DNA repair defects in prostate cancer: impact for screening, prognostication and treatment.

Failure of effective DNA damage repair is a hallmark of cancer, but was previously underappreciated as a driver of aggressive prostate cancer. However, recent international sequencing efforts have revealed that both germline and somatic alterations within the homologous recombination and mismatch repair pathways are relatively common in lethal metastatic disease. BRCA2 gene alterations are particularly prevalent and are linked to poor prognosis as well as poor responses to systemic therapy for castration-resistant prostate cancer, although there is conflicting support for the latter. Defective DNA repair contributes to tumour heterogeneity, evolution and progression, but there are high hopes that management of this aggressive subset will be transformed by biomarker-driven use of poly-ADP ribose polymerase (PARP) inhibitors and platinum-based chemotherapy. In this review, we detail the relationship between DNA repair defects and prostate cancer, highlighting the prevalence of mutations in key genes and their controversial association with clinical outcomes.

Reversal of Severe Visual Loss from Syphilitic Chorioretinitis Following Penicillin Treatment.

A 51-year-old Caucasian male was referred to neuro-ophthalmology clinic for an evaluation of acute onset of painless visual loss in the left eye. The ocular examination revealed subtle retinal changes suspicious for chorioretinitis. Laboratory workup revealed a reactive Treponema pallidum particle agglutination assay (TP-PA), confirming the diagnosis of ocular syphilis. The patient was treated with intravenous infusion of penicillin with complete recovery of vision and resolution of retinal abnormalities.

Peripheral ulcerative keratitis associated with tralokinumab therapy: a case report and review of IL-13 inhibitor-associated ocular surface disease.

BACKGROUND: Dupilumab and tralokinumab are interleukin-binding monoclonal antibodies used to treat systemic atopic disease. Use of these medications in management of atopic dermatitis (AD) is known to cause conjunctivitis. Dupilumab therapy has also been associated with more severe ocular surface disease, which has not previously been described in association with tralokinumab. This report describes a case of tralokinumab-associated conjunctivitis and peripheral ulcerative keratitis and reviews the spectrum and proposed mechanisms of ocular surface disease triggered by these medications. CASE PRESENTATION: A 61-year-old male with no rheumatologic or ocular history presented with bilateral papillary conjunctivitis and right eye peripheral ulcerative keratitis (PUK). PUK was arrested using oral corticosteroids and doxycycline, and long-term control of papillary conjunctivitis was achieved using topical tacrolimus ointment, allowing continuation of effective AD management with tralokinumab. CONCLUSION: This case report documents ulcerative keratitis occurring in association with tralokinumab therapy for AD, which has previously been described with dupilumab but not tralokinumab. This report demonstrates the need for vigilant ocular surface monitoring for patients on tralokinumab and illustrates successful management and long-term control of adverse ocular events associated with this medication.

A rare case of acantholytic squamous cell carcinoma presenting on non-sun exposed palpebral conjunctiva.

Purpose: This report describes the clinical and histological characteristics and management of a keratinized lesion of the palpebral conjunctiva in a 59-year-old male. The lesion was identified as a rare acantholytic variant of squamous cell carcinoma that atypically arose from a non-sun exposed region of palpebral conjunctiva. Management was complete excision via Mohs surgery. Observations: A 59-year-old male presented with ocular irritation and chronic foreign body sensation in the right eye. Exam revealed a keratinized lesion in the right lower tarsal conjunctiva, and an initial shave biopsy was non-diagnostic. 12 months later, the patient presented with similar symptoms and a larger, more irregular lesion for which histopathology of a tarsal-involving excisional biopsy was consistent with acantholytic squamous cell carcinoma with involved margins. The patient subsequently underwent complete excision via Mohs surgery and a secondary reconstruction. Conclusions and importance: Acantholytic variants of squamous cell carcinoma are rare and are described as arising from areas with routine sun exposure. This case reports such a lesion arising from non-sun exposed tarsal conjunctiva, as identified by histopathology of a full-thickness excisional biopsy. The lesion was successfully managed with complete excision via Mohs surgery and secondary reconstruction. Given that this histologic variant may be more aggressive and have higher rates of recurrence than other forms of squamous cell carcinoma, this case highlights the importance of complete excisional biopsy and accurate histopathology of concerning periocular lesions and offers a template for management of similar lesions. The unique presenting location should bring awareness to consideration of this type of malignancy developing on palpebral conjunctiva.

