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UK's NICE Seeks Comments on Updated Guidelines for Familial Breast Cancer Genetic Testing, Treatment

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The UK's National Institute for Health and Clinical Excellence has released a draft update to its guidelines for familial breast cancer testing, screening, and treatment. The draft includes new recommendations for how to determine which women should be referred for genetic testing and adds recommendations for chemopreventive therapy in some patients for the first time.

The new draft outlines several changes to how practitioners should use family history and risk assessment tools to determine which women should undergo genetic testing for hereditary breast cancer mutations.

For example, the draft updates the BRCA1 and BRCA2 mutation carrier probability threshold for referral to genetic testing to 10 percent — a change from 20 percent in the current guideline. In other words, under the new draft guidelines, clinicians are instructed to recommend genetic testing if a patient has ten percent or more probability of carrying a mutation in BRCA1 or 2, based on family history risk assessment tools.

In addition, the draft includes a new recommendation that clinical genetics laboratories record gene variants of unknown or uncertain significance, and review these periodically for evidence of causality.

This is in line with a paper from researchers at Duke University and elsewhere published last year in the European Journal of Human Genetics that urged greater sharing of data on variants of unknown significance. Among the suggestions, the authors of this paper advised payors and regulatory agencies that are part of national health systems to enact policies requiring labs and test developers to report variant data that would enable independent validation of their tests (PGx Reporter 11/2/2012).

NICE's draft update also recommends for the first time that physicians offer chemoprevention treatment to some women at high risk of breast cancer.

According to Laura Gibson, a NICE spokesperson, the institute expects to publish the final updated guidelines in June. Stakeholders have until Feb. 25 to submit comments.

"Although clinical guidelines are not mandatory, NICE would hope that the [National Health Service] begins to consider the new and updated recommendations in the guideline once the update has been published," Gibson said in an email to PGx Reporter.

According to Gibson, NICE hopes that use of these new guidelines will "help healthcare practitioners, in partnership with patients, to better identify who is at risk and how their care and future wellbeing can be optimized to detect breast cancer as early as possible when treatment is likely to be more successful, or ideally, prevent it occurring in the first place."

According to Gibson, genetic centers in the UK use various familial breast risk assessment tools to assess mutation probabilities in people with a family history of cancer. The draft guidance mentions two specifically — the Manchester scoring system and BOADICEA — which Gibson said are two of the most frequently used tools.

The Manchester scoring system scores each breast or ovarian cancer in a patient's family based on age at diagnosis, and BOADICEA is a computer program used to estimate BRCA mutation carrier probabilities on the basis of family history.

According to the research recommendation section of the draft, these methods can give variable results, and the authors call for "further research into developing and validating models for calculating carrier probability" that would incorporate additional data, such as the molecular pathology of tumors and the prevalence of mutations in different ethnic groups.

Overall, the draft update lowers its recommended probability thresholds for when to refer or consider genetic testing by at least 10 percent and in some cases 15 percent. Five specific cases are outlined.

For a person with no personal history of breast cancer, the draft guide states that doctors should "offer genetic testing in tertiary care to a family member with breast or ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10 [percent] or more," and "consider genetic testing" if their carrier probability is between five and 10 percent.

The guide also recommends that clinicians offer genetic testing to a person with no personal history of breast or ovarian cancer if their combined BRCA1 and BRCA2 mutation carrier probability is 10 percent or more, "when they have a first-degree affected relative with a carrier probability of 20 percent in the family but is unavailable for testing," and consider testing in the same case if their carrier probability is between five and 10 percent.

For patients with a personal history of breast and/or ovarian cancer, clinicians should offer genetic testing if their carrier probability is 10 percent or more and consider testing at a carrier probability of between five and 10 percent.

Myriad Genetics, which markets the bestselling test for inherited breast and ovarian cancer risk, BRACAnalysis, currently has established a presence in France, Italy, Spain, Germany, and Switzerland. There are several European labs that offer BRCA mutation testing, as well.

If followed, the new recommendations should result in more women being tested for inherited mutations in BRCA1 and BRCA2. However, Gibson wrote that there can be wide variations in how patients are treated in the real world, despite best practice recommendations.

A study last year in the US found that many breast care centers that collect information about family history are not following recommendations from the US Preventive Services Task Force to refer women with suggestive history to genetic counseling and testing (PGx Reporter 6/13/2012).

Gibson suggested similar disparities may exist in the UK. "Organizations continue to report that patients and their families experience wide variations in practice, services, and responsiveness," she wrote.

But, she added, "Although NICE guidelines are not mandatory, they are regarded as best practice and, in general, doctors, nurses, and other healthcare professionals in the NHS are expected to take account of NICE clinical guidelines when developing treatment plans for their patients," she said.

In addition to specifying probability thresholds for genetic testing referral, the new draft guide also makes a blanket recommendation against "fast track" testing — within four weeks of diagnosis — unless in the context of a clinical trial.

According to the draft, "there is no clear evidence base for rapid genetic testing at the time of diagnosis of primary breast cancer."

For those women who are found to be at inherited genetic risk of breast cancer, the draft guide also makes recommendations for the first time that NHS doctors offer, or consider, chemopreventive drug therapy.

According to the draft, clinicians must "discuss and give written information on the absolute risks and benefits … of all options for preventive treatment to women at high risk of breast cancer."

For pre-menopausal women at high risk of breast cancer doctors should offer chemopreventive tamoxifen for five years and for post-menopausal women doctors should offer tamoxifen or raloxifene for five years, unless patients have a past history of thromboembolic disease or endometrial cancer, the draft states.

For women at a moderate risk of breast cancer, meeting the same past history criteria, doctors should "consider" offering the same treatments within ten years.

According to the draft, tamoxifen and ralodifene do not currently have a UK marketing authorization for chemoprevention indications, so prescribers "should follow relevant professional guidance, taking full responsibility for the decision," and "informed consent should be obtained and documented."

"Although neither agent has a UK marketing authorization for chemoprevention in women who do not have a diagnosis of breast cancer, the [guideline development group] felt that the evidence of benefit was sufficiently strong to outweigh the potential harms of side effects and recommended their use for women at high risk of breast cancer, Gibson wrote.

"For women at moderate risk," she added, "the GDG were less certain of the balance between benefits and harms. However they agreed that it would not be appropriate to prevent women at moderate risk of breast cancer from accessing these drugs, providing they were aware of the risks and benefits."

As part of its research recommendations, the draft also pushes for a randomized controlled trial to compare the clinical and cost effectiveness of aromatase inhibitors and tamoxifen for reducing the incidence of breast cancer in women with a family history of breast or ovarian cancer.

According to the document, "such a trial could better inform women of the best available approach for chemoprevention of breast cancer."

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