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Armstrong AJ, Taylor A, Haffner MC, Abida W, Bryce AH, Karsh LI, Tagawa ST, Twardowski P, Serritella AV, Lang JM. Germline and somatic testing for homologous repair deficiency in patients with prostate cancer (part 1 of 2). Prostate Cancer Prostatic Dis 2024:10.1038/s41391-024-00901-4. [PMID: 39354185 DOI: 10.1038/s41391-024-00901-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2024] [Revised: 08/08/2024] [Accepted: 09/20/2024] [Indexed: 10/03/2024]
Abstract
BACKGROUND/OBJECTIVES Unfortunately, not all metastatic castration resistant prostate cancer (mCRPC) patients receive available life-prolonging systemic therapies, emphasizing the need to optimize mCRPC treatment selections. Better guidelines are necessary to determine genetic testing in prostate cancer. SUBJECTS/METHODS In this two-part expert opinion-based guide, we provide an expert consensus opinion on the utilization of germline and somatic testing to detect HRR alterations in patients with mCRPC. This guide was developed by a multidisciplinary expert panel that convened in 2023-2024, including representatives from medical oncology, urology, radiation oncology, pathology, medical genomics, and basic science. RESULTS/CONCLUSION We argue for the widespread adoption of germline testing in all patients with prostate cancer and for somatic mutations testing in patients at the time of recurrent/metastatic disease. In this first part, we review how genomic testing is performed. We also review how to overcome certain barriers to integrate genetic and biomarker testing into clinical practice.
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Affiliation(s)
- Andrew J Armstrong
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University Medical Center, Durham, NC, USA
| | - Amy Taylor
- University of Wisconsin, Madison, WI, USA
| | | | - Wassim Abida
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
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Tao J, Bian X, Zhou J, Zhang M. From microscopes to molecules: The evolution of prostate cancer diagnostics. Cytojournal 2024; 21:29. [PMID: 39391208 PMCID: PMC11464998 DOI: 10.25259/cytojournal_36_2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Accepted: 05/27/2024] [Indexed: 10/12/2024] Open
Abstract
In the ever-evolving landscape of oncology, the battle against prostate cancer (PCa) stands at a transformative juncture, propelled by the integration of molecular diagnostics into traditional cytopathological frameworks. This synthesis not only heralds a new epoch of precision medicine but also significantly enhances our understanding of the disease's genetic intricacies. Our comprehensive review navigates through the latest advancements in molecular biomarkers and their detection technologies, illuminating the potential these innovations hold for the clinical realm. With PCa persisting as one of the most common malignancies among men globally, the quest for early and precise diagnostic methods has never been more critical. The spotlight in this endeavor shines on the molecular diagnostics that reveal the genetic underpinnings of PCa, offering insights into its onset, progression, and resistance to conventional therapies. Among the genetic aberrations, the TMPRSS2-ERG fusion and mutations in genes such as phosphatase and tensin homolog (PTEN) and myelocytomatosis viral oncogene homolog (MYC) are identified as significant players in the disease's pathology, providing not only diagnostic markers but also potential therapeutic targets. This review underscores a multimodal diagnostic approach, merging molecular diagnostics with cytopathology, as a cornerstone in managing PCa effectively. This strategy promises a future where treatment is not only tailored to the individual's genetic makeup but also anticipates the disease's trajectory, offering hope for improved prognosis and quality of life for patients.
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Affiliation(s)
- Junyue Tao
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Xiaokang Bian
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Jun Zhou
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
| | - Meng Zhang
- Department of Urology, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui, China
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Allen TA. The Role of Circulating Tumor Cells as a Liquid Biopsy for Cancer: Advances, Biology, Technical Challenges, and Clinical Relevance. Cancers (Basel) 2024; 16:1377. [PMID: 38611055 PMCID: PMC11010957 DOI: 10.3390/cancers16071377] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 03/23/2024] [Accepted: 03/26/2024] [Indexed: 04/14/2024] Open
Abstract
Cancer remains a leading cause of mortality worldwide, with metastasis significantly contributing to its lethality. The metastatic spread of tumor cells, primarily through the bloodstream, underscores the importance of circulating tumor cells (CTCs) in oncological research. As a critical component of liquid biopsies, CTCs offer a non-invasive and dynamic window into tumor biology, providing invaluable insights into cancer dissemination, disease progression, and response to treatment. This review article delves into the recent advancements in CTC research, highlighting their emerging role as a biomarker in various cancer types. We explore the latest technologies and methods for CTC isolation and detection, alongside novel approaches to characterizing their biology through genomics, transcriptomics, proteomics, and epigenetic profiling. Additionally, we examine the clinical implementation of these findings, assessing how CTCs are transforming the landscape of cancer diagnosis, prognosis, and management. By offering a comprehensive overview of current developments and potential future directions, this review underscores the significance of CTCs in enhancing our understanding of cancer and in shaping personalized therapeutic strategies, particularly for patients with metastatic disease.
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Alqualo NO, Campos-Fernandez E, Picolo BU, Ferreira EL, Henriques LM, Lorenti S, Moreira DC, Simião MPS, Oliveira LBT, Alonso-Goulart V. Molecular biomarkers in prostate cancer tumorigenesis and clinical relevance. Crit Rev Oncol Hematol 2024; 194:104232. [PMID: 38101717 DOI: 10.1016/j.critrevonc.2023.104232] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Revised: 12/08/2023] [Accepted: 12/09/2023] [Indexed: 12/17/2023] Open
Abstract
Prostate cancer (PCa) is the second most frequent type of cancer in men and assessing circulating tumor cells (CTCs) by liquid biopsy is a promising tool to help in cancer early detection, staging, risk of recurrence evaluation, treatment prediction and monitoring. Blood-based liquid biopsy approaches enable the enrichment, detection and characterization of CTCs by biomarker analysis. Hence, comprehending the molecular markers, their role on each stage of cancer development and progression is essential to provide information that can help in future implementation of these biomarkers in clinical assistance. In this review, we studied the molecular markers most associated with PCa CTCs to better understand their function on tumorigenesis and metastatic cascade, the methodologies utilized to analyze these biomarkers and their clinical significance, in order to summarize the available information to guide researchers in their investigations, new hypothesis formulation and target choice for the development of new diagnostic and treatment tools.