Molecular features of prostate cancer after neoadjuvant therapy in the phase 3 CALGB 90203 trial.

BACKGROUND: The phase 3 CALGB 90203 (Alliance) trial evaluated neoadjuvant chemohormonal therapy for high-risk localized prostate cancer before radical prostatectomy. We dissected the molecular features of post-treated tumors with long-term clinical outcomes to explore mechanisms of response and resistance to chemohormonal therapy. METHODS: We evaluated 471 radical prostatectomy tumors, including 294 samples from 166 patients treated with 6 cycles of docetaxel plus androgen deprivation therapy before radical prostatectomy and 177 samples from 97 patients in the control arm (radical prostatectomy alone). Targeted DNA sequencing and RNA expression of tumor foci and adjacent noncancer regions were analyzed in conjunction with pathologic changes and clinical outcomes. RESULTS: Tumor fraction estimated from DNA sequencing was significantly lower in post-treated tumor tissues after chemohormonal therapy compared with controls. Higher tumor fraction after chemohormonal therapy was associated with aggressive pathologic features and poor outcomes, including prostate-specific antigen-progression-free survival. SPOP alterations were infrequently detected after chemohormonal therapy, while TP53 alterations were enriched and associated with shorter overall survival. Residual tumor fraction after chemohormonal therapy was linked to higher expression of androgen receptor-regulated genes, cell cycle genes, and neuroendocrine genes, suggesting persistent populations of active prostate cancer cells. Supervised clustering of post-treated high-tumor-fraction tissues identified a group of patients with elevated cell cycle-related gene expression and poor clinical outcomes. CONCLUSIONS: Distinct recurrent prostate cancer genomic and transcriptomic features are observed after exposure to docetaxel and androgen deprivation therapy. Tumor fraction assessed by DNA sequencing quantifies pathologic response and could be a useful trial endpoint or prognostic biomarker. TP53 alterations and high cell cycle transcriptomic activity are linked to aggressive residual disease, despite potent chemohormonal therapy.

Multiregion sampling of de novo metastatic prostate cancer reveals complex polyclonality and augments clinical genotyping.

De novo metastatic prostate cancer is highly aggressive, but the paucity of routinely collected tissue has hindered genomic stratification and precision oncology. Here, we leveraged a rare study of surgical intervention in 43 de novo metastatic prostate cancers to assess somatic genotypes across 607 synchronous primary and metastatic tissue regions plus circulating tumor DNA. Intra-prostate heterogeneity was pervasive and impacted clinically relevant genes, resulting in discordant genotypes between select primary restricted regions and synchronous metastases. Additional complexity was driven by polyclonal metastatic seeding from phylogenetically related primary populations. When simulating clinical practice relying on a single tissue region, genomic heterogeneity plus variable tumor fraction across samples caused inaccurate genotyping of dominant disease; however, pooling extracted DNA from multiple biopsy cores before sequencing can rescue misassigned somatic genotypes. Our results define the relationship between synchronous treatment-sensitive primary and metastatic lesions in men with de novo metastatic prostate cancer and provide a framework for implementing genomics-guided patient management.

Orbital fibrous histiocytoma mimicking cavernous hemangioma on dynamic contrast-enhanced MRA imaging.

Orbital lesions include a broad spectrum of tumors, vascular abnormalities, and inflammatory conditions. High-resolution imaging has become an invaluable tool toward formulating an accurate diagnosis, and facilitates proper counseling regarding appropriate interventions. Imaging may guide whether partial excision to minimize damage to orbital structures, or en bloc removal to prevent potential recurrence, as seen in mesenchymal tumors, is indicated., Recently, dynamic contrast-enhanced magnetic resonance angiography (MRA) has demonstrated use in helping differentiate orbital vascular lesions. This imaging modality uses rapid MRI acquisition to provide noninvasive, dynamic flow information with high spatial resolution. However, even with modern imaging, reaching a diagnosis prior to histopathological analysis can be challenging. We present a case of orbital fibrous histiocytoma that appeared nearly identical to cavernous hemangioma on dynamic contrast-enhanced MRA.

A generalizable machine learning framework for classifying DNA repair defects using ctDNA exomes.

