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BRCA Screening Guidelines Too Reliant on Family History, Stakeholders Tell USPSTF


This article has been updated to clarify the consumer-facing genetic testing models of Invitae and Color.

NEW YORK (GenomeWeb) – Patient advocates, researchers, and leading testing labs are disappointed with the US Preventive Services Task Force's draft recommendations on genetic testing for BRCA-related cancers for not reflecting the growing body of evidence that shows that a family history-focused screening strategy misses a significant swathe of the at-risk population.

The USPSTF, an independent expert panel appointed by the HHS' Agency for Healthcare Research and Quality that issues recommendations on preventive services, recently published a draft statement on how primary care doctors should assess patients for their risk of cancers associated with BRCA1 and BRCA2 mutations, and determine if they should receive further counseling and genetic testing.

The group has proposed that doctors should first use a screening tool to determine if there is a family history of certain cancers, or if the patients is of an ethnicity (e.g. Ashkenazi Jewish)  that places them at high risk for cancer. If so, doctors should refer these patients for genetic counseling, and provide genetic testing upon the counselor's recommendation. However, the group has recommended against routine screening, counseling, or testing for women without a family or personal history of cancer and for those who don't belong to a high-risk ethnic group. This latest statement is similar to the USPSTF's recommendations from 2013, except there is more emphasis on using ethnicity as a factor for deciding who should receive counseling and testing.

Compared to women in the general population, who by 70 years of age have an 8 percent chance of getting breast cancer and a 2 percent chance of getting ovarian cancer, women with BRCA1/2 mutations have up to a 65 percent chance of getting breast cancer and a 70 percent chance of getting ovarian cancer by that age. It is estimated that 1 in 400 people in the general population have a mutation in one of these genes and 1 in 40 people of Ashkenazi Jewish descent have them.

Stakeholders have until March 18 to provide feedback to the USPSTF on these draft recommendations. Experts in the genetic testing industry and population health researchers have criticized the USPSTF for relying too heavily on family history in the face of evidence that doing so miss a lot of at risk individuals.

"They call themselves the Preventive Services Task Force but … I think they've missed the boat when they rely so heavily on family history," said Robert Nussbaum, chief medical officer at Invitae, a molecular diagnostics firm that aims to provide affordable comprehensive genetic testing services and has done research to try to illustrate the insufficiency of existing testing guidelines.

Color, another low-cost genetic testing provider, is also of the view that the USPSTF's recommendations will miss a lot of opportunities for cancer prevention. "There is an abundance of data that shows that 50 percent of individuals who have a [pathogenic] BRCA1 and BRCA2 variant do not meet clinical criteria for having a personal or family history of cancer and therefore would be missed by this type of recommendation," said Alicia Zhou, Color's VP of research and scientific affairs. "We think the right thing to do is give more people access to this technology rather than limiting the access."

Others have pointed out that while the USPSTF's draft statement mentions ethnicity as a high risk factor along with family history, there is enough evidence to propose a population screening strategy in the Ashkenazi Jewish population, for example. Still others noted the USPSTF's failure to address screening strategies for men, who can not only help identify mutations in families that would otherwise be missed, but are themselves at increased risk for prostate cancer when they are BRCA mutation carriers.

USPSTF member Carol Mangione explained that the group's charge is to issue recommendations based on an evaluation of the evidence on the benefits and harms of a screening intervention. In this case, the group identified evidence showing that testing more people for BRCA mutations would increase the false-positive rate and expose more women to unnecessary imaging tests, mastectomies, and oophorectomies.

The USPSTF has particular concerns that a broader screening strategy would result in more people getting unclear BRCA test results, in the form of variants of unknown significance, and that this might exacerbate anxiety and prompt unnecessary surgeries. "It's very important to realize that there are harms associated with these tests," said Mangione. "Until we have a good feel for the magnitude of those harms and the magnitude of benefit, we can't really come out with a solid recommendation."

Balancing benefits and harms

Pioneering breast cancer researcher Mary-Claire King co-led a study that kickstarted an international conversation about the need to expand existing BRCA testing guidelines that decide who should be tested largely based on a personal or family history of cancer. In this study, published in 2014 and involving 8,000 healthy Ashkenazi Jewish men, researchers led by King and Ephrat Levy-Lahad of Shaare Zedek Medical Center in Israel, showed that half the men who had one of three BRCA1/2 mutations prevalent in the Ashkenazi Jewish population came from families without a strong history of breast and ovarian cancers.

Men rarely get breast cancer, and modern families are smaller. As such, this study demonstrated that not only can these mutations be passed on from fathers to daughters, but also the pitfalls of relying too heavily on a family history of breast and ovarian cancer to determine who should receive BRCA testing. In a recent interview with CNN, King said the USPSTF was "short sighted" in issuing its draft guidelines, which "could cost lives."