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Affiliation(s)
- Nathalia Oliveira Alqualo
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Esther Campos-Fernandez
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Bianca Uliana Picolo
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Emanuelle Lorrayne Ferreira
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Laila Machado Henriques
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Sabrina Lorenti
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Danilo Caixeta Moreira
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Maria Paula Silva Simião
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Luciana Beatriz Tiago Oliveira
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil
| | - Vivian Alonso-Goulart
- Laboratory of Nanobiotechnology, Prof. Dr. Luiz Ricardo Goulart Filho, Institute of Biotechnology, Universidade Federal de Uberlândia, Uberlandia, MG 38400-902, Brazil.
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Barnett ES, Schultz N, Stopsack KH, Lam ET, Arfe A, Lee J, Zhao JL, Schonhoft JD, Carbone EA, Keegan NM, Wibmer A, Wang Y, Solit DB, Abida W, Wenstrup R, Scher HI. Analysis of BRCA2 Copy Number Loss and Genomic Instability in Circulating Tumor Cells from Patients with Metastatic Castration-resistant Prostate Cancer. Eur Urol 2023; 83:112-120. [PMID: 36123219 PMCID: PMC10228632 DOI: 10.1016/j.eururo.2022.08.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2022] [Revised: 07/13/2022] [Accepted: 08/10/2022] [Indexed: 02/01/2023]
Abstract
BACKGROUND BRCA2 alterations predict for a response to poly-ADP-ribose polymerase inhibition in metastatic castration-resistant prostate cancer (mCRPC). However, detection is hindered by insufficient tumor tissue and low sensitivity of cell-free DNA for detecting copy number loss. OBJECTIVE To evaluate the BRCA2 loss detection using single-cell, shallow whole-genome sequencing (sWGS) of circulating tumor cells (CTCs) in patients with mCRPC. DESIGN, SETTING, AND PARTICIPANTS We analyzed CTC samples collected concurrently with tumor biopsies intended for clinical sequencing in patients with progressing mCRPC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Differences in proportions were evaluated using the chi-square test. Correlations between assays were analyzed in linear regression models. Associations between alterations and genomic instability were assessed on the single-cell level using mixed-effect negative binomial models. RESULTS AND LIMITATIONS We identified 138 patients with concurrent CTC and biopsy samples. CTC sWGS generated copy number profiles in a similar proportion of patients to biopsy samples (83% vs 78%, p = 0.23), but was more effective than bone biopsies (79% vs 50%; p = 0.009). CTC sWGS detected BRCA2 loss in more patients than tissue at the ≥1 (42% vs 16%; p < 0.001) and ≥2 (27% vs 16%; p = 0.028) CTC thresholds. The overall prevalence of BRCA2 loss was not increased in CTCs using sample-level composite z scores (p = 0.4), but was significantly increased compared with a lower-than-expected prevalence in bone samples (21% vs 3%, p = 0.014). Positive/negative predictive values for CTC BRCA2 loss were 89%/96% using the ≥1 CTC threshold and 67%/92% using the composite z score. CTC BRCA2 loss was associated with higher genomic instability in univariate (1.4-fold large-scale transition difference, 95% confidence interval [CI]: 1.2-1.6; p < 0.001) and multivariable analysis (1.4-fold difference, 95% CI: 1.2-1.6; p < 0.001). CONCLUSIONS Copy number profiles can reliably be generated using CTC sWGS, which detected a majority of tissue-confirmed BRCA2 loss and "CTC-only" losses. BRCA2 losses were supported by increases in genomic instability. PATIENT SUMMARY Current testing strategies have limitations in their ability to detect BRCA2 loss, a relatively common alteration in prostate cancer that is used to identify patients who may benefit from targeted therapy. In this paper, we evaluated whether we could detect BRCA2 loss in individual tumor cells isolated from patient blood samples and found this method to be suitable for further analysis.
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Affiliation(s)
- Ethan S Barnett
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nikolaus Schultz
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Konrad H Stopsack
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Andrea Arfe
- Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Jimmy L Zhao
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Emily A Carbone
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Niamh M Keegan
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Andreas Wibmer
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - David B Solit
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Wassim Abida
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Howard I Scher
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA.
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Zhang D, Xu X, Wei Y, Chen X, Li G, Lu Z, Zhang X, Ren X, Wang S, Qin C. Prognostic Role of DNA Damage Response Genes Mutations and their Association With the Sensitivity of Olaparib in Prostate Cancer Patients. Cancer Control 2022; 29:10732748221129451. [PMID: 36283420 PMCID: PMC9608002 DOI: 10.1177/10732748221129451] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Objective Evidence shows that gene mutation is a significant proportion of genetic factors associated with prostate cancer. The DNA damage response (DDR) is a signal cascade network that aims to maintain genomic integrity in cells. This comprehensive study was performed to determine the link between different DNA damage response gene mutations and prostate cancer. Materials and methods A systematic literature search was performed using PubMed, Web of Science, and Embase. Papers published up to February 1, 2022 were retrieved. The DDR gene mutations associated with prostate cancer were identified by referring to relevant research and review articles. Data of prostate cancer patients from multiple PCa cohorts were obtained from cBioPortal. The OR or HR and 95% CIs were calculated using both fixed-effects models (FEMs) and random-effects models (REMs). Results Seventy-four studies were included in this research, and the frequency of 13 DDR genes was examined. Through the analysis of 33 articles that focused on the risk estimates of DDR genes between normal people and PCa patients, DDR genes were found to be more common in prostate cancer patients (OR = 3.6293 95% CI [2.4992; 5.2705]). Also, patients in the mutated group had a worse OS and DFS outcome than those in the unmutated group (P < .05). Of the 13 DDR genes, the frequency of 9 DDR genes in prostate cancer was less than 1%, and despite differences in race, BRCA2 was the potential gene with the highest frequency (REM Frequency = .0400, 95% CI .0324 - .0541). The findings suggest that mutations in genes such as ATR, BLM, and MLH1 in PCa patients may increase the sensitivity of Olaparib, a PARP inhibitor. Conclusion These results demonstrate that mutation in any DDR pathway results in a poor prognosis for PCa patients. Furthermore, mutations in ATR, BLM, and MLH1 or the expression of POLR2L, PMS1, FANCE, and other genes significantly influence Olaparib sensitivity, which may be underlying therapeutic targets in the future.
