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UK-Led Team Pushes for Broader BRCA Screening Policies With Data on Ashkenazi Population

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NEW YORK – Ranjit Manchanda knows evidence alone does not inevitably lead to policy changes. But that hasn't stopped him from generating it.

The Queen Mary University of London researcher — a clinical senior lecturer in experimental cancer medicine and consultant gynecological oncologist at the QMUL Barts Cancer Institute — is convinced that a significant number of breast and ovarian cancer cases could be staved off by screening for a handful of inherited founder mutations in the BRCA1 and BRCA2 genes in individuals of Ashkenazi Jewish ancestry.

"There is enough evidence now to support policy change in the Jewish population, but no health system across the world has done that, as yet, which I think is unfortunate," he said. "I hope decision-makers take notice of the evidence and change policy, but generating evidence and bringing change to the bedside are two different things." 

For several years, Manchanda's team has been exploring a range of issues related to population-based testing in this ancestry group, from the price tag to participant experiences.

In the American Journal of Obstetrics and Gynecology in 2017, for example, Manchanda and colleagues from the UK, Israel, and Australia tallied the cost-effectiveness of population-based germline BRCA1/2 testing in women in the UK or the US with one, two, three, or four Ashkenazi Jewish grandparents. Based on their comparisons to family history-based testing in these individuals, the authors suggested that "[p]opulation testing for BRCA mutations with varying levels of Ashkenazi-Jewish ancestry is cost-effective in the United Kingdom and the United States."

For their latest study, published online in the journal BJOG last week, Manchanda and his colleagues presented findings from a randomized controlled trial that included more than 1,000 men and women with self-reported Jewish ancestry in North London, who were randomized to receive traditional, family history-based testing or population testing for three Ashkenazi Jewish founder mutations.

"The BRCA-related risk for the Ashkenazi Jewish population is specific to these three founder mutations," Manchanda explained. "The chance of a non-founder mutation causing a BRCA-associated cancer is very small [in this population]."

Based on validated questionnaire data for the 504 individuals randomized to the traditional testing arm and 530 participants who got population-based germline testing for the BRCA1/2 mutations, the investigators did not see significant quality of life changes or adverse psychological effects associated with the population screening arm.

Instead, there appeared to be a statistically significant drop in anxiety and in the combined anxiety and depression score in the population screening arm after three years. Moreover, the team noted, the widespread screening strategy found far more BRCA1/2 founder mutation carriers than the conventional family-based approach. 

An estimated one in every 40 Ashkenazi Jewish individuals, on average, carry risky BRCA1/2 mutations. Even so, he noted, around 90 percent of carriers are not aware of their status, according to a study his team published in the Journal of Medical Genetics in 2018. That's partly due to the family-based focus of current testing strategies. But it also reflects the perennial problem of testing under-utilization in individuals who are eligible.

"There's a huge issue with limited awareness, restricted access, and under-utilization of gene testing" Manchanda said, noting that more work is needed to increase awareness among the public and health professionals.

The latest results complement the team's prior research into the feasibility of such testing, its cost-effectiveness, and potential for finding more at-risk individuals. Still, Manchanda said, "testing currently, whether it be through [the UK's National Health Service] or in any other part of the world, still is driven by family history."

He and his colleagues are trying to change that, though the process is expected to take time and occur gradually, given the complexity associated with making such policy and coverage changes in the UK's single-payer health system.

While a group called the National Screening Committee is tasked with advising the National Health Service (NHS) and government ministers on screening efforts aimed at the general population in the UK, the team's early discussions suggest BRCA screening in individuals with Ashkenazi Jewish ancestry, a specific sub-population group may not fall directly under that committee's purview.

Consequently, the researchers are starting to have important conversations with colleagues and stakeholders at NHS England (representatives from NHS England could not be reached for comment prior to the deadline for this article).

In a statement released last week, Amanda Begley, director of the NHS Innovation Accelerator (NIA), called the Ashkenazi Jewish population-based approach to BRCA testing "an innovative concept fully supported by the NIA," which has "huge potential to drive forward a new strategy of early detection and prevention to reduce the burden of cancers in the Jewish population."

In March of this year, Manchanda garnered an NIA fellowship for his work on population genetic testing. Although he sees" clear beginnings of support" in the UK, there have been, "so far, no policy changes."

"It's a process, and one will have to engage the stakeholders, looking at the context, and the model of implementation," Manchanda said.

He was encouraged by a recent development across the pond: the US Preventive Services Task Force specifically mentioned ancestry in its recently updated BRCA1/2 screening guidance, although members of the US panel "haven't quite clearly stated whether ancestry alone is enough."

"It's a big step in the right direction," he said, "but it's open to interpretation."

In Israel, Ephrat Levy-Lahad, director of the Shaare Zedek Medical Center's Medical Genetics Institute at the Hebrew University of Jerusalem, is all too familiar with the challenges associated with trying to broaden BRCA1/2 testing to encompass individuals from Ashkenazi Jewish populations.

For the past few years, she has submitted related applications to an Israeli government committee that convenes annually to review new drugs and technologies, and settle on those that will be covered by the country's national health system.

"Health systems like the UK and Israel are centralized, so there are centralized authorities that make decisions about when a technology is worth paying for, essentially. Because it's centralized, some form of government, directly or indirectly, pays for the testing and for the subsequent follow up," explained Levy-Lahad, a co-author on Manchanda's 2017 study looking at the cost-effectiveness of BRCA testing in individuals with Ashkenazi Jewish ancestry.

She is waiting to hear how that screening proposal fares this year. In the past, it was not been approved, in part, she suspects, due to financial considerations and potential social issues related to identifying and offering genetic testing to individuals from a specific ancestry group (in Manchanda's latest UK study, Ashkenazi Jewish ancestry was self-reported).

At the moment, her focus is on increasing screening specifically for individuals with Ashkenazi ancestry, which corresponds to roughly 40 percent of Israel's population. Still Levy-Lahad explained, such discussions inevitably lead to debates over even broader screening beyond individuals from high-risk ancestry groups or with strong relevant family histories.

"I don't think there are arguments as to the efficacy or the need, but I think there are concerns that depend on how you plan to implement it," she said. "The question is really whether to do population-based screening or open access screening — meaning every woman can go get tested."

Manchanda's team is doing a pilot study to take a look at the feasibility of doing broader, multigene panel testing for hereditary cancer mutations in the general population in the UK. There are also related studies underway in the US and Australia.