Testosterone accumulation in prostate cancer cells is enhanced by facilitated diffusion.

BACKGROUND: Testosterone is a driver of prostate cancer (PC) growth via ligand-mediated activation of the androgen receptor (AR). Tumors that have escaped systemic androgen deprivation, castration-resistant prostate cancers (CRPC), have measurable intratumoral levels of testosterone, suggesting that a resistance mechanism still depends on androgen-simulated growth. However, AR activation requires an optimal intracellular concentration of androgens, a situation challenged by low circulating testosterone concentrations. Notably, PC cells may optimize their androgen levels by regulating the expression of steroid metabolism enzymes that convert androgen precursors into androgens. Here we propose that testosterone entry into the cell could be another control point. METHODS: To determine whether testosterone enters cells via a transporter, we performed in vitro 3 H-testosterone uptake assays in androgen-dependent LNCaP and androgen and AR-independent PC3 cells. To determine if the uptake mechanism depended on a concentration gradient, we modified UGT2B17 levels in LNCaP cells and measured androgen levels by liquid-liquid extraction-mass spectrometry. We also analyzed CRPC metastases for expression of AKR1C3 to determine whether this enzyme that converts adrenal androgens to testosterone was present in the tumor stroma (microenvironment) in addition to its expression in the tumor epithelium. RESULTS: Testosterone uptake followed a concentration gradient but unlike in passive diffusion, was saturable and temperature-dependent, thus suggesting facilitated transport. Suppression of UGT2B17 to abrogate a testosterone gradient reduced testosterone transport while overexpression of the enzyme enhanced it. The facilitated transport suggests a paracrine route of testosterone uptake for maintaining optimal intracellular levels. We found that AKR1C3 was expressed in the tumor microenvironment of CRPC metastases in addition to epithelial cells and the pattern of relative abundance of the enzyme in epithelium vs stroma varied substantially between the metastatic sites. CONCLUSIONS: Our findings suggest that in addition to testosterone transport and metabolism by tumor epithelium, testosterone could also be produced by components of the tumor microenvironment. Facilitated testosterone uptake by tumor cells supports a cell nonautonomous mechanism for testosterone signaling in CRPC.

Setting wait times to achieve targeted left-without-being-seen rates.

BACKGROUND: Although several studies have demonstrated that wait time is a key factor that drives high leave-without-being-seen (LWBS) rates, limited data on ideal wait times and impact on LWBS rates exist. STUDY OBJECTIVES: We studied the LWBS rates by triage class and target wait times required to achieve various LWBS rates. METHODS: We conducted a 3-year retrospective analysis of patients presenting to an urban, tertiary, academic, adult emergency department (ED). We divided the 3-year study period into 504 discrete periods by year, day of the week, and hour of the day. Patients of same triage level arriving in the same bin were exposed to similar ED conditions. For each bin, we calculate the mean actual wait time and the proportion of patients that abandoned. We performed a regression analysis on the abandonment proportion on the mean wait time using weighted least squares regression. RESULTS: A total of 143,698 patients were included for analysis during the study period. The R(2) value was highest for Emergency Severity Index (ESI) 3 (R(2) = 0.88), suggesting that wait time is the major factor driving LWBS of ESI 3 patients. Assuming that ESI 2 patients wait less than 10 minutes, our sensitivity analysis shows that the target wait times for ESI 3 and ESI 4/5 patients should be less than 45 and 60 minutes, respectively, to achieve an overall LWBS rate of less than 2%. CONCLUSION: Achieving target LWBS rates requires analysis to understand the abandonment behavior and redesigning operations to achieve the target wait times.

Prognostic value of ERG oncoprotein in prostate cancer recurrence and cause-specific mortality.