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Affiliation(s)
- Dong Zhang
- The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xinchi Xu
- The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Yuang Wei
- The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xinglin Chen
- The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Guangyao Li
- The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Zhongwen Lu
- The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xu Zhang
- The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xiaohan Ren
- The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Shangqian Wang
- The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China,Chao Qin, The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. ; Shangqian Wang, The State Key Lab of Reproductive; Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
| | - Chao Qin
- The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China,Chao Qin, The State Key Lab of Reproductive, Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China. ; Shangqian Wang, The State Key Lab of Reproductive; Department of Urology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
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7
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Lu L, Hu W, Liu B, Yang T. Insights into Circulating Tumor Cell Clusters: A Barometer for Treatment Effects and Prognosis for Prostate Cancer Patients. Cancers (Basel) 2022; 14:cancers14163985. [PMID: 36010983 PMCID: PMC9406494 DOI: 10.3390/cancers14163985] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/09/2022] [Accepted: 08/16/2022] [Indexed: 11/16/2022] Open
Abstract
Simple Summary Circulating tumor cells (CTCs) are a promising biomarker for the risk of prostate cancer aggressiveness and metastasis and play a role in the processes of tumor migration and metastasis. CTC clusters, which have different physical and biological properties from individual CTCs, are collections of tumor cells and non-malignant cells, resulting in greater metastatic potential. Therefore, this review aims to summarize the current knowledge of CTC clusters in metastasis as well as related biological properties and to suggest possibilities for their usage in diagnostic and therapeutic practice. Abstract Prostate cancer (PCa) exhibits high cellular heterogeneity across patients. Therefore, there is an urgent need for more real-time and accurate detection methods, in both prognosis and treatment in clinical settings. Circulating tumor cell (CTC) clusters, a population of tumor cells and non-malignant cells in the blood of patients with tumors, are a promising non-invasive tool for screening PCa progression and identifying potential benefit groups. CTC clusters are associated with tumor metastasis and possess stem-like characteristics, which are likely attributable to epithelial–mesenchymal transition (EMT). Additionally, these biological properties of CTC clusters, particularly androgen receptor V7, have indicated the potential to reflect curative effects, guide treatment modalities, and predict prognosis in PCa patients. Here, we discuss the role of CTC clusters in the mechanisms underlying PCa metastasis and clinical applications, with the aim of informing more appropriate clinical decisions, and ultimately, improving the overall survival of PCa patients.
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Affiliation(s)
- Linyao Lu
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
| | - Wei Hu
- Department of Urology, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
| | - Bingli Liu
- Department of Orthopedics, Shanghai Pudong New Area People’s Hospital, Shanghai 201299, China
- Correspondence: (B.L.); (T.Y.); Tel./Fax: +86-21-2050-9000 (B.L.); +86-21-6803-6506 (T.Y.)
| | - Tao Yang
- Center for Medical Research and Innovation, Shanghai Pudong Hospital, Fudan University Pudong Medical Center, Shanghai 201399, China
- Correspondence: (B.L.); (T.Y.); Tel./Fax: +86-21-2050-9000 (B.L.); +86-21-6803-6506 (T.Y.)
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Kwan EM, Wyatt AW. Androgen receptor genomic alterations and treatment resistance in metastatic prostate cancer. Prostate 2022; 82 Suppl 1:S25-S36. [PMID: 35657159 DOI: 10.1002/pros.24356] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 03/16/2022] [Accepted: 04/04/2022] [Indexed: 12/28/2022]
Abstract
BACKGROUND Genomic alterations to the androgen receptor (AR) are common in metastatic castration-resistant prostate cancer (mCRPC). AR copy number amplifications, ligand-binding domain missense mutations, and intronic structural rearrangements can all drive resistance to approved AR pathway inhibitors and their detection via tissue or liquid biopsy is linked to clinical outcomes. With an increasingly crowded treatment landscape, there is hope that AR genomic alterations can act as prognostic and/or predictive biomarkers to guide patient management. METHODS In this review, we evaluate the current evidence for AR genomic alterations as clinical biomarkers in mCRPC, focusing on correlative studies that have used plasma circulating tumor DNA to characterize AR genotype. RESULTS We highlight data that demonstrates the complexity of AR genotype within individual patients, and suggest that future studies should account for cancer clonal heterogeneity and variable tumor content in liquid biopsy samples. Given the potential for cooccurrence of multiple AR genomic alterations in the same or competing subclones of a patient, it is distinctly challenging to attribute blanket clinical significance to any individual alteration. This challenge is further complicated by the varied treatment exposures in contemporary patients, and the fact that AR genotype continues to evolve in the mCRPC setting across sequential lines of systemic therapy. CONCLUSIONS As treatment access and liquid biopsy technology continues to improve, we posit that real-time measures of AR biology are likely to play a key role in emerging precision oncology strategies for metastatic prostate cancer.
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Affiliation(s)
- Edmond M Kwan
- Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - Alexander W Wyatt
- Department of Urologic Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada
- Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, British Columbia, Canada
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Corvigno S, Johnson AM, Wong KK, Cho MS, Afshar-Kharghan V, Menter DG, Sood AK. Novel Markers for Liquid Biopsies in Cancer Management: Circulating Platelets and Extracellular Vesicles. Mol Cancer Ther 2022; 21:1067-1075. [PMID: 35545008 DOI: 10.1158/1535-7163.mct-22-0087] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 04/05/2022] [Accepted: 05/05/2022] [Indexed: 02/03/2023]
Abstract
Although radiologic imaging and histologic assessment of tumor tissues are classic approaches for diagnosis and monitoring of treatment response, they have many limitations. These include challenges in distinguishing benign from malignant masses, difficult access to the tumor, high cost of the procedures, and tumor heterogeneity. In this setting, liquid biopsy has emerged as a potential alternative for both diagnostic and monitoring purposes. The approaches to liquid biopsy include cell-free DNA/circulating tumor DNA, long and micro noncoding RNAs, proteins/peptides, carbohydrates/lectins, lipids, and metabolites. Other approaches include detection and analysis of circulating tumor cells, extracellular vesicles, and tumor-activated platelets. Ultimately, reliable use of liquid biopsies requires bioinformatics and statistical integration of multiple datasets to achieve approval in a Clinical Laboratory Improvement Amendments setting. This review provides a balanced and critical assessment of recent discoveries regarding tumor-derived biomarkers in liquid biopsies along with the potential and pitfalls for cancer detection and longitudinal monitoring.
