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  • American Society of Clinical Oncology (ASCO)  (7)
  • 1
    Online Resource
    Online Resource
    Development and Validation of a Genomic Tool to Predict Seminal Vesicle Invasion in Adenocarcinoma of the Prostate
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  JCO Precision Oncology , No. 4 ( 2020-11), p. 1228-1238
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 4 ( 2020-11), p. 1228-1238
    Abstract: Pretreatment estimates of seminal vesicle invasion (SVI) are challenging and significantly influence the management of prostate cancer. We sought to improve current models to predict SVI through the development of an SVI prediction genomic signature. PATIENTS AND METHODS A total of 15,889 patients who underwent radical prostatectomy (RP) with available baseline clinical, pathology, and transcriptome data were retrieved from the GRID registry (ClinicalTrials.gov identifier: NCT02609269 ) and other retrospective cohorts. These data were divided into a training (n = 6,766), test (n = 3,363), and two validation (n = 5,062 and 698) cohorts. Multivariable logistic regression was performed to assess the predictive effect of the genomic SVI (gSVI) classifier in the presence of established nomograms (Partin Tables and Memorial Sloan Kettering Cancer Center [MSKCC]). RESULTS In the training cohort, univariable filtering identified 2,132 genes that were differentially expressed between RP tumors with and without SVI. Model parameters were tuned to maximize the area under the curve (AUC) in the testing cohort, resulting in a logistic generalized linear model with 581 genes. The gSVI model scores range from 0 to 1. In the first validation set, gSVI showed superior discrimination of patients with and without SVI at RP compared with other prognostic signatures trained to predict distant metastasis or clinical recurrence. Of the 698 patients in the second validation set, gSVI combined with the MSKCC nomogram had a superior AUC (0.86) compared with either nomogram individually (0.81). CONCLUSION The gSVI represents a novel and validated expression signature to predict the presence of SVI before treatment with surgery. This genomic tool adds discriminatory power to existing clinical predictive nomograms and may help with pretreatment counseling and decision making.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.20.00013
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 2
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    Online Resource
    Genomic characterization of ductal adenocarcinoma of the prostate.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 15_suppl ( 2018-05-20), p. 5030-5030
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 15_suppl ( 2018-05-20), p. 5030-5030
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.15_suppl.5030
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 3
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    Online Resource
    Genomic Characterization of Prostatic Ductal Adenocarcinoma Identifies a High Prevalence of DNA Repair Gene Mutations
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  JCO Precision Oncology , No. 3 ( 2019-12), p. 1-9
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 3 ( 2019-12), p. 1-9
    Abstract: Ductal prostate cancer (dPC) is a rare variant of prostatic adenocarcinoma associated with poor outcomes. Although its histopathologic features are well characterized, the underlying molecular hallmarks of this aggressive subtype are not well described. We sought to provide a comprehensive overview of the spectrum of mutations associated with dPC. METHODS Three case series across multiple institutions were assembled. All patients had a diagnosis of dPC, and histopathologic classification was confirmed by an expert genitourinary pathologist. Case series 1 included men who were prospectively enrolled in a tumor sequencing study at the University of Washington (n = 22). Case series 2 and 3 included archival samples from men treated at Johns Hopkins Hospital (n = 21) and University of Calgary (n = 8), respectively. Tumor tissue was sequenced on a targeted next-generation sequencing assay, UW-OncoPlex, according to previously published methods. The frequency of pathogenic/likely pathogenic mutations are reported. RESULTS Overall, 25 patients (49%) had at least one DNA damage repair gene alteration, including seven (14%) with a mismatch repair gene mutation and 16 (31%) with a homologous repair mutation. Germline autosomal dominant mutations were confirmed or suspected in 10 patients (20%). Activating mutations in the PI3K pathway (n = 19; 37%), WNT pathway (n = 16; 31%), and MAPK pathway (n = 8; 16%) were common. CONCLUSION This study strongly suggests that dPCs are enriched for actionable mutations, with approximately 50% of patients demonstrating DNA damage repair pathway alteration(s). Patients with dPC should be offered next-generation sequencing to guide standard-of-care treatment (eg, immune checkpoint inhibitors) or triaged toward an appropriate clinical trial (eg, poly [ADP-ribose] polymerase inhibitors).