Specific classes of DNA damage repair (DDR) defect can drive sensitivity to emerging therapies for metastatic prostate cancer. However, biomarker approaches based on DDR gene sequencing do not accurately predict DDR deficiency or treatment benefit. Somatic alteration signatures may identify DDR deficiency but historically require whole-genome sequencing of tumour tissue. We assembled whole-exome sequencing data for 155 high ctDNA fraction plasma cell-free DNA and matched leukocyte DNA samples from patients with metastatic prostate or bladder cancer. Labels for DDR gene alterations were established using deep targeted sequencing. Per sample mutation and copy number features were used to train XGBoost ensemble models. Naive somatic features and trinucleotide signatures were associated with specific DDR gene alterations but insufficient to resolve each class. Conversely, XGBoost-derived models showed strong performance including an area under the curve of 0.99, 0.99 and 1.00 for identifying BRCA2, CDK12, and mismatch repair deficiency in metastatic prostate cancer. Our machine learning approach re-classified several samples exhibiting genomic features inconsistent with original labels, identified a metastatic bladder cancer sample with a homozygous BRCA2 copy loss, and outperformed an existing exome-based classifier for BRCA2 deficiency. We present DARC Sign (DnA Repair Classification SIGNatures); a public machine learning tool leveraging clinically-practical liquid biopsy specimens for simultaneously identifying multiple types of metastatic prostate cancer DDR deficiencies. We posit that it will be useful for understanding differential responses to DDR-directed therapies in ongoing clinical trials and may ultimately enable prospective identification of prostate cancers with phenotypic evidence of DDR deficiency.

Comprehensive genomic profiling of treatment resistant metastatic castrate sensitive prostate cancer reveals high frequency of potential therapeutic targets.

INTRODUCTION: While comprehensive genomic profiling (CGP) data is becoming increasingly important in the management of prostate cancer, it remains under-utilized in the setting of metastatic castrate sensitive prostate cancer (mCSPC). We aimed to explore the feasibility and potential utility of CGP in mCSPC. PATIENTS AND METHODS: Patients with mCSPC were prospectively recruited at the Princess Margaret Cancer Centre to the OCTANE trial (NCT02906943). The objective was to assess the feasibility of profiling archival standard diagnostic tumor tissue using next generation sequencing with a custom hybridization capture DNA-based or a targeted DNA/RNA amplicon-based panel. Clinical data were extracted from electronic health records. RESULTS: Among 39 mCSPC patients enrolled, 21 (54%) had sufficient archival tissue for CGP. Most had high volume (71%) or de novo (71%) mCSPC, with the majority being androgen deprivation therapy (ADT) naïve. In total, 62% of patients had a pathogenic and/or a likely pathogenic variant, many of which involved DNA damage repair (DDR, 19%), cell cycle (24%), and Androgen Receptor (AR, 10%) pathways. After median follow-up of 32.1 months, 18 of 21 patients progressed, with median time to mCRPC of 14.3 months (95% CI 10.2-21.0). Patients with AR and DDR variants seemed to have shorter median time to mCRPC; 10.2 (95% CI 9.50-NR) and 10.3 months (95% CI 6.6-14.3) respectively. CONCLUSION: In this cohort of highly treatment resistant mCSPC, most of which were ADT-naïve, CGP using archival tumor tissue was feasible for over half of patients, and 62% of patients profiled had a pathogenic and/or a likely pathogenic variant. The presence of de novo variants provides biological basis for evaluating intensification strategies of systemic therapy. This highlights the potential role of routine CGP in biomarker development and clinical trial design in the setting of mCSPC.

Tissue- and Blood-derived Genomic Biomarkers for Metastatic Hormone-sensitive Prostate Cancer: A Systematic Review.

CONTEXT: Multiple studies have reported on the genomic characteristics of metastatic hormone-sensitive prostate cancer (mHSPC). The impact of these findings on prognostication, treatment selection, and clinical trial design remains unclear. OBJECTIVE: To summarise genomic alteration prevalences in liquid and/or tissue biopsies, infer their clinical implications, and compare genomic alteration frequencies across different disease states and clinical phenotypes. EVIDENCE ACQUISITION: The PubMed and Web of Knowledge databases were systematically searched up to January 2021. Quality assessment was performed using the Joanna Briggs Institute Critical Appraisal tools. EVIDENCE SYNTHESIS: In total, 11 studies encompassing 1682 mHSPC patients were included. High-volume disease was associated with more frequent alterations in TP53, DNA damage repair, and Wnt pathways. Tumours from patients with de novo mHSPC were enriched for alterations in TP53 and CDK12 compared with recurrent disease. Alterations in AR, TP53, cell cycle signalling, and MYC were associated with a poorer clinical outcome. A comparative analysis of gene alteration frequencies across disease states revealed a relative increase from localised to castration-resistant tumours, with noteworthy enrichment of CTNNB1 alterations in mHSPC (5%), which warrants further investigation. This study was limited by variability in methodology and definitions used among the eligible studies, including differences in sequencing methods, analytes (being either tissue or liquid), alteration calling thresholds, and target patient populations with a relative under-representation of recurrent metastatic disease. CONCLUSIONS: Several genomic alterations are associated with differential prognosis and clinical phenotypes in mHSPC. We urge that emerging data on these potential predictive biomarkers must be validated in biomarker-driven randomised controlled trials before any clinical implementation. Alignment of the assay methodology and reporting will be critical for ensuring rapid scalability. PATIENT SUMMARY: We reviewed current data on genomic alterations of metastatic hormone-sensitive prostate cancer, and summarised key genomic subtypes that associate with specific clinical phenotypes and treatment outcomes.

