scholarly journals Clonal origin and spread of metastatic prostate cancer

2016 ◽  
Vol 23 (4) ◽  
pp. R207-R217 ◽  
Author(s):  
Jamie L Van Etten ◽  
Scott M Dehm
Keyword(s):  
Prostate Cancer ◽  
Metastatic Disease ◽  
Large Scale ◽  
Clonal Evolution ◽  
Circulating Tumor Dna ◽  
Response To Therapy ◽  
Small Scale ◽  
Genetic Evolution ◽  
Castration Resistant Prostate Cancer ◽  
Origin And Evolution

Metastatic disease is responsible for the majority of prostate cancer deaths. The standard treatment for metastatic disease is surgical or chemical castration in the form of androgen deprivation therapy. Despite initial success and disease regression, resistance to therapy ultimately develops and the disease transitions to castration-resistant prostate cancer, which is uniformly fatal. Thus, developing an understanding of genetic evolution in metastasis and in response to therapy has been a focus of recent studies. Large-scale sequencing studies have provided an expansive catalog of the mutation events that occur in the prostate cancer genome at various stages of disease progression. Small-scale studies have interrogated the genomic composition of multiple metastatic sites within individual patients or have tracked clonal evolution longitudinally in tissues, circulating tumor cells, or circulating tumor DNA. Collectively, these efforts have provided a new conceptual framework for understanding the origin of prostate cancer, as well as the origin and evolution of metastatic disease. In this review, we highlight these recent insights into the spatiotemporal landscape of genetic evolution of prostate cancer.

Metacure: Multi-arm multimodality therapy for very high risk localized and low volume metastatic prostatic adenocarcinoma.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS349-TPS349 ◽  
Author(s):  
Min Yuen Teo ◽  
Mary-Ellen Taplin ◽  
James Andrew Eastham ◽  
Hannah Benoliel ◽  
Adam S. Kibel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
High Risk ◽  
Metastatic Disease ◽  
Large Scale ◽  
Residual Disease ◽  
Pathologic Complete Response ◽  
Retroperitoneal Lymph Node Dissection ◽  
Castration Resistant Prostate Cancer ◽  
Low Volume ◽  
Very High

TPS349 Background: Therapeutic advances in the management of metastatic castration-resistant prostate cancer (mCRPC) have not been matched in non-castrate states. A key obstacle is the traditional paradigm in which therapies with significant benefit in mCRPC are then studied in patients (pts) with localized, rising PSA or early metastatic disease using time-to-event (TTE) outcomes (e.g. biochemical recurrence, radiographic progression or death). These trials are costly, lengthy and often give inconclusive results that do not change practice nor provide a methodology to rank regimens based on efficacy. A new strategy is needed that gives a rapid efficacy readout and prioritizes approaches for large-scale testing. Methods: Metacure is a multi-arm, multi-stage randomized Phase 2 trial in which novel systemic therapies are studied in the context of a multimodality approach, which includes radical prostatectomy + pelvic and retroperitoneal lymph node dissection, if applicable, stereotactic radiotherapy (RT) to osseous metastases, and an option for adjuvant RT based on risk factors. The arms include combinations of ADT + apalutamide +/- abiraterone acetate and prednisone. Non-castrate prostate cancer pts with high probability of relapse or death from disease ranging from very high risk localized to low-volume metastatic disease are eligible. The primary endpoint is pathologic complete response and minimal residual disease. The secondary endpoint is undetectable PSA with non-castrate levels of testosterone. Both are binary endpoints that circumvent interpretations of the clinical relevance of TTE outcomes, providing a read-out of success or failure in a shorter time frame with fewer pts. The uniform entry criteria and continuous randomization enables ranking and prioritization of the strategies evaluated for further development in large-scale trials so that only the most effective ones move forward. This multicenter trial is managed by the Prostate Cancer Clinical Trials Consortium, funded by Janssen and is currently open and actively accruing. Future plans include opening a cohort of pts with aggressive non-castrate disease harboring DNA damage repair alterations. Clinical trial information: NCT03436654.

