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A, Technetium Tc 99m bone scan shows focal activity in the left side of the manubrium (arrow) consistent with a metastasis. B, Computed tomographic image shows focal sclerosis in the left side of the manubrium (arrow) corresponding to the bone scan and consistent with a metastasis. C, Computed tomographic image obtained during biopsy shows an 11-gauge bone biopsy device (arrowheads) sampling the metastasis. D, Computed tomographic image obtained during second biopsy event 4 months later, showing 13-gauge needle through an 11-gauge introducer.
Source publication
Objective
To determine histopathologic, exome, and transcriptome nucleic acid material yield from prospectively collected metastatic tissue biopsy specimens in patients with metastatic castration-resistant prostate cancer (mCRPC).
Patients and Methods
Patients with mCRPC initiating abiraterone acetate therapy underwent 2 serial metastatic site cor...
Contexts in source publication
Context 1
... the second biopsy (visit 2), a new target was preferred when present on the 12-week repeated imaging over the original target lesion biopsied; if a new target was not available, the same lesion was targeted again. All biopsies were performed using standard technique, including computed tomography or ultra- sound guidance, sterile technique, and local anesthesia (Figure 1). Moderate intravenous sedation was administered at the discretion of the performing interventional radiologist. ...
Context 2
... diploid tumors, if X represents the purity (defined as the percent of tumors cells), the log 2 ratio of þ1 gains is log 2 (Gain) we solved for the gain purity and deletion pu- rity and reported the average. For samples without major CN alterations, we used the 2 Â the median of the mutant allele frequency (MAF), defined as reads supporting mutant allele divided by total reads at mutation site (Supplemental Figure 1, available online at http://mcpiqojournal.org). Samples with 10% or greater tumoral DNA purity were consid- ered positive. ...
Citations
... Biomarkers based on the stagespecific landscape of genomic alterations in PC are under investigation [3] but are not yet incorporated into clinical practice for CRPC-stage disease. Abiraterone acetate, a CYP17A1 inhibitor that is a standard treatment option for patients with metastatic CRPC (mCRPC) (5,6) has no well-defined predictive genomic biomarkers. Recently, we reported that increased expression of genes in the Wnt pathway and cell cycle proliferation in pre-treatment metastases were associated with 12 week-primary resistance to abiraterone acetate/prednisone (AA/P) in metastatic CRPC patients [4]. ...
... The (Prostate Cancer Medically Optimized Genome-Enhanced Therapy) PROMOTE study, initiated in May 2013 after approval by the Mayo Clinic Institutional Review Board (IRB), enrolled patients with metastatic castration-resistant prostate cancer (mCRPC) after the failure of androgen deprivation therapy. All patients provided written informed consent to undergo two serial metastatic tissue or bone biopsies [5], with the first biopsy performed prior to the initiation of AA/P treatment (visit 1 -pretreatment) and the second after 12-weeks of treatment (visit 2 -post-treatment). The eligibility criteria and the study protocol have been reported previously [4]. ...
We identified resistance mechanisms to abiraterone acetate/prednisone (AA/P) in patients with metastatic castration-resistant prostate cancer (mCRPC) in the Prostate Cancer Medically Optimized Genome-Enhanced Therapy (PROMOTE) study.
We analyzed whole-exome sequencing (WES) and RNA-sequencing data from 83 patients with metastatic biopsies before (V1) and after 12 weeks of AA/P treatment (V2). Resistance was determined by time to treatment change (TTTC).
At V2, 18 and 11 of 58 patients had either short-term (median 3.6 months; range 1.4–4.5) or long-term (median 29 months; range 23.5–41.7) responses, respectively. Nonresponders had low expression of TGFBR3 and increased activation of the Wnt pathway, cell cycle, upregulation of AR variants, both pre- and posttreatment, with further deletion of AR inhibitor CDK11B posttreatment. Deletion of androgen processing genes, HSD17B11, CYP19A1 were observed in nonresponders posttreatment. Genes involved in cell cycle, DNA repair, Wnt-signaling, and Aurora kinase pathways were differentially expressed between the responder and non-responder at V2. Activation of Wnt signaling in nonresponder and deactivation of MYC or its target genes in responders was detected via SCN loss, somatic mutations, and transcriptomics. Upregulation of genes in the AURKA pathway are consistent with the activation of MYC regulated genes in nonresponders. Several genes in the AKT1 axis had increased mutation rate in nonresponders. We also found evidence of resistance via PDCD1 overexpression in responders.