BACKGROUND: ETS-related gene (ERG) protein is present in 40-70% of prostate cancer and is correlated with TMPRSS2-ERG gene rearrangements. This study evaluated ERG expression at radical prostatectomy to determine whether it was predictive of earlier relapse or prostate cancer-specific mortality (PCSM). METHODS: One hundred patients who underwent radical prostatectomy at Virginia Mason in Seattle between 1991 and 1997 were identified. Recurrence was confirmed by tissue diagnosis or radiographic signs. PCSM was confirmed by death certificates. Thirty-three patients with metastases or PCSM were matched to patients without recurrence at a 1:2 ratio. Paraffin embedded tissue was stained with two anti-ERG monoclonal antibodies, EPR3864 and 9FY. Nuclear expression intensity was evaluated as present/absent, on a 4-point relative intensity scale, and as a composite score (0-300). RESULTS: Mean follow-up was 10.26 years. The two antibodies were highly correlated (P < 0.0001). Patients with higher ERG expression intensity and composite scores were significantly more likely to develop biochemical relapse, metastases, and PCSM. Kaplan-Meier survival curve analysis for the composite score of ERG expression revealed a significant association between higher ERG expression (EPR3864) and shorter PCa-specific survival (P = 0.047). CONCLUSIONS: While the presence of ERG expression at the time of surgery was not predictive of earlier relapse or PCSM, the relative intensity and composite score for ERG expression was prognostic for the development of biochemical relapse, metastases, and PCSM. Quantitative ERG scoring may be useful to identify patients who would benefit from adjuvant treatment or closer follow-up, allowing more accurate individual patient treatment plans.

Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor through cMYC Repression and Recruitment of the DREAM Complex.

The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. The AR represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer, and targeting AR has a remarkable therapeutic index. Though most approaches directed toward AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA) results in growth repression and improved outcomes in subsets of patients with prostate cancer. A better understanding of the mechanisms contributing to SPA response and resistance could help guide patient selection and combination therapies to improve efficacy. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses indicated that the dimerization partner, RB-like, E2F, and multivulval class B (DREAM) complex mediates growth repression and downregulation of E2F targets in response to SPA. Notably, prostate cancers with complete genomic loss of RB1 responded to SPA treatment, whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Overexpression of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repression of E2F target genes. These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM complex. The integrity of MYC signaling and DREAM complex assembly may consequently serve as determinants of SPA responses and as pathways mediating SPA resistance. SIGNIFICANCE: Determining the molecular pathways by which supraphysiological androgens promote growth arrest and treatment responses in prostate cancer provides opportunities for biomarker-selected clinical trials and the development of strategies to augment responses.

Nucleosome Patterns in Circulating Tumor DNA Reveal Transcriptional Regulation of Advanced Prostate Cancer Phenotypes.

Advanced prostate cancers comprise distinct phenotypes, but tumor classification remains clinically challenging. Here, we harnessed circulating tumor DNA (ctDNA) to study tumor phenotypes by ascertaining nucleosome positioning patterns associated with transcription regulation. We sequenced plasma ctDNA whole genomes from patient-derived xenografts representing a spectrum of androgen receptor active (ARPC) and neuroendocrine (NEPC) prostate cancers. Nucleosome patterns associated with transcriptional activity were reflected in ctDNA at regions of genes, promoters, histone modifications, transcription factor binding, and accessible chromatin. We identified the activity of key phenotype-defining transcriptional regulators from ctDNA, including AR, ASCL1, HOXB13, HNF4G, and GATA2. To distinguish NEPC and ARPC in patient plasma samples, we developed prediction models that achieved accuracies of 97% for dominant phenotypes and 87% for mixed clinical phenotypes. Although phenotype classification is typically assessed by IHC or transcriptome profiling from tumor biopsies, we demonstrate that ctDNA provides comparable results with diagnostic advantages for precision oncology. SIGNIFICANCE: This study provides insights into the dynamics of nucleosome positioning and gene regulation associated with cancer phenotypes that can be ascertained from ctDNA. New methods for classification in phenotype mixtures extend the utility of ctDNA beyond assessments of somatic DNA alterations with important implications for molecular classification and precision oncology. This article is highlighted in the In This Issue feature, p. 517.

The monoamine oxidase A gene promoter repeat and prostate cancer risk.