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Affiliation(s)
- Sara Corvigno
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anna Maria Johnson
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Kwong-Kwok Wong
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.,The University of Texas Graduate School of Biomedical Sciences at Houston, Houston, Texas
| | - Min Soon Cho
- Division of Internal Medicine, Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Vahid Afshar-Kharghan
- Division of Internal Medicine, Benign Hematology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - David G Menter
- Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Anil K Sood
- Department of Gynecologic Oncology & Reproductive Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.,Center for RNA Interference and Non-Coding RNA, The University of Texas MD Anderson Cancer Center, Houston, Texas
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10
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Khan T, Becker TM, Scott KF, Descallar J, de Souza P, Chua W, Ma Y. Prognostic and Predictive Value of Liquid Biopsy-Derived Androgen Receptor Variant 7 (AR-V7) in Prostate Cancer: A Systematic Review and Meta-Analysis. Front Oncol 2022; 12:868031. [PMID: 35372002 PMCID: PMC8971301 DOI: 10.3389/fonc.2022.868031] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 02/21/2022] [Indexed: 12/21/2022] Open
Abstract
In advanced prostate cancer, access to recent diagnostic tissue samples is restricted and this affects the analysis of the association of evolving biomarkers such as AR-V7 with metastatic castrate resistance. Liquid biopsies are emerging as alternative analytes. To clarify clinical value of AR-V7 detection from liquid biopsies, here we performed a meta-analysis on the prognostic and predictive value of androgen receptor variant 7 (AR-V7) detected from liquid biopsy for patients with prostate cancer (PC), three databases, the Embase, Medline, and Scopus were searched up to September 2021. A total of 37 studies were included. The effects of liquid biopsy AR-V7 status on overall survival (OS), radiographic progression-free survival (PFS), and prostate-specific antigen (PSA)-PFS were calculated with RevMan 5.3 software. AR-V7 positivity detected in liquid biopsy significantly associates with worse OS, PFS, and PSA-PFS (P <0.00001). A subgroup analysis of patients treated with androgen receptor signaling inhibitors (ARSi such as abiraterone and enzalutamide) showed a significant association of AR-V7 positivity with poorer OS, PFS, and PSA-PFS. A statistically significant association with OS was also found in taxane-treated patients (P = 0.04), but not for PFS (P = 0.21) or PSA-PFS (P = 0.93). For AR-V7 positive patients, taxane treatment has better OS outcomes than ARSi (P = 0.01). Study quality, publication bias and sensitivity analysis were integrated in the assessment. Our data show that liquid biopsy AR-V7 is a clinically useful biomarker that is associated with poor outcomes of ARSi-treated castrate resistant PC (CRPC) patients and thus has the potential to guide patient management and also to stratify patients for clinical trials. More studies on chemotherapy-treated patients are warranted.
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Affiliation(s)
- Tanzila Khan
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
- Medical Oncology, Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia
- Centre of Circulating Tumour Cell Diagnostics & Research, Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia
| | - Therese M. Becker
- Medical Oncology, Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia
- Centre of Circulating Tumour Cell Diagnostics & Research, Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia
- South West Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool, NSW, Australia
| | - Kieran F. Scott
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
- Medical Oncology, Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia
| | - Joseph Descallar
- South West Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool, NSW, Australia
- Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia
| | - Paul de Souza
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
- Medical Oncology, Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia
- School of Medicine, University of New South Wales, Kensington, NSW, Australia
| | - Wei Chua
- School of Medicine, Western Sydney University, Campbelltown, NSW, Australia
- Medical Oncology, Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia
- South West Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool, NSW, Australia
- Medical Oncology, Liverpool Hospital, Liverpool, NSW, Australia
| | - Yafeng Ma
- Medical Oncology, Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia
- Centre of Circulating Tumour Cell Diagnostics & Research, Ingham Institute of Applied Medical Research, Liverpool, NSW, Australia
- South West Sydney Clinical School, University of New South Wales, Liverpool Hospital, Liverpool, NSW, Australia
- *Correspondence: Yafeng Ma,
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11
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Huang J, Hagberg Thulin M, Damber JE, Welén K. The roles of RUNX2 and osteoclasts in regulating expression of steroidogenic enzymes in castration-resistant prostate cancer cells. Mol Cell Endocrinol 2021; 535:111380. [PMID: 34216642 DOI: 10.1016/j.mce.2021.111380] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/01/2021] [Revised: 06/08/2021] [Accepted: 06/29/2021] [Indexed: 12/25/2022]
Abstract
Intratumoral steroidogenesis is involved in development of castration-resistant prostate cancer (CRPC) as bone metastases. The osteoblast transcription factor RUNX2 influences steroidogenesis and is induced in CRPC cells by osteoblasts. This study investigates osteoclastic influence on RUNX2 in intratumoral steroidogenesis. Steroidogenic enzymes and steroid receptors were detected with immunohistochemistry in xenograft intratibial tumors from CRPC cells. In vitro, expression of RUNX2 was increased by osteoclasts in osteoblastic LNCaP-19 cells, but not in osteolytic PC-3. Silencing of RUNX2 downregulates expression of CYP11A1, CYP17A1 and HSD3B1 in LNCaP-19 cells co-cultured with osteoclasts, leading to inhibition of KLK3 expression. Osteoclasts promoted CYP11A1 and RUNX2 promoted AKR1C3, HSD17B3 and CYP19A1, but suppressed ESR2 in PC-3 cells. This study shows that osteoclasts promote RUNX2 regulated induction of key steroidogenic enzymes, influencing activation of androgen receptor in CRPC cells. The potential of RUNX2 as a target to inhibit progression of skeletal metastases of CRPC needs further investigation.
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Affiliation(s)
- Junchi Huang
- Department of Urology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Malin Hagberg Thulin
- Department of Urology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden; Department of Internal Medicine and Clinical Nutrition, Centre for Bone and Arthritis Research, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Sweden
| | - Jan-Erik Damber
- Department of Urology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden; Region Västra Götaland, Sahlgrenska University Hospital, Department of Urology, Gothenburg, Sweden
| | - Karin Welén
- Department of Urology, Sahlgrenska Center for Cancer Research, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Sweden.
