Clinical Context

Prostate cancer is the most prevalent nonskin cancer in men. The only well-established risk factors thus far are age, family history or genetics, and race/ethnicity.

Across cancer types, disparities by race or ancestry are greatest in prostate cancer, with significant racial disparities in incidence, mortality, outcomes, and treatment patterns. Highly Eurocentric precision oncology initiatives could potentially widen disparities if genomic risk models and targeted therapies continue to be developed on the basis of homogeneous study populations.

Study Synopsis and Perspective

Men of African ancestry have higher incidence of prostate cancer, have worse clinical outcomes, and are more likely to die from the disease when compared with men of other ancestries.

Trying to uncover the reason for this disparity has been the subject of much research. Potential explanations for this phenomenon include differences in environmental exposures, socioeconomic factors affecting access to care, explicit and structural racism in health care, and underlying biological or genetic variations.

But a new genomic study dispels this last explanation. This study had 1 of the largest samples of genomes of Black men to date, and found that the prevalence of alterations in medically actionable genes is largely similar across a large range of backgrounds. The results suggest that the worse outcomes among men of African ancestry are unlikely to be primarily a result of genomic differences, say the authors. 

The study was published online in the June issue of Lancet Digital Health.

“Overall, our findings suggest that genomic differences in actionable genes are unlikely to be the major driver of ancestry-based disparities among men diagnosed with aggressive prostate cancer,” concluded Smruthy Sivakumar, PhD, from Foundation Medicine in Cambridge, Massachusetts and colleagues.

In addition, the authors found that men of African ancestry on average received more lines of therapy before undergoing comprehensive genomic profiling (CGP) than men of European ancestry, and that after undergoing profiling, men of African heritage were less likely to be enrolled in clinical trials based on those results.

They suggest that “equitable use of CGP testing, subsequent precision medicine or treatment pathways, and downstream clinical trial enrolment could lead to a reduction in disparities.”

Only One Piece of the Puzzle

An oncologist who studies racial disparities in genitourinary cancers but was not involved in the study told Medscape Medical News that the findings underscore the complex challenges in addressing racial inequities.

“There are differences in the genomic profiles from a population perspective of men with African ancestry and men of European ancestry, and we see that in this paper, with different prevalence of certain mutations, either higher or lower. But the changes aren’t dramatic, and those that actually are actionable by treatment are relatively modestly different,” commented Daniel J. George, MD, a medical oncologist at Duke Cancer Center in Durham, North Carolina.

He added, however, that more widespread adoption of genomic profiling alone is not sufficient to reduce racial disparities.

“It’s not likely that even with perfect and comprehensive genetic profiling that we would be able to create a balanced outcome by race. It’s not those actionable targets alone; we’re going to need more treatments that can benefit these populations in order to bring together these disparate outcomes,” he said.

Dr George noted that in the discussion section of the article, Dr Sivakumar and colleagues cited disparities in access to care, including prostate cancer screening, diagnosis, access to therapies, and inclusion in clinical trials, as the primary driver of racial disparities in prostate cancer care.

“But what can be lost in the concern over this access to care is that there are also biologic factors,” Dr George said. “Yes, race is a social construct, but it’s also a biologic construct; they’re not mutually exclusive, and we know there are differences in biology by race. The question is how does that pertain to cancer outcomes, and I think understanding that in the context of our clinical trials, in our drug and therapy development, is critical.”

Retrospective Study

For their study, Dr Sivakumar and colleagues performed a retrospective analysis of comprehensive genomic profiling performed on biopsy samples from 11,741 men with prostate cancer. They inferred each patient’s ancestry on the basis of patterns of single nucleotide polymorphisms (SNPs), classifying each patient as being of European, African, East Asian, South Asian, or American admixed heritage.

The authors also looked at real-world treatment patterns and overall survival rates of a subset of patients for whom clinic-genomic data were available. This cohort included 130 men of African ancestry and 1017 men of European ancestry, and the remainder were of Asian or mixed heritage.

The investigators found that although there were differences in ancestry-specific mutational patterns, the prevalence of alterations in the gene AR, which codes for the androgen receptor, in DNA damage-response pathways and in other “actionable” genes were similar across ancestries, including those with mixed genetic heritage.

“Of note, men of African ancestry were less likely to receive CGP early in their treatment course (after fewer lines of therapy). Furthermore, men of African ancestry were less likely to be treated on clinical trials after CGP, which could affect the genomic landscape, outcomes, and ultimately disparities in prostate cancer,” the investigators write.

The study was supported by the American Society for Radiation Oncology, Department of Defense, Flatiron Health, Foundation Medicine, Prostate Cancer Foundation, and Sylvester Comprehensive Cancer Center. Dr Sivakumar and multiple coauthors are employees of Foundation Medicine and have equity interests in Roche. Dr George have disclosed no relevant financial relationships.

Lancet Digit Health. Published in the June 2023 edition.^[1]

Clinical Implications

• Men of African or European ancestry with aggressive prostate cancer had similar rates of gene alterations with therapy implications.
• Differences in actionable genes (including AR and DNA damage response pathway genes) that would have therapeutic and predictive implications may not be a main driver of disparities across ancestries in advanced prostate cancer.
• Equitable use of CGP testing, subsequent precision medicine or treatment pathways, and downstream clinical trial enrollment could help reduce disparities. Members of the healthcare team should stay abreast of advances in fields of genomics and precision medicine to best address the health needs of the populations they serve.

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