Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5072-5072
Author(s):  
Simon Yuen Fai Fu ◽  
Elie Ritch ◽  
Cameron Herberts ◽  
Steven Yip ◽  
Daniel Khalaf ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Median Time ◽  
Somatic Mutation ◽  
Clinical Data ◽  
Castration Resistant Prostate Cancer ◽  
Control Cohort ◽  
Mutational Signatures ◽  
Whole Exome ◽  
Mutation Burden ◽  
Homozygous Deletions

5072 Background: A small proportion of metastatic PC exhibit outlier somatic mutation (mut) rates exceeding the average of 4.4 mut/Mb. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing from a panel of PC genes using plasma cell-free DNA samples collected from metastatic castration-resistant prostate cancer (mCRPC) pts and calculated somatic mutation burden. HM samples were additionally subjected to whole exome sequencing to determine trinucleotide mutational signatures and microsatellite instability (MSI). Clinical data was retrospectively collected and compared to a control cohort of 199 mCRPC pts. Results: 671 samples from 434 pts had ctDNA > 2% and were evaluable. 32 samples from 24 pts had > 11 mut/Mb and fell above the 95th percentile for mutation burden with a median mutation burden of 34 mut/Mb. 11 pts had deleterious mutations or homozygous deletions in mismatch repair (MMR) genes and 4 further pts had evidence of MMR deficiency (MMRd) from mutational signatures and MSI status. The remaining 9 pts had either BRCA2 mutations (n = 4), Kataegis (localized hypermutation, n = 3), or undefined causes for HM (n = 2). The incidence of MMRd was 3.5% (15/434), and germline MMRd was 0.2% (1/434). For MMRd pts with available clinical data (10/15) at diagnosis, the median age was 73.6 y, 70% had Gleason score ≥8, and 50% presented with M1 disease. Comparing the MMRd with the control cohort, median time from ADT to CRPC was 9.1 m (95% CI 6.9–11.4) vs. 18.2 m (95% CI 15.1–21.3), p = 0.001; median time from CRPC to death was 13.1 m (95% CI 0.3–25.9) vs. 40.1 m (95% CI 32.4–47.8), p < 0.001. Conclusions: HM and MMRd can be identified using liquid biopsy and could help to select pts for immunotherapy.

Identification, incidence and clinical outcomes of patients (pts) with hypermutated prostate cancer (PC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 195-195
Author(s):  
Simon Yuen Fai Fu ◽  
Elie Ritch ◽  
Steven Yip ◽  
Daniel Khalaf ◽  
Sinja Taavitsainen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Somatic Mutation ◽  
Nonnegative Matrix ◽  
Castration Resistant Prostate Cancer ◽  
Control Cohort ◽  
Castration Resistant ◽  
Whole Exome ◽  
Mutation Burden ◽  
Selection For ◽  
Poor Outcomes

195 Background: A small proportion of metastatic PC exhibit outlier somatic mutation rates. The incidence, clinical course and treatment response of pts with hypermutation (HM) is poorly characterised. Methods: We performed targeted sequencing of 1047 plasma cell-free DNA samples and calculated somatic mutation burden. HM samples and available matched archival tissue were additionally subjected to whole exome sequencing. Trinucleotide mutational signatures and microsatellite instability (MSI) were determined via nonnegative matrix factorization and mSINGS, respectively. We evaluated PSA decline ≥50% from baseline (PSA50), time from androgen deprivation therapy (ADT) to castration-resistant prostate cancer (CRPC), median duration of 1st line CRPC therapy (1L CRPCT) and median OS (time from CRPC to death). The control cohort consisted of 199 CRPC pts treated with 1L abiraterone + prednisone (ABI+P) or enzalutamide (ENZ). Results: 671 samples from 434 pts had ctDNA% > 2 and were evaluable. The median mutation rate was 2.59/Mb (range, 0.9 – 155.6/Mb). 32 samples from 24 pts had > 11/Mb and fell above the 95th percentile for mutational burden. 10/24 pts had biallelic loss of mismatch repair (MMR) genes MSH2/6, and a further 5 pts without confirmed MMR defects had enrichment of trinucleotide signatures associated with MMR and/or were MSI high by mSINGS. The remaining 9 pts had either BRCA2 mutations or Kataegis (localized hypermutation). Clinical data was available for 10/15 MMR defective pts. Median age was 73.6 y. At diagnosis, 70% had Gleason score ≥8, 50% with M1 disease, median PSA was 22.8 (6.8 – 820). PSA50 with ADT (n = 8) or ADT + docetaxel (n = 2) was 100% in the castration sensitive setting. 5 pts had ENZ, 4 ABI + P, and 1 cabazitaxel in 1L CRPCT. Comparing the MMR defective with the control cohort, median time from ADT to CRPC was 9.1 m (95% CI 6.9 – 11.4) vs. 18.2 m (95% CI 15.1 – 21.3), p = 0.001; 1L CRPCT duration was 3.9 m (95% CI 1.3 – 6.5) vs. 8.4 m (95% CI 7.2 – 9.6), p = < 0.001; median OS was 13.1 m (95% CI 0.33 – 25.9) vs. 40.1 m (95% CI 32.4 – 47.8), p < 0.001. Conclusions: HM and MMR defects can be identified in a liquid biopsy. Although these pts can have poor outcomes with standard therapy, ctDNA may help selection for immunotherapy.

