Comparative analysis of 1152 African-American and European-American men with prostate cancer identifies distinct genomic and immunological differences

Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P<0.001) and ETS (P=0.02) expression, decreased SPINK1 expression (P<0.001), and basal-like (P<0.001) molecular subtypes. After adjusting for confounders, 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) (p<0.001 for all). At the pathway level, the AAM group had higher expression of genes sets related to the immune response, apoptosis, hypoxia, and reactive oxygen species. 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 higher potential response to DNA damage. In conclusion, biological characteristics of prostate tumor were substantially different in AAM when compared to EAM. Walter Rayford, Alp Tuna Beksac et al. investigated gene expression alterations in African-American and European-American men who underwent radical prostatectomy for prostate cancer. The observed differences include higher expression of inflammation genes and lower expression of mismatch repair genes in African-American men

Abstract 3509: Racial variation in molecularly-defined prostate cancer subtypes

Abstract Background: Socioeconomic, environmental, and healthcare utilization factors are likely drivers of the persistent prostate cancer disparities between African-American (AA) and European-American (EA) men. Tumor molecular heterogeneity may also contribute, and Eurocentric studies and initiatives have the potential to widen disparities through the development of prognostic signatures and targeted therapeutics that do not account for genetic diversity. Methods: The Decipher Genomics Resource Information Database (GRID) contains tumor mRNA expression and clinical data generated through use of the Decipher test to predict prostate cancer prognosis. We matched 426 AA and 426 EA patients with localized prostate cancer using a propensity score accounting for age and tumor clinicopathological factors. We then applied five validated prostate cancer molecular subtype classifiers by Alshalalfa et al (Neuroendocrine, Adenocarcinoma), Kamoun et al (S1-S3), Tomlins et al(ERG+, ETS+, SPINK1+, ERG-/ETS-/SPINK1-), You et al (PCS1-PCS3), and Zhang et al (Basal, Luminal) to assign tumor subtypes. Heterogeneity in subtype frequency by self-identified race (SIR) was evaluated using chi-squared tests. Differences in subtype prognostic value by SIR were evaluated in logistic regression models using a high Decipher tumor genomic risk score of ≥0.6 as a surrogate for higher risk of metastases. Results: AA men were more likely to have a Decipher score ≥0.6 than EA men (25.6% vs. 20.0%, p<0.001). Subtypes reflecting SPINK1 overexpression were more frequent among AA men, while subtypes reflecting the presence of ERG or ETS fusions were more common among EA men (all p<0.001). The distribution of Basal vs. Luminal tumors did not differ by SIR (p=0.19), nor did Neuroendocrine vs. Adenocarcinoma (p=0.14). Across SIR groups, the ERG+, Basal, PCS1, and Neuroendocrine tumors were the most likely to have high Decipher scores, while the S2 subtype was associated with a lower Decipher score. However, associations between subtypes and the Decipher score differed by SIR for three of five classifiers. The ERG+ subtype (relative to ERG-/ETS-/SPINK1-) was associated with a higher risk of metastases in AA men (OR=3.18 95% CI 1.59-6.37), but not in EA men (OR=0.69, 95% CI 0.39-1.24, p-het=0.002). A similar pattern was observed in the PCS3 subtype, which is also characterized by the presence of ERG or ETS fusions (p-het=0.003). The hypothesized low-risk S2 subtype was associated with lower risk of metastases (relative to S1) among EA men (OR=0.31, 95% CI 0.15-0.61), but not among AA men (OR=0.99, 95% CI 0.39-2.49, p-het=0.001). The Zhang (p-het=0.36) and Alshalalfa (p-het=0.85) classifiers did not show heterogeneous associations between subtype and Decipher score by SIR. Conclusions: Prostate cancer molecular subtype distributions differed by SIR, with AA men generally more likely to have aggressive subtypes across classification schemes. Furthermore, AA and EA had a heterogeneous risk of metastases (defined by Decipher genomic risk score) for several subtypes. Further research is needed to better define subtyping classifiers and the prognostic value thereof in AA men. Citation Format: Kevin H. Kensler, Mohamed Alshalalfa, Brandon A. Mahal, Yang Liu, Elai Davicioni, Shivanshu Awasthi, Kosj Yamoah, Timothy R. Rebbeck. Racial variation in molecularly-defined prostate cancer subtypes [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3509

Molecular, immunologic, and clinicodemographic landscape of MYC-amplified (MYCamp) advanced prostate cancer (PCa)