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.18.00327
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
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  • 4
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    Validation of a genomic classifier to predict adverse pathology in men diagnosed with low risk prostate cancer.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 6_suppl ( 2018-02-20), p. 71-71
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 6_suppl ( 2018-02-20), p. 71-71
    Abstract: 71 Background: The Decipher 22-feature genomic classifier (GC) has been validated to predict metastasis and prostate cancer specific mortality in needle biopsy (Bx) tissue of men with intermediate and high-risk prostate cancer. We validate GC in diagnostic Bx specimens for the prediction of high-grade/stage (HGS) disease at radical prostatectomy (RP) in men with low and favorable-intermediate (fav-int) NCCN risk group disease. Methods: We identified 176 men diagnosed with low or fav-int NCCN risk group disease who had available Bx GC scores and pathological information after RP from Cedars-Sinai, University of Calgary, Cleveland Clinic, MD Anderson, and Johns Hopkins. The GC score was calculated based on a locked random forest model. Scores range from 0-1 with cut points for GC low, intermediate and high risk groups as 〈 0.45, 0.45-0.6, and 〉 0.6, respectively. The primary endpoint was HGS (Gleason group 3-5 or pT3b or lymph node invasion (LNI)). Univariable (UVA) and multivariable (MVA) logistic regression models were used to evaluate GC and CAPRA. Results: Median age of the cohort was 62 years, 87% and 13% had Bx grade group (GG) 1 or 2 disease. 76% and 24% were NCCN low and fav-int risk, respectively. CAPRA classified 70% as low (0-2) and 30% as average risk (3-5). GC classified 80% low, 16% intermediate and 4% high genomic risk. After RP, 41% had RP GG 1, 46% GG 2 and 13% had GG 3-5 disease. pT3b or positive lymph nodes were observed in 7 men (4%), overall 27 (15%) of men had HGS at RP. In the UVA and MVA, GC was the only significant predictor of HGS with odds ratio (OR) of 1.38 and 1.34 per 10% unit increase, before and after adjusting for CAPRA (p=0.011, 0.027). A low risk score (GC 〈 0.45) had a negative predictive value (NPV) of 92% to identify men who do not have HGS at RP. In exploratory analysis, a very low risk cut-point (GC 〈 0.2) was found which had a sensitivity of 96% and an NPV of 99%. 26% of men had GC 〈 0.2. Conclusions: We validated GC in a multi-institutional study to predict HGS at RP among men with NCCN low and fav-int risk disease with high sensitivity and NPV. Future studies will aim to validate the very low risk genomic cut-point to guide decision-making and follow-up biopsy protocols for men considering or in active surveillance.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.6_suppl.71
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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  • 5
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    Prognostic biomarkers and clinical outcomes in neuroendocrine prostate cancer (NEPC).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 6_suppl ( 2023-02-20), p. 209-209
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 209-209
    Abstract: 209 Background: NEPC includes both pure small cell carcinoma and mixed tumors with varying degrees of adenocarcinoma and neuroendocrine histology. It arises de novo or is treatment associated (TA) post androgen deprivation therapy. Clinical outcome data and prognostic biomarkers are limited and were thus explored. Methods: Patients with high grade prostate cancer and morphologic and/or immunohistochemical (IHC) NEPC features were included in this retrospective multicentre study. Clinical stage, Gleason score, and serum biomarkers were recorded. Kaplan-Meier method and log-rank test calculated and compared overall survival (OS) from time of NEPC diagnosis.Cox proportional hazards regression assessed prognostic impact of serum biomarkers at diagnosis and de novo vs TA status, adjusting for clinical stage and castration resistance. Results: 135 NEPC cases were identified. 124 (92%) were mixed tumors. 56 (41%) arose de novo. 79 (59%) were TA. 77% of those with a Gleason score (N=85/110) were grade group 5. Median PSA pre-NEPC biopsy was 11.6 ng/mL. At NEPC diagnosis, 19 (14%) had localized disease (median OS 123.0 mo); 33 (24%) non-metastatic castrate-sensitive disease (median OS 42.3 mo); 6 (4%) non-metastatic castrate-resistant disease (median OS 14.3 mo); 35 (26%) metastatic castrate-sensitive disease (median OS 17.6 mo); and 42 (31%) metastatic castrate-resistant disease (median OS 9.6 mo). Median OS for those with visceral metastases was 8.6 mo (95% CI 6.0 – 14.6), compared to patients with non-visceral metastases (11.1 mo; 95% CI 13.7 – 21.5) and no metastases (42.3 mo; 95% CI 47 – 89). Anemia (adjusted HR 1.66; 95% CI 1.05 - 2.16, p = 0.031) and NLR 〉 3 (adjusted HR 1.51; 95% CI 1.01 - 2.52, p = 0.045) were associated with increased risk of death. De novo disease, elevated LDH, serum PSA, and Gleason score were not prognostic. Conclusions: This study identifies NEPC clinical outcomes by stage, with survival poorer than expected in pure prostate adenocarcinoma. Anemia and elevated NLR 〉 3 are prognostic biomarkers that may help risk stratify and guide treatment intensification, including platinum-based chemotherapy. Further biomarker characterization of NEPC through IHC-staining pattern and genomic analysis is currently underway by this group.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.6_suppl.209
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 6
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    Analysis of the role of PI3K-AKT and DNA damage repair (DDR) genomic biomarkers as predictors of clinical outcomes in nonmetastatic castration-resistant prostate cancer (nmCRPC).