Correlation between human epidermal growth factor receptor 2 (HER2) status and central nervous system (CNS) involvement in metastatic castration-resistant prostate cancer (mCRPC).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 210-210
Author(s):  
Angela Gernone ◽  
Vincenzo Pagliarulo ◽  
Francesco Silvestris ◽  
Arcangelo Pagliarulo
Keyword(s):  
Prostate Cancer ◽  
Median Time ◽  
Performance Status ◽  
Neurological Symptoms ◽  
Her2 Status ◽  
Castration Resistant Prostate Cancer ◽  
Cns Metastases ◽  
Whole Brain ◽  
Increased Risk ◽  
Her 2

210 Background: The incidence of CNS metastasesin prostate cancer is very low. Recent data suggest that HER-2/neu is involved in progression of prostate cancer. Docetaxel-based chemotherapy has provided a survival advantage for mCRPC. The purpose of this retrospective study was to evaluate the relation between HER-2 status and risk of CNS metastases in pts with mCRPC treated with docetaxel. Methods: From 2003 to 2010, 130 pts with mCRPC were treated with 3wk docetaxel 75 mg/mq. 72/130 pts were retreated with the same regimen on disease progression. 50 out of these 72 pts received second docetaxel retreatment. All pts had bone metastases. Pts underwent total body CT scan before starting docetaxel chemotherapy and every 6 months during treatment. The median age was 66 (41–88), median baseline PSA: 110 ng/ml (range 5–1100), median ECOG Performance Status: 1 (range 0–2). The data on 130 pts, who underwent diagnostic biopsy or potentially curative resection , were reviewed. Tissue blocks from primary prostate cancer tissues were obtained. Grade 3 of the HER-2 by IHC staining was defined as a positive result or gene amplification by FISH. 10 out of these 50 pts receiving second docetaxel retreatment were diagnosed with CNS metastases. Results: CNS metastases were observed in HER-2 positive pts. 6/10 pts presented parenchymal metastases: 4 pts were asymptomatic, 3 pts underwent metastasectomy and all of them received palliative whole-brain RT. 4/10 pts presented leptomeningeal metastases with neurological symptoms and 2 of them received palliative whole-brain RT. The median time from prostate cancer diagnosis to the date of diagnosis of CNS metastases was 6 years (1–8). The median time from first cycle of docetaxel to the date of diagnosis of CNS metastases was 3 years (1.5–4). Conclusions: These preliminary data demonstrated that HER-2 expression confers an increased risk of CNS metastases in mCRPC and constitutes a therapeutic challenge. The apparent increase of CNS presentation may be related to the effectiveness of systemic therapy. These informations support the further evaluation of neurological symptoms in long-term docetaxel treated pts.

Long-term follow-up from STAMP, a phase II trial, evaluating sipuleucel-T and concurrent (CON) vs sequential (SEQ) abiraterone acetate + prednisone in metastatic castration-resistant prostate cancer patients (pts).

