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  • 1
    In: Cancer Communications, Wiley
    Type of Medium: Online Resource
    ISSN: 2523-3548 , 2523-3548
    Language: English
    Publisher: Wiley
    Publication Date: 2023
    detail.hit.zdb_id: 2922913-3
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  • 2
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 241-241
    Abstract: 241 Background: We previously reported on the use of gene expression profiling to characterize four primary subtypes in an analysis of over 100,000 prostate cancer primary tumors. Here we examine these subtypes and response to radiation (RT) after prostatectomy or chemotherapy in addition to androgen deprivation therapy (ADT) in hormone-sensitive metastatic prostate cancer (mHSPC). Methods: We examined a 215-gene prostate subtyping classifier (PSC) which groups luminal and basal gene expression profiles into one of four subtypes; luminal differentiated (LD), luminal proliferating (LP), basal immune (BI) and basal neuroendocrine-like (BN). The log-rank method was used to compare (i) metastasis-free survival between patients who did and did not receive salvage RT in the META855 cohort of localized disease patients treated with radical prostatectomy (n=855) and the (ii) overall survival of patients on the Phase III mHSPC EA3805 CHAARTED trial of ADT or ADT + docetaxel chemotherapy (n=160). Results: After radical prostatectomy, patients with BI tumors derived benefit from RT in terms of metastasis-free survival ( P=9.23e-4) while those with other subtype tumors did not (Each Log-rank P≥0.5). Patients with metastatic disease and LP tumors derived benefit from docetaxel (Log-rank P=0.002) while those with other subtypes tumors did not (Log-rank P=0.2). Conclusions: Basal-luminal subtyping segments tumors by relevant biological processes with potential implications for identifying patients who benefit from salvage radiation post prostatectomy and addition of docetaxel to ADT in mHSPC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 3
    In: Journal of Urology, Ovid Technologies (Wolters Kluwer Health), Vol. 209, No. 2 ( 2023-02), p. 362-363
    Type of Medium: Online Resource
    ISSN: 0022-5347 , 1527-3792
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    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2023
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 273-273
    Abstract: 273 Background: The Decipher 22-gene genomic classifier (GC) has been shown to predict for metastasis and survival in predominantly Caucasian and African-American men from Western cohorts. There is however little data on the clinical utility of GC in Asian prostate cancer (PCa). We investigated if GC prognosticates for metastasis-free survival (MFS) in an Asian cohort of localized PCa. Additionally, we performed comparative genomic analyses between our Asian patients and non-Asian cases from a large Decipher GRID database (Veracyte, San Francisco, CA). Methods: We used a cohort of PCa patients who were treated at a single institution from East Asia between 2006 to 2021. Patients underwent active surveillance or radical prostatectomy (RadP) and/or radiotherapy (RT) +/- hormonal therapy (HT). The GC assay (Decipher Biosciences, CA) was performed on diagnostic biopsies, following central review of the Gleason’s grade (GG) and tumor cellularity by an expert GU pathologist. MFS was the primary endpoint for survival analysis. Comparative analyses of 273 gene-signatures were performed against the full and a propensity-score matched (PSM) cohort identified from the Decipher GRID database. Adjusted p-values from Wilcoxon tests were used to select from these signatures. Results: We profiled 126 unique patient tumors, comprising of 19 (15.1%) NCCN-defined low-/favorable intermediate-, 22 (17.5%) unfavorable intermediate-, 34 (27.0%) high-, and 51 (40.5%) very high-risk groups. 