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12
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Daniel M, Knutson TP, Sperger JM, Li Y, Singh A, Stahlfeld CN, Passow C, Auch B, Lang JM, Dehm SM. AR gene rearrangement analysis in liquid biopsies reveals heterogeneity in lethal prostate cancer. Endocr Relat Cancer 2021; 28:645-655. [PMID: 34280123 PMCID: PMC8363559 DOI: 10.1530/erc-21-0157] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 07/19/2021] [Indexed: 01/01/2023]
Abstract
Castration-resistant prostate cancer (CRPC) is driven by AR gene aberrations that arise during androgen receptor (AR)-targeted therapy. AR amplification and mutations have been profiled in circulating tumor cells (CTCs), but whether AR gene rearrangements can be assessed in CTCs is unknown. In this study, we leveraged CRPC cell lines with defined AR gene rearrangements to develop and validate a CTC DNA analysis approach that utilized whole genome amplification and targeted DNA-sequencing of AR and other genes important in CRPC. We tested the utility of this approach by analyzing matched CTC DNA and plasma cell-free DNA (cfDNA) from a case series of ten CRPC patients. One of ten CTC samples and two of ten cfDNA samples were positive for AR gene rearrangements. All AR gene rearrangements were discordant between matched liquid biopsy samples. One patient harbored separate AR gene rearrangements in CTC DNA and cfDNA, but concordant AR amplification and AR T878A mutation. This patient also displayed concordant loss of TP53 and PTEN, but the loss of RB1 in cfDNA only. The overall frequency of discordant alterations in these genes between matched CTC DNA and cfDNA was high. This study establishes the technical feasibility of analyzing structural rearrangements, mutations, and copy number variants in AR and other CRPC genes using two different sources of DNA from a single blood sample. Paired CTC DNA and cfDNA analysis may have utility for capturing the heterogeneity of genetic alterations in CRPC patients.
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Affiliation(s)
- Mark Daniel
- Masonic Cancer Center, University of Minnesota; Minneapolis, MN, USA
- Graduate Program in Microbiology, Immunology, and Cancer Biology, University of Minnesota; Minneapolis, MN, USA
| | - Todd P. Knutson
- University of Minnesota Supercomputing Institute, University of Minnesota; Minneapolis, MN, USA
| | - Jamie M. Sperger
- Department of Medicine, University of Wisconsin-Madison; Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin-Madison; Madison, WI, USA
| | - Yingming Li
- Masonic Cancer Center, University of Minnesota; Minneapolis, MN, USA
| | - Anupama Singh
- Carbone Cancer Center, University of Wisconsin-Madison; Madison, WI, USA
| | - Charlotte N. Stahlfeld
- Department of Medicine, University of Wisconsin-Madison; Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin-Madison; Madison, WI, USA
| | - Courtney Passow
- University of Minnesota Genomics Center, University of Minnesota; Minneapolis, MN, USA
| | - Benjamin Auch
- University of Minnesota Genomics Center, University of Minnesota; Minneapolis, MN, USA
| | - Joshua M. Lang
- Department of Medicine, University of Wisconsin-Madison; Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin-Madison; Madison, WI, USA
| | - Scott M. Dehm
- Masonic Cancer Center, University of Minnesota; Minneapolis, MN, USA
- Department of Laboratory Medicine and Pathology, University of Minnesota; Minneapolis, MN, USA
- Department of Urology, University of Minnesota; Minneapolis, MN, USA
- Corresponding Author: Scott M. Dehm, MCRB 560D, Mayo Mail Code 806, 420 Delaware St. SE, Minneapolis, MN 55455. Tel: (612) 625-1504. Fax: (612) 626-4915.
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13
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Dasari K, Somarelli JA, Kumar S, Townsend JP. The somatic molecular evolution of cancer: Mutation, selection, and epistasis. PROGRESS IN BIOPHYSICS AND MOLECULAR BIOLOGY 2021; 165:56-65. [PMID: 34364910 DOI: 10.1016/j.pbiomolbio.2021.08.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 07/30/2021] [Accepted: 08/03/2021] [Indexed: 12/17/2022]
Abstract
Cancer progression has been attributed to somatic changes in single-nucleotide variants, copy-number aberrations, loss of heterozygosity, chromosomal instability, epistatic interactions, and the tumor microenvironment. It is not entirely clear which of these changes are essential and which are ancillary to cancer. The dynamic nature of cancer evolution in a patient can be illuminated using several concepts and tools from classical evolutionary biology. Neutral mutation rates in cancer cells are calculable from genomic data such as synonymous mutations, and selective pressures are calculable from rates of fixation occurring beyond the expectation by neutral mutation and drift. However, these cancer effect sizes of mutations are complicated by epistatic interactions that can determine the likely sequence of gene mutations. In turn, longitudinal phylogenetic analyses of somatic cancer progression offer an opportunity to identify key moments in cancer evolution, relating the timing of driver mutations to corresponding landmarks in the clinical timeline. These analyses reveal temporal aspects of genetic and phenotypic change during tumorigenesis and across clinical timescales. Using a related framework, clonal deconvolution, physical locations of clones, and their phylogenetic relations can be used to infer tumor migration histories. Additionally, genetic interactions with the tumor microenvironment can be analyzed with longstanding approaches applied to organismal genotype-by-environment interactions. Fitness landscapes for cancer evolution relating to genotype, phenotype, and environment could enable more accurate, personalized therapeutic strategies. An understanding of the trajectories underlying the evolution of neoplasms, primary, and metastatic tumors promises fundamental advances toward accurate and personalized predictions of therapeutic response.
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Affiliation(s)
| | | | - Sudhir Kumar
- Institute for Genomics and Evolutionary Medicine, and Department of Biology, Temple University, Philadelphia, PA, 19122, USA
| | - Jeffrey P Townsend
- Yale College, New Haven, CT, USA; Department of Biostatistics, Yale School of Public Health, New Haven, CT, USA; Yale Cancer Center, Yale University, New Haven, CT, USA; Department of Ecology and Evolutionary Biology, Yale University, New Haven, CT, USA; Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA.
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14
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Fu G, Cheng KS, Chen A, Xu Z, Chen X, Tian J, Xu C, Sun Y, Neoh KH, Dai Y, Han RPS, Jin B. Microfluidic Assaying of Circulating Tumor Cells and Its Application in Risk Stratification of Urothelial Bladder Cancer. Front Oncol 2021; 11:701298. [PMID: 34178700 PMCID: PMC8222714 DOI: 10.3389/fonc.2021.701298] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 05/20/2021] [Indexed: 12/13/2022] Open
Abstract
Bladder cancer is characterized by its frequent recurrence and progression. Effective treatment strategies need to be based on an accurate risk stratification, in which muscle invasiveness and tumor grade represent the two most important factors. Traditional imaging techniques provide preliminary information about muscle invasiveness but are lacking in terms of accuracy. Although as the gold standard, pathological biopsy is only available after the surgery and cannot be performed longitudinally for long-term surveillance. In this work, we developed a microfluidic approach that interrogates circulating tumor cells (CTCs) in the peripheral blood of bladder cancer patients to reflect the risk stratification of the disease. In a cohort of 48 bladder cancer patients comprising 33 non-muscle invasive bladder cancer (NMIBC) cases and 15 muscle invasive bladder cancer (MIBC) cases, the CTC count was found to be considerably higher in the MIBC group compared with the NMIBC group (4.67 vs. 1.88 CTCs/3 mL, P=0.019), and was significantly higher in high-grade bladder cancer patients verses low-grade bladder cancer patients (3.69 vs. 1.18 CTCs/3mL, P=0.024). This microfluidic assay of CTCs is believed to be a promising complementary tool for the risk stratification of bladder cancer.
