"This study is the logical extension of our ongoing efforts to combat the racial disparity," Dr. Ash Tewari of the Icahn School of Medicine at Mount Sinai and the Tisch Cancer Institute in New York City told Reuters Health by email.
"This study demonstrated that EAM and AAM groups have distinct genomic profiles, with clinical implications for managing active surveillance, adjuvant treatment, recurrence management, and metastatic disease treatment," he said.
"In addition," he noted, "we found that the tumor genomic factors were substantially different between the races. Specifically, we found that African American tumors had higher expression of genes related to immune response and inflammation and lower expression of DNA mismatch repair genes."
"Our results could explain the underlying molecular mechanism of the differential response to radiotherapy and possible differences in outcome among AAM," he added, "and support the rationale for immunotherapy in AAM with prostate cancer."
As reported in Communications Biology, Dr. Tewari and colleagues analyzed samples from 1,152 patients (596 AAM and 556 EAM) who underwent radical prostatectomy (RP). The mean age at surgery was about 64.
Compared to EAM, AAM presented with significantly higher pretreatment PSA levels (7.9 vs. 6.5 ng/ml); higher combined pathologic T3b and 4 stage (17.4% vs.11.3%); higher post-RP CAPRA-S scores (14.9% vs. 9.7%); and higher genomic risk of metastasis (Decipher high-risk group 38.2 vs. 33.2%).
The EAM group had increased ERG and ETS gene expression, decreased SPINK1 expression, and basal-like molecular subtypes.
After adjustment, the AAM group was associated with higher expression of CRYBB2, GSTM3, and inflammation genes (IL33, IFNG, CCL4, CD3, ICOSLG), and lower expression of mismatch repair genes (MSH2, MSH6).
At the pathway level, the AAM group had higher expression of gene sets related to the immune response, apoptosis, hypoxia, and reactive oxygen species, whereas the EAM group was associated with higher levels of fatty acid metabolism, DNA repair, and WNT/beta-catenin signaling.
Based on cell lines data, AAM were predicted to have a higher potential response to DNA damage.
Summing up, the authors state, "Taken together, our data indicate that key biological processes associated with cell growth and survival pathways are upregulated in the EAM group. Our results define a role for immune signaling pathways in the AAM group and establish that up-regulation of the immune-inflammation axis is a hallmark of AAM tumors."
Dr. Tewari said, "Although we can extrapolate the gene alterations and commercially available genomic tests to individualize treatment selection among AAM, more work is warranted in this area before it is implemented in the clinic."
Urologist Dr. Alex Sankin, Director, Clinical Trials Program at Montefiore Health System in New York City commented in an email to Reuters Health, "Since AAM are under-represented in clinical trials and genomic profiling investigations, this study offers unique insight into the molecular origins of their disease and provides supporting evidence for conducting clinical trials specifically tailored for the uniquely aggressive disease commonly present in the AAM population."
Nonetheless, he added, "The study is a retrospective exploratory analysis of archived biospecimens, and therefore, any results are merely hypothesis-generating. In order to determine if these novel genetic signatures in AAM men can truly guide treatment decisions, a prospective clinical trial should be conducted with patients assigned to treatment arms based on their unique gene alterations."
SOURCE: https://go.nature.com/354SQCx Communications Biology, online June 3, 2021.
By Marilynn Larkin
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