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Prostate Cancer Genomics Study IDs PARP Inhibitors as Potentially Beneficial to Black Men

NEW YORK – A new study on the genomics of prostate cancer has found that although there are some novel genetic differences between African-American men and men of European ancestry, the frequencies of genomic alterations in current therapeutic targets were similar between the two groups, suggesting that some of the differences in their mortality rates are related to social and environmental factors.

In their paper published in Clinical Cancer Research on Friday, researchers at the University of California, San Francisco, Boston University School of Medicine, and elsewhere noted that African Americans have the highest mortality rate from prostate cancer compared to men of other racial or ancestral groups, and that differences in the spectrum of somatic genome alterations in tumors between African Americans and other populations have not been well-characterized because Black men haven't been included in genomic studies in large numbers.

In their study, the researchers analyzed data from four publicly available datasets comprising 250 African-American men and 611 European-American men, and a targeted sequencing dataset from a commercial platform of 436 African Americans and 3,018 European Americans. They found that mutations in ZFHX3 as well as focal deletions in ETV3 were more frequent in tumors from African Americans, and that MYC amplifications were more frequent in tumors from African Americans with metastatic prostate cancer. They also found that deletions in PTEN and rearrangements in TMPRSS2-ERG were less frequent in tumors from African Americans and that KMT2D truncations and CCND1 amplifications were more frequent in primary prostate cancer from African Americans.

However, the researchers also found that the genomic features that could affect clinical decision-making — including tumor mutational burden, MSI status, and genomic alterations in select DNA repair genes — were not significantly different between the two groups. Further, the frequencies of genomic alterations in current therapeutic targets for prostate cancer were similar between African Americans and European Americans, suggesting that existing precision medicine approaches could be equally beneficial to Black men as they have been to white men, if they were applied equitably.

In May, the FDA approved PARP inhibitors as a therapy for men with prostate cancers driven by specific genetic mutations, but it is not known how prevalent these mutations are in people of African descent.

"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," corresponding author and UCSF Assistant Professor Franklin Huang said in a statement. "This highlights the need to examine the environmental and social inequities that are well known to influence health outcomes across the board. 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."

The researchers did note that a major limitation of their meta-analysis was that some cohorts lacked matched tumors from European-American men, limiting their ability to control for cohort-specific effects that could arise due to differences in region, clinical setting, or sequencing assay. Another limitation was that the meta-analysis was limited to 15 genes because two of the four cohorts relied on smaller targeted sequencing panels for profiling.

However, on the basis of their analysis, the researchers believed that a single gene alteration is unlikely to account for the observed prostate cancer disparities. Additional studies that profile large numbers of well-matched tumors from African-American men 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, such as the genomic differences in MYC, ZFHX3, PTEN, and TMPRSS2-ERG, which suggested that different pathways of carcinogenesis may be active in African-American men, the researchers added.

The study's findings echo data presented at the American Urological Association's 2020 Annual Meeting in May, where a group of researchers showed a poster on Exact Sciences' Oncotype DX Genomic Prostate Score (GPS) assay as a predictor of outcomes in African Americans with prostate cancer. The researchers performed a composite analysis of six independent cohorts of men with newly diagnosed prostate cancer treated with radical prostatectomy, including more than 200 African-American men. The results showed that tumor biology as measured by Oncotype GPS was similar in African American and Caucasian men, and that the assay was similarly predictive in both groups.

According to Jennifer Cullen, an associate director of cancer population sciences at the Case Comprehensive Cancer Center who participated in the Oncotype study, the data highlighted a point in the longstanding debate as to whether the higher prostate cancer incidence and mortality for African Americans compared to Caucasians is driven by biology or social determinants.

"I think what we see, especially in the military cohorts and in the DoD program … is that when the patients are diagnosed and treated and followed within an equal-access healthcare system like the military, we don't necessarily see differences in outcome," she said. "So, there may still be biological differences in why they get cancer in the first place, but how they're treated and how early they're detected are key variables that also predict bad outcome."