Implications
Finally, we identified candidates drugs to reverse AA/P resistance: topoisomerase inhibitors and drugs targeting the cell cycle via the MYC/AURKA/AURKB/TOP2A and/or PI3K_AKT_MTOR pathways.
... Jimenez et al similarly found biopsy specimens from metastatic sites of CRPC not able to achieve nucleic acid purity in some samples. 17 The level of ctDNA and the number of mutations detected consistently correlates with more aggressive tumors that progress over time. Kohli et al followed a longitudinal prospective cohort of over 300 patients grouped into treatmentnaive metastatic hormone-sensitive prostate cancer (mHSPC), mHSPC on androgen deprivation therapy (ADT), mCRPC based on biochemical progression, and mCRPC with clinical progression. ...
Prostate cancer is one of the most common malignancies in men. Over time, it can metastasize and become lethal once it exhausts hormonal therapies and transitions into castration-resistant prostate cancer (CRPC). Several therapies have been recently approved for advanced prostate cancer, but identifying biomarkers for current treatments and searching for more effective treatments are urgently needed. Liquid biopsy is a powerful tool for isolating genetic material, proteins, and whole tumor cells from the blood. In recent decades, this technology has rapidly advanced, allowing for better insights into the pathogenesis and treatment response in different stages of prostate cancer. In this review, we summarize important clinical studies involving liquid biopsies in prostate cancer with a focus on advanced disease, notably regarding circulating tumor DNA, circulating tumor cells, and exosomes. We highlight the progress and the challenges that still exist for these technologies. Finally, we discuss promising avenues that will further expand the importance of liquid biopsy in the care for prostate cancer patients.
... The evaluation of PTEN, RB1, and TP53 copy number loss in primary tumor tissue samples during the progression of prostate cancer has established the clinical utility of these tumor suppressor genes as biomarkers for prognosis, response to therapy, and therapeutic resistance (1,2). Due to the challenges of obtaining high-purity tumor tissue from skeletal metastatic sites, which are common in prostate cancer (3), liquid biopsy constitutes a surrogate approach for tracking genomic alterations in tumor cells during treatment and metastatic progression (4). However, cell-free DNA (cfDNA) derived from tumor cells is often present at very low quantities in liquid biopsy samples, making it challenging to detect copy number loss (5). ...
Current liquid biopsy assays lack sufficient sensitivity to detect copy number loss, which limits the interrogation of critical tumor suppressor gene deletions during cancer progression and treatment. Here we describe a liquid biopsy assay with improved sensitivity for detection of copy number loss in blood samples with low levels of circulating tumor DNA, and demonstrate its utility by profiling PTEN, RB1, and TP53 genetic loss in metastatic prostate cancer patients.
... Germline genetic testing can be performed on lymphocyte DNA from blood or a combination of lymphocyte and buccal cells from saliva, obtained non-invasively; on the other hand, somatic testing is complex and requires prostate tumor material from biopsies, or in some cases, circulating tumor cells/DNA (ctDNA) in the blood. Additionally, outside the clinical trials in the real-world settings, obtaining sufficient and high-quality tumor tissue for complicated somatic analysis is not a trivial process in patients with mCRPC [41]. Using archived tissue samples may enable wider testing, but there are risks of missing the evolution of somatic mutations in the tumor tissue due to genetic instability [42]. ...
The therapeutic landscape of metastatic castration-resistant prostate cancer (mCRPC) has evolved considerably with the introduction of newer agents, such as poly-ADP ribose polymerase (PARP) inhibitors targeting DNA damage repair mutations. Combining and sequencing novel and existing therapies appropriately is necessary for optimizing the management of mCRPC and ensuring better treatment outcomes. The purpose of this review is to provide evidence-based answers to key clinical questions on treatment selection, treatment sequencing patterns, and factors influencing treatment decisions in the management of mCRPC in the era of PARP inhibitors. This article can also serve as a comprehensive guide to clinicians for optimizing genetic testing and counseling and management of patients with mCRPC. Although the PROfound study has validated the concept of PARP sensitivity across multiple genes associated with homologous recombination repair (HRR) in mCRPC and highlighted the importance of genomic testing in this at-risk patient population, it still remains unclear how patients with rarer HRR mutations will respond to PARP inhibitors. Therefore, real-world data obtained through registry-based randomized controlled trials in the future may help produce robust scientific evidence for supporting optimal clinician decision-making in the management of mCRPC.
