Genomic Profiles Differ for African American Men With Prostate Cancer, But Current Therapies Still Work

Although there is a known predisposition for prostate cancer among African American males, research has not yet discovered why there is a disproportionate incidence and mortality rate in the African American population. The national RESPOND study is looking to determine potential underlying factors for the increased burden among African American males compared with American men of European descent and has identified novel variations among the African American population; however, an analysis from the study concluded that genomic alterations in known therapeutic targets show similar frequencies between the 2 racial groups.¹

“African American men are often underrepresented in clinical trials and genomics research, so one key takeaway is that in this study is we find that African American men have similar frequencies of genomic alterations in genes and pathways that are being targeted by currently approved drugs so they could benefit from these therapies if we ensure access to them,” investigator Franklin W. Huang, MD, of the University of California San Francisco, told Targeted Oncology.

RESPOND is an ongoing national study from the National Cancer Institute that includes a team of prostate cancer researchers and experts from across the country; it is the largest study to ever examine genetic differences in patients with prostate cancer. To carry out the study, investigators evaluated frequencies of alterations from 4 publicly available datasets. Huang and the other co-investigators used assessed the first dataset from the Pan-Cancer Atlas Project of The Cancer Genome Atlas and assessed somatic mutation calls for the second and third data sets.

Patients self-reported their racial background and overall 250 (29.0%) African American and 611 (71.0%) European American patients were included in the analysis.¹

Genomic Diversity Between African American and European American Men

The assessment revealed 15 genes present in all 4 datasets that were mutated in 2 or more patients. Somatic mutations in ZHFX3 were found at a significantly increased rate in African American patients than European American patients at 6.0% versus 2.1% respectively, (P =7E-5; false discovery rate [FDR] = 0.001). Contrarily, TP53 mutations were observed in 40 African American patients and 39 European patients (P = .02, FDR = 0.13), meaning race was not a correlating factor for TP53. Truncating mutations, however, were significantly higher among African American patients compared with European American patients (FDR = 0.05). Mutations in FOXA1 and SPOP were associated with age rather than race (FDA <0.05).

In terms of deletions, novel focal deletion peaks were observed with African American patients on chromosome 1q23.1 centered on ETV3, which was not detected in European American men. Deep ETV3 deletion frequency was also significantly higher in African American men than European American men in this analysis at 6.3% versus 2.3%, respectively (P = .021).

Tumors with deletions in ZFHX3 were significantly enriched in African American patients (8.8%) compared with European American patients (3.2%), as were deletions in NKX3-1, which occurred in 11.1% and 5.9%, respectively (FDR <0.05). PTEN deletions showed higher frequency in European Americans (15.3%) and were significantly decreased in African American men (5.9%). The difference had an FDR less than 0.05. Finally, MYC amplifications were associated with higher Gleason scores instead of race.

"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," said co-corresponding author Joshua Campbell, PhD, assistant professor of medicine at BUSM, in a statement.²

Differences in Tumor Status Between Cohorts

In a sub-analysis of 3454 patients with prostate cancer, Huang et al sequenced localized and metastatic tumors using a comprehensive genomic profiling assay. A Fischer exact test showed that a number of tumor alterations were more frequent in African American than European American patients, including CCND1 amplification (6.0% vs 3.1%), HGF amplification (3.4% vs 1.4%), KMT2D truncation (10.1% vs 4.7%, respectively), MYC amplification (15.8% vs 9.4%), SPOP point mutation (10.8% vs 6.9%), and KEL (2.1% vs 0.5%), NOTCH2 (1.8% vs 0.5%), and PTCH1 alterations (1.8% vs 0.4%). The overall difference had an FDR of 0.05.

Some alterations, like PTEN deletions (13.1% vs 22.2%) and TMPRSS2-ERG (13.8% vs 32.9%) rearrangements, were significantly more frequent among European Americans.

In the population of patients with localized prostate cancer, results were consistent with the overall analysis, showing higher frequency in European American (31.6%) than African American patients (14.1%). The same was true for PTEN deletions (37.5% vs 24.3%; FDR <0.05). All other alterations were more frequent in African Americans.

The group of African American patients with metastatic disease showed more frequent RB1 and MYC alterations versus that observed in localized tumors (FDR <0.05). For European American men, RB1, MYC, AR, TP53, PTEN, APC, and CCND1 alterations were all more frequent in patients with metastatic disease versus localized disease.

In regard to the difference observed between the 2 racial groups and the potential for further research, Huang stated, “there's a lot of research underway for some mutations, like TMPRSS2-ERG and PTEN, which are less common in tumors from African American men, as well as research targeting the MYC oncogene, which appeared more common in metastatic African American prostate cancer patients in our study. Other mutations that we describe are not well-researched yet in terms of new treatments.”

Genomic Variants by Disease Severity

A meta-analysis also assessed the frequency of mutations according to patients’ disease severity and revealed a higher frequency of MYC amplifications and PTEN deletion enrichments in European Americans. In patients with metastatic disease, AR gene alterations were more prevalent, and TP53 was the most frequent of all the nonsynonymous mutations in all groups, excluding patients with low-grade tumors. SPOP was the second most frequent mutation in all cohorts, with the exception of European patients with metastatic disease.

Overall, the data from this study showed novel differences in the genomic profiling of African American men compared with European American men; however, the findings of alterations in therapeutic targets for which targeted therapies already exist suggests that many African American patients can derive benefit from available therapies and respond as well as European American men, granted treatment is administered equitably.

“Since many targeted therapies are based on specific genomic alterations, we believe it is important to understand who could benefit from these therapies by studying a diverse group of cancer patients from different racial/ancestral groups. This improves oncologic treatment overall because it helps us fulfill the promise of precision medicine, finding the right treatments for the right patient, and helping us understand the different mechanisms that may drive cancer in different populations and groups,” Huang noted on the importance of exploring genomic difference by race in clinical trials.

_References:

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

_{Largest-ever study of prostate cancer genomics in black men ids potential targets for precision therapies. News release. University of California San Francisco. July 10, 2020. Accessed July 14, 2020. https://bit.ly/3j5Gfoi}