Study of South African Males With Prostate Cancer Reveals Limits of Current Germline Testing

A deep dive into the genetic variants of Black South African men with prostate cancer revealed that the genes tested in current germline panels may not be adequate for those with African ancestry, indicating that testing guidelines specific to ethnicity are needed in prostate cancer.

The findings, published today in the Journal of the National Comprehensive Cancer Network (JNCCN) add to the evidence—and frustration—that oncology’s shift to precision medicine has been built on data developed largely from patients with European ancestry, making everything from genomic tests to therapies to clinical guidelines less effective for patients of color.

Investigators from South Africa and Australia collaborated in the study, which used deep sequencing to interrogate the 20 most common germline testing panel genes in 113 Black male patients from South Africa who had advanced prostate cancer. As the authors note, current NCCN guidelines call for germline testing for patients with metastatic, regional, very-high-risk localized and high-risk localized prostate cancer.

However, right now, there are no specific testing criteria for ethnic minorities, despite the fact that Black men in the United States are more likely to be diagnosed with prostate cancer and twice as likely to die from the disease as White men. In sub-Saharan Africa, the authors wrote, death rates are even higher: Mortality for Black men with prostate cancer is 2.7 times higher than global estimates.

The authors say their study is the first of its kind. They used variant data from the 20-gene panel made available from the South African Prostate Cancer Study Data Access Committee, and the sequence data were deposited in the European Genome-Phenome Archive. The genes selected for study were based on current NCCN guidelines.

DNA was collected from whole blood samples of the 113 patients. From these samples, investigators identified 38 predicted deleterious variants (PDVs) and 1 predicted deleterious structural variant (SV) in 16 genes. Additional annotation of the data classified 17 variants as potentially oncogenic; this represented 12 genes and 17.7% of the patients. According to the authors, rare pathogenic variants included CHEK2 Arg95Ter, BRCA2 Trp31Arg, ATM Arg3047Ter (found in 2 patients), and TP53 Arg282Trp.

Important oncogenic variants of unknown pathogenicity included novel BRCA2 Leu3038Ile in a patient with early-onset disease, as well as patients with FANCA Arg504Cys and RAD51C Arg260Gln who reported prostate cancer in their family history.

The authors found that rare pathogenic and early onset or familial-associated oncogenic variants were seen in 6.9% (5/72) of patients with a Gleason score of at least 8 and 9.2% (8/87) of patients presenting with a Gleason score of at least 4+3 prostate cancer.

“Noting that 10.2% of the PDVs/SVs were novel, we find that the bias toward variants of uncertain pathogenic significance, together with the identification of a single known [prostate cancer] pathogenic variant, CHEK2 p.Arg95Ter, further emphasizes the need for further African-specific investigation to establish tailored [prostate cancer] screening panels,” they concluded.

The authors called on entities that develop clinical guidelines to revisit their diagnostic inclusion criteria and called for “further genome-wide interrogation to ensure the best possible African-relevant prostate cancer gene panel.”

“Comprehensive genomic testing, including germline testing, holds a key not only to identifying targeted therapies in patients with homologous recombination deficiency, but also would enable science to understand unexplainable differences in outcomes,” said Kashyap Patel, MD, an oncologist who is CEO of Carolina Blood and Cancer Care Associates. Patel’s patients include many racial and ethnic minority men with prostate cancer.

“These findings are just a start, but this type of knowledge will enable new drug development that may be reflective of truly personalized approaches,” he said.

Reference

Gheybi K, Jiang J, Mutambirwa SBA, et al. Evaluating germline testing panels in Southern African males with advanced prostate cancer. J Natl Compr Canc Netw. 2023;21(3):289-296.e3. doi:10.6004/jnccn.2002.7097