24 (19.0%) patients had RadP as primary treatment, 98 (77.8%) had RT +/- HT, while 4 (3.2%) underwent active surveillance or HT alone. Using the GC, 70 (55.6%), and 56 (44.4%) were stratified as low/intermediate- (≤0.6) and high-risk ( 〉 0.6), respectively. GC high-risk was significantly associated with an inferior MFS than GC low/intermediate-risk ( HR 5.22 [95% CI:1.08–25.3], P = 0.04). Comparison between our Asian and the full unmatched GRID cohort (N = 80,703) revealed a lower proportion of ERG+ PCa (14% vs 41%, P 〈 0.001) and a higher proportion of PAM50 basal subtypes (41% vs 30%, P 〈 0.001), as well as a lower T-cell exclusion (median 0.080 vs 0.097; P 〈 0.001) and angiogenesis (-0.37 vs -0.08; P 〈 0.001) signature scores. These trends were also observed when comparing with the PSM-subset (N = 630; 5:1 ratio for NCCN, GG, age at diagnosis, and assay quality score). Interestingly, both high angiogenesis and T-cell exclusion signatures were associated with a worse MFS ( HR not available due to no events for low angiogenesis, P = 0.0015 by log-rank test; HR 5.12 [1.03–26.5], P = 0.046, respectively). Conclusions: We validated the Decipher 22-gene GC for prognostication of MFS in a predominantly high-risk PCa cohort. We also identified several gene expression signatures that were significantly different between Asian PCa and other cohorts. These observations may have implications for customizing treatment recommendations to an Asian popula tion.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 5
    Online Resource
    Online Resource
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 6_suppl ( 2022-02-20), p. 383-383
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 383-383
    Abstract: 383 Background: The ability to risk stratify patient’s post-nephrectomy is critical to select candidates for surveillance and adjuvant therapy. Whether transcriptomic information adds value to current prognostic information is unclear. Methods: Data from confirmed clear cell renal cell carcinoma (ccRCC) used in the TCGA Pan-RCC analysis was downloaded from cBioportal and GDC bioportal. Clinicopathologic variables were used to calculate the integrated staging system, SSIGN (stage, size, grade, and necrosis). The 16 gene recurrence score (RS) signature was generated as described in Rini 2015 using the TCGA data with log TPM normalization. The RS was stratified into high and low risk groups by median. SSIGN was divided into low (0-1) intermediate (2-4) and high ( 〉 = 5) risk groups. RS and SSIGN prognostic significance were evaluated using disease recurrence as an end point, censoring by death. Results: SSIGN and recurrence scores (RS) were calculated for 369 (71.2%) of 518 available TCGA subjects with non-metastatic clear cell renal carcinoma. On multivariable analysis, the RS (continuous variable) was independently associated with disease-free status (HR 1.18 [95%CI (1.02-1.37)], p = 0.031) for each 10 point increase in RS) after adjusting for SSIGN. Categorizing SSIGN into low, intermediate and high-risk groups showed 3.9%, 18.5% and 39.8% 3-year recurrence rates. Stratifying SSIGN risk groups by RS scores we found an RS to further risk stratify the SSIGN intermediate risk group (HR 1.60 [95%CI 1.21-2.12] , p 〈 0.001]). The AUC for at 3 years for SSIGN in the intermediate risk group was 0.68, for RS was 0.74 and the combination was 0.78 (with boot-strapping for optimism adjustment). At 3 years, patients with SSIGN intermediate risk disease (n = 135) with low RS had 3-year recurrence rate of 7.1% compared to 31.0% for those with high RS scores. Conclusions: Transcriptomic recurrence scores can risk stratify intermediate SSIGN clinical risk patients. Patients with intermediate risk disease but a high RS score had poorer outcomes similar to clinically high risk patients. Transcriptomic signatures may add value to existing clinicopathologic variables in ccRCC and clinical implementation is warranted.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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  • 6
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. e17083-e17083
    Abstract: e17083 Background: Metastatic castration-sensitive prostate cancer (mCSPC) is commonly partitioned into high- and low-volume subgroups which have demonstrated differential biology, prognosis, and response to therapy. Timing of metastasis has similarly demonstrated differences in clinical outcomes, however less is known about any potential underlying biologic differences between these disease states. Herein we aim to compare transcriptomic differences between synchronous and metachronous mCSPC and identify any differential responses to therapy. Methods: We performed an international multi-institutional retrospective review of men with mCSPC who completed RNA expression profiling evaluation