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African American Prostate Cancer Patients Get More VUS, Fewer Actionable Results, Studies Show

NEW YORK – African American men with prostate cancer are receiving more limited germline genetic testing for cancer risk and getting more uncertain results, researchers reported at the American Society of Clinical Oncology's annual meeting in Chicago on Monday.

There, Veda Giri from Thomas Jefferson University and the Sidney Kimmel Cancer Center's Cancer Risk Assessment and Clinical Cancer Genetics Program described differences in the types of variants identified in African American prostate cancer patients undergoing cancer susceptibility testing.

"Germline testing for prostate cancer is central now to informing treatment in metastatic, castration-resistant disease," Giri explained, adding that "there's an evolving role [for germline testing] in the localized disease management setting, as well."

In individuals with prostate cancer, germline genetic testing can be used to gauge inherited disease risk, classify tumors, guide treatment, predict prognoses, and inform access to appropriate clinical trials. When testing identifies a patient with a germline mutation in a cancer-risk gene, such as BRCA1 or BRCA2, for example, doctors may decide to follow that patient more closely for disease relapse and encourage family members to get tested for the same risk variant.

Current National Comprehensive Cancer Network (NCCN) guidelines call for germline genetic testing in individuals with metastatic prostate cancer as well as in prostate cancer patients from other high-risk groups based on disease presentation, ancestry, or family disease history. The guidelines further state that germline testing "may be considered" in patients with intermediate-risk prostate cancer or if they have prostate cancer and a history of certain other tumors, such as in the pancreas, colon, or intestines.

Research teams have suggested that these guidelines miss a subset of individuals with cancer susceptibility.

Although prostate cancer disproportionately burdens African American men in comparison to men of other ancestries, Giri said, germline testing rates tend to be low in this patient group, potentially contributing to an inability to fully understand the suite of germline variants that bump up cancer susceptibility in African American men and in their families.

She and her colleagues looked at data from 427 prostate cancer patients — 190 white and 237 African American men — who had germline cancer susceptibility testing on a 14-gene panel from April of 2012 to the end of 2020. Most of the men had a family history of prostate cancer or another cancer type, namely a first- or second-degree relative with cancer.

All told, the team tracked down pathogenic or likely pathogenic germline variants in more than 8 percent of the prostate cancer patients, Giri reported. When those results were broken down by ancestry, though, germline risk differences became clear.

While germline testing unearthed risky genetic variants in more than 11 percent of white men with prostate cancer, they flagged such variants in fewer than 6 percent of the African American prostate cancer patients.

The suite of affected genes also tended to be more limited in the African American men, who most often carried known pathogenic or likely pathogenic variants in genes such as BRCA2, PALB2, ATM, or BRCA.

In contrast, variants of uncertain significance (VUS) rates jumped from just over 16 percent in the white participants to more than 25 percent in the prostate cancer patients with African American ancestry. Just one man in the white group had multiple VUSs, compared to 12 African American men. Across the full cohort, 21.3 percent of prostate cancer patients had VUSs in their germlines.

"Our results confirm prior studies of the narrower spectrum of pathogenic variants in African Americans compared to white males when uniform multigene panel testing is employed," said Giri. She further called for broader panel testing so the field can better understand the germline variants that contribute to prostate cancer risk in the African American men and improve the treatments available to them.

She noted that additional functional studies bringing to bear RNA sequencing, familial testing, and other approaches will be needed to classify the higher rate of VUSs being identified in African American men. Additional details on Giri and colleagues' analysis were published in the JCO Precision Oncology on Monday.

"There's a critical need to engage more African American males and families in genetic testing and in research," Giri emphasized. "Collaboration across medical disciplines, genetic counseling, community outreach, engagement, and advocacy is essential to enhance equity in germline testing."

The results echo and expand on those reported by other teams, both at the current ASCO meeting and in the past.

At the American College of Medical Genetics and Genomics virtual annual meeting in 2020, for example, Invitae genetic counselor Sarah Nielsen shared data on germline genetic risk variants found in prostate cancer patients enrolled in Invitae's Detect Hereditary Prostate Cancer program.

Among more than 2,250 participants profiled in that analysis, the Invitae team saw particularly low rates of prostate cancer-related pathogenic variants in germline tests from participants with African American or Asian ancestry.

Likewise, data from a nationwide, prospective prostate cancer registry developed by the PROCLAIM Consortium in collaboration with Invitae so far suggests that pathogenic variant detection tends to be lower in nonwhite participants, while VUS rates rise. At the same meeting, Neal Shore, medical director of the Carolina Urologic Research Center, shared prostate cancer-related germline genetic data from that effort for 982 prostate cancer patients.

The participants were treated at more than a dozen community or academic cancer care sites across the country and received germline genetic testing on Invitae's 84-gene panel test. In this project, investigators intentionally included individuals who did not meet NCCN 2019 criteria for germline genetic testing, Shore said. About half of patients met NCCN criteria.

In that analysis, just over 21 percent of study participants were nonwhite, but made up just 4 percent of cases with pathogenic germline variants and nearly 69 percent of the VUS cases. These disparities are expected to impact clinical care.

The presence of pathogenic germline variants in the study led to treatment changes in about 18 percent of carriers, including some patients who would not be eligible for testing under existing criteria. Treatment follow-up plans changed or intensified for 64 percent of those with a pathogenic germline variant, Shore reported. And in most cases, family members of patients with pathogenic germline variants also went on to get genetic counseling and/or genetic testing.

In another talk in the same session, Hiba Khan, a fellow at the Fred Hutchinson Cancer Center, outlined results from the exploratory GIFTS (Genetic information to inform testing and screening for prostate cancer) study, which considered germline genetic testing uptake among men with metastatic prostate cancer, as well as potential barriers to testing.

The GIFTS team recruited advanced prostate cancer patients using a population-based strategy using the Cancer Surveillance System in western Washington state and, between early 2018 and March 2022, tested them for germline risk variants, particularly for mutations in DNA damage response genes such as BRCA1/2, CHEK2, or ATM.

"The impact of having pathogenic variants in these genes can be broad and significant," Khan noted, explaining that pathogenic variants in DNA damage response genes may help direct patients to precision therapies or clinical trials, provide prognostic clues, and inform family members of cancer risk or recommended screening strategies.

For example, in the US, several PARP inhibitors, including Merck's Lynparza (olaparib) and Clovis Oncology's Rubraca (rucaparib), are approved for metastatic castration-resistant prostate cancer patients with defects in DNA damage repair, and many others are being explored in clinical trials.

In the GIFTS trial, researchers identified ethnicity-related differences in germline genetic test uptake among the metastatic prostate cancer patients, who are all recommended to have such testing. "We know that disparities in genetic testing do exist in nonwhite and more vulnerable populations," Khan said.

She acknowledged that in the GIFTS trial, white or Native American patients with metastatic prostate cancer were more likely to respond to an invitation to participate in the study and complete a questionnaire, while the number of patients with African American, Asian, Pacific Islander, or unknown ancestry who responded and ultimately enrolled was much lower.

"There have been significant discoveries in the area of hereditary cancer research. But still, much work needs to be done in the area of clinical implementation," appealed Kathleen Cooney, interim director of the Duke Center for Applied Genomics and Precision Medicine, while discussing all three studies at the ASCO meeting. It will be "absolutely critical that we include diverse populations in our work."