Treatment Outcomes and Tumor Loss of Heterozygosity in Germline DNA Repair–deficient Prostate Cancer
TL;DR: Patients with mCRPC who have germline DNA repair defects exhibit attenuated responses to AR-targeted therapy, suggesting that this patient subset could be prioritized for therapies exploiting defective DNA repair using a liquid biopsy.
About: This article is published in European Urology.The article was published on 2017-07-01. It has received 177 citations till now. The article focuses on the topics: Germline mutation & DNA repair.
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University of Bern1, Institute of Cancer Research2, Oregon Health & Science University3, Cornell University4, Princess Margaret Cancer Centre5, Yonsei University6, University of Salford7, University of Copenhagen8, Monash University9, University of São Paulo10, Columbia University11, The Royal Marsden NHS Foundation Trust12, University of Texas MD Anderson Cancer Center13, University of California, Davis14, University of Bologna15, University of California, San Francisco16, University of Paris-Sud17, University of British Columbia18, Duke University19, University of Cologne20, Fred Hutchinson Cancer Research Center21, University of Birmingham22, Memorial Sloan Kettering Cancer Center23, University of Tampere24, American University of Beirut25, Medical University of Vienna26, Vanderbilt University27, Tata Memorial Hospital28, Icahn School of Medicine at Mount Sinai29, Ghent University30, University of Washington31, Université de Montréal32, Tulane University33, Tel Aviv University34, Harvard University35, Prostate Cancer Foundation36, Toho University37, University College London38, University of Toronto39, Université catholique de Louvain40, University of Milan41, University of Ulm42
TL;DR: The presented expert voting results can be used for support in areas of management of men with APC where there is no high-level evidence, but individualised treatment decisions should as always be based on all of the data available.
539 citations
Cites background from "Treatment Outcomes and Tumor Loss o..."
...Two large single-institution studies of metastatic prostate cancer found similar rates of germline BRCA2, BRCA1, and ATM mutations, with much lower rates in low risk indolent disease [174,175]....
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TL;DR: Improved disease management will also benefit from artificial intelligence-based expert decision support systems for proper standard of care, prognostic determinant biomarkers to minimize overtreatment of localized disease, and new standards of care accelerated by next-generation adaptive clinical trials.
Abstract: Despite the high long-term survival in localized prostate cancer, metastatic prostate cancer remains largely incurable even after intensive multimodal therapy The lethality of advanced disease is driven by the lack of therapeutic regimens capable of generating durable responses in the setting of extreme tumor heterogeneity on the genetic and cell biological levels Here, we review available prostate cancer model systems, the prostate cancer genome atlas, cellular and functional heterogeneity in the tumor microenvironment, tumor-intrinsic and tumor-extrinsic mechanisms underlying therapeutic resistance, and technological advances focused on disease detection and management These advances, along with an improved understanding of the adaptive responses to conventional cancer therapies, anti-androgen therapy, and immunotherapy, are catalyzing development of more effective therapeutic strategies for advanced disease In particular, knowledge of the heterotypic interactions between and coevolution of cancer and host cells in the tumor microenvironment has illuminated novel therapeutic combinations with a strong potential for more durable therapeutic responses and eventual cures for advanced disease Improved disease management will also benefit from artificial intelligence-based expert decision support systems for proper standard of care, prognostic determinant biomarkers to minimize overtreatment of localized disease, and new standards of care accelerated by next-generation adaptive clinical trials
377 citations
TL;DR: 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 and suggest that liquid biopsy analysis can guide the use of AR-targeted therapy in general practice.
Abstract: Primary resistance to androgen receptor (AR)-directed therapies in metastatic castration-resistant prostate cancer (mCRPC) is poorly understood. We randomized 202 patients with treatment-naive 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.
345 citations
Cites background from "Treatment Outcomes and Tumor Loss o..."
...Although copy-number calling is challenging in patients with low ctDNA% (3, 10), the copynumber landscape in patients with ctDNA% > 30% was characteristic of mCRPC (13), including recurrent loss of the tumor suppressors TP53, RB1, and PTEN and amplification of the oncogenes MYC and AR (Fig....