of their primary tumor. Patients were stratified according to disease timing (synchronous vs metachronous). The primary endpoint was to identify differences in transcriptomic profiles between disease time. Median genomic scores between groups were compared with Mann-Whitney U test. Secondary analyses included determining clinical and transcriptomic variables associated with overall survival (OS) from time of metastasis. Survival analysis was performed with the Kaplan-Meier Method and Multivariable Cox regression. Results: 252 patients were included with a median follow-up of 39.6 months. Patients with synchronous disease experienced worse 5-yr OS (39% vs 79%, p 〈 0.01) and demonstrated lower median Androgen Receptor Activity (AR-A) (11.78 vs 12.64, p 〈 0.01) and Hallmark Androgen Response (HAR) (3.15 vs 3.32; p 〈 0.01). Multivariable cox-regression identified only high-volume disease (HR=4.97, 95%CI 2.71-9.10; p 〈 0.01) and HAR score (HR=0.51, 95%CI 0.28-0.88; p=0.02 significantly associated with OS. Finally, patients with synchronous (HR=0.47, 95%CI 0.30-0.72; 〈 0.01) but not metachronous (HR=1.37, 95%CI 0.50-3.92; p=0.56) disease were found to have better OS with Androgen Receptor (AR) + non-AR combination therapy as compared to monotherapy (p value for interaction = 0.05). Conclusions: We have demonstrated a potential biologic difference between metastatic timing of mCSPC. Specifically, for patients with low volume disease, those with metachronous low volume disease have a more hormone dependent transcriptional profile and exhibit a better prognosis than synchronous low volume disease. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 7
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 371-371
    Abstract: 371 Background: SBRT is a treatment option for men with prostate cancer. PREPARE-SBRT (NCT03663218) is a clinical trial testing the safety of neoadjuvant MRI-guided SBRT for men with high-risk localized prostate cancer. We leveraged paired samples from pre-treatment biopsy (Bx) and irradiated prostatectomy (RP) specimens to evaluate immune-related transcriptomic changes in irradiated tumors at acute timepoints following neoadjuvant SBRT. Methods: Transcriptomic profiles were generated using Decipher GRID (Veracyte, Inc). Differences in transcriptional signatures were assessed between Bx samples taken before treatment and RP samples post-treatment using a paired T-Test. A control cohort of transcriptomic profiles of 803 untreated Bx samples and matching RP samples from the same patients were used to account for differential effects in tissue preservation between Bx and RP. Linear regression model with the interaction effect of cohort (SBRT vs control) and by treatment status (Bx vs RP) to select signatures significantly impacted by neoadjuvant SBRT. Signatures with interaction p-value 〈 0.01 and paired T-test value 〈 0.05 were considered statistically significant. Results: 10 patients with paired pre-treatment Bx and post-SBRT RP specimens (n=20 samples) were analyzed with a median interval from completion of SBRT to RP of 5 days. Neoadjuvant SBRT was associated with upregulation of the T-cell inflamed signature (p=0.028) and immune190 signature (p=0.0031) supported by enrichment of transcriptomic features associated with IFN-gamma response (p=0.022), TCR signaling (p=0.0052) and antigen presentation (p=0.0048). Increased gene expression associated with effector memory/activated CD4 T-cells (p=0.0005 and p=0.0013, respectively) and effector memory/activated CD8 T-cells (p=0.0015 and p=0.013, respectively) were paralleled by a significant reduction in immunosuppressive regulatory T-cell (Treg; p=0.0015) and myeloid derived suppressor cell (MDSC; p=0.005) signatures. Additionally, macrophage-specific signatures were significantly enriched among SBRT-irradiated samples including CD68 and CSF1 gene clusters (both p=0.0041) as well as a decreased expression of the M2-to-M1 ratio signature (p=0.0052). Interestingly, WNT/β-catenin signaling, a putative oncogenic mediator of immune exclusion, was significantly downregulated in irradiated RP samples relative to pre-treatment Bx (p=2.6x10 -5 ). Conclusions: Neoadjuvant SBRT was associated with significant immune remodeling of the irradiated prostate microenvironment. Collectively, immune-related transcriptional signatures skewed towards immune activation, increased effector T-cell and macrophage signatures and a reduction in immunosuppressive transcriptomic features.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 8