BACKGROUND: Amine catabolism by monoamine oxidase A (MAOA) contributes to oxidative stress, which plays a role in prostate cancer (PCa) development and progression. An upstream variable-number tandem repeat (uVNTR) in the MAOA promoter influences gene expression and activity, and may thereby affect PCa susceptibility. METHODS: Caucasian (n = 2,572) men from two population-based case-control studies of PCa were genotyped for the MAOA-VNTR. Logistic regression was used to assess PCa risk in relation to genotype. RESULTS: Common alleles of the MAOA-VNTR were not associated with the relative risk of PCa, nor did the relationship differ by clinical features of the disease. The rare 5-copy variant (frequency: 0.5% in cases; 1.8% in controls), however, was associated with a reduced PCa risk (odds ratio, OR = 0.30, 95% CI 0.13-0.71). CONCLUSIONS: A rare polymorphism of the MAOA promoter previously shown to confer low expression was associated with a reduced risk of developing PCa. This novel finding awaits confirmation in other study populations.

Unplanned admission to the intensive care unit after total hip arthroplasty.

Triage to the intensive care unit (ICU) after elective total hip arthroplasty proves a complex medical and resource decision point. A total of 1259 consecutive total hip arthroplasties were reviewed; 89 patients experienced unplanned ICU admissions. Significant risk factors for ICU admission in univariate analysis were age greater than 75 years, revision surgery, obstructive sleep apnea, creatinine clearance less than 60 mL/min, prior myocardial infarction, American Society of Anesthesiologist class 3 or greater, use of vasopressors intraoperatively, and body mass index greater than 35 kg/m(2). With multiple regression, age greater than 75 years (odds ratio [OR], 2.6 [1.2-5.6]), revision surgery (OR, 5.8 [3.0-11.4]), creatinine clearance less than 60 mL/min (OR, 6.5 [2.5-16.3]), prior myocardial infarction (OR, 7.2 [2.0-25.4]), and body mass index greater than 35 kg/m(2) (OR, 2.9 [1.4-6.2]) were predictive of unplanned ICU admission. With 1 risk factor, the risk of ICU admission was 40%, 2 (75%), 3 (93.5%), 4 (98.5%), and 5 (>99%). A prospective study of these risk factors is needed to establish a threshold for planned ICU admission.

Comprehensive assessment of anaplastic lymphoma kinase in localized and metastatic prostate cancer reveals targetable alterations.

Anaplastic lymphoma kinase (ALK) is a tyrosine kinase with genomic and expression changes in many solid tumors. ALK inhibition is first line therapy for lung cancers with ALK alterations, and an effective therapy in other tumor types, but has not been well-studied in prostate cancer. Here, we aim to delineate the role of ALK genomic and expression changes in primary and metastatic prostate cancer. We determined ALK expression by immunohistochemistry and RNA-Seq, and genomic alterations by NGS. We assessed functional consequences of ALK overexpression and pharmacological ALK inhibition by cell proliferation and cell viability assays. Among 372 primary prostate cancer cases we identified one case with uniformly high ALK protein expression. Genomic analysis revealed a SLC45A3-ALK fusion which promoted oncogenesis in in vitro assays. We observed ALK protein expression in 5/52 (9%) of metastatic prostate cancer cases, of which 4 of 5 had neuroendocrine features. ALK-expressing neuroendocrine prostate cancer had a distinct transcriptional program, and earlier disease progression. An ALK-expressing neuroendocrine prostate cancer model was sensitive to pharmacological ALK inhibition. In summary, we found that ALK overexpression is rare in primary prostate cancer, but more frequent in metastatic prostate cancers with neuroendocrine differentiation. Further, ALK fusions similar to lung cancer are an occasional driver in prostate cancer. Our data suggest that ALK-directed therapies could be an option in selected patients with advanced prostate cancer.

A causal role for ERG in neoplastic transformation of prostate epithelium.

A significant proportion of human prostate cancers carry a chromosomal rearrangement resulting in the overexpression of the ETS transcription factor, ERG; however, the functional significance of this event is poorly understood. We report here that up-regulation of ERG transcript is sufficient for the initiation of prostate neoplasia. In agreement with measurements of ERG transcripts, we found that ERG protein is expressed in neoplastic human prostate epithelium. Overexpression of ERG in prostate cell lines increased cell invasion. Moreover, targeted expression of this transcript in vivo in luminal prostate epithelial cells of transgenic mice results in initiation of prostate neoplasia observed as the development of focal precancerous prostatic intraepithelial neoplasia (PIN). Similar to human cancers, luminal epithelial cells in these PIN lesions displace diminishing in numbers basal epithelial cells and establish direct contact with the stromal cell compartment. Loss of basal cells is considered to be one of the critical hallmarks of human prostate cancer; however, the mechanisms responsible for this event were unknown. We propose that up-regulation of ERG in human prostate cancer activates cell invasion programs that subsequently displace basal cells by neoplastic epithelium. Our data demonstrate that ERG plays an important causal role in the transformation of prostate epithelium and should be considered as a target for prevention or early therapeutic intervention.