2017 ◽  
Vol 35 (6_suppl) ◽  
pp. 190-190 ◽  
Author(s):  
Eric Jay Small ◽  
Raymond S. Lance ◽  
Charles H. Redfern ◽  
Frederick E. Millard ◽  
Thomas A. Gardner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Clinical Outcomes ◽  
Median Time ◽  
Abiraterone Acetate ◽  
Castration Resistant Prostate Cancer ◽  
Castration Resistant ◽  
Long Term Follow Up ◽  
Safety Signals

190 Background: The optimal sequence and combination of life-extending anticancer therapies in mCRPC pts remains unknown. Sipuleucel-T (sip-T), an autologous cellular immunotherapy approved for the therapy of asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC) pts, was evaluated in combination with abiraterone acetate and prednisone (abi) in the phase II STAMP trial (NCT01487863), with pts randomly assigned to receive CON sip-T + abi or SEQ sip-T followed by abi. The combination was well-tolerated and did not alter the immune response parameters that correlate with overall survival (OS) (Small Clin Can Res 2015). Here, we present long-term follow-up of clinical outcomes, including OS. Methods: mCRPC pts were randomized 1:1 to CON or SEQ therapy with sip-T and abi. Abi began 1 day after (CON) or at wk 10 (SEQ) after the first sip-T infusion and continued for 26 wk of therapy, after which continued abi therapy was permitted. Long-term clinical outcomes included OS, disease-specific death (DSS), progressive disease (PD), time to first anticancer intervention (tACI), and safety. Results: 69 pts were enrolled (35 CON; 34 SEQ). Median OS was 34.0 mo (95% CI, 24.4-not estimable [NE]; 30.0 mo CON; 34.2 mo SEQ; p = 0.921), and median time to DSS was not reached (CON vs SEQ; p = 0.733). Median time to PD was 17.3 mo (95% CI, 9.7–NE; 17.7 mo CON vs 13.9 mo SEQ; p = 0.914; consistent with higher rates of abi discontinuation due to PD in SEQ [26.5% vs 14.3% in CON]). tACI was similar between arms at 15.4 mo (95% CI, 11.0–19.9). No new safety signals were observed with the combination, and no discernable difference in clinical outcomes was observed with CON or SEQ treatments. Conclusions: Long-term follow-up data confirm that sip-T + CON or SEQ abi is well-tolerated, with no new safety signals. No clear differences were observed in clinical outcomes between arms, although the study was not powered to detect these differences. Future and more appropriately powered studies on the effect of sip-T + continuous abi for responding pts may provide further insights on the benefit of combination therapy. Clinical trial information: NCT01487863.

scholarly journals Predictive Biomarkers of Dicycloplatin Resistance or Susceptibility in Prostate Cancer

2021 ◽  
Vol 12 ◽  
Author(s):  
Minglu Liu ◽  
Xiaoyu Zhou ◽  
Jun Liu ◽  
Chelong Lu ◽  
Guoqing Zhang ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Somatic Mutations ◽  
Copy Number Variants ◽  
Predictive Biomarkers ◽  
Mutational Signatures ◽  
Whole Exome ◽  
Group A ◽  
Resistant Group ◽  
Six Genes ◽  
Sensitive Group

BackgroundProstate cancer (PCa) is among the leading causes of cancer mortality. Dicycloplatin is a newer generation platinum-based drug that has less side effects than cisplatin and carboplatin. However, its effects in PCa is mixed due to lack of appropriate stratifying biomarkers. Aiming to search for such biomarkers, here, we analyze a group of PCa patients with different responses to dicycloplatin.MethodsWe carried out whole-exome sequencing on cell-free DNA (cfDNA) and matched leukocyte DNA from 16 PCa patients before treatment with dicycloplatin. We then compared the clinical characteristics, somatic mutations, copy number variants (CNVs), and mutational signatures between the dicycloplatin-sensitive (nine patients) and dicycloplatin-resistant (seven patients) groups and tested the identified mutations, CNV, and their combinations as marker of dicycloplatin response.ResultsThe mutation frequency of seven genes (SP8, HNRNPCL1, FRG1, RBM25, MUC16, ASTE1, and TMBIM4) and CNV rate of four genes (CTAGE4, GAGE2E, GAGE2C, and HORMAD1) were higher in the resistant group than in the sensitive group, while the CNV rate in six genes (CDSN, DPCR1, MUC22, TMSB4Y, VARS, and HISTCH2AC) were lower in the resistant group than in the sensitive group. A combination of simultaneous mutation in two genes (SP8/HNRNPCL1 or SP8/FRG1) and deletion of GAGE2C together were found capable to predict dicycloplatin resistance with 100% sensitivity and 100% specificity.ConclusionWe successfully used cfDNA to monitor mutational profiles of PCa and designed an effective composite marker to select patients for dicycloplatin treatment based on their mutational profile.

