The Molecular, Immunologic, and Clinicodemographic Landscape of MYC-Amplified Advanced Prostate Cancer.

BACKGROUND: MYC is a commonly amplified, potentially targetable gene in prostate cancer (PCa). We sought to define the molecular, immunologic, and clinicodemographic landscape of MYC amplification (MYCamp) in advanced PCa to establish a rationale for personalized treatment combinations. METHODS: Hybrid capture-based comprehensive genomic profiling (CGP) was performed on PCa tumor samples. MYCamp = copy number ≥6 (CN). Patients treated between January 2011 and December 2020 were selected from a nationwide deidentified (280 clinics) EHR-derived clinicogenomic database (CGDB). RESULTS: Of 12,528 hormone-sensitive and castrate-resistant (CRPC) samples, MYCamp was detected in 10.6% (median CN = 8). MYCamp was more frequent in men with African versus European ancestry (12.9% vs. 10.2% P = .002), in metastatic vs. primary tissue (15.7% vs. 6.2% P < .001), and enriched in metastatic liver lesions (20.2%), but inversely associated with high microsatellite-instability (0.8% vs. 2.4%, P < .001). MYC CN≥15 was associated with PD-L1 expression (26.1% vs. 9.8%, P = .025). Amplification of AR, RAD21, LYN, CCND1, ZNF703, FGF3/4/19, and FGFR1 was enriched in MYCamp vs. MYCwt (all P < .001). In liquid samples with tumor fraction [TF]>0, MYCamp was detected in 2.0% (28/1,402), and 4.5% (20/445) with TF>20%. In the CGDB, (67 MYCamp and 658 MYCwt), patients received similar treatments; most received hormone therapies (35.8% MYCamp vs. 31.5% MYCwt) or chemotherapy (37.3% MYCamp vs. 27.7% MYCwt) as first therapy after CGP report. CONCLUSION: MYCamp defines a biologically distinct subset of PCa patients and is characterized with multiple proxies of advanced disease. These data suggest that MYCamp may be prognostic; independent cohorts are needed to validate these findings.

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 ERα 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.

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 >0.6) 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.

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.

Does Perioperative Testosterone Predict Post-Prostatectomy Genomic Risk Score?

PURPOSE: The role of endogenous testosterone in de novo prostate cancer pathogenesis in humans remains unclear. The effect of testosterone on the tumor genome is not explored. We sought to explore the correlation between perioperative testosterone level and genomic risk score in a cohort of men who underwent radical prostatectomy. MATERIALS AND METHODS: We included patients who underwent radical prostatectomy (2013-2018) and had adverse pathological features in their final surgical specimens (positive margin, and/or pT3a or higher). The outcome of interest was the genomic risk score: low (<0.45), intermediate (0.45-0.6) and high (>0.6). The associations between serum testosterone level and 188 gene expression-based signatures were examined. Secondary outcomes of interest included biochemical recurrence and receipt of secondary treatment. RESULTS: The median genomic risk score was lower in the low testosterone group compared to the intermediate and normal testosterone groups (0.38 vs 0.52 vs 0.53, respectively; p=0.049). There was no difference in biochemical recurrence-free survival between the 3 testosterone groups (p=0.9). Patients with low testosterone levels had higher odds of receiving secondary treatment (OR: 2.27; 95% CI: 1.14-4.50; p=0.02) than those with normal levels. A total of 43 (of 188) gene expression signatures were associated with testosterone level (p <0.05). In total, 33 signatures were positively associated with serum testosterone levels, including 12 signatures involved in DNA repair pathways. CONCLUSIONS: This is the first study to assess the correlation of preoperative testosterone level on the tumor transcriptome and showed no clinical correlation between pre-defined genomic risk score groups and testosterone groups. This study adds to the notion of the limited role of endogenous testosterone on the development of de novo high-risk localized prostate cancer.