Genomic analysis of circulating tumor DNA in 3,334 patients with advanced prostate cancer to identify targetable BRCA alterations and AR resistance mechanisms.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 25-25
Author(s):  
Hanna Tukachinsky ◽  
Russell Madison ◽  
Jon Chung ◽  
Lucas Dennis ◽  
Bernard Fendler ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Advanced Prostate Cancer ◽  
Acquired Resistance ◽  
Genomic Analysis ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Cancer Tissue ◽  
Castration Resistant Prostate Cancer ◽  
High Level ◽  
Tumor Dna

25 Background: Comprehensive genomic profiling (CGP) by next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) from plasma provides a minimally invasive method to identify targetable genomic alterations (GAs) and resistance mechanisms in patients with metastatic castration-resistant prostate cancer (mCRPC). The circulating tumor fraction in patients with mCRPC and the clinical validity of GAs detected in plasma remain unknown. We evaluated the landscape of GAs using ctDNA-based CGP and assessed concordance with tissue-based CGP. Methods: Plasma from 3,334 patients with advanced prostate cancer (including 1,674 mCRPC screening samples from the TRITON2/3 trials and 1,660 samples from routine clinical CGP) was analyzed using hybrid-capture-based gene panel NGS assays. Results were compared with CGP of 2,006 metastatic prostate cancer tissue biopsies. Concordance was evaluated in 837 patients with both tissue (archival or contemporaneous) and plasma NGS results. Results: 3,127 patients [94%] had detectable ctDNA. BRCA1/2 were mutated in 295 patients [8.8%]. In concordance analysis, 72/837 [8.6%] patients had BRCA1/2 mutations detected in tissue, 67 [93%] of whom were also identified by ctDNA, and 20 patients were identified using ctDNA but not tissue [23% of all patients identified using ctDNA]. ctDNA detected subclonal BRCA1/2 reversions in 10 of 1,660 [0.6%] routine clinical CGP samples. AR alterations, including amplifications and hotspot mutations, which were detected in 940/2,213 patients [42%]. Rare AR compound mutations, rearrangements, and novel in-frame deletions were identified. Altered pathways included PI3K/AKT/mTOR [14%], WNT/β-catenin [17%], and RAS/RAF/MEK [5%]. Microsatellite instability was detected in 31/2,213 patients [1.4%]. Conclusions: In the largest study of mCRPC plasma samples conducted to date, CGP of ctDNA recapitulated the genomic landscape detected in tissue biopsies, with a high level of agreement in detection of BRCA1/2 alterations. It also identified patients who may have gained somatic BRCA1/2 alterations since archival tissue was collected. ctDNA detected more acquired resistance GAs than tissue, including novel AR-activating variants. The large percentage of patients with rich genomic signal from ctDNA, and the sensitive, specific detection of BRCA1/2 alterations position liquid biopsy as a compelling clinical complement to tissue CGP for patients with mCRPC.

Role of detection of metastatic disease as a leading cause of screening failure in an ongoing phase III trial of zibotentan versus placebo in patients with nonmetastatic castration-resistant prostate cancer (CRPC).

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 135-135 ◽  
Author(s):  
E. Y. Yu ◽  
F. E. Nathan ◽  
C. S. Higano
Keyword(s):  
Prostate Cancer ◽  
Metastatic Disease ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Castration Resistant Prostate Cancer ◽  
Asymptomatic Patients ◽  
Primary Endpoints ◽  
Number Of Patients ◽  
Definitive Therapy ◽  
Patients Experience

