cultures one needs to study are the specific cultures of biomedicine.

Genetic tests will probably play a key role in twenty-first century medicine. It is important to continue discussing broad political and ethical issues related to the use of these tests. It is equally important not to limit debates to “big questions,” but to investigate the incorporation of values into techniques and procedures, especially into those which tend to be taken for granted in a given setting, such as the division of labor in laboratories and hospital wards, the administrative organization of medical services, or the system of health insurance. The BRCA story illustrates the need to pay attention to national and local differences in medical care, and to the sites where health, economics, politics, and law come together and determine the uses of our genetic knowledge.

Ilana Löwy is a senior researcher at INSERM, the Institut National de la Santé et de la Recherche Médicale, and a Fellow at the Radcliffe Institute for Advanced Study, Harvard University. Jean Paul Gaudillière is also a senior researcher at INSERM, and lectures in History and Philosophy of Science at Ecole Polytechnique, Paris.