BRCA2, ATM, and CDK12 Defects Differentially Shape Prostate Tumor Driver Genomics and Clinical Aggression.

PURPOSE: DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features. EXPERIMENTAL DESIGN: We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically. RESULTS: BRCA2, ATM, and CDK12 were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele-specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous BRCA2 deletions. Tumor suppressors TP53, RB1, and PTEN were controlled via disruptive chromosomal rearrangements in BRCA2-defective samples, but via oncogene amplification in context of CDK12 defects. TP53 mutations were rare in cases with ATM defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of BRCA2 and CDK12, but not ATM, was associated with poor clinical outcomes. CONCLUSIONS: BRCA2, ATM, and CDK12 defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.

Evolution of Castration-Resistant Prostate Cancer in ctDNA during Sequential Androgen Receptor Pathway Inhibition.

PURPOSE: Cross-resistance renders multiple lines of androgen receptor (AR) signaling inhibitors increasingly futile in metastatic castration-resistant prostate cancer (mCRPC). We sought to determine acquired genomic contributors to cross-resistance. EXPERIMENTAL DESIGN: We collected 458 serial plasma cell-free DNA samples at baseline and progression timepoints from 202 patients with mCRPC receiving sequential AR signaling inhibitors (abiraterone and enzalutamide) in a randomized phase II clinical trial (NCT02125357). We utilized deep targeted and whole-exome sequencing to compare baseline and posttreatment somatic genomic profiles in circulating tumor DNA (ctDNA). RESULTS: Patient ctDNA abundance was correlated across plasma collections and independently prognostic for sequential therapy response and overall survival. Most driver alterations in established prostate cancer genes were consistently detected in ctDNA over time. However, shifts in somatic populations after treatment were identified in 53% of patients, particularly after strong treatment responses. Treatment-associated changes converged upon the AR gene, with an average 50% increase in AR copy number, changes in AR mutation frequencies, and a 2.5-fold increase in the proportion of patients carrying AR ligand binding domain truncating rearrangements. CONCLUSIONS: Our data show that the dominant AR genotype continues to evolve during sequential lines of AR inhibition and drives acquired resistance in patients with mCRPC.

Activating AKT1 and PIK3CA Mutations in Metastatic Castration-Resistant Prostate Cancer.