135 Background: Many patients with biochemical relapse after definitive therapy for prostate cancer receive androgen deprivation therapy. Although most patients experience a decline in PSA, PSA eventually rises despite a castrate level of testosterone. Many of these patients have non-metastatic disease and do not develop metastases for a median of 30 mos (Smith MR. JCO, 2005). However, there is no standard therapy for asymptomatic patients with non-metastatic CRPC. ENTHUSE M0 (Study 15) is an ongoing global phase III study comparing zibotentan 10 mg (an oral specific endothelin A receptor antagonist) vs placebo in non-metastatic CRPC patients. Co-primary endpoints are overall survival and progression-free survival; secondary endpoints are safety, PSA, quality of life, and time to symptomatic progression. Eligible patients are screened for metastases by bone and CT/MRI scan and other parameters. An unexpectedly high number of patients failed screening, prompting this analysis. Methods: All patients who were screened were included in the analysis. Reasons for exclusion were recorded. Results: As of June 3, 2010, 1,756 patients completed screening. Of these patients, 960 (55%) were randomized and 796 (45%) failed screening. The leading causes of screen failures are listed in the table. Exclusion rates by investigator specialty and country will be reported. Conclusions: As 30% of patients had metastatic disease on screening and were excluded, these data suggest that the frequency of asymptomatic metastases is high in men thought to have non-metastatic CRPC. These findings stress the value of periodic staging studies in men progressing from hormone sensitive to non-metastatic CRPC as metastatic CRPC patients may benefit from standard treatments or research treatments on other protocols. [Table: see text] [Table: see text]

Patterns of metastatic disease progression after treatment with first-line enzalutamide or abiraterone in castration-resistant prostate cancer (CRPC).

2016 ◽  
Vol 34 (15_suppl) ◽  
pp. e16539-e16539 ◽  
Author(s):  
Elizabeth K Lee ◽  
Benjamin A. Teply ◽  
Benjamin Louis Maughan ◽  
Michael Anthony Carducci ◽  
Emmanuel S. Antonarakis ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Disease Progression ◽  
Metastatic Disease ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Castration Resistant

Circulating tumor DNA fraction (ctDNA) as a surrogate predictive biomarker in metastatic castration-resistant prostate cancer (mCRPC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5039-5039
Author(s):  
Vincenza Conteduca ◽  
Daniel Wetterskog ◽  
Emanuela Scarpi ◽  
Alessandro Romanel ◽  
Giorgia Gurioli ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Plasma Sample ◽  
Tumour Response ◽  
Predictive Biomarker ◽  
Complete Response ◽  
Circulating Tumor Dna ◽  
Castration Resistant Prostate Cancer ◽  
Sample Collection ◽  
Early Assessment ◽  
Targeted Next Generation Sequencing

5039 Background: Plasma ctDNA is a promising minimally invasive biomarker in mCRPC. Pre-treatment high levels of ctDNA reflect poor prognosis (Romanel et al, Sci Transl Med 2015; Annala et al, Cancer Discov 2018). However, the role of plasma ctDNA in prostate tumour monitoring is largely unexplored. We aimed to determine if monitoring tumour response by quantifying ctDNA levels in plasma could enable early assessment of therapy efficacy for mCRPC. Methods: Between January 2011 and June 2016, 132 sequential plasma samples from 54 mCRPC patients (pts) (30 pre- and 24 post-chemotherapy) treated with abiraterone (abi) were collected. Targeted next-generation sequencing was performed on the PGM Ion Torrent using a 316 or 318 Chip to account for 1000X expected coverage per target. We estimated the global tumour content for each sequential plasma sample from study patients by using the approach developed in (Carreira et al, Sci Trasl Med 2014; Romanel et al, Sci Transl Med 2015 ), which extends the CLONET framework (Prandi et al, Genome Biol 2014). Prostate Cancer Working Group -3 (PCWG3) criteria were used to assess clinical, biochemical (PSA) and radiographic (RAD) progression disease (PD). We considered ctDNA PD any increase of ctDNA from baseline value. Results: In our cohort of 54 pts (median age: 75 years, range 70-78), we observed 17 (31.5%) PD, 14 (25.9%) stable disease, and 23 (42.6%) partial/complete response after the first 3 months (mo) abi therapy. The odds ratio (OR) for PD having any increase in ctDNA and a PSA decline < 50% at ~3-mo therapy was 10.83, 95% CI 2.55-45.95, P = 0.001, and 3.27, 95% CI 0.89-12.3, P = 0.074, respectively. In addition, we assessed all 3 types of median PD time from starting abi treatment, suggesting the ability of ctDNA variation to predict overall PD [RAD PD = 6.8 mo, PSA PD = 4.4 mo, and ctDNA PD = 3.0 mo, P = 0.008). An increase of ctDNA levels during the first 3-mo abi treatment was significantly associated with a long-term androgen deprivation therapy (ADT) before plasma sample collection (previous ADT > 24 mo vs 12 > previous ADT ≤23 mo vs < 12 mo: P = 0.036). Conclusions: In mCRPC, an early change in ctDNA fraction may be considered as a predictive biomarker playing a key role in individualized disease monitoring. Prospective evaluation of treatment decisions based on ctDNA is now required.