... These studies have identified recurrent somatic mutations, copy number alterations (CNAs), oncogenic structural DNA rearrangements [5][6][7][8][9], and alterations in AR and the androgen signaling pathways that may be associated with clinical outcomes [10]. Several of these studies were conducted using metastatic tissue biopsies, which is clinically impractical, given the invasive nature of the biopsies, and the difficulty in obtaining sufficient metastatic tissue for genomic analyses [11]. At present, circulating tumor cell (CTC) counts is the only blood-based biomarker to receive FDA clearance for mCRPC prognosis [12]. ...
The combination of abiraterone acetate and prednisone (AA/P) is used to treat metastatic prostate cancer, but molecular predictors of treatment response are not well elucidated. We evaluated plasma circulating tumor DNA- (ctDNA-) based copy number alterations (CNAs) to determine treatment-related predictive and prognostic biomarkers for metastatic castration-resistant prostate cancer (mCRPC).
Serial plasma specimens were prospectively collected from 88 chemotherapy-naive mCRPC patients before and after 12 weeks of AA/P treatment. Sequencing-based CNA analyses were performed on 174 specimens. We evaluated CNA-associated 12-week responses for primary resistance, time to treatment change (TTTC) for secondary resistance, and overall survival for prognosis (P < 0.05). Associations with primary resistance were analyzed using the Fisher exact test. Kaplan–Meier survival curves and Cox regression analyses were used to determine the associations of CNAs with acquired resistance and overall survival.
ctDNA reduced by 3.89% in responders and increased by 0.94% in nonresponders (P = 0.0043). Thirty-one prostate cancer-related genes from whole genome CNAs were tested. AR and AR enhancer amplification were associated with primary resistance (P = 0.0039) and shorter TTTC (P = 0.0003). ZFHX3 deletion and PIK3CA amplification were associated with primary resistance (P = 0.026 and P = 0.017, respectively), shorter TTTC (P = 0.0008 and P = 0.0016, respectively), and poor survival (P = 0.0025 and P = 0.0022, respectively). CNA-based risk scores combining selected significant associations (AR, NKX3.1, and PIK3CA) at the univariate level with TTTC were predictive of secondary resistance (P = 0.0002). and established prognoses for survival based on CNAs in ZFHX3, RB1, PIK3CA, and OPHN1 (P = 0.002). Multigene risk scores were more predictive than individual genes or clinical risk factors (P < 0.05).
Plasma ctDNA CNAs and risk scores can predict mCRPC-state treatment and survival outcomes.
... Our group previously reported the mutational landscape of solid metastases in patients with treatmentnaive mCRPC before abiraterone acetate/prednisone drug therapy [11]. We successfully sequenced tumor nucleic acids from solid metastases, including bone, but obtaining a high yield and purity of nucleic acids from skeletal metastases before and after treatments was particularly challenging [14]. Additionally, the invasiveness of performing metastatic solid tissue biopsies for sequencing is not feasible in routine clinical practice. ...
Background:
Metastatic prostate cancer is a clonally heterogeneous disease state characterized by progressive somatic perturbations. The aim of this study was to identify cell free DNA- (cfDNA-) based alterations and their associations with outcomes in progressive metastatic prostate cancer.
Methods:
In this longitudinal prospective cohort study plasma cfDNA/circulating tumor DNA (ctDNA) was analyzed before, during, and after androgen deprivation therapy (ADT) in 4 independent patient groups ranging from untreated metastatic hormone sensitive prostate cancer (mHSPC) to metastatic castrate resistant prostate cancer (mCRPC). Next generation sequencing was performed on ctDNA and germline DNA to characterize alterations and associations with clinical outcomes were determined for each group.