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Affiliation(s)
- Guanghou Fu
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Kok Suen Cheng
- Jiangzhong Cancer Research Center, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
- Department of Material Science and Engineering, College of Engineering, Peking University, Beijing, China
| | - Anqi Chen
- Department of Material Science and Engineering, College of Engineering, Peking University, Beijing, China
| | - Zhijie Xu
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Xiaoyi Chen
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Junjie Tian
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Congcong Xu
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Yukun Sun
- Department of Material Science and Engineering, College of Engineering, Peking University, Beijing, China
| | - Kuang Hong Neoh
- Department of Material Science and Engineering, College of Engineering, Peking University, Beijing, China
| | - Yun Dai
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
| | - Ray P. S. Han
- Jiangzhong Cancer Research Center, Jiangxi University of Traditional Chinese Medicine, Nanchang, China
| | - Baiye Jin
- Department of Urology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
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15
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Gupta S, Halabi S, Kemeny G, Anand M, Giannakakou P, Nanus DM, George DJ, Gregory SG, Armstrong AJ. Circulating Tumor Cell Genomic Evolution and Hormone Therapy Outcomes in Men with Metastatic Castration-Resistant Prostate Cancer. Mol Cancer Res 2021; 19:1040-1050. [PMID: 33771885 PMCID: PMC8178231 DOI: 10.1158/1541-7786.mcr-20-0975] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/11/2021] [Accepted: 03/01/2021] [Indexed: 01/24/2023]
Abstract
Men with circulating tumor cell (CTC) AR-V7-positive metastatic castration-resistant prostate cancer (mCRPC) have worse outcomes when treated with enzalutamide/abiraterone. However, most men lack CTC AR-V7 detection, and additional predictive biomarkers are needed. We conducted a retrospective secondary analysis of the prospective PROPHECY trial (NCT02269982) of men with mCRPC undergoing treatment with enzalutamide/abiraterone, analyzing pooled CTC and germline DNA for whole-genome copy-number alterations (CNA) in 73 samples from 48 men over time along with pooled CTC and germline whole-exome sequencing on 22 paired samples before and following progression on androgen receptor (AR) inhibitor therapy to identify somatic genomic alterations associated with acquired resistance. We observed broad interpatient and longitudinal CTC genomic heterogeneity from AR-V7-negative men with mCRPC, including common gains of KDM6A, MYCN, and AR, and loss of ZFHX3, BRCA1, and PTEN. Men who had progression-free survival of ≤3 months despite enzalutamide/abiraterone treatment were more likely to have baseline CTC genomic loss of CHD1, PTEN, PHLPP1, and ZFHX3 and gains of BRCA2, KDM5D, MYCN, and SPARC. After progression on abiraterone/enzalutamide, we observed clonal evolution of CTCs harboring TP53 mutations and gain of ATM, KDM6A, and MYC, and loss of NCOR1, PTEN, RB1, and RUNX2. CTC genomic findings were independently confirmed in a separate cohort of mCRPC men who progressed despite prior treatment with abiraterone/enzalutamide (NCT02204943). IMPLICATIONS: We identified common and reproducible genomic alterations in CTCs from AR-V7-negative mCRPC men associated with poor outcomes during enzalutamide/abiraterone treatment, including CNAs in genes linked to lineage plasticity and epigenetic signaling, DNA repair, AR, TP53/RB1, PTEN, and WNT pathways.
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Affiliation(s)
- Santosh Gupta
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolin
- Epic Sciences, San Diego, California
| | - Susan Halabi
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina
- Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
| | - Gabor Kemeny
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina
| | - Monika Anand
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina
| | | | - David M Nanus
- Department of Medicine, Weill Cornell Medicine, New York, New York
| | - Daniel J George
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina
- Departments of Medicine, Surgery, Pharmacology and Cancer Biology, Duke University, Durham, North Carolina
| | - Simon G Gregory
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolin
| | - Andrew J Armstrong
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Duke University, Durham, North Carolina.
- Departments of Medicine, Surgery, Pharmacology and Cancer Biology, Duke University, Durham, North Carolina
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16
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Abstract
Ecological fitness is the ability of individuals in a population to survive and reproduce. Individuals with increased fitness are better equipped to withstand the selective pressures of their environments. This paradigm pertains to all organismal life as we know it; however, it is also becoming increasingly clear that within multicellular organisms exist highly complex, competitive, and cooperative populations of cells under many of the same ecological and evolutionary constraints as populations of individuals in nature. In this review I discuss the parallels between populations of cancer cells and populations of individuals in the wild, highlighting how individuals in either context are constrained by their environments to converge on a small number of critical phenotypes to ensure survival and future reproductive success. I argue that the hallmarks of cancer can be distilled into key phenotypes necessary for cancer cell fitness: survival and reproduction. I posit that for therapeutic strategies to be maximally beneficial, they should seek to subvert these ecologically driven phenotypic responses.