Neuroendocrine differentiation in usual-type prostatic adenocarcinoma: Molecular characterization and clinical significance.

BACKGROUND: Small cell neuroendocrine (NE) carcinomas of the prostate classically lose androgen receptor (AR) expression, may harbor loss of the RB1, TP53, and PTEN tumor suppressor genes, and are associated with a poor prognosis. However usual-type adenocarcinomas may also contain areas of NE differentiation, and in this context the molecular features and biological significance are less certain. METHODS: We examined the molecular phenotype and oncologic outcomes of primary prostate adenocarcinomas with ≥5% NE differentiation (≥5% chromogranin A-positive NE cells in any given tumor spot on tissue microarray) using three independent study sets: a set of tumors with paneth cell-like NE differentiation (n = 26), a retrospective case-cohort of intermediate- and high-risk patients enriched for adverse outcomes (n = 267), and primary tumors from a retrospective series of men with eventual castration-resistant metastatic prostate cancer (CRPC) treated with abiraterone or enzalutamide (n = 55). RESULTS: Benign NE cells expressed significantly lower quantified AR levels compared with paired benign luminal cells (P < .001). Similarly, paneth-like NE carcinoma cells or carcinoma cells expressing chromogranin A expressed significantly lower quantified AR levels than paired non-NE carcinoma cells (P < .001). Quantified ERG protein expression, was also lower in chromogranin A-labeled adenocarcinoma cells compared with unlabeled cells (P < .001) and tumors with NE differentiation showed lower gene expression scores for AR activity compared with those without. Despite evidence of lower AR signaling, adenocarcinomas with NE differentiation did not differ by prevalence of TP53 missense mutations, or PTEN or RB1 loss, compared with those without NE differentiation. Finally, NE differentiation was not associated with time to metastasis in intermediate- and high-risk patients (P = .6 on multivariate analysis), nor with progression-free survival in patients with CRPC treated with abiraterone or enzalutamide (P = .9). CONCLUSION: NE differentiation in usual-type primary prostate adenocarcinoma is a molecularly and clinically distinct form of lineage plasticity from that occurring in small cell NE carcinoma.

Multiparametric Magnetic Resonance Imaging Features Identify Aggressive Prostate Cancer at the Phenotypic and Transcriptomic Level.

PURPOSE: Multiparametric magnetic resonance imaging is a diagnostic tool for prostate cancer with limited data on prognostic use. We sought to determine whether multiparametric magnetic resonance could predict aggressive prostate cancer features. MATERIALS AND METHODS: We retrospectively analyzed the records of 206 patients who underwent radical prostatectomy between 2013 and 2017. All patients had available RNA expression data on the final pathology specimen obtained from a location corresponding to a lesion location on multiparametric magnetic resonance imaging. The association between the PIRADS™ (Prostate Imaging Reporting and Data System) score and adverse pathology features were analyzed. We also performed differential transcriptomic analysis between the PIRADS groups. Factors associated with adverse pathology were analyzed using a multivariable logistic regression model. RESULTS: Lesion size (p = 0.03), PIRADS score (p = 0.02) and extraprostatic extension (p = 0.01) associated significantly with the Decipher® score. Multivariable analysis showed that the PIRADS score (referent PIRADS 3, OR 8.1, 95% CI 1.2-57.5, p = 0.04), the Gleason Grade Group (referent 3, OR 5.6, 95% CI 1.5-21.1, p = 0.01) and prostate specific antigen (OR 1.103, 95% CI 1.011-1.203) were risk factors for adverse pathology findings. The difference between PIRADS 4 and 5 did not reach significance (OR 1.9, 95% CI 0.8-4.5, p = 0.12). However, the PI3K-AKT-mTOR, WNT-ß and E2F signaling pathways were more active in PIRADS 5 than in PIRADS 4 cases. CONCLUSIONS: The PIRADS score is associated with adverse pathology results, increased metastatic risk and differential genomic pathway activation.