scholarly journals Harbingers of Aggressive Prostate Cancer: Precision Oncology Case Studies

2021 ◽  
Author(s):  
Joanna Cyrta ◽  
Davide Prandi ◽  
Arshi Arora ◽  
Daniel H. Hovelson ◽  
Andrea Sboner ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Phylogenetic Reconstruction ◽  
Genomic Analysis ◽  
Routine Practice ◽  
Molecular Heterogeneity ◽  
Precision Oncology ◽  
Gleason Grade ◽  
Metastatic Progression ◽  
Castration Resistant Prostate Cancer ◽  
Pathology Review

Primary prostate cancer (PCa) can show marked molecular heterogeneity. However, systematic analyses comparing primary PCa and matched metastases in individual patients are lacking. We aimed to address the molecular aspects of metastatic progression while accounting for heterogeneity of primary PCa. In this pilot study, we collected 12 radical prostatectomy (RP) specimens from men who subsequently developed metastatic castration-resistant prostate cancer (mCRPC). We used histomorphology (Gleason grade, focus size, stage) and immunohistochemistry (IHC) (ERG and p53) to identify independent tumors and/or distinct subclones of primary PCa. We then compared molecular profiles of these primary PCa areas to matched metastatic samples using whole exome sequencing (WES) and amplicon-based DNA and RNA sequencing. Based on combined pathology and molecular analysis, seven (58%) RP specimens harbored monoclonal and topographically continuous disease, albeit with some degree of intra-tumor heterogeneity; four (33%) specimens showed true multifocal disease; and one displayed monoclonal disease with discontinuous topography. Early (truncal) events in primary PCa included SPOP p.F133V (one patient), BRAF p.K601E (one patient), and TMPRSS2:ETS rearrangements (nine patients). Activating AR alterations were seen in eight (67%) mCRPC patients, but not in matched primary PCa. Hotspot TP53 mutations, found in metastases from three patients, were readily present in matched primary disease. Alterations in genes encoding epigenetic modifiers were observed in several patients (either shared between primary foci and metastases or in metastatic samples only). WES-based phylogenetic reconstruction and/or clonality scores were consistent with the index focus designated by pathology review in six out of nine (67%) cases. The three instances of discordance pertained to monoclonal, topographically continuous tumors, which would have been considered as unique disease in routine practice. Overall, our results emphasize pathologic and molecular heterogeneity of primary PCa, and suggest that comprehensive IHC-assisted pathology review and genomic analysis are highly concordant in nominating the ″index″ primary PCa area.

PSMA heterogeneity and DNA repair defects in prostate cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 5002-5002 ◽  
Author(s):  
Alec Paschalis ◽  
Beshara Sheehan ◽  
Ruth Riisnaes ◽  
Daniel Nava Rodrigues ◽  
Bora Gurel ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genomic Analysis ◽  
Predictive Biomarkers ◽  
Parp Inhibition ◽  
Gleason Grade ◽  
Castration Resistant Prostate Cancer ◽  
Damage Repair ◽  
Promising Target ◽  
Molecular Aberrations ◽  
Next Generation Sequencing Ngs

5002 Background: Prostate-specific membrane antigen (PSMA) is a promising target for theranostics in metastatic castration resistant prostate cancer (mCRPC). Methods: Membranous PSMA (mPSMA) expression was immunohistochemically evaluated in castration sensitive (CSPC) (n = 38) and mCRPC (n = 60) tissue biopsies, and associations with molecular aberrations (next-generation sequencing; NGS) and clinical outcome were determined. Results: mPSMA expression was significantly higher (p = 0.005) in mCRPC biopsies (median H-score [interquartile range]; 55.0 [2.8-117.5]) compared to CSPC biopsies (17.5 [0.0-60.0]). Furthermore, patients with higher mPSMA expression ( > median H-score) at diagnosis had higher Gleason Grade (p = 0.04) and shorter OS (p = 0.006). Critically, 42% (16/38) of CSPC biopsies and 27% (16/60) of mCRPC biopsies were completely negative for mPSMA expression. In addition, CSPC and mCRPC biopsies expressing mPSMA demonstrated marked intra-tumor heterogeneity in expression levels, commonly exhibiting areas without detectable PSMA (CSPC – 100%; mCRPC – 84%), while heterogeneous mPSMA expression between metastases from the same patient was also observed. Subsequent genomic analysis showed that mCRPC patients with deleterious DNA damage repair (DDR) aberrations have higher (p = 0.016) mPSMA expression (87.5 [25.0-247.5]) than those without these (20 [0.3-98.8]). Furthermore, 9 of the 11 patients (82%) responding to PARP inhibition had a mPSMA H-Score above the median. The association between mPSMA expression and DDR aberrations was validated in an independent cohort with known DDR aberrations. Tumors with DDR aberrations had significantly higher mPSMA (ATM 212.5 [136.3-300] p = 0.005; BRCA2 300 [165-300] p = < 0.001) than unselected mCRPC biopsies (55.0 [2.75-117.5]). Finally, analyses of 122 mCRPC biopsy transcriptomes confirmed a negative correlation between PSMA and BRCA2 mRNA expression (p = 1.5x10-5). Conclusions: mPSMA expression in CSPC and mCRPC exhibits marked intra- and inter-patient heterogeneity, limiting the clinical utility of PSMA-targeted theranostics. We show for the first time that DDR gene aberrations associate with high mPSMA expression and may serve as predictive biomarkers for PSMA-targeted therapies.