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...APRIL 2018 CANCER DISCOVERY | 447 tumor-derived cfDNA) above 2% (3, 5, 6, 10, 11)....
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...In a previous retrospective study we demonstrated a link between germline HRR defects and poor response to AR-targeted therapies (10)....
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TL;DR: This work discusses advances in noncastrate disease states, identification of biomarkers for prognosis and treatment selection, and opportunities in locoregional therapy to delay androgen deprivation therapy.
Abstract: The therapeutic landscape of prostate cancer has been transformed over the last decade by new therapeutics, advanced functional imaging, next-generation sequencing, and better use of existing therapies in early-stage disease. Until 2004, progression on androgen deprivation therapy for metastatic disease was treated with the addition of secondary hormonal manipulation; in the last decade, six systemic agents have been approved for the treatment of castration-resistant prostate cancer. We review clinical trials and survival benefit for these therapies and assess how the understanding of the disease shifted as these therapies were developed. We also discuss advances in noncastrate disease states, identification of biomarkers for prognosis and treatment selection, and opportunities in locoregional therapy to delay androgen deprivation therapy.
340 citations
TL;DR: The emergence of new drugs for mCRPC has improved treatment options dramatically and the best strategies for patient selection and optimal sequential use to achieve the longest cumulative survival improvement and to prevent early resistance remain unclear.
313 citations
References
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TL;DR: Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.
Abstract: As the rate of sequencing increases, greater throughput is demanded from read aligners. The full-text minute index is often used to make alignment very fast and memory-efficient, but the approach is ill-suited to finding longer, gapped alignments. Bowtie 2 combines the strengths of the full-text minute index with the flexibility and speed of hardware-accelerated dynamic programming algorithms to achieve a combination of high speed, sensitivity and accuracy.
37,898 citations
TL;DR: A new software suite for the comparison, manipulation and annotation of genomic features in Browser Extensible Data (BED) and General Feature Format (GFF) format, which allows the user to compare large datasets (e.g. next-generation sequencing data) with both public and custom genome annotation tracks.
Abstract: Motivation: Testing for correlations between different sets of genomic features is a fundamental task in genomics research. However, searching for overlaps between features with existing webbased methods is complicated by the massive datasets that are routinely produced with current sequencing technologies. Fast and flexible tools are therefore required to ask complex questions of these data in an efficient manner. Results: This article introduces a new software suite for the comparison, manipulation and annotation of genomic features in Browser Extensible Data (BED) and General Feature Format (GFF) format. BEDTools also supports the comparison of sequence alignments in BAM format to both BED and GFF features. The tools are extremely efficient and allow the user to compare large datasets (e.g. next-generation sequencing data) with both public and custom genome annotation tracks. BEDTools can be combined with one another as well as with standard UNIX commands, thus facilitating routine genomics tasks as well as pipelines that can quickly answer intricate questions of large genomic datasets. Availability and implementation: BEDTools was written in C++. Source code and a comprehensive user manual are freely available at http://code.google.com/p/bedtools
18,858 citations
TL;DR: The ANNOVAR tool to annotate single nucleotide variants and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP is developed.
Abstract: High-throughput sequencing platforms are generating massive amounts of genetic variation data for diverse genomes, but it remains a challenge to pinpoint a small subset of functionally important variants. To fill these unmet needs, we developed the ANNOVAR tool to annotate single nucleotide variants (SNVs) and insertions/deletions, such as examining their functional consequence on genes, inferring cytogenetic bands, reporting functional importance scores, finding variants in conserved regions, or identifying variants reported in the 1000 Genomes Project and dbSNP. ANNOVAR can utilize annotation databases from the UCSC Genome Browser or any annotation data set conforming to Generic Feature Format version 3 (GFF3). We also illustrate a 'variants reduction' protocol on 4.7 million SNVs and indels from a human genome, including two causal mutations for Miller syndrome, a rare recessive disease. Through a stepwise procedure, we excluded variants that are unlikely to be causal, and identified 20 candidate genes including the causal gene. Using a desktop computer, ANNOVAR requires ∼4 min to perform gene-based annotation and ∼15 min to perform variants reduction on 4.7 million variants, making it practical to handle hundreds of human genomes in a day. ANNOVAR is freely available at http://www.openbioinformatics.org/annovar/.