Inspired by King's work, however, genetic testing companies like Color and Invitae in the US have embraced a consumer-facing model in which individuals can ask their doctors to order hereditary cancer testing and pay a few hundred dollars out of pocket for it, or go online and initiate the testing themselves and a doctor from a third-party physician network will approve the order. The aim is to make cancer risk testing more accessible to individuals who may find it difficult to get insurance coverage because the tests don't meet USPSTF and other guidelines.

USPSTF's Mangione acknowledged the Israeli study, but said more research is needed.

Since the Israeli study was conducted, several studies in the US have come to similar conclusions. Geisinger Health System in Pennsylvania, for example, published research involving more than 50,000 individuals who had their exomes sequenced. Within this cohort, 267 had pathogenic variants in BRCA1/2, of which 55.4 percent were women and 44.6 percent were men, and 82 percent of carriers had not been previously tested. Researchers concluded that the prevalence of BRCA1/2 variants in the general population may be much higher than previously thought and that existing family history-based guidelines were missing a lot of carriers who could benefit from this knowledge.

Responding to the criticism that the USPSTF is leaving out men at the detriment of public health, Mangione pointed out that the task force is recommending doctors consider family history on the father's and mother's side using standardized screening tools, which would help identify the risk arising in both sides of the family.

However, recent research has demonstrated that men with BRCA mutations are also at increased risk for prostate cancer at a younger age and for more aggressive disease. "There's nothing in the guidelines that takes into account the evidence on prostate cancer," said Nussbaum.

The management of a man's cancer risk and how testing might benefit men, was beyond the scope of this evidence review process, Mangione said. Anyone can nominate a topic for the task force to consider, and there is a process by which the USPSTF decides, based on the available evidence, which topics to take up. Should a member of the public suggest the group evaluate the topic of testing men for BRCA mutations, "it's very possible that the task force would take this up in the future," Mangione said.

Some stakeholders have noted that it's about time USPSTF address the need for confirmatory testing for individuals who find out from consumer genetics companies, such as 23andMe, that they are BRCA mutation carriers. Mangione agreed this is a topic of increasing importance, but said there is not enough evidence for the USPSTF to address this in recommendations.  

"When patients come in with positive results, I refer them to genetic counselors and hopefully, with careful counseling, the ones who need confirmatory tests get them," said Mangione, chief of general internal medicine and a primary care physician at the University of California, Los Angeles. "But right now there are not studies supporting what you should do with those test results."

While the taskforce couldn't address this issue in the latest guidelines, Mangione recognized "this is an evidence gap and it is something that we definitely need more research in."

She noted that the task force reads and considers all public comments, which could lead the group to refine language in the clinical considerations section of the recommendations and note areas for further research, which funding bodies pay attention to. "But between the draft recommendation and the final recommendation the evidence review can't be redone," which is a two-and-a-half to three-year process, Mangione said.

Policy lags behind research

The debate around whether to broaden BRCA screening recommendations is not unique to the US, and there are examples around the world where despite advancing research, policy has lagged behind. Based on the large Israeli study, King and others have been advocating for the Israeli government to implement a screening program for the three BRCA founder mutations for all Ashkenazi Jewish women from age 30, regardless of family history, but this has yet to be achieved. In the Ashkenazi Jewish population in Israel, the three mutations account for 11 percent of breast and 40 percent of ovarian cancers.

In the UK's National Health Service, genetic testing to assess cancer risk is offered to individuals from high-risk families or if there is a known mutation in a family and a family member requests a referral to a genetic clinic. However, researchers published a study in 2014 involving 1,000 Ashkenazi Jewish men and women recruited from a north London Jewish community and randomly assigned them either to an arm where everyone was tested for the three founder mutations, or to an arm that followed the NHS' family history-based criteria. There was no difference between the arms in terms of anxiety, emotional distress, and quality of life, but the study found that 56 percent of individuals who did not meet family history criteria had mutations.

Ranjit Manchanda, who led the above study and is a consultant gynecological oncologist at Barts Cancer Institute in Queen Mary University of London, said that there is sufficient data supporting a population screening strategy in the Ashkenazi Jewish population. "I'm not quite sure what else people want to see from the research point of view to say that we should be testing the Jewish population," said Manchanda, who recently became a fellow for the NHS Innovation Accelerator to further facilitate implementation of population screening in the Ashkenazi population.

