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To Screen or not to Screen: Large Israeli Cancer Genetics Study Shows Limits of Family History


NEW YORK (GenomeWeb) – Genetics researchers in the US and Israel have screened more than 8,000 healthy Ashkenazi men for three cancer-associated BRCA mutations and gauged in an unbiased fashion the risk these markers pose to female relatives irrespective of a personal or family history of the disease.

Noting that half of the tested men with BRCA mutations came from families without a strong history of breast and ovarian cancers, the authors, led by Ephrat Levy-Lahad of Shaare Zedek Medical Center in Israel, concluded that their study provides support for implementing a general screening program for these markers for all Ashekanzi Jewish women from age 30 and could even provide a springboard for investigating under what circumstances cancer genetic screening strategies may be appropriate in the broader population. The trial was funded by several cancer research foundations in the US and Israel, and involved among the authors genetics and breast cancer research pioneer Mary-Claire King from the University of Washington.

Among Ashkenazi Jews, 2.5 percent of the population harbor three mutations – BRCA1 185delAG, BRCA1 5382insC, and BRCA2 6174delT – which account for most of the inherited cancer risk in the population due to BRCA mutations. In this group, 11 percent of breast cancers and 40 percent of ovarian cancers in women are a result of inheriting these mutations.

Despite the higher prevalence of BRCA mutations in the subgroup, population screening irrespective of family history is not currently provided within Israel's single payor healthcare system. Ashkenazi Jews comprise 35 percent of the country's total population.

However, since the 2000s, nationally sponsored non-genetic screening initiatives (ie. mammography) have helped doctors identify more early-stage breast cancers, and avoid more deadly invasive tumors, according to the Israel Cancer Association. Approximately 4,500 women are newly diagnosed with breast cancer annually, and 900 women die from the disease. Among diagnosed women, the percentage of those with early-stage disease increased from 57 percent in 2007 to 62 percent in 2009.

The prevalence of BRCA mutations in Ashkenazi Jewish population, coupled with increasing early-stage breast cancer rates, has sparked debate in the country about the risks and benefits of a broad genetic screening strategy. "Young women in these families would not have been tested in the absence of a general screening program," Levy-Lahad and colleagues noted in their study published in the Proceedings of the National Academy of Sciences. "This study is performed in the Ashkenazi Jewish population, but its results are widely applicable," they further concluded.

According to the authors, the cancer incidence among the Ashkenazi Jewish population in Israel fulfills the WHO criteria for population screening for these markers. The researchers also asserted that "the time has come to apply our knowledge of these genes to consideration of a general screening program, with the aim of reducing the burden of breast and ovarian cancer."

This recommendation for genetically screening the general population is likely to be unpopular among healthcare policymakers. In recent years, the medical community in the US has pulled back non-genetic, annual screening strategies for a number of cancer conditions. For example, US Preventive Services Task Force (USPSTF) has controversially recommended that a woman start getting mammograms begin at age 50, instead of age 40, and has indicated that the screening frequency should be every two years instead of annually. Although other expert groups disagree with this recommendation, the USPSTF's guidelines stem from concerns that diagnostic advances are identifying early-stage tumors that wouldn't threaten a woman's life and leading to unnecessary treatment.

Following the publication of the paper from Levy-Lahad's group, the National Society of Genetic Counselors issued a statement noting that the US healthcare system is unprepared to implement a population-based genetic testing scheme.

In the Ashkenazi population one in 40 people will carry a BRCA mutation, while in the general US population these mutations show up in between 1 in 300 people to 1 in 500 people. "When we have a population that has a higher likelihood of having a mutation, it makes sense to do screening," Joy Larsen Haidle, president-elect of NSGC, told PGx Reporter. Also, because only three BRCA mutations confer the majority of cancer risk from those two genes, broadly testing for these markers would be cheaper and easier to interpret than it would be in the general population.

Outside of the Ashkenazi Jewish subpopulation, people harbor mutations in genes other than BRCA that confer a risk for breast and ovarian cancer, and not all of these markers are fully understood in terms of their association to disease. Even testing the general population just for BRCA1 and BRCA2 mutations would reveal markers with unclear links to breast and ovarian cancer. With growing adoption of sequencing tools in cancer treatment, a broad screening program would face cost hurdles and introduce the risk of finding these so-called variants of unknown significance (VUS).

"For the general US population, we would have to do full sequence and large rearrangement analysis of both BRCA1/2 because there are thousands of mutations reported in those genes in individuals of other ethnic backgrounds," Larsen Haidle said. "So, the cost of that type of a test ranges from between $2,000 to up to $4,000 dollars. And we'd have to have agreement on the type of test being done and the quality because … they are not all identical with regard to how well BRCA1 and BRCA2 are covered." Comparatively, testing for three specific mutations important for the Ashkenazi Jewish population amounts to a few hundred dollars, without factoring in the cost of follow up medical interventions.

To date healthcare policymakers have limited testing to women with a family history of breast and ovarian cancers. For example, the USPSTF in December 2013 released updated screening guidelines for BRCA1/2 mutations recommending testing in this manner.

However, the Levy-Lahad team tried to show in the PNAS paper that a screening strategy based on family or personal history of cancer would miss a lot of women at risk of breast and ovarian cancer due to BRCA mutations. The researchers approached the study unconventionally, by screening approximately 8,200 healthy Ashkenazi Jewish men between 2004 and 2010. They had to be at least 30 years old with no personal history of cancer. The patients who agreed to participate were tested for the three high-penetrance BRCA mutations.