5041 Background: The MYC oncogene is one of the most commonly amplified genes in PCa, contributes to androgen independent growth, and is potentially targetable. We sought to define the molecular, immunologic, and clinicodemographic landscape of MYCamp in advanced PCa to better understand progression and establish rationale for personalized treatments and combinations. Methods: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on tumor samples from predominantly advanced PCa samples. MYCamp was defined as copy number (CN) ≥6. PD-L1 IHC was performed using Dako 22C3. A subset of patients (pts) with advanced PCa were selected from the Flatiron Health- Foundation Medicine (FM) clinicogenomic database (CGDB), a nationwide de-identified EHR-derived clinical DB linked to FM CGP data for pts treated from 01/2011-12/2020. The de-identified data originated from approximately 280 US cancer clinics (̃800 sites of care). Results: The genomic profiles of 12,528 tissue samples from unique PCa pts (including hormone sensitive and castrate resistant) were evaluated. MYCamp was detected in 10.6%, with a median MYC CN of 8. Median age was 67 years (67 for MYCwt versus 68 for MYCamp). MYCamp occurred at a higher frequency in men with African (N = 190/1,473, 12.9%) versus European (N = 996/9,796, 10.2%) ancestry (P = 0.002), was more frequent in metastatic biopsy sites vs primary (15.7% vs 6.2%, P 15 was enriched for PD-L1 positivity (26.1%) compared with MYCwt (9.8%) or MYCamp CN 6-15 (11.5%) (CN > 15 vs wt P = 0.025). In pts with MYCamp vs MYCwt PCa AR, RAD21, PTEN, CCND1, ZNF703, FGF19, FGFR1, and FGF3 each had significantly higher rates of CN changes (all p 0) from PCa pts MYCamp was detected in 2.0% (28/1,402), and in 4.5% (20/445) with cTF > 20%. Among evaluable PCa pts in the CGDB, (67 MYCamp and 658 MYCwt) MYCamp did not significantly impact treatment decisions, with the majority receiving novel hormone therapies (35.8% MYCamp vs. 31.5% MYCwt) or chemotherapy containing regimens (37.3% MYCamp vs. 27.7% MYCwt) as first therapy after CGP report. Conclusions: Herein, we report the largest analysis to date of molecular, immunologic, and clinicodemographic features of MYCamp advanced PCa. These findings suggest that MYCamp defines a biologically distinct subset of PCa pts for whom personalized combination treatments utilizing targeted and/or immunotherapies may be effective. Independent cohorts are needed to validate these findings

Determinants of widespread metastases and of metastatic tropism in patients with prostate cancer: A genomic analysis of primary and metastatic tumors

5067 Background: A growing body of evidence suggests that metastatic cancer is better described as a spectrum of disease rather than a binarily defined state, ranging from oligometastatic cancer to widespread metastases. Widespread metastases represent the most common cause of cancer-related death among patients with prostate cancer. Therefore, a greater understanding of the genomic features that determine the extent and location of metastatic spread may inform risk stratification, treatment, and monitoring. We identify genomic alterations from primary prostate tumors that are predictive of widespread metastatic potential. Methods: Genomic and clinical data for 1,312 patients with primary prostate adenocarcinomas were extracted from the MSK-MET cohort through cBioPortal. Metastatic site counts and overall survival (OS) data were publicly available for all patients. All samples from primary tumors were profiled using the MSK-IMPACT targeted sequencing platform. Our study focused on 58 genes frequently altered in prostate cancer. Cox proportional hazard analyses defined hazard ratios (HRs) and 95% confidence intervals (CIs) for overall mortality in patients with different metastatic outcomes. Patterns of genomic alterations of the primary tumor associated with metastatic extent and location were compared. Results: Out of 1,312 patients, 939 (71%) developed metastases, and 113 (8.6%) had metastases to 5 or more distinct anatomical sites (defining wide-spread metastases, WSM). Bone was the most common site of metastasis (36%), and 80% of patients with liver metastases had 4 or more additional sites of metastasis. Among patients with metastases, increasing number of metastatic sites was associated with increased risk of death (HR:1.8, 95%CI:1.63-1.99, p<0.001). To define genomic determinants of WSM, we characterized genomic alterations in 58 prostate cancer related genes. Alterations in the following genes were enriched in tumors from patients with WSM vs others: TP53 mutation (40% vs 20%, p<0.0001), FOXA1-amplification (8% vs 3%, p=0.02), AR-amplification (4.4% vs 1%, p=0.01), RB1-deletion (5.3% vs 0.7%, p=0.001), and BRCA2-deletion (4.4% vs 0.7%, p=0.01). In a univariable survival analysis, all these alterations were predictive of OS (p<0.05). However, on multivariable analysis, only TP53 mutations, and FOXA1 and AR amplifications were independent prognostic factors. Amplifications of FOXA1 (n=37) and AR (n=13) were mutually exclusive (0 overlap), and we found that patients who have either AR or FOXA1 amplifications experienced very poor OS (HR:3.57, 95%CI:2.26-5.6, p p<0.001]. Conclusions: We identified genomic alterations (TP53 mutations, FOXA1 and AR amplification, RB1 and BRCA2 deletions) from primary prostate tumors that are predictive of wide-spread metastases and poor outcomes

Selective vulnerabilities in the proteostasis network of castration-resistant prostate cancer