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17
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Brown LC, Halabi S, Schonhoft JD, Yang Q, Luo J, Nanus DM, Giannakakou P, Szmulewitz RZ, Danila DC, Barnett ES, Carbone EA, Zhao JL, Healy P, Anand M, Gill A, Jendrisak A, Berry WR, Gupta S, Gregory SG, Wenstrup R, Antonarakis ES, George DJ, Scher HI, Armstrong AJ. Circulating Tumor Cell Chromosomal Instability and Neuroendocrine Phenotype by Immunomorphology and Poor Outcomes in Men with mCRPC Treated with Abiraterone or Enzalutamide. Clin Cancer Res 2021; 27:4077-4088. [PMID: 33820782 DOI: 10.1158/1078-0432.ccr-20-3471] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 12/07/2020] [Accepted: 03/31/2021] [Indexed: 12/15/2022]
Abstract
PURPOSE While the detection of AR-V7 in circulating tumor cells (CTC) is associated with resistance to abiraterone or enzalutamide in men with metastatic castration-resistant prostate cancer (mCRPC), it only accounts for a minority of this resistance. Neuroendocrine (NE) differentiation or chromosomal instability (CIN) may be additional mechanisms that mediate resistance. EXPERIMENTAL DESIGN PROPHECY was a multicenter prospective study of men with high-risk mCRPC starting abiraterone or enzalutamide. A secondary objective was to assess Epic CTC CIN and NE phenotypes before abiraterone or enzalutamide and at progression. The proportional hazards (PH) model was used to investigate the prognostic importance of CIN and NE in predicting progression-free survival and overall survival (OS) adjusting for CTC number (CellSearch), AR-V7, prior therapy, and clinical risk score. The PH model was utilized to validate this association of NE with OS in an external dataset of patients treated similarly at Memorial Sloan Kettering Cancer Center (MSKCC; New York, NY). RESULTS We enrolled 118 men with mCRPC starting on abiraterone or enzalutamide; 107 were evaluable on the Epic platform. Of these, 36.4% and 8.4% were CIN positive and NE positive, respectively. CIN and NE were independently associated with worse OS [HR, 2.2; 95% confidence interval (CI), 1.2-4.0 and HR 3.8; 95% CI, 1.2-12.3, respectively] when treated with abiraterone/enzalutamide. The prognostic significance of NE positivity for worse OS was confirmed in the MSKCC dataset (n = 173; HR, 5.7; 95% CI, 2.6-12.7). CONCLUSIONS A high CIN and NE CTC phenotype is independently associated with worse survival in men with mCRPC treated with abiraterone/enzalutamide, warranting further prospective controlled predictive studies to inform treatment decisions.
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Affiliation(s)
- Landon C Brown
- Department of Medicine, Duke Prostate and Urologic Cancer Center, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Susan Halabi
- Department of Medicine, Duke Prostate and Urologic Cancer Center, Duke Cancer Institute, Duke University, Durham, North Carolina
- Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
| | | | - Qian Yang
- Department of Biostatistics and Bioinformatics, Duke University, Durham, North Carolina
| | - Jun Luo
- Department of Urology, Johns Hopkins University, Baltimore, Maryland
| | | | | | | | - Daniel C Danila
- Weill Cornell Medical College, New York, New York
- Memorial Sloan Kettering Cancer Center, New York, New York
| | | | | | - Jimmy L Zhao
- Memorial Sloan Kettering Cancer Center, New York, New York
| | | | - Monika Anand
- Department of Medicine, Duke Prostate and Urologic Cancer Center, Duke Cancer Institute, Duke University, Durham, North Carolina
| | | | | | - William R Berry
- Department of Medicine, Duke Prostate and Urologic Cancer Center, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Santosh Gupta
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | - Simon G Gregory
- Duke Molecular Physiology Institute, Duke University, Durham, North Carolina
| | | | | | - Daniel J George
- Department of Medicine, Duke Prostate and Urologic Cancer Center, Duke Cancer Institute, Duke University, Durham, North Carolina
| | - Howard I Scher
- Weill Cornell Medical College, New York, New York
- Memorial Sloan Kettering Cancer Center, New York, New York
| | - Andrew J Armstrong
- Department of Medicine, Duke Prostate and Urologic Cancer Center, Duke Cancer Institute, Duke University, Durham, North Carolina.
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18
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Fundamentals of liquid biopsies in metastatic prostate cancer: from characterization to stratification. Curr Opin Oncol 2020; 32:527-534. [PMID: 32675591 DOI: 10.1097/cco.0000000000000655] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
PURPOSE OF REVIEW In this review, we provide an overview of the recent developments and prospects on the applications of blood-based liquid biopsies, including circulating tumor DNA and circulating tumor cells, in metastatic prostate cancer. RECENT FINDINGS Guidelines and consensus statements have been formulated to standardize preanalytical conditions that affect liquid biopsy analysis. Currently, there are four FDA approved assays for the analysis of liquid biopsies and many quantitative and qualitative assays are being developed. Comprehensive analyses of cell-free tumor DNA (ctDNA) and circulating tumor cells (CTCs) demonstrate that they adequately reflect the genomic makeup of the tumor and may thus complement or even replace tumor biopsies. The assessment of genomic aberrations in ctDNA can potentially predict therapy response and detect mechanisms of resistance. CTC count is not only a strong prognosticator in metastatic prostate cancer but can also measure therapy response. SUMMARY Liquid biopsies may provide a temporal snapshot of the biologic variables that affect tumor growth and progression in metastatic prostate cancer. Liquid biopsies could inform on prognostic, predictive, and response measures. However, prospective clinical trials need to be performed to provide definitive validation of the clinical value of the most advanced assays.
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19
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Turnham DJ, Bullock N, Dass MS, Staffurth JN, Pearson HB. The PTEN Conundrum: How to Target PTEN-Deficient Prostate Cancer. Cells 2020; 9:E2342. [PMID: 33105713 PMCID: PMC7690430 DOI: 10.3390/cells9112342] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 10/17/2020] [Accepted: 10/20/2020] [Indexed: 12/17/2022] Open
Abstract
Loss of the tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN), which negatively regulates the PI3K-AKT-mTOR pathway, is strongly linked to advanced prostate cancer progression and poor clinical outcome. Accordingly, several therapeutic approaches are currently being explored to combat PTEN-deficient tumors. These include classical inhibition of the PI3K-AKT-mTOR signaling network, as well as new approaches that restore PTEN function, or target PTEN regulation of chromosome stability, DNA damage repair and the tumor microenvironment. While targeting PTEN-deficient prostate cancer remains a clinical challenge, new advances in the field of precision medicine indicate that PTEN loss provides a valuable biomarker to stratify prostate cancer patients for treatments, which may improve overall outcome. Here, we discuss the clinical implications of PTEN loss in the management of prostate cancer and review recent therapeutic advances in targeting PTEN-deficient prostate cancer. Deepening our understanding of how PTEN loss contributes to prostate cancer growth and therapeutic resistance will inform the design of future clinical studies and precision-medicine strategies that will ultimately improve patient care.
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Affiliation(s)
- Daniel J. Turnham
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; (D.J.T.); (N.B.); (M.S.D.)
| | - Nicholas Bullock
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; (D.J.T.); (N.B.); (M.S.D.)
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK;
| | - Manisha S. Dass
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; (D.J.T.); (N.B.); (M.S.D.)
| | - John N. Staffurth
- Division of Cancer and Genetics, School of Medicine, Cardiff University, Heath Park, Cardiff CF14 4XN, UK;
| | - Helen B. Pearson
- The European Cancer Stem Cell Research Institute, School of Biosciences, Cardiff University, Hadyn Ellis Building, Cardiff CF24 4HQ, UK; (D.J.T.); (N.B.); (M.S.D.)