Researchers identified 172 men who carried a mutation in either BRCA1 or BRCA2; three men carried a mutation in both genes. They then asked these male carriers to recommend their female relatives for testing. Out of approximately 431 women enrolled, Levy-Lahad and colleagues identified 211 women with BRCA mutations. Among these women, the cumulative incidence of breast or ovarian cancer was 0.60 by age 60 and 0.83 by age 80 for BRCA1 mutation carriers; and 0.33 and 0.76, respectively, for BRCA2 carriers. Among the families found to carry BRCA mutations, 51 percent had little or no history of breast and ovarian cancers.

Indeed, a screening strategy that depends heavily on family or personal history has serious limitations. Family members can refuse to reveal their medical history and doctors are often not skilled in ascertaining family history accurately. Surveys have revealed that only 19 percent of primary care physicians in the US accurately took a family history for BRCA1/2 testing, while in France relatives of mutation carriers who should receive testing often don't get it. In this study, Levy-Lahad noted that doctors had referred for genetic counseling only 35 percent of families with a high cancer incidence.

Advances in diagnostic technologies make it possible not to rely so heavily on family history and identify more people at risk of cancer, the PNAS study authors suggest. "It is now possible to identify, in one test and at reasonable cost, all actionable mutations in BRCA1 and BRCA2, as well as in all other known breast and ovarian cancer genes," Levy-Lahad and his team noted in their study. Next-generation sequencing based panels interrogating a panel of disease-linked genes can now identify more patients at risk of hereditary cancers compared to older, single-gene tests.

Myriad Genetics, for example, recently published a study showing that its 25-gene, next-generation sequencing myRisk Hereditary Cancer panel identified variants in BRCA1 and BRCA2 in 9.3 percent of 1,781 breast cancer patients, and mutations in other cancer susceptibility genes in an additional 4.3 percent of patients. Similarly, other companies such as InVitae and GeneDx have developed multigene hereditary cancer tests. King's lab from the University of Washington also performs a hereditary cancer panel called BROCA.

While these more powerful tests can identify additional patients with deleterious cancer mutations, they also have the capability to pick up greater numbers of VUS, and this is where it becomes tricky for policy makers to back population-based genetic screening.

While in the Ashkenazi Jewish population three BRCA mutations confer a majority of the genetic risk for breast and ovarian cancer, there are many mutations within these genes that could be associated with disease risk for the general population. Some of them are so infrequently seen in people that researchers don't yet know whether they are associated with cancer risk. "To extend population screening to the general population, not just Ashkenazi Jewish individuals, the variation found in those BRCA genes is extensive," Heidi Rehm, chief laboratory director of the Laboratory for Molecular Medicine at Partners Healthcare Personalized Medicine, told PGx Reporter. "And we've now launched major projects to bring all this data together."

VUS are a major bottleneck in genomics research, and Rehm is part of several projects trying to bring the life sciences community together around classifying these variants. One such program is ClinGen, a National Institutes of Health-funded effort to build a public, annotated database of genomic variants (called ClinVar) using standardized classification methods. The aim of this effort is to lower the VUS rate in all genes, including BRCA1/2.

The Global Alliance for Genomics and Health recently launched another project focused on improving understanding of BRCA variants. The effort, dubbed the BRCA Challenge, is trying to collect information on BRCA mutations from researchers and labs around the world and get consensus around the markers that are benign and those that are deleterious, and research those that remain uncertain.

Levy-Lahad's group recommends focusing screening strategies for the general population on "clearly damaging mutations" that are "considered to be sufficiently actionable to require reporting." But getting the research community and policy makers to agree on which markers are clearly deleterious isn't easy. In fact, there is hardly consensus in the medical community around when to report well-vetted and known deleterious mutations.

The American College of Medical Genetics and Genomics (ACMG) recommended last year that for patients who have had their exomes or genomes sequenced, doctors should report to them clinically actionable mutations they might have on a list of 56 genes linked to a risk for various medical conditions. BRCA1/2 mutations are included in this list.

The recommendations didn't receive a warm reception from many in the medical community, who felt that patients should have the option of not learning unexpected or unwanted incidental findings. Based on this feedback, the group revised its guidelines to allow patients to opt out of having the genes on the list analyzed when their exomes and genomes are assessed in a lab.

Rehm, a member of the ACMG working group that authored the recommendations, is generally supportive of reporting patients' incidental findings when there is a strong medical reason to do so, but she acknowledges that there are situations where the patients can make an educated decision to not know. "When a patient sees a doctor for a skin rash on their arm, and the physician incidentally notices a melanoma, they would not have had a discussion in advance requiring opt-in [for the patient] to receive that information. They're just going to say, 'There's a melanoma on your arm,'" she said. "Similarly, if we think that genetic information is useful or at least learning about pathogenic variants in a short list of disorders with actionable approaches is useful, then let's take the approach we take in medicine and return that very useful information."

But then, Rehm also can envision situations where a patient may be justified in refusing to learn an incidental finding. She gave the hypothetical example of a person with a concussion from a bike accident, who has to get a brain scan to look for other adverse effects of the injury. This person, however, has a strong family history of Huntington's disease, and knows he or she is at risk for inheriting a mutation. "There is no treatment for Huntington's and the person might not want to learn any information related to that," Rehm said. "As a physician I would absolutely respect that wish, which was clearly made … by a patient educated about the disorder."

A population-based genetic screening program would cast a much wider net, identifying never-before-seen mutations in patients, and physicians would encounter far more complex scenarios where they would have to weigh the benefits and risks of revealing the findings to the patient. "When you're arguing for population-based screening, as opposed to opportunistic use of existing data, there is a different cost and risk model you need to look at," Rehm said. Particularly as advanced sequencing tests pick up more VUS in people, "the question becomes, 'Have you done more harm than if the patient had never been screened, never had that information?'"

This article has been updated with additional Israeli breast cancer incidence statistics.