Comparative Analysis of 1152 African-American and European-American Men with Prostate Cancer Identifies Distinct Genomic and Immunological Differences - Beyond the Abstract

The Uro-Oncological community has been aware of racial differences in prostate cancer (PCa) incidence and treatment outcomes for many years. In the USA, the lifetime risk for African American (AA) men dying from PCa is twice that of Non-Hispanic White (NHW) men. Since the observation was first made, potential causes have been suggested as socio-economic, including the influence of comorbidities, differences in tumor biology, or some combination of both. Interestingly, two recent studies found that once socioeconomic issues were equalized, differences in treatment outcomes were eradicated. Dess et al. (2019)1 examined 306,100 patients with localized or locally advanced PCa from Surveillance, Epidemiology and End Results (SEER), Veterans Affairs (VA) Health System, and 4 pooled National Cancer institute Radiation Therapy Oncology Group phase 3 randomised controlled trial databases, over 55,482 (18.1%) of whom were AA men. Once treatment was standardized, and healthcare access issues resolved, stage for stage PCa mortality in AA men was not significantly different to NHW men, although other cause mortality rates remained higher.

Riviere et al. (2020),2 also investigated a cohort of VA Health System men, using the VA informatics and Computing Infrastructure to source data on 60,035 PCa patients, 30.3% of whom were AA. Their cohort included men with all stages of disease including metastatic (M stage 2.7% AA men vs 3.1% NHW men). The VA Healthcare System provides the opportunity for equal access to eligible members and the results of their study found no significant difference in stage at presentation or treatment outcomes between AA and NHW men. This again supports the hypothesis that socio-economic and health care access issues are the main factor in disparities in disease outcomes.

Investigating the other source of potential differences in disease outcomes, a recent article published in Communications Biology specifically explored differences in tumor biology between AA and NHW men, to shed more light on its contribution to incidence and outcome disparities. In one of the largest comparative studies on this topic to date, the clinical and pathology data of a cohort of 1152 men (596 AA and 556 NHW) undergoing surgery for localized PCa at a single center by a single surgeon were examined retrospectively. Analysis of individual genome-wide expression profiles included 46,000 gene and noncoding genes, 56 markers of known cancer pathways, 20 cancer prognostic gene signatures as well as decipher scores (Decipher Biosciences, San Diego, California) on all post-surgical specimens (Rayford et al., 2021).3 Given the large number of AA men in the cohort, not only did this allow a comprehensive comparison of specific genomic differences for AA men, but it also provided the basis for a discussion on the immune responses and inflammatory pathways activity which may drive differences in incidence as well as how this may specifically affect differential responses to treatment.

In their cohort, AA men presented with higher PSAs had a higher risk of locally advanced disease (pT3b or T4 on post-surgical pathology), higher CAPRA-S post-surgical scores, and higher genomic risk scores on diagnostic biopsy. On post-surgical pathology specimens, further examination of prognostic signatures including decipher and average genomic risk scores (which refers to 19 prognostic signatures not covered by decipher) found a significant association with GGGs for both AA and NHW men, although AA men had significantly higher genomic scores for low-risk GGGs (GGG 1 and 2) whereas NHW men had significantly higher genomic scores for high-risk GGGs (GGG 4 and 5). Further investigating molecular subtypes, genomic differences, and genome-wide differential expression, NHW men were found to have increased ERG and ETS expression, reduced SPINK1 expression, and a predominance of basal type molecular genes. Conversely, AA men had increased expression of GSTM3, CRYBB2, and inflammatory genes (CCL4, IL33, CD3, IFNG, ICOSLG) but lower mismatch repair gene expression (MSH6, MHS2). Examining molecular pathway activity for pathways implicated in PCa development and progression, NHW men have increased activity in DNA repair, fatty acid and glycolytic metabolism, and WNT / beta-catenin gene signaling whereas AA men have higher activity in immune response, hypoxia, reactive oxygen, and apoptosis-related genes. With this in mind, the authors then calculated individual chemotherapy response scores based on previously defined in vitro drug sensitivity and microarray data. They found anti-microtubule chemotherapy would potentially prove more efficacious for NHW men, whereas AA men have a predicted higher-level response to DNA damage and alkylating-based chemotherapy.