Genomic attributes of homology-directed DNA repair deficiency in metastatic prostate cancer.

Cancers with homology-directed DNA repair (HRR) deficiency exhibit high response rates to poly(ADP-ribose) polymerase inhibitors (PARPi) and platinum chemotherapy. Though mutations disrupting BRCA1 and BRCA2 associate with HRR deficiency (HRRd), patterns of genomic aberrations and mutation signatures may be more sensitive and specific indicators of compromised repair. Here, we evaluated whole-exome sequences from 418 metastatic prostate cancers (mPCs) and determined that one-fifth exhibited genomic characteristics of HRRd that included Catalogue Of Somatic Mutations In Cancer mutation signature 3. Notably, a substantial fraction of tumors with genomic features of HRRd lacked biallelic loss of a core HRR-associated gene, such as BRCA2. In this subset, HRRd associated with loss of chromodomain helicase DNA binding protein 1 but not with mutations in serine-protein kinase ATM, cyclin dependent kinase 12, or checkpoint kinase 2. HRRd genomic status was strongly correlated with responses to PARPi and platinum chemotherapy, a finding that supports evaluating biomarkers reflecting functional HRRd for treatment allocation.

BET Bromodomain Inhibition Blocks an AR-Repressed, E2F1-Activated Treatment-Emergent Neuroendocrine Prostate Cancer Lineage Plasticity Program.

PURPOSE: Lineage plasticity in prostate cancer-most commonly exemplified by loss of androgen receptor (AR) signaling and a switch from a luminal to alternate differentiation program-is now recognized as a treatment resistance mechanism. Lineage plasticity is a spectrum, but neuroendocrine prostate cancer (NEPC) is the most virulent example. Currently, there are limited treatments for NEPC. Moreover, the incidence of treatment-emergent NEPC (t-NEPC) is increasing in the era of novel AR inhibitors. In contradistinction to de novo NEPC, t-NEPC tumors often express the AR, but AR's functional role in t-NEPC is unknown. Furthermore, targetable factors that promote t-NEPC lineage plasticity are also unclear. EXPERIMENTAL DESIGN: Using an integrative systems biology approach, we investigated enzalutamide-resistant t-NEPC cell lines and their parental, enzalutamide-sensitive adenocarcinoma cell lines. The AR is still expressed in these t-NEPC cells, enabling us to determine the role of the AR and other key factors in regulating t-NEPC lineage plasticity. RESULTS: AR inhibition accentuates lineage plasticity in t-NEPC cells-an effect not observed in parental, enzalutamide-sensitive adenocarcinoma cells. Induction of an AR-repressed, lineage plasticity program is dependent on activation of the transcription factor E2F1 in concert with the BET bromodomain chromatin reader BRD4. BET inhibition (BETi) blocks this E2F1/BRD4-regulated program and decreases growth of t-NEPC tumor models and a subset of t-NEPC patient tumors with high activity of this program in a BETi clinical trial. CONCLUSIONS: E2F1 and BRD4 are critical for activating an AR-repressed, t-NEPC lineage plasticity program. BETi is a promising approach to block this program.

Identification of Therapeutic Vulnerabilities in Small-cell Neuroendocrine Prostate Cancer.