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. 175-175
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 175-175
    Abstract: 175 Background: Clinically relevant outcomes in nmCRPC treated with androgen receptor-axis-targeted therapies (ARAT) may be inferior in patients with tumors harboring mutations bypassing androgen receptor signalling. This final update of a retrospective, multicenter analysis explores the association between genomic mutations in the PI3K-AKT and DDR signalling pathways with ARAT treatment outcomes in nmCRPC patients. Methods: Relevant clinical endpoint were collected for high-risk nmCRPC patients treated with an ARAT at APCaRI affiliated cancer centers, including median metastasis-free survival (MFS), overall survival (OS), PSA decline ≥ 50% (PSA50), and second progression free survival (PFS2). Archival tumor tissue was accessed for next generation gene sequencing, examining for genomic alterations in 500 genes, including those involved in the DDR and the PI3K-AKT signalling pathways. Comparison of outcomes of patients with DDR and PI3K-AKT pathway mutations was conducted using Cox proportional hazards regression using wildtype cases as the reference group, adjusting for PSA doubling time and pelvic lymphadenopathy. Results: Of the 37 patients included, 30 (82%) received apalutamide, 5 (13%) received darolutamide, and 2 (6%) received enzalutamide. 10 patients (27%) had PI3K-AKT pathway mutations (4 PTEN, 3 PIK3Ca, 2 PIK3C2G, 1 PIK3C2b), 8 patients (22%) had DDR gene mutations (3 ATM, 2 CHEK1, 1 BRCA2, 1 CDK12, 1 CHEK2, 1 FANCD2, 1 FANCL), and 1 patient (3%) had 2 MLH1 mutations (microsatellite instability). Of those who had subsequent treatment, 1 received enzalutamide and 5 received abiraterone. Patients with PI3K-AKT pathway mutations had significantly shorter MFS (4.8 mo; HR 4.2; 95% CI 1.2 – 15.0; p = 0.025). Those with DDR mutations had a trend towards shorter MFS (23.3 mo HR 3.7; 95% CI 0.71 – 13.4; p = 0.134). OS data remains immature. 4 (11%) patients did not achieve PSA50, including a patient with 2 MLH1 mutations. Conclusions: This final analysis demonstrates that nmCRPC with PI3K and DDR signalling pathway mutations have poor clinical outcomes when treated with ARAT, likely secondary to decreased reliance on the androgen receptor signalling pathway. These results highlight the potential value of exploring targeted therapies, such as PARP or AKT inhibitors in patients with these mutations.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2022.40.6_suppl.175
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 7
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    Evaluating the use of circulating tumor DNA (ctDNA) in patients with urothelial cancer in the context of FGFR-targeted therapy.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 4577-4577
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4577-4577
    Abstract: 4577 Background: Fibroblast growth factor receptor (FGFR) inhibitors (e.g., erdafitinib) are increasingly important in the management of FGFR-mutated urothelial carcinoma. FDA-approved archival tissue testing for specific FGFR alterations was implemented as a companion diagnostic for erdafitinib. However, longitudinal sequencing studies indicate variable tumor FGFR status over time, and erdafitinib resistance mechanisms in metastatic urothelial carcinoma (mUC) are underreported. This ongoing study aims to evaluate the accuracy of cell-free DNA (cfDNA) compared to archival tissue testing in mUC for FGFR alterations detection, and to evaluate genomic mechanisms of erdafitinib resistance in cfDNA at progression. Methods: Patients with progressing mUC who were undergoing archival tissue testing for FGFR1-3 mutations and/or fusions and who had blood samples drawn during the management of their metastatic disease were eligible. Plasma cfDNA and matched leukocyte DNA were subjected to deep targeted sequencing with a custom panel including UC-specific gene loci and all clinically approved hotspots in FGFR1+2 and all exons and introns of FGFR3. Results: As of January 2023, 109 patients from 6 sites were enrolled. Median age at diagnosis was 71, 33% had upper urinary tract primaries, and 76% were male. Tissue and cfDNA results for comparison were available for 69 patients to date. Actionable somatic FGFR alterations were found in the tissue of 15 patients (31%); the most common alteration was the FGFR3 p.S249C mutation (67%). 50 of the analyzed cfDNA samples had detectable somatic circulating tumor DNA (ctDNA) variant allele fraction of 0.5% (72%). Of those, 49 had an evaluable tissue test result. Analysis of this subset revealed high concordance (92%) between the two test methods. With the assumption that archival tissue testing is considered the ‘gold standard’, sensitivity is 93% and specificity is 91%. The four discordant results comprised one cfDNA test with undetectable FGFR3-TACC3 fusion, which was detected in tissue and three positive ctDNA test results in patients with FGFR wild-type tissue tests. In one case at erdafitinib progression, ctDNA revealed multiple subclonal populations with distinct FGFR3 gatekeeper mutations suggesting polyclonal resistance. Conclusions: This ongoing study suggests cfDNA is a valuable minimally invasive adjunct to tissue-based assays for the detection of FGFR alterations to identify patients for FGFR inhibitor therapy and to monitor for mechanisms of resistance.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.4577
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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