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.