scholarly journals Best Paper Selection

2018 ◽  
Vol 27 (01) ◽  
pp. 226-226
Keyword(s):  
Prostate Cancer ◽  
Knowledge Base ◽  
Prediction Models ◽  
Precision Oncology ◽  
Castration Resistant Prostate Cancer ◽  
Short Term ◽  
Castration Resistant

Chakravarty D, Gao J, Phillips SM, Kundra R, Zhang H, Wang J, Rudolph JE, Yaeger R, Soumerai T, Nissan MH, Chang MT, Chandarlapaty S, Traina TA, Paik PK, Ho AL, Hantash FM, Grupe A, Baxi SS, Callahan MK, Snyder A, Chi P, Danila D, Gounder M, Harding JJ, Hellmann MD, Iyer G, Janjigian Y, Kaley T, Levine DA, Lowery M, Omuro A, Postow MA, Rathkopf D, Shoushtari AN, Shukla N, Voss M, Paraiso E, Zehir A, Berger MF, Taylor BS, Saltz LB, Riely GJ, Ladanyi M, Hyman DM, Baselga J, Sabbatini P, Solit DB, Schultz N. OncoKB: a precision oncology knowledge base. JCO Precis Oncol 2017 Jul;2017 https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/28890946/ Newton Y, Novak AM, Swatloski T, McColl DC, Chopra S, Graim K, Weinstein AS, Baertsch R, Salama SR, Ellrott K, Chopra M, Goldstein TC, Haussler D, Morozova O, Stuart JM. TumorMap: exploring the molecular similarities of cancer samples in an interactive portal. Cancer Res 2017 Nov 1;77(21):e111-e114 https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/29092953/ Seyednasrollah F, Koestler DC, Wang T, Piccolo SR, Vega R, Greiner R, Fuchs C, Gofer E, Kumar L, Wolfinger RD, Winner KK, Bare C, Neto EC, Yu T, Shen L, Abdallah K, Norman T, Stolovitzky G, Soule HR, Sweeney CJ, Ryan CJ, Scher HI, Sartor O, Elo LL, Zhou FL, Guinney J, Costello JC, and Prostate Cancer DREAM Challenge Community. A DREAM challenge to build prediction models for short-term discontinuation of docetaxel in metastatic castration-resistant prostate cancer. JCO Clin Cancer Inform 2017 Aug 4;(1):1-15 http://ascopubs.org/doi/abs/10.1200/CCI.17.00018

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.

Genomic analysis of localised prostate cancer identifies AZIN1 as driver of metastatic progression

2019 ◽  
Vol 18 (8) ◽  
pp. e3127
Author(s):  
T. Van Den Broeck ◽  
L. Moris ◽  
T. Gevaert ◽  
E. Smeets ◽  
C. Helsen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Genomic Analysis ◽  
Metastatic Progression

Genomic analysis of castration sensitive and resistant prostate cancer patients by multiple-gene targeted sequencing.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e17525-e17525
Author(s):  
Liancheng Fan ◽  
Xiaochen Fei ◽  
Baijun Dong ◽  
Wei Xue ◽  
Tingting Zhao ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Cancer Patients ◽  
Genomic Analysis ◽  
Genomic Diversity ◽  
Targeted Sequencing ◽  
Castration Resistant Prostate Cancer ◽  
Chi Square ◽  
Multiple Gene ◽  
Somatic Gene ◽  
Gene Alterations

e17525 Background: Previous studies showed the significant diversity of the genomic landscapes between castration sensitive prostate cancer (CSPC) and castration resistant prostate cancer (CRPC). AR, TP53/RB1, and BRCA2/ATM have been reported to contribute to the development of CRPC. In addition, CDK12 has recently reported to lead to the worse response to AR-targeted therapies. We are aimed to clarify the landscape of somatic gene alterations in CSPC and CRPC by multiple-gene targeted sequencing and discover the differential genes between the two treatment stages in order to guide clinical treatment. Methods: We recruited 413 prostate cancer patients including 230 CSPC and 183 CRPC. Cell-free DNA was extracted from plasma samples. Targeted sequencing of 50 genes was performed, which involved in DNA damage repair (DDR) pathway, AR pathway, TP53/RB1, etc. Chi square test or Fisher test were used to analyze the differences between two cohorts. Results: A total of 33.04% (76/230) CSPC patients carried somatic gene alterations, including 16.96% (39/230) in DDR pathway, 19.57% (45/230) in AR pathway and 7.39% (17/230) in TP53/RB1. The most frequent altered gene in CSPC was FOXA1 (9.13%,21/230), followed by NCOR2 (6.52%,15/230) and TP53 (5.65%,13/230). For CRPC patients, 66.67% (122/183) carried somatic gene alterations, including 44.81% (82/230) in DDR pathway, 49.73% (91/230) in AR pathway and 25.68% (47/183) in TP53/RB1. The most frequent mutated gene in CRPC was AR (33.33%,61/183), followed by FOXA1 (23.50%,43/183) and CDK12 (17.49%,32/183). Mutation frequencies of certain genes in CRPC patients were significantly higher than CSPC patients, including CDK12 (p < 0.001), BRCA2 (p = 0.006), ATM (p = 0.003), ATR (p = 0.007), AR (p < 0.001), FOXA1 (p = 0.001), SPOP (p = 0.002), ZBTB16 (p = 0.02), TP53 (p = 0.001), RB1 (p = 0.04) and PTEN (p = 0.001). Conclusions: It was the first study which explored the genomic alterations in Chinese CSPC and CRPC patients by liquid biopsy. These findings confirmed the genomic diversity between CSPC patients and CRPC patients, which could guide the individualized and precise management of prostate cancer in general practice. Furthermore, our findings indicated that somatic alterations in AR, CDK12, BRCA2, ATM and TP53/RB1 might contribute to the development of CRPC.