BACKGROUND: Activating mutations in AKT1 and PIK3CA are undercharacterised in metastatic castration-resistant prostate cancer (mCRPC), but are linked to activation of phosphatidylinositol 3-kinase (PI3K) signalling and sensitivity to pathway inhibitors in other cancers. OBJECTIVE: To determine the prevalence, genomic context, and clinical associations of AKT1/PIK3CA activating mutations in mCRPC. DESIGN, SETTING, AND PARTICIPANTS: We analysed targeted cell-free DNA (cfDNA) sequencing data from 599 metastatic prostate cancer patients with circulating tumour DNA (ctDNA) content above 2%. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: In patients with AKT1/PIK3CA mutations, cfDNA was subjected to PTEN intron sequencing and matched diagnostic tumour tissue was analysed when possible. RESULTS AND LIMITATIONS: Of the patients, 6.0% (36/599) harboured somatic clonal activating mutation(s) in AKT1 or PIK3CA. Mutant allele-specific imbalance was common. Clonal mutations in mCRPC ctDNA were typically detected in pretreatment primary tissue and were consistent across serial ctDNA collections. AKT1/PIK3CA-mutant mCRPC had fewer androgen receptor (AR) gene copies than AKT1/PIK3CA wild-type mCRPC (median 4.7 vs 10.3, p = 0.003). AKT1 mutations were mutually exclusive with PTEN alterations. Patients with and without AKT1/PIK3CA mutations showed similar clinical outcomes with standard of care treatments. A heavily pretreated mCRPC patient with an AKT1 mutation experienced a 50% decline in prostate-specific antigen with Akt inhibitor (ipatasertib) monotherapy. Ipatasertib also had a marked antitumour effect in a patient-derived xenograft harbouring an AKT1 mutation. Limitations include the inability to assess AKT1/PIK3CA correlatives in ctDNA-negative patients. CONCLUSIONS: AKT1/PIK3CA activating mutations are relatively common and delineate a distinct mCRPC molecular subtype with low-level AR copy gain. Clonal prevalence and evidence of mutant allele selection propose PI3K pathway dependency in selected patients. The use of cfDNA screening enables prospective clinical trials to test PI3K pathway inhibitors in this population. PATIENT SUMMARY: Of advanced prostate cancer cases, 6% have activating mutations in the genes AKT1 or PIK3CA. These mutations can be identified using a blood test and may help select patients suitable for clinical trials of phosphatidylinositol 3-kinase inhibitors.

Identification of Hypermutation and Defective Mismatch Repair in ctDNA from Metastatic Prostate Cancer.

PURPOSE: DNA mismatch repair defects (MMRd) and tumor hypermutation are rare and under-characterized in metastatic prostate cancer (mPC). Furthermore, because hypermutated MMRd prostate cancers can respond to immune checkpoint inhibitors, there is an urgent need for practical detection tools. EXPERIMENTAL DESIGN: We analyzed plasma cell-free DNA-targeted sequencing data from 433 patients with mPC with circulating tumor DNA (ctDNA) purity ≥2%. Samples with somatic hypermutation were subjected to 185 × whole-exome sequencing and capture of mismatch repair gene introns. Archival tissue was analyzed with targeted sequencing and IHC. RESULTS: Sixteen patients (3.7%) had somatic hypermutation with MMRd etiology, evidenced by deleterious alterations in MSH2, MSH6, or MLH1, microsatellite instability, and characteristic trinucleotide signatures. ctDNA was concordant with mismatch repair protein IHC and DNA sequencing of tumor tissue. Tumor suppressors such as PTEN, RB1, and TP53 were inactivated by mutation rather than copy-number loss. Hotspot mutations in oncogenes such as AKT1, PIK3CA, and CTNNB1 were common, and the androgen receptor (AR)-ligand binding domain was mutated in 9 of 16 patients. We observed high intrapatient clonal diversity, evidenced by subclonal driver mutations and shifts in mutation allele frequency over time. Patients with hypermutation and MMRd etiology in ctDNA had a poor response to AR inhibition and inferior survival compared with a control cohort. CONCLUSIONS: Hypermutated MMRd mPC is associated with oncogene activation and subclonal diversity, which may contribute to a clinically aggressive disposition in selected patients. In patients with detectable ctDNA, cell-free DNA sequencing is a practical tool to prioritize this subtype for immunotherapy.See related commentary by Schweizer and Yu, p. 981.

Laser in Situ Keratomileusis Flap Free-Floating on Interface Edema in Acute Corneal Hydrops.

This case report describes a patient with a history of laser in situ keratomileusis who presented with pain, photophobia, and blurred vision secondary to a corneal flap free-floating on interface edema in the setting of acute hydrops.

Circulating Tumor DNA Abundance and Potential Utility in De Novo Metastatic Prostate Cancer.