scholarly journals Observational study on time on treatment with abiraterone and enzalutamide

PLoS ONE ◽  
2020 ◽  
Vol 15 (12) ◽  
pp. e0244462
Author(s):  
Giuseppe Fallara ◽  
Ingela Franck Lissbrant ◽  
Johan Styrke ◽  
Francesco Montorsi ◽  
Hans Garmo ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Median Time ◽  
Cox Regression ◽  
Medication Possession Ratio ◽  
Sensitivity Analyses ◽  
Time Interval ◽  
Drug Supply ◽  
Castration Resistant Prostate Cancer ◽  
Adherence To Treatment ◽  
The Impact

Introduction The aim of this study was to assess time on treatment with abiraterone and enzalutamide, two androgen receptor targeted (ART) drugs, the impact on time on treatment of time interval without drug supply between prescription fillings, and adherence to treatment. Material and methods By use of data from The National Prostate Cancer Register, The Prescribed Drug Registry and the Patient Registry, time on treatment with the abiraterone and enzalutamide was analyzed in all men with castration resistant prostate cancer (CRPC) in Sweden 2015–2019. Three time intervals between consecutive fillings, i.e. time without drug supply, were assessed. Adherence to the treatment was evaluated by use of the Medication Possession Ratio. Kaplan Meier analysis and multivariable Cox regression model were used to assess factors affecting time on treatment. Results Between January 2015 and October 2019, 1803 men filled a prescription for abiraterone and 4 534 men filled a prescription for enzalutamide. With a time interval of 30 days or less between two fillings, median time on treatment was 4.9 months (IQR 2.6–11.7) for abiraterone and 8.0 months (IQR 3.6–16.4) for enzalutamide. In sensitivity analyses, allowing for no more than 14 days without drug supply between fillings, median time on treatment was 3.9 months (IQR 2.1–9.0) for abiraterone and 5.9 months (IQR 2.8–12.1) for enzalutamide. Allowing for any time period without drug between fillings, median time on treatment was 5.7 months (IQR 2.7–14.0) for abiraterone and 9.8 months (IQR 4.4–21.0) for enzalutamide. Adherence to treatment was above 90% for both drugs. Conclusion Time on treatment with abiraterone and enzalutamide was shorter in clinical practice than in randomized controlled trials and varied almost two-fold with time interval without drug. Adherence to treatment was high. The main limitation of our study was the lack of data on use of chemotherapy.

scholarly journals CANCERSIGN: a user-friendly and robust tool for identification and classification of mutational signatures and patterns in cancer genomes

2018 ◽  
Author(s):  
Masroor Bayati ◽  
Hamid Reza Rabiee ◽  
Mehrdad Mehrbod ◽  
Fatemeh Vafaee ◽  
Diako Ebrahimi ◽  
...  
Keyword(s):  
Somatic Mutation ◽  
Whole Genome ◽  
Mutational Signatures ◽  
Coding Regions ◽  
Whole Exome ◽  
Cancer Genomes ◽  
Genome Consortium ◽  
User Friendly ◽  
Pooled Samples

Analyses of large somatic mutation datasets, using advanced computational algorithms, have revealed at least 30 independent mutational signatures in tumor samples. These studies have been instrumental in identification and quantification of responsible endogenous and exogenous molecular processes in cancer. The quantitative approach used to deconvolute mutational signatures is becoming an integral part of cancer research. Therefore, development of a stand-alone tool with a user-friendly graphical interface for analysis of cancer mutational signatures is necessary. In this manuscript, we introduce CANCERSIGN as an open access bioinformatics tool that uses raw mutation data (BED files) as input, and identifies 3-mer and 5-mer mutational signatures. CANCERSIGN enables users to identify signatures within whole genome, whole exome or pooled samples. It can also identify signatures in specific regions of the genome (defined by user). Additionally, this tool enables users to perform clustering on tumor samples based on the raw mutation counts as well as using the proportion of mutational signatures in each sample. Using this tool, we analysed all the whole genome somatic mutation datasets profiled by the International Cancer Genome Consortium (ICGC) and identified a number of novel signatures. By examining signatures found in exonic and non-exonic regions of the genome using WGS and comparing this to signatures found in WES data we observe that WGS can identify additional non-exonic signatures that are enriched in the non-coding regions of the genome while the deeper sequencing of WES may help identify weak signatures that are otherwise missed in shallower WGS data.

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