10,461 citations
"Treatment Outcomes and Tumor Loss o..." refers methods in this paper
...Protein-level consequences of variants were predicted using ANNOVAR [25], and inspected in IGV....
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University of Michigan1, Massachusetts Institute of Technology2, Harvard University3, Memorial Sloan Kettering Cancer Center4, University of Washington5, The Royal Marsden NHS Foundation Trust6, Institute of Cancer Research7, Cornell University8, Brigham and Women's Hospital9, Beth Israel Deaconess Medical Center10, University of Washington Medical Center11, University of Trento12, Wayne State University13, Johns Hopkins University14
TL;DR: This cohort study provides clinically actionable information that could impact treatment decisions for affected individuals and identified new genomic alterations in PIK3CA/B, R-spondin, BRAF/RAF1, APC, β-catenin, and ZBTB16/PLZF.
2,713 citations
"Treatment Outcomes and Tumor Loss o..." refers background or methods in this paper
...truncating germline mutations in DNA repair genes may be less than the 8–12% previously reported [3,4]....
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...Two recent studies reported that germline mutations in DNA damage repair genes, including BRCA2, are present in 8–12% of patients with metastatic prostate cancer [3,4]....
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...Somatic alterations were consistent with mCRPC including amplification/ mutation of AR, and deletion/mutation of key tumor suppressors TP53, PTEN, and RB1 (Supplementary Table 2) [3]....
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Oregon Health & Science University1, Duke University2, Memorial Sloan Kettering Cancer Center3, University of Paris-Sud4, University of Washington5, Guy's and St Thomas' NHS Foundation Trust6, Institute of Cancer Research7, University of California, Berkeley8, University Health Network9, Nippon Medical School10, Charité11, Astellas Pharma12, Université de Montréal13, Harvard University14, University of Alberta15, Cliniques Universitaires Saint-Luc16
TL;DR: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer.
Abstract: BACKGROUND: Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with metastatic castration-resistant prostate cancer in whom the disease has progressed after chemotherapy. New treatment options are needed for patients with metastatic prostate cancer who have not received chemotherapy, in whom the disease has progressed despite androgen-deprivation therapy. METHODS: In this double-blind, phase 3 study, we randomly assigned 1717 patients to receive either enzalutamide (at a dose of 160 mg) or placebo once daily. The coprimary end points were radiographic progression-free survival and overall survival. RESULTS: The study was stopped after a planned interim analysis, conducted when 540 deaths had been reported, showed a benefit of the active treatment. The rate of radiographic progression-free survival at 12 months was 65% among patients treated with enzalutamide, as compared with 14% among patients receiving placebo (81% risk reduction; hazard ratio in the enzalutamide group, 0.19; 95% confidence interval [CI], 0.15 to 0.23; P<0.001). A total of 626 patients (72%) in the enzalutamide group, as compared with 532 patients (63%) in the placebo group, were alive at the data-cutoff date (29% reduction in the risk of death; hazard ratio, 0.71; 95% CI, 0.60 to 0.84; P<0.001). The benefit of enzalutamide was shown with respect to all secondary end points, including the time until the initiation of cytotoxic chemotherapy (hazard ratio, 0.35), the time until the first skeletal-related event (hazard ratio, 0.72), a complete or partial soft-tissue response (59% vs. 5%), the time until prostate-specific antigen (PSA) progression (hazard ratio, 0.17), and a rate of decline of at least 50% in PSA (78% vs. 3%) (P<0.001 for all comparisons). Fatigue and hypertension were the most common clinically relevant adverse events associated with enzalutamide treatment. CONCLUSIONS: Enzalutamide significantly decreased the risk of radiographic progression and death and delayed the initiation of chemotherapy in men with metastatic prostate cancer. (Funded by Medivation and Astellas Pharma; PREVAIL ClinicalTrials.gov number, NCT01212991.).
2,426 citations
"Treatment Outcomes and Tumor Loss o..." refers background in this paper
...In this setting, additional targeting of the androgen receptor (AR) signaling axis with abiraterone or enzalutamide is efficacious in the majority of patients, but duration of response is highly variable [8,9]....
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...o typically cited for this population [8,9]....
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