King and others are advocating that a similar population screening approach in the US would benefit non-Jewish American women as well. Manchanda, who also advocates for such an approach not only for mutations in BRCA but other cancer-linked genes with demonstrated clinical utility, said that more research is needed before policy can be changed in this regard. A population-based screening strategy in the general population would mean the health system would have to contend with more people receiving "variants of unknown significance" (VUS), which are variants without sufficient evidence to definitively classify as pathogenic or benign. "This is an area that needs addressing," he said.

VUS aren't an issue when screening the Ashkenazi Jewish population for just three founder mutations known to be pathogenic, but they are a concern for general population screening since thousands of BRCA variants have been identified. The majority of VUS turn out to be benign, and so the American College of Medical Genetics and Genomics tell doctors not to make medical decisions based on these variants. However, there are studies and anecdotes that show that some doctors and patients may not fully understand this about VUS, and still may proceed to have mastectomies or oophorectomies, particularly if the patient already has cancer or a family history of cancer.

"We're already struggling to provide the infrastructure that's needed for the high-risk communities. [A broader screening approach] could potentially inundate the system and cause all kinds of problems," said Lisa Schlager, VP of community affairs and public policy at the patient advocacy organization Facing Our Risk of Cancer Empowered. "But that's not enough reason not to do it. The guidelines are missing a lot of people."

A population screening approach in the general population would necessitate more counseling support, education, and a standardized variant classification process. "The most important thing is going to be, once we have the test results, how are they managed and are they managed appropriately for patients and families," said Allison Kurian, associate professor of medicine and of health research and policy at Stanford University, who has done research to demonstrate the impact of increasing BRCA testing rates and uncertain results.

With decreasing testing costs, this debate around who should get tested may soon become moot, predicted Kurian. "We're in an extremely interesting time with germline genetic testing," she said. "All the rules of the game have changed now that it's become so inexpensive."

From another era

While the USPSTF doesn't factor in cost when crafting its recommendations, payors do consider how guidelines-backed screening strategies would impact their spending, and insurance coverage is a big factor in patient access. Therefore, industry players and researchers found it impossible not to mention the decreasing cost of testing when discussing the current state of BRCA screening. "The cost of access is so low that there is no longer a financial argument to withhold the information from people," said Color CEO Othman Laraki. "So, the only question is, is the information valid and is it carrying enough signal that it will benefit people's health."

The 2013 US Supreme Court's decision determining that gene sequences, as they occur in the body, are unpatentable, opened up competition and pushed down genetic test prices. "We're not going to be able to put the genie back in the bottle. There was an age of expensive, scarce testing where we had to pay $3,000 to test BRCA1 and BRCA2, and that age ended around 2013," said Kurian. "No one is going back to that age, nor do I think we want to. It's wonderful that there is inexpensive testing of many genes available. That's a huge advance for patients."

For many industry observers, however, the USPSTF's recommendations seems stuck in this bygone era. Today, companies like Color are offering next-generation sequencing-based testing for 30 cancer-linked genes (including BRCA1/2), as well as genes associated with cardiovascular conditions and pharmacogenetics, for $250.  

"Sequencing is only going to become more and more affordable," said Zhou. "I don't think we've seen the bottom of that yet, and so, to continue to be so restrictive feels a little bit outdated."

Manchanda, who is advocating for BRCA screening all Ashkenazi Jewish women, has shown that this approach is cost effective in the US and UK population for those that have one to four grandparents of that ethnicity. "There are very few interventions in medicine that save lives and money. But BRCA testing in the Jewish population is one of them," he said.

He has also done similar analysis for screening in the general population and shown that testing women in the UK and US starting at age 30 for mutations in BRCA1/2 and four other high and moderate penetrance breast and ovarian cancer risk genes is cost-effective compared to using a clinical and family history-based screening strategy. Based on this modeling, the population screening approach could result in around 17,500 fewer ovarian and 64,500 fewer breast cancers among British women, and 65,200 fewer ovarian and 237,600 breast cancers among American women. "I don't understand why the health system needs to wait for people to get cancer before we can identify other, unaffected relatives, in whom we can prevent cancer," said Manchanda.

Zhou pointed out that the NIH's All of Us Research Program is essentially an experiment in population screening. All of Us, which aims to recruit 1 million Americans, will genetically test all consenting participants and report mutations in certain disease-linked genes, including BRCA1 and BRCA2. Color is analyzing participants' genomic data within All of Us, and collaborates with experts at the Laboratory for Molecular Medicine at Partners HealthCare to address the most challenging genomic variants.

"It's the individual's choice if they want to see that result, but the design of the study reflects the consensus of experts in the field that this information is important to everyone to have," Zhou said, expressing disappointment that the USPSTF is not in line with these views. However, if the USPSTF believes there is a dearth of data to support broader BRCA testing at the moment, then the All of Us study may produce that very evidence on the benefits and risks of genetic screening in a general population.