Moreover, based on their increased expression of inflammatory genes, their findings advocate the use of immunotherapy in AA men, which supports the findings of a subanalysis of the PROCEED trial demonstrating a survival advantage in AA men with metastatic castrate-resistant PCa treated with sipuleucel-T (Rayford et al., 2021).3 The finding of higher genomic scores for AA men with low-risk PCa also has implications for clinical decisions regarding recruitment to active surveillance programs.

Given there is a paucity of genomic data on AA men with PCa, the results of this study pose some interesting questions, especially in the light of the recent epidemiological studies presented above, suggesting equal healthcare access corrects outcomes disparities. Of note in Riviere’s paper, median follow up was 5.79 years for AA men and 5.89 years for NHW men (Riviere et al., 2020),2 and in Dess’ study, the median range of follow up in the 3 sources of data ranged from 70 months to 105 months (Dess et al., 2019).1 For these studies, it may be that the follow up is too short to make a real comparison in mortality outcomes, and, at least in Rayford’s cohort,  AA men do seem to present with not only more advanced disease, which would be counteracted by expedited healthcare access, but also with disease that has a higher risk of metastasis long term, based on their genomic scores. With the emergence of “precision medicine”, detailed knowledge of tumor biology is advantageous regardless of any comparisons to different ethnic groups. For AA men, impaired DNA repair activity may underly recent findings of improved response to radiotherapy (Mckay et al., 2020),4 and based on Rayford et al.’s findings, both AA men and NHW have improved efficacy with carefully chosen chemo- and immuno-therapy regimes. Nevertheless, a multifactorial approach is required to improve outcomes for the PCa patient community as a whole with improved education, access to diagnostic and treatments services, and a deeper scientific understanding of tumor biology so that all patients can be offered the most efficacious treatments that are available, tailored to their own specific disease.

Written by: Zach S. Dovey, MD, Sujit S. Nair, PhD, and Ashutosh K. Tewari, MD, Icahn School of Medicine at Mount Sinai, New York, NY, USA

References:

  1. Dess RT, Hartman HE, Mahal BA, et al. Association of black race with prostate cancer–specific and other-cause mortality. JAMA Oncol. 2019;5:975-983.
  2. Riviere P, Luterstein E, Kumar A, et al. Survival of African American and non-Hispanic white men with prostate cancer in an equal-access health care system. Cancer. 2020;126:1683-1690.
  3. Rayford W, Beksac AT, Alger J, et al. Comparative analysis of 1152 African-American and European-American men with prostate cancer identifies distinct genomic and immunological differences. Commun Biol. 2021 Jun 3;4(1):670. doi: 10.1038/s42003-021-02140-y. PMID: 34083737; PMCID: PMC8175556.
  4. McKay RR, Sarkar RR, Kumar A, Einck JP, Garraway IP, Lynch JA, Mundt AJ, Murphy JD, Stewart TF, Yamoah K, Rose BS. Outcomes of Black men with prostate cancer treated with radiation therapy in the Veterans Health Administration. Cancer. 2021 Feb 1;127(3):403-411. doi: 10.1002/cncr.33224. Epub 2020 Oct 9. PMID: 33036065.
  5. Tewari A, Horninger W, Pelzer AE, et al. Factors contributing to the racial differences in prostate cancer mortality. BJU Int. 2005;96:1247-1252.
  6. Tewari AK, Taffet Gold H, Demers RY, et al. Effect of socioeconomic factors on long-term mortality in men with clinically localized prostate cancer. Urology. 2009;73:624-630.
  7. Lundon DJ, Dovey Z, Tewari AK. Access and socioeconomic status play an important role in outcomes for African American patients with prostate cancer. Cancer. 2020 Sep 15;126(18):4257-4258. doi: 10.1002/cncr.33063. Epub 2020 Jul 9. PMID: 32644195.

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