Table 3. The prevalence of TP53, PTEN and TMPRSS2-ERG mutations in AAM and EAM with metastatic PCa.
We also examined the specific racial differences between the mutation rate of the top 5 mutations in metastatic PCa: AR, TP53, PTEN, TMPRSS2-ERG and RB1. Out of these 5 mutations, TP53, PTEN and TMPRSS2-ERG are shown of have significant differences in mutation rate between AAM and EAM with metastatic PCa according to more than one study. For this reason, we focused on these 3 mutations to analyze the differences between the two ethnicities specifically in metastatic PCa (Table 3). The most strikingly consistent dissimilarities may be the lower frequencies of rearrangements and PTEN mutations67. Mutation of TP53, PTEN, and TMPRSS2-ERG fusion are among the most prevalent genetic defects found in lethal metastatic prostate cancer. Koga et al67 showed that in prostate cancer, TMPRSS2-ERG rearrangements (31.6% vs 14.1%) and PTEN deletions (37.5% vs 24.3%) were less frequent in AAM. It also showed that AAM had a 43.2% mutation range versus 45.3% for EAM in TP53 mutation. An analysis by Kamran et al69 also demonstrated similar trend: TP 53 mutation in 38.1% of EAM participants and in 25.4% of AAM; PTEN aberration in 10.4% of EAM and in 7% of AAM. However, TMPRSS2-ERG fusion is lower in EAM participant than in AAM (0.9% vs. 2.8% respectively), which is different from the trend found in the Koga et al.67 study. Even though various studies analyzing these genetic aberrations in metastatic PCa have yielded agreeable findings where AAM has lower mutational frequencies in these genes compared to their EAM counterparts64-69 , more studies are needed to confirm the racial differences in mutational frequencies in these genes.
These findings conflict with the more aggressive features of prostate cancer in AAM men. It is hard to imagine that less frequent deletions of these genes can contribute to more aggressive features of prostate cancer in AAM. The lower prevalence of PTEN mutation, TP53 aberration and TMPRSS2-ERG fusion among AAM tumors suggests that other molecular alterations or pathways are likely to account for racial disparities in PCa outcomes. Therefore, the emergence of precision medicine targeting these mutations might further exacerbate racial disparity in PCa.
Racial Disparity in Clinical Trials Enrollment :
Despite racial disparities in prostate cancer incidence and outcome, there is a low enrollment of AAM patients in clinical trials. In a study analyzing 72 prostate cancer trials with start date ranging between 1987 and 2016, EAM accounted for 96% of all trials’participants77. With the advancement of precision medicine, it is imperative to improve representation in trial enrollment in order to ensure a proper validated biomarkers, and subsequently, an appropriate treatment decision for the general population, especially for those from marginalized, high-risk background78. This review identifies clinical trials started after 2016 that investigated personalized therapy for prostate cancer in order to examine the representation of AAM across prostate cancer precision therapy trials. We carried out a literature search on clinical trial registries (ClinicalTrials.gov) using the keywords: PDL-1, Pembrolizumab, Nivolumab, Cemiplimab, Durvalumab, PARPi, Veliparib, Olaparib, Niraparib, Rucaparib, Talazoparib, Lutetium and 177Lu. The objective was to find clinical trials that started after 2016, have been completed or active but not enrolling, have results, and show reports of participant’s race/ethnicity. We eliminated the trials that did not meet this condition and we found a total of 14 trials. Of these, we eliminated 1 trial that was irrelevant, leaving us with 13 trials79- 91.