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Color Panel Reveals Hereditary Cancer Risk in Trinidad and Tobago Breast Cancer Patients

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CHICAGO (GenomeWeb) – Researchers from Yale University, Trinidad and Tobago's National Radiotherapy Center (NRC), and Color have identified risky inherited cancer-related variants in a pronounced proportion of women treated for breast cancer in the Caribbean country.

As they reported in a poster presented at the American Society of Clinical Oncology annual meeting here this weekend, the team used Color's 30-gene panel to search for cancer-related variants in more than 200 individuals treated for breast cancer in Trinidad and Tobago. The investigators uncovered pathogenic or likely pathogenic germline variants in more than 20 percent of the breast cancer patients profiled so far.

The project started small, but it is growing into an effort that may ultimately make hereditary cancer variant testing available to individuals in Trinidad and Tobago who bear the greatest inherited cancer risk — at least, that's what Gerneiva Parkinson hopes.

The Yale School of Medicine surgical resident grew up in Trinidad and Tobago, a Caribbean country with a population of around 1.3 million people, and was struck by the high rates of breast cancer mortality, particularly in relatively young women.

"In the United States, the average age of [breast cancer] diagnosis is early '60s. For us, it's between 45 and 50," Parkinson explained. "So something is going on, whether it's genetics or environmental."

A few years ago, she saw an opportunity to dig into the problem.

Through an initial study funded with her own savings, a fellowship she received in the US, and money contributed by her parents, Parkinson teamed up with investigators in the US and Trinidad and Tobago to do germline testing on a few dozen individuals. In the first 60 breast cancer patients profiled on a 19-gene Color panel, they identified germline risk variants in 25 percent of individuals.

"It made us think, 'Okay, maybe there is a higher rate of cancer genetic mutations in this population. And maybe that explains, or starts to explain, why women are more likely to get breast cancer at a younger age than the population in the United States."

Medical oncologist Erin Hofstatter, who co-directs Yale's cancer genetics and prevention program, is senior author on the study. She credits Parkinson for coming to her with the testing scheme, and for getting the project off the ground — from building relationships with local cancer clinicians to navigating the logistics of shipping samples to the US.

That first foray into genetic research in Trinidad and Tobago's cancer-affected population marked an important step in establishing relationships with local community members, Parkinson explained, and showing that the work could constitute a legitimate research endeavour and not "just some idea that a medical student is throwing around."

The project coincided with Color's launch in 2015, and the advent of a cheaper testing option. Before then, she said, testing came with a hefty price tag, leaving it out of reach for those without the means to purchase it privately.

After sharing their initial results, the investigators secured a Color grant to complete the larger genetic study, which aims to bring the number of individuals tested up to 250 individuals.

Using chart reviews or doctor referrals, the team recruited women with breast cancer who met current National Comprehensive Cancer Network guidelines for hereditary breast and ovarian cancer testing at the NRC in the country's capital, Port of Spain. They also considered some cases from a second treatment center in the eastern region in Trinidad.

The women participating in the study had self-reported ancestry from African, Asian, Hispanic, and other populations, with more than one-third reporting mixed ancestry. Along with two dozen women who were 60 or older, the cohort included 71 women were between the ages of 40 and 49. Sixteen of those women — more than 37 percent— had pathogenic or likely pathogenic variants identified on the Color panel.

Among the 39 women between 30 and 39 years old, the team identified 10 women with pathogenic or likely pathogenic variants in the genes tested. Three of the five breast cancer patients who were 29 years old or younger had risky inherited variants.

In the BRCA1 and BRCA2 genes, for example, pathogenic or likely pathogenic germline variants occurred in around 7.5 percent and 6.1 percent of those tested, respectively. For comparison, rates of BRCA1 and/or BRCA2 the US, which has a population that's nearly 250 times larger, mutations in BRCA1 and/or BRCA2 combined have been identified in anywhere from 5 percent to 10 percent of breast cancer patients, depending on the study.

Although there have been individual reports in some breast cancer populations about hereditary cancer variants with a prevalence similar to that being reported in Trinidad and Tobago, such patient testing typically turned up cancer-related risk variants in 9 percent to 13 percent of patients, Ranjit Manchanda, a consultant gynecological oncologist at Queen Mary University of London's Barts Cancer Institute, said in an email.

"Clearly, there is a significant proportion of cancers in the under 50s in this population," added Manchanda, who was involved in the study.

In a related poster presented at ASCO this weekend, researchers from the Mayo Clinic, Ambry Genetics, UC Irvine, and the University of Utah described variable rates of pathogenic or likely pathogenic variants identified by germline multigene panel testing on 77,900 women with breast cancer from African American, Caucasian, Hispanic, Asian, and Ashkenazi Jewish ancestry in the US.

"[T]he now documented differences in the prevalence of mutations in breast cancer genes among major racial and ethnic population in the US underscores two issues: the importance of considering all ethnicities when developing guidelines and best practices for genetic testing, screening, and management of patients predisposed to breast cancer; and a need for larger study cohorts in ethnic minority populations," Brigette Tippin Davis, Ambry Genetics senior vice president of research and development, said in a statement.

Back in Trinidad and Tobago, Parkinson and her colleagues found that the genes most prone to risky germline changes so far were BRCA1, BRCA2, PALB2, TP53, and PTEN, though several other affected genes turned up, including ATM, RAD51C, MUTYH, MSH6, CHEK2, and BRIP1. But individuals' family histories are not necessarily meshing with the types of cancer usually linked to some of the inherited cancer genes, Parkinson said.

"The defined cancer syndrome for an American or European population may not be the same definition for us," she explained.

As an example, she said, an individual with a mutation previously implicated in gastrointestinal risk might present with a fatal breast cancer and a family history of prostate cancer. Even so, she cautioned against reading too much into those patterns, since cancer is often a taboo discussion culturally in the country, making family histories difficult to discern.

Kellie Alleyne-Mike, head of oncology at the NRC and medical director at the St. James Medical Complex, was Parkinson's supervisor on the ground in Trinidad and Tobago and a co-author on the study. She further explained that the country lacks a comprehensive cancer registry or other resources that might make it more straightforward to track the population prevalence of the various cancer types more broadly in Trinidad and Tobago.

The researchers hope to do a more general study on individuals treated across additional cancer types in Trinidad and Tobago, to look at whether the germline changes predisposing individuals to certain cancer types do differ in Trinidad and Tobago — information that could theoretically inform future screening guidelines that are specific to that country rather than built on results in individuals with European ancestry.

"We've seen a lot of interesting things in the data that show that maybe the patterns that fit American models or Canadian models or European models don't really fit ours," Parkinson said. "If we were to adopt blanket standards [based on other populations] … we might miss people."

Their current efforts to profile individuals with a history of breast cancer on the smaller island of Tobago are currently at the ethics committee stage, she said.

More generally, Parkinson and her collaborators are optimistic that demonstrating the prevalence of hereditary cancer risk in the country may ultimately motivate changes to the country's national health coverage that support germline genetic testing in potentially high-risk individuals — from funding for testing services to genetic counseling.

At the moment, genetic testing is not offered in the public sector, in part because there is insufficient data to convince the government to take the leap of making that investment.

While Manchanda's own work focuses on broader population screening, he, too, noted that policy change in the genetic testing setting "requires a robust evidence base."

"That's part of the project, to help guide policy, or at least bring awareness that the government could offer genetic testing the same way it offers chemo, radiation, and surgery for free in the public sector," Parkinson said. 

The team is also making the results available to individuals and their doctors so that they and their families have as much information available as possible when making future screening or treatment decisions.