Castration-resistant prostate cancer (CRPC) is associated with an increased reliance on heat shock protein 70 (HSP70), but it is not clear what other protein homeostasis (proteostasis) factors might be involved. To address this question, we performed functional and synthetic lethal screens in four prostate cancer cell lines. These screens confirmed key roles for HSP70, HSP90, and their co-chaperones, but also suggested that the mitochondrial chaperone, HSP60/HSPD1, is selectively required in CRPC cell lines. Knockdown of HSP60 does not impact the stability of androgen receptor (AR) or its variants; rather, it is associated with loss of mitochondrial spare respiratory capacity, partly owing to increased proton leakage. Finally, transcriptional data revealed a correlation between HSP60 levels and poor survival of prostate cancer patients. These findings suggest that re-wiring of the proteostasis network is associated with CRPC, creating selective vulnerabilities that might be targeted to treat the disease

Endocrine resistance and breast cancer plasticity are controlled by CoREST

Resistance to cancer treatment remains a major clinical hurdle. Here, we demonstrate that the CoREST complex is a key determinant of endocrine resistance and ER+ breast cancer plasticity. In endocrine-sensitive cells, CoREST is recruited to regulatory regions co-bound to ER alpha and FOXA1 to regulate the estrogen pathway. In contrast, during temporal reprogramming towards a resistant state, CoREST is recruited to AP-1 sites. In reprogrammed cells, CoREST favors chromatin opening, cJUN binding to chromatin, and gene activation by controlling SWI/SNF recruitment independently of the demethylase activity of the CoREST subunit LSD1. Genetic and pharmacological CoREST inhibition reduces tumorigenesis and metastasis of endocrine-sensitive and endocrine-resistant xenograft models. Consistently, CoREST controls a gene signature involved in invasiveness in clinical breast tumors resistant to endocrine therapies. Our studies reveal CoREST functions that are co-opted to drive cellular plasticity and resistance to endocrine therapies and tumorigenesis, thus establishing CoREST as a potential therapeutic target for the treatment of advanced breast cancer. Morey and colleagues identify a dual function of CoREST in regulating sensitivity and resistance to endocrine therapies in breast cancer. This work also provides a pre-clinical model for study of the conversion of luminal/ER+ to basal/ER- breast cancer

Variation in Molecularly Defined Prostate Tumor Subtypes by Self-identified Race

Background: Socioeconomic and health care utilization factors are major drivers of prostate cancer (PC) mortality disparities in the USA; however, tumor molecular heterogeneity may also contribute to the higher mortality among Black men. Objective: To compare differences in PC subtype frequency and genomic aggressiveness by self-identified race. Design, setting, and participants: Five molecular subtype classifiers were applied for 426 Black and 762 White PC patients in the Decipher Genomics Resource Information Database (GRID). Outcome measurements and statistical analysis: Differences in subtype frequency and tumor genomic risk (Decipher score \u3e0.6) by race were evaluated using χ2 tests and multivariable-adjusted logistic regression models. Results and limitations: Subtype frequencies differed by race for four classifiers. Subtypes characterized by the presence of SPOP mutations, SPINK1 overexpression, and neuroendocrine differentiation were more common among Black men. ERG and ETS fusion-positive subtypes were more frequent among White men, with no clear differences for subtypes reflecting luminal versus basal lineage. The hypothesized low-risk Kamoun S2 subtype was associated with a lower Decipher score among White men only (p = 0.01 for heterogeneity), while the aggressive You PCS1 subtype was associated with a higher Decipher score among White men only (p = 0.001 for heterogeneity). The Tomlins ERG+ subtype was associated with a higher Decipher score relative to all other subtypes among Black men, with no association among White men (p = 0.007 for heterogeneity). Conclusions: The frequency of PC molecular subtypes differed by self-identified race. Additional studies are required to evaluate whether our observations suggest differences in the tumor genomic risk of progression by self-identified race. Patient summary: We studied five classifiers that identify subtypes of prostate tumors and found that subtypes differed in frequency between Black and White patients. Further research is warranted to evaluate how differences in tumor subtypes may contribute to disparities in prostate cancer mortality

Comparative analysis of 1152 African-American and European-American men with prostate cancer identifies distinct genomic and immunological differences.

Racial disparities in prostate cancer have not been well characterized on a genomic level. Here we show the results of a multi-institutional retrospective analysis of 1,152 patients (596 African-American men (AAM) and 556 European-American men (EAM)) who underwent radical prostatectomy. Comparative analyses between the race groups were conducted at the clinical, genomic, pathway, molecular subtype, and prognostic levels. The EAM group had increased ERG (P \u3c 0.001) and ETS (P = 0.02) expression, decreased SPINK1 expression (P \u3c 0.001), and basal-like (P \u3c 0.001) molecular subtypes. After adjusting for confounders, 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) (p \u3c 0.001 for all). At the pathway level, the AAM group had higher expression of genes sets related to the immune response, apoptosis, hypoxia, and reactive oxygen species. 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 higher potential response to DNA damage. In conclusion, biological characteristics of prostate tumor were substantially different in AAM when compared to EAM