scholarly journals Treatment Landscape of Nonmetastatic Castration-Resistant Prostate Cancer: A Window of Opportunity

2021 ◽  
Vol 11 (11) ◽  
pp. 1190
Author(s):  
Fernando López-Campos ◽  
Antonio Conde-Moreno ◽  
Marta Barrado Los Arcos ◽  
Antonio Gómez-Caamaño ◽  
Raquel García-Gómez ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Treatment Guidelines ◽  
Standard Of Care ◽  
Phase Iii ◽  
Metastatic Progression ◽  
Castration Resistant Prostate Cancer ◽  
Phase Iii Clinical Trials ◽  
Castration Resistant ◽  
Medical Need ◽  
Clinical Benefits

The treatment for nonmetastatic castration-resistant prostate cancer (nmCRPC) is a highly unmet medical need. The classic treatment approach for these patients—androgen deprivation therapy (ADT) alone—until metastatic progression is now considered suboptimal. Several randomized phase III clinical trials have demonstrated significant clinical benefits—including significantly better overall survival (OS)—for treatments that combine ADT with apalutamide, enzalutamide, and darolutamide. As a result, these approaches are now included in treatment guidelines and are considered a standard of care. In the present article, we discuss the changing landscape of the management of patients with nmCRPC.

scholarly journals CDK12-Mutated Prostate Cancer: Clinical Outcomes With Standard Therapies and Immune Checkpoint Blockade

2020 ◽  
pp. 382-392 ◽  
Author(s):  
Michael T. Schweizer ◽  
Gavin Ha ◽  
Roman Gulati ◽  
Landon C. Brown ◽  
Rana R. McKay ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Overall Survival ◽  
Checkpoint Inhibitors ◽  
Specific Antigen ◽  
High Rate ◽  
Gleason Grade ◽  
Castration Resistant Prostate Cancer ◽  
First Line ◽  
Grade Group ◽  
Distinct Subgroup

PURPOSE Translational studies have shown that CDK12 mutations may delineate an immunoresponsive subgroup of prostate cancer, characterized by high neo-antigen burden. Given that these mutations may define a clinically distinct subgroup, we sought to describe outcomes to standard drugs and checkpoint inhibitors (CPI). PATIENTS AND METHODS Clinical data from consecutive patients with CDK12 mutations were retrospectively collected from 7 centers. Several clinical-grade sequencing assays were used to assess CDK12 status. Descriptive statistics included PSA50 response rate (≥ 50% decline in prostate-specific antigen from baseline) and clinical/radiographic progression-free survival (PFS). RESULTS Of 52 patients with CDK12-mutated prostate cancer, 27 (52%) had detected biallelic CDK12 alterations. At diagnosis, 44 (88%) had Gleason grade group 4-5, 52% had T3-T4, and 14 (27%) had M1 disease. Median follow-up was 8.2 years (95% CI, 5.6 to 11.1 years), and 49 (94%) developed metastatic disease. Median overall survival from metastasis was 3.9 years (95% CI, 3.2 to 8.1 years). Unconfirmed PSA50 response rates to abiraterone and enzalutamide in the first-line castration-resistant prostate cancer setting were 11 of 17 (65%) and 9 of 12 (75%), respectively. Median PFS on first-line abiraterone and enzalutamide was short, at 8.2 months (95% CI, 6.6 to 12.6 months) and 10.6 months (95% CI, 10.2 months to not reached), respectively. Nineteen patients received CPI therapy. PSA50 responses to CPI were noted in 11%, and PFS was short; however, the estimated 9-month PFS was 23%. PFS was higher in chemotherapy-naïve versus chemotherapy-pretreated patients (median PFS: not reached v 2.1 months, P = .004). CONCLUSION CDK12 mutations define an aggressive prostate cancer subgroup, with a high rate of metastases and short overall survival. CPI may be effective in a minority of these patients, and exploratory analysis supports using anti–programmed cell death protein 1 drugs early. Prospective studies testing CPI in this subset of patients with prostate cancer are warranted.

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