Prospective trial of nivolumab (Nivo) plus radium-223 (RA) in metastatic castration-resistant prostate cancer (mCRPC) evaluating circulating tumor DNA (ctDNA) levels as a biomarker of response.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS267-TPS267
Author(s):  
Benjamin Louis Maughan ◽  
Roberto Nussenzveig ◽  
Umang Swami ◽  
Sumati Gupta ◽  
Neeraj Agarwal
Keyword(s):  
Checkpoint Inhibitors ◽  
Immune Therapy ◽  
Prospective Trial ◽  
Progression Free Survival ◽  
Metastatic Gastric Cancer ◽  
Circulating Tumor Dna ◽  
Alpha Particles ◽  
Response To Therapy ◽  
Castration Resistant Prostate Cancer ◽  
Radium 223

TPS267 Background: RA is a calcium-mimetic radiopharmaceutical emitter of alpha particles that has been approved for treatment of mCRPC. Radiation plus checkpoint inhibitors has demonstrated promising efficacy in previous clinical trials (PMID 27466265, 23535954). Alteration to PD-1 expression has been observed with radium-223, suggesting potential synergy with Nivo (PMID 29137877). ctDNA concentration may accurately reflect overall tumor burden and response to immune therapy. ctDNA testing after 6 weeks of therapy predicts efficacy of immunotherapy in patients with metastatic NSCLC and urothelial carcinoma (PMID 30093454) and metastatic gastric cancer (PMID 30013197). Reduction of ctDNA correlated with both radiographic progression free survival (rPFS) and overall survival. We hypothesize that RA + Nivo will be safe and decrease ctDNA, which may predict response to therapy earlier than conventional scans. Methods: This is a single-arm phase I/II investigator initiated trial (NCT04109729). Primary objectives: 1) Safety, 2) Change in ctDNA after 6 weeks treatment compared to baseline. Secondary objectives: 1) PSA-PFS; 2) PSA 50% response rate; 3) Time to skeletal related event; 4) Bone metabolism marker response. Inclusion criteria: symptomatic bone metastasis, mCRPC, adequate hematopoiesis. Exclusion criteria: visceral metastasis, history of autoimmune disease and current use of immune suppression therapy. A total of 36 patients will be enrolled. Cycles are 28 days. ctDNA concentration will be measured using GuardantOMNI research platform which evaluates 500 genes. Treatment: RA (55 kBq/kg IV) monotherapy lead in for two cycles followed by RA plus Nivo (480mg IV) for an additional 4 cycles. Nivo monotherapy then continues for up to 2 years. ctDNA collected prior to combination therapy and 6 weeks after. Restaging scans done every 2 cycles while on radium-223 and every 3 cycles while on nivolumab. Clinical trial information: NCT04109729.

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