Analysis identifies genomic treatment targets in African American men with prostate cancer

Joshua Campbell, PhD

Researchers have identified genes more commonly altered in tumors from African American men with prostate cancer, opening the potential to develop precision medicine therapies for these patients.^1,2

"These results reinforce the idea that there can be biological differences in prostate cancers between different ancestral groups and that samples from Black Americans need to be included in future molecular studies to fully understand these differences," co-corresponding author Joshua Campbell, PhD, assistant professor of medicine at Boston University School of Medicine (BUSM), stated in a press release.

Despite detecting these novel genomic differences, the study also found that genomic alterations in therapeutic targets related to currently available treatments occurred at similar frequencies in African American men and men of European descent, indicating the treatments should be beneficial in both groups.

Franklin Huang, MD, PhD

“The poorer health outcomes we see in Black men with prostate cancer are not easily explained by any of the distinct gene mutations we identified in prostate tumors from men of African ancestry. This highlights the need to examine the environmental and social inequities that are well known to influence health outcomes across the board,” co-corresponding author Franklin Huang, MD, PhD, an assistant professor in the UC San Francisco (UCSF) Division of Hematology/Oncology and member of the UCSF Helen Diller Family Comprehensive Cancer Center, UCSF Institute for Human Genetics, and UCSF Bakar Computational Health Sciences Institute, stated in the press release.

“On the other hand, our tumor genomic analysis also showed that current precision medicine approaches ought to be as effective in Black Americans as they have been for other groups—if we can ensure that these drugs are applied equitably going forward," added Huang.

Investigators from BUSM, UCSF, and Northwestern University undertook the study because, despite the prostate cancer mortality rate being higher in African Americans than any other racial/ancestral group, there is a paucity of available data regarding potential differences in somatic gene alterations in tumors in African American men compared to other populations. These potential differences remain unknown because African American men have not been well-represented in genomic research.

The study included data from 4 publicly available datasets that comprised 250 African American men and 611 European American men with prostate cancer, as well as data for 436 African American men and 3018 European American men obtained from a targeted sequencing dataset from a commercial platform. The investigators evaluated the occurrence of somatic alterations in prostate cancer in these patient populations.

Results showed that, in tumors from African American men, focal deletions in ETV3 and mutations in ZFHX3 were more common. CCND1 amplifications and KMT2D truncations were detected more often in in primary prostate cancer from African American patients. TP53 mutations were linked with an increasing Gleason score. Rearrangements in TMPRSS2-ERG and PTEN deletions were detected less frequently in tumors from African American patients. MYC amplifications occurred more commonly in tumors from African American men with metastatic prostate cancer.

“Additional studies that profile large numbers of well-matched tumors from African American and non–African American men from the same clinical setting will be needed to confirm the novel associations reported in this study and to understand the clinical significance,” the investigators wrote.

As noted, significant differences between the 2 groups were not detected, however, in genomic features related to FDA-approved treatments. These features included microsatellite instability (MSI) status, tumor mutation burden (TMB), and genomic alterations in AR, select DNA repair genes, and CDK12. Thus, approved treatments, such as the immune checkpoint inhibitor pembrolizumab (Keytruda) for patients with TMB-high tumors, and PARP inhibitors for patients with BRCA-mutated (rucaparib [Rubraca]) or HRR-mutated (olaparib [Lynparza]) tumors, should equally benefit both patient populations.

Looking ahead, Campbell stated, “These types of studies will remain important to understand when certain therapies may preferentially benefit Black patients, who continue to remain underrepresented in clinical trials.”

Specifically, the authors noted that the results will inform the ongoing efforts of the National Cancer Institute–supported RESPOND study. The RESPOND study is partnering with African American communities nationwide to enroll 10,000 African American men with prostate cancer to improve the overall understanding of the specific drivers of prostate cancer’s highly disproportionate burden on African American men.

"Previous studies have looked in isolation at different biological, social, and environmental drivers of well-known racial disparities in prostate cancer,” stated Huang. “RESPOND is a nationwide effort to integrate all these components and ultimately identify specific steps that can be taken to eliminate prostate cancer’s unequal burden in Black communities.”

References

1. Largest-Ever Study of Prostate Cancer Genomics in Black Men IDs Potential Targets for Precision Therapies. Published online July 10, 2020. https://bit.ly/38QnIrq. Accessed July 13, 2020.

2. Koga Y, Song H, Chalmers ZR, et al. Genomic profiling of prostate cancers from men with African and European ancestry [published online July 10, 2020]. Clin Cancer Res. doi: 10.1158/1078-0432.CCR-19-4112