PURPOSE: Small-cell neuroendocrine prostate cancer (SCNPC) exhibits an aggressive clinical course and incidence rates seem to be increasing following resistance to potent androgen receptor (AR) antagonists. Currently, treatment options are limited and few model systems are available to identify new approaches for treatment. We sought to evaluate commonalities between SCNPC and other aggressive neuroendocrine carcinomas to identify therapeutic targets. EXPERIMENTAL DESIGN: We generated whole transcriptome RNA-sequencing data from AR-active prostate cancers (ARPCs) and SCNPCs from tumors collected at rapid autopsy and two other neuroendocrine carcinomas, Merkel cell carcinoma (MCC), and small-cell lung cancer. We performed cross-tumor comparisons to identify conserved patterns of expression of druggable targets. We tested inhibitors to highly upregulated drug targets in a panel of prostate cancer cell lines and in vivo patient-derived xenograft (PDX) models. RESULTS: We identified BCL2 as highly upregulated in SCNPC compared with ARPC. Inhibitors targeting BCL2 induced apoptotic cell death in SCNPC cell lines at nanomolar concentrations while ARPC cell lines were resistant. Treatment with the BCL2 inhibitor navitoclax leads to a reduction of growth of SCNPC PDX tumors in vivo, whereas ARPC PDX models were more resistant. We identified Wee1 as a second druggable target upregulated in SCNPC. Treatment with the combination of navitoclax and the Wee1 inhibitor AZD-1775 repressed the growth of SCNPC PDX resistant to single-agent BCL2 inhibitors. CONCLUSIONS: The combination of BCL2 and Wee1 inhibition presents a novel therapeutic strategy for the treatment of SCNPC.

Combined TP53 and RB1 Loss Promotes Prostate Cancer Resistance to a Spectrum of Therapeutics and Confers Vulnerability to Replication Stress.

Prostate cancers (PCs) with loss of the potent tumor suppressors TP53 and RB1 exhibit poor outcomes. TP53 and RB1 also influence cell plasticity and are frequently lost in PCs with neuroendocrine (NE) differentiation. Therapeutic strategies that address these aggressive variant PCs are urgently needed. Using deep genomic profiling of 410 metastatic biopsies, we determine the relationships between combined TP53 and RB1 loss and PC phenotypes. Notably, 40% of TP53/RB1-deficient tumors are classified as AR-active adenocarcinomas, indicating that NE differentiation is not an obligate consequence of TP53/RB1 inactivation. A gene expression signature reflecting TP53/RB1 loss is associated with diminished responses to AR antagonists and reduced survival. These tumors exhibit high proliferation rates and evidence of elevated DNA repair processes. While tumor cells lacking TP53/RB1 are highly resistant to all single-agent therapeutics tested, the combination of PARP and ATR inhibition is found to produce significant responses, reflecting a clinically exploitable vulnerability resulting from replication stress.

Molecular determinants of response to high-dose androgen therapy in prostate cancer.

Clinical trials of high-dose androgen (HDA) therapy for prostate cancer (PC) have shown promising efficacy but are limited by lack of criteria to identify likely responders. To elucidate factors that govern the growth-repressive effects of HDAs, we applied an unbiased integrative approach using genetic screens and transcriptional profiling of PC cells with or without demonstrated phenotypic sensitivity to androgen-mediated growth repression. Through this comprehensive analysis, we identified genetic events and related signaling networks that determine the response to both HDA and androgen withdrawal. We applied these findings to develop a gene signature that may serve as an early indicator of treatment response and identify men with tumors that are amenable to HDA therapy.

Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage.

Prostate cancer (PC) is initially dependent on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to suppress AR activity serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations can produce paradoxical responses leading to PC growth inhibition. We sought to discern the mechanisms by which SPA inhibits PC and to determine if molecular context associates with anti-tumor activity. SPA produced an AR-mediated, dose-dependent induction of DNA double-strand breaks (DSBs), G0/G1 cell cycle arrest and cellular senescence. SPA repressed genes involved in DNA repair and delayed the restoration of damaged DNA which was augmented by PARP1 inhibition. SPA-induced DSBs were accentuated in BRCA2-deficient PCs, and combining SPA with PARP or DNA-PKcs inhibition further repressed growth. Next-generation sequencing was performed on biospecimens from PC patients receiving SPA as part of ongoing Phase II clinical trials. Patients with mutations in genes mediating homology-directed DNA repair were more likely to exhibit clinical responses to SPA. These results provide a mechanistic rationale for directing SPA therapy to PCs with AR amplification or DNA repair deficiency, and for combining SPA therapy with PARP inhibition.

Androgen Receptor Pathway-Independent Prostate Cancer Is Sustained through FGF Signaling.