Findings:
cfDNA yields were different in progressive mHSPC and mCRPC states (P < .001). In mHSPC, a higher than median ctDNA fraction was predictive of shorter time to ADT failure (HR, 2.29 [95% CI, 1.13-4.65]; Log-Rank P = .02). cfDNA, ctDNA taken with volume of metastatic disease in mHSPC and with alkaline phosphatase levels prognosticated survival better than clinical factors alone in mHSPC and mCRPC states (Log Rank P = 0.03). ctDNA-based AR, APC mutations were increased in mCRPC compared to mHSPC (P < ·05).TP53 mutations, RB1 loss, and AR gene amplifications correlated with poorer survival in mCRPC. Mutations in multiple DNA repair genes (ATM, BRCA1, BRCA2, CHEK2) were associated with time to ADT treatment failure and survival in mHSPC.
Interpretation:
ctDNA fraction can further refine clinical prognostic factors in metastatic prostate cancer. Somatic ctDNA alterations have potential prognostic, predictive, and therapeutic implications in metastatic prostate cancer management.
Funding:
Several funding sources have supported this study. A full list is provided in the Acknowledgments. No funding was received from Predicine, Inc. during the conduct of the study.
Background
Olaparib has been proven for the treatment of metastatic castration-resistant prostate cancer (mCRPC). This meta-analysis aims to comprehensively evaluate the efficacy and safety of the combination of olaparib and abiraterone in patients with mCRPC.
Methods
The literature in PubMed, Embase, and Cochrane Library up until April 27, 2023, was systematically searched. In the studies included in this meta-analysis, olaparib combined with abiraterone was compared with abiraterone combined with placebo.
Results
Two randomized controlled trials involving a total of 938 patients were included. Analysis indicated that olaparib combined with abiraterone significantly prolonged radiographic progression-free survival (rPFS: relative risk [RR] 0.66, 95% confidence interval [CI] 0.55–0.79), time to secondary progression or death (PFS2: hazard ratio [HR] 0.72, 95% CI 0.56–0.93), time to first subsequent therapy or death (TFST: HR 0.75, 95% CI 0.63–0.89), time to second subsequent therapy or death (TSST: HR 0.73, 95% CI 0.58–0.93), and confirmed prostate-specific antigen (PSA) response (RR 1.14, 95% CI 1.05–1.24). However, no statistically significant differences were found in the overall survival (OS: HR 0.87 95% CI 0.70–1.09), objective response rate (ORR: RR 0.97, 95% CI 0.70–1.33), and incidence of total adverse events (RR 1.07, 95% CI 0.94–1.22). A notable detail that the combination of olaparib and abiraterone was associated with an increased incidence of high-grade anemia (RR 7.47, 95% CI 1.36–40.88).
Conclusion
Olaparib combined with abiraterone is effective for patients with mCRPC. However, combination therapy has treatment-related adverse events compared with monotherapy, and this could be improved in future treatment management.
Systematic review registration
https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42023432287.
Purpose:
The phase III PROfound study (NCT02987543) evaluated olaparib versus abiraterone or enzalutamide (control) in metastatic castration-resistant prostate cancer (mCRPC) with tumor homologous recombination repair (HRR) gene alterations. We present exploratory analyses on the use of ctDNA testing as an additional method to identify mCRPC patients with HRR gene alterations who may be eligible for olaparib treatment.
Patients and methods:
Plasma samples collected during screening in PROfound were retrospectively sequenced using the FoundationOne® Liquid CDx test for BRCA1, BRCA2 (BRCA) and ATM alterations in ctDNA. Only patients from Cohort A (BRCA/ATM-alteration positive by tissue testing) were evaluated. We compared clinical outcomes, including radiographic progression-free survival (rPFS) between the ctDNA subgroup and Cohort A.
Results:
Of the 181 (73.9%) Cohort A patients who gave consent for plasma sample ctDNA testing, 139 (76.8%) yielded a result and BRCA/ATM alterations were identified in 111 (79.9%). Of these, 73 patients received olaparib and 38 received control. Patients' baseline demographics and characteristics, and the prevalence of HRR alterations were comparable to the Cohort A ITT population. rPFS was longer in the olaparib group versus control (median 7.4 vs. 3.5 months; hazard ratio [HR] 0.33; 95% confidence interval [CI], 0.21-0.53; nominal P < 0.0001), which is consistent with Cohort A ITT population (HR 0.34 [95% CI, 0.25-0.47]).
Conclusions:
When tumor tissue testing is not feasible or has failed, ctDNA testing may be a suitable alternative to identify patients with mCRPC carrying BRCA/ATM alterations who may benefit from olaparib treatment.