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20
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Sobhani N, Sirico M, Generali D, Zanconati F, Scaggiante B. Circulating cell-free nucleic acids as prognostic and therapy predictive tools for metastatic castrate-resistant prostate cancer. World J Clin Oncol 2020; 11:450-463. [PMID: 32821651 PMCID: PMC7407926 DOI: 10.5306/wjco.v11.i7.450] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Revised: 05/12/2020] [Accepted: 05/28/2020] [Indexed: 02/06/2023] Open
Abstract
Metastatic castrate-resistant prostate cancer remains a disease hard to cure, and for this reason predictive tools to monitor disease progression and therapy response are an urgent need. In this respect, liquid biopsy on circulating cell-free nucleic acids represents an interesting strategy based on robust data. The low invasiveness and the possibility to target circulating cell-free tumor deoxyribonucleic acid underline the high specificity, sensitivity and clinical usability of the technique. Moreover, it has been observed that the cell-free tumor deoxyribonucleic acid of metastatic castrate-resistant prostate cancer patients can be representative of the tumor heterogeneity. Cell-free tumor deoxyribonucleic acids express the same behaviors as mutations: Variation in gene copy number or the methylation rate of the tumor tissue. Recently, circulating cell-free ribonucleic acid molecules have emerged as interesting markers to stratify the disease. Due to high-throughput technologies, liquid biopsy on circulating cell-free nucleic acids will soon be utilized in the clinical management of metastatic castrate-resistant prostate cancer patients.
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Affiliation(s)
- Navid Sobhani
- Texas Medical Centre, Baylor College of Medicine, Alkek Building, Houston, TX 77030, United States
| | - Marianna Sirico
- Multidisciplinary Operative Unit of Mammary Pathology and Translational Research, ASST of Cremona, Cremona 26100, Italy
| | - Daniele Generali
- Multidisciplinary Operative Unit of Mammary Pathology and Translational Research, ASST of Cremona, Cremona 26100, Italy
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Academic Hospital, Trieste 34149, Italy
| | - Fabrizio Zanconati
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Academic Hospital, Trieste 34149, Italy
| | - Bruna Scaggiante
- Department of Life Sciences, University of Trieste, Trieste 34127, Italy
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21
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Cieślikowski WA, Budna-Tukan J, Świerczewska M, Ida A, Hrab M, Jankowiak A, Mazel M, Nowicki M, Milecki P, Pantel K, Alix-Panabières C, Zabel M, Antczak A. Circulating Tumor Cells as a Marker of Disseminated Disease in Patients with Newly Diagnosed High-Risk Prostate Cancer. Cancers (Basel) 2020; 12:E160. [PMID: 31936460 PMCID: PMC7017349 DOI: 10.3390/cancers12010160] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2019] [Revised: 01/03/2020] [Accepted: 01/07/2020] [Indexed: 12/13/2022] Open
Abstract
The aim of this study was to investigate whether the enumeration of circulating tumor cells (CTCs) in blood can differentiate between true localized and metastatic prostate cancer. A cross-sectional study of 104 prostate cancer patients with newly diagnosed high-risk prostate cancer was conducted. In total, 19 patients presented metastatic disease and 85 were diagnosed with localized disease. Analyses included intergroup comparison of CTC counts, determined using the CellSearch® system, EPISPOT assay and GILUPI CellCollector®, and ROC analysis verifying the accuracy of CTC count as a maker of disseminated prostate cancer. The vast majority (94.7%) of patients with advanced-stage cancer tested positively for CTCs in at least one of the assays. However, significantly higher CTC counts were determined with the CellSearch® system compared to EPISPOT assay and GILUPI CellCollector®. Identification of ≥4 CTCs with the CellSearch® system was the most accurate predictor of metastatic disease (sensitivity 0.500; specificity 0.900; AUC (95% CI) 0.760 (0.613-0.908). Furthermore, we tried to create a model to enhance the specificity and sensitivity of metastatic prediction with CTC counts by incorporating patient's clinical data, including PSA serum levels, Gleason score and clinical stage. The composite biomarker panel achieved the following performance: sensitivity, 0.611; specificity, 0.971; AUC (95% CI), 0.901 (0.810-0.993). Thus, although the sensitivity of CTC detection needs to be further increased, our findings suggest that high CTC counts might contribute to the identification of high-risk prostate cancer patients with occult metastases at the time of diagnosis.
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Affiliation(s)
- Wojciech A. Cieślikowski
- Department of Urology, Poznan University of Medical Sciences, 61-285 Poznan, Poland; (A.I.); (M.H.); (A.A.)
| | - Joanna Budna-Tukan
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (J.B.-T.); (M.Ś.); (A.J.); (M.N.)
| | - Monika Świerczewska
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (J.B.-T.); (M.Ś.); (A.J.); (M.N.)
| | - Agnieszka Ida
- Department of Urology, Poznan University of Medical Sciences, 61-285 Poznan, Poland; (A.I.); (M.H.); (A.A.)
| | - Michał Hrab
- Department of Urology, Poznan University of Medical Sciences, 61-285 Poznan, Poland; (A.I.); (M.H.); (A.A.)
| | - Agnieszka Jankowiak
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (J.B.-T.); (M.Ś.); (A.J.); (M.N.)
| | - Martine Mazel
- Laboratory of Rare Human Circulating Cells, University Medical Center, 34093 Montpellier CEDEX 5, France; (M.M.); (C.A.-P.)
| | - Michał Nowicki
- Department of Histology and Embryology, Poznan University of Medical Sciences, 60-781 Poznan, Poland; (J.B.-T.); (M.Ś.); (A.J.); (M.N.)
| | - Piotr Milecki
- Department of Electroradiology, Poznan University of Medical Sciences, 61-868 Poznan, Poland;
| | - Klaus Pantel
- Department of Tumor Biology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany;
| | - Catherine Alix-Panabières
- Laboratory of Rare Human Circulating Cells, University Medical Center, 34093 Montpellier CEDEX 5, France; (M.M.); (C.A.-P.)
| | - Maciej Zabel
- Division of Histology and Embryology, Department of Human Morphology and Embryology, Wroclaw Medical University, 50-368 Wroclaw, Poland;
- Division of Anatomy and Histology, University of ZielonaGóra, 65-046 ZielonaGóra, Poland
| | - Andrzej Antczak
- Department of Urology, Poznan University of Medical Sciences, 61-285 Poznan, Poland; (A.I.); (M.H.); (A.A.)
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