Androgen receptor (AR) signaling is a distinctive feature of prostate carcinoma (PC) and represents the major therapeutic target for treating metastatic prostate cancer (mPC). Though highly effective, AR antagonism can produce tumors that bypass a functional requirement for AR, often through neuroendocrine (NE) transdifferentiation. Through the molecular assessment of mPCs over two decades, we find a phenotypic shift has occurred in mPC with the emergence of an AR-null NE-null phenotype. These "double-negative" PCs are notable for elevated FGF and MAPK pathway activity, which can bypass AR dependence. Pharmacological inhibitors of MAPK or FGFR repressed the growth of double-negative PCs in vitro and in vivo. Our results indicate that FGF/MAPK blockade may be particularly efficacious against mPCs with an AR-null phenotype.

Long non-coding RNA: A newly deciphered "code" in prostate cancer.

As one of the most frequently diagnosed cancers in males, the development and progression of prostate cancer remains an open area of research. The role of lncRNAs in prostate cancer is an emerging field of study. In this review, we summarize what is currently known about lncRNAs in prostate cancer while focusing on a few key lncRNAs. PCA3 was the first lncRNA identified in prostate cancer and has been shown to be expressed in a majority of prostate cancer cases. It may act in both an androgen dependent and independent fashion and has clinical utility as a biomarker. Other lncRNAs are known to interact directly with the androgen receptor pathway including PlncRNA-1, HOTAIR, PRNCR1 and PCGEM1. Additionally, lncRNAs have been shown to interfere with tumor suppressors, DNA break repair, transcription and alternate RNA splicing. While only in its infancy, an understanding of the role of lncRNAs in prostate cancer development should present ample opportunities for the discovery of new cancer biomarkers and therapeutic targets.

A proteolytic modification of AIM promotes its renal excretion.

Apoptosis inhibitor of macrophage (AIM, encoded by cd5l) is a multi-functional circulating protein that has a beneficial role in the regulation of a broad range of diseases, some of which are ameliorated by AIM administration in mice. In blood, AIM is stabilized by association with IgM pentamers and maintains its high circulating levels. The mechanism regulating the excessive accumulation of blood AIM remains unknown, although it is important, since a constitutive increase in AIM levels promotes chronic inflammation. Here we found a physiological AIM-cleavage process that induces destabilization of AIM and its excretion in urine. In blood, IgM-free AIM appeared to be cleaved and reduced in size approximately 10 kDa. Cleaved AIM was unable to bind to IgM and was selectively filtered by the glomerulus, thereby excreted in urine. Amino acid substitution at the cleavage site resulted in no renal excretion of AIM. Interestingly, cleaved AIM retained a comparable potency with full-length AIM in facilitating the clearance of dead cell debris in injured kidney, which is a key response in the recovery of acute kidney injury. Identification of AIM-cleavage and resulting functional modification could be the basis for designing safe and efficient AIM therapy for various diseases.

Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer.

Tumor heterogeneity may reduce the efficacy of molecularly guided systemic therapy for cancers that have metastasized. To determine whether the genomic alterations in a single metastasis provide a reasonable assessment of the major oncogenic drivers of other dispersed metastases in an individual, we analyzed multiple tumors from men with disseminated prostate cancer through whole-exome sequencing, array comparative genomic hybridization (CGH) and RNA transcript profiling, and we compared the genomic diversity within and between individuals. In contrast to the substantial heterogeneity between men, there was limited diversity among metastases within an individual. The number of somatic mutations, the burden of genomic copy number alterations and aberrations in known oncogenic drivers were all highly concordant, as were metrics of androgen receptor (AR) activity and cell cycle activity. AR activity was inversely associated with cell proliferation, whereas the expression of Fanconi anemia (FA)-complex genes was correlated with elevated cell cycle progression, expression of the E2F transcription factor 1 (E2F1) and loss of retinoblastoma 1 (RB1). Men with somatic aberrations in FA-complex genes or in ATM serine/threonine kinase (ATM) exhibited significantly longer treatment-response durations to carboplatin than did men without defects in genes encoding DNA-repair proteins. Collectively, these data indicate that although exceptions exist, evaluating a single metastasis provides a reasonable assessment of the major oncogenic driver alterations that are present in disseminated tumors within an individual, and thus may be useful for selecting treatments on the basis of predicted molecular vulnerabilities.