BACKGROUND: Several systemic therapeutic options exist for metastatic castrate-sensitive prostate cancer (mCSPC). Circulating tumor DNA (ctDNA) can molecularly profile metastatic castration-resistant prostate cancer and can influence decision-making, but remains untested in mCSPC. OBJECTIVE: To determine ctDNA abundance at de novo mCSPC diagnosis and whether ctDNA provides complementary clinically relevant information to a prostate biopsy. DESIGN, SETTING, AND PARTICIPANTS: We collected plasma cell-free DNA (cfDNA) from 53 patients newly diagnosed with mCSPC and, where possible, during treatment. Targeted sequencing was performed on cfDNA and DNA from diagnostic prostate tissue. RESULTS AND LIMITATIONS: The median ctDNA fraction was 11% (range 0-84%) among untreated patients but was lower (1.0%, range 0-51%) among patients after short-term (median 22d) androgen deprivation therapy (ADT). TP53 mutations and DNA repair defects were identified in 47% and 21% of the cohort, respectively. The concordance for mutation detection in matched samples was 80%. Combined ctDNA and tissue analysis identified potential driver alterations in 94% of patients, whereas ctDNA or prostate biopsy alone was insufficient in 19 cases (36%). Limitations include the use of a narrow gene panel and undersampling of primary disease by prostate biopsy. CONCLUSIONS: ctDNA provides additional information to a prostate biopsy in men with de novo mCSPC, but ADT rapidly reduces ctDNA availability. Primary tissue and ctDNA share relevant somatic alterations, suggesting that either is suitable for molecular subtyping in de novo mCSPC. The optimal approach for biomarker development should utilize both a tissue and liquid biopsy at diagnosis, as neither captures clinically relevant somatic alterations in all patients. PATIENT SUMMARY: In men with advanced prostate cancer, tumor DNA shed into the bloodstream can be measured via a blood test. The information from this test provides complementary information to a prostate needle biopsy and could be used to guide management strategies. Sequencing data were deposited in the European Genome-phenome Archive (EGA) under study identifier EGAS00001003351.

Circulating Tumor DNA Genomics Correlate with Resistance to Abiraterone and Enzalutamide in Prostate Cancer.

Primary resistance to androgen receptor (AR)-directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naïve mCRPC to abiraterone or enzalutamide and performed whole-exome and deep targeted 72-gene sequencing of plasma cell-free DNA prior to therapy. For these agents, which have never been directly compared, time to progression was similar. Defects in BRCA2 and ATM were strongly associated with poor clinical outcomes independently of clinical prognostic factors and circulating tumor DNA abundance. Somatic alterations in TP53, previously linked to reduced tumor dependency on AR signaling, were also independently associated with rapid resistance. Although detection of AR amplifications did not outperform standard prognostic biomarkers, AR gene structural rearrangements truncating the ligand binding domain were identified in several patients with primary resistance. These findings establish genomic drivers of resistance to first-line AR-directed therapy in mCRPC and identify potential minimally invasive biomarkers.Significance: Leveraging plasma specimens collected in a large randomized phase II trial, we report the relative impact of common circulating tumor DNA alterations on patient response to the most widely used therapies for advanced prostate cancer. Our findings suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice. Cancer Discov; 8(4); 444-57. ©2018 AACR.See related commentary by Jayaram et al., p. 392This article is highlighted in the In This Issue feature, p. 371.

Impact of Therapy on Genomics and Transcriptomics in High-Risk Prostate Cancer Treated with Neoadjuvant Docetaxel and Androgen Deprivation Therapy.

Purpose: The combination of docetaxel chemotherapy and androgen deprivation therapy (ADT) has become a standard treatment for patients with metastatic prostate cancer. The recently accrued phase III CALGB 90203 trial was designed to investigate the clinical effectiveness of this treatment approach earlier in the disease. Specimens from this trial offer a unique opportunity to interrogate the acute molecular response to docetaxel and ADT and identify potential biomarkers.Experimental Design: We evaluated baseline clinical data, needle biopsies, and radical prostatectomy (RP) specimens from 52 (of 788) patients enrolled on CALGB 90203 at one high volume center. Pathology review, tumor and germline-targeted DNA sequencing (n = 72 genes), and expression profiling using NanoString platform (n = 163 genes) were performed to explore changes in critical prostate cancer pathways linked to aggression and resistance.Results: Three of 52 patients had only microfocal residual cancer at prostatectomy. The most common alterations included TMPRSS2-ERG fusion (n = 32), TP53 mutation or deletion (n = 11), PTEN deletion (n = 6), FOXA1 (n = 6), and SPOP (n = 4) mutation, with no significant enrichment in posttreated specimens. We did not observe AR amplification or mutations. The degree of AR signaling suppression varied among treated tumors and there was upregulation of both AR and AR-V7 expression as well as a subset of neuroendocrine and plasticity genes.Conclusions: These data support the feasibility of targeted and temporal genomic and transcriptome profiling of neoadjuvant-treated prostate cancer with limited formalin-fixed paraffin embedded tissue requirement. Characterization of the heterogeneity of treatment response and molecular outliers that arise posttreatment provides new insight into potential early markers of resistance. Clin Cancer Res; 23(22); 6802-11. ©2017 AACR.