    In: JCO Global Oncology, American Society of Clinical Oncology (ASCO), Vol. 9, No. Supplement_1 ( 2023-08), p. 75-75
    Abstract: 75 Background: Aberrations of the DDR pathway have been shown to be prognostic of survival and predictive of PARP inhibition in PCa. We have previously reported on the prevalence of germline DDR mutations based on a 32-gene set in localized PCa in EA men, and observed comparable rates with that of White men. Here, we performed additional analyses investigating for associations between DDR variants to the somatic transcriptome of localized PCa. Methods: We utilized a prospectively recruited cohort of 172 EA patients, with centrally assessed Gleason’s score (GS) by an expert pathologist. Germline profiling was performed by whole exome sequencing (100X) using the Illumina Novaseq (CA). Joint genotyping was performed to annotate variants that were deemed to be pathogenic (P)/likely pathogenic (LP)/conflict of interest pathogenic (CIP) based on the CADD and REVEL scores. Tumor transcriptome was profiled using the Decipher Genomic Classifier (GC, Veracyte, CA) based on the Affymetrix ST array (ThermoFisher, CA). Results: Among the subset of 172 EA men, we observed DDR variants in 26 (15%) patients, which was comparable to the larger cohort of 890 men from the same institution. Among the DDR mutations, 2 (7.7%) were classified as P/LP, while 24 (92.3%) were CIP. Decipher GC scores were comparable between patients with and without DDR mutations (median GC score 0.87 vs 0.53, Mann-Whitney U P=0.10). For luminal-basal subtyping by either the PAM50 and Prostate specific subtyping models, we did not observe a difference for the basal (P=0.48) and luminal subtypes (P=0.21). Interestingly, DNA repair gene-set expression were comparable between patients with DDR mutations versus those without (median score -0.2 vs -0.17). However, we observed microenvironment differences for immune-related genes, where patients harboring DDR mutations manifested a less immune-suppressive environment versus those without (PDL2: -0.15 vs 0.2; Treg: 0.09 vs 0.13; MDSC: 0.03 vs 0.07, respectively). Conclusions: Herein, we report an extension of our previous work (Lua, et al. ASCO GU, 2023), where we show potential linkages between the germline DDR variant status and the tumor transcriptome. Our findings suggest the influence of germline DDR variants that extends beyond tumorigenesis.
    Type of Medium: Online Resource
    ISSN: 2687-8941
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 3018917-2
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  • 9
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 375-375
    Abstract: 375 Background: Pre-Prostatectomy MRI-Guided Stereotactic Body Radiotherapy for High-Risk Prostate Cancer Trial (PREPARE SBRT; NCT03663218) is an ongoing clinical trial testing the safety of preoperative MRI-guided SBRT for men with clinically localized high-risk prostate cancer. We sought to compare transcriptomic profiles of biopsy (Bx) specimens to acutely irradiated radical prostatectomy (RP) specimens. Methods: Biopsy and post-irradiated RP specimens from 10 subjects were examined. The median interval between the end of RT and the date of RP was 5 days. Transcriptomic profiles were generated using Decipher GRID (Veracyte, Inc). Differences in transcriptional signatures were assessed between Bx samples taken before irradiation and RP samples post-irradiation using a paired T-Test. A control cohort of transcriptomic profiles of 803 untreated Bx samples and matching RP samples from the same patients were used to account for effects in tissue preservation from the procedure different of Bx vs RP. Linear regression model with the interaction effect of cohort (SBRT vs control) by procedure (Bx vs RP) to select signatures impacted by radiation treatment. Results: Transcriptomic signatures associated with Androgen Receptor (AR) activity were significantly downregulated (p=0.002) in irradiated RP specimens compared with pre-treatment biopsies. Analysis of DNA damage repair (DDR) pathways demonstrated that nucleotide excision repair (NER) and non-homologous end joining (NHEJ) signatures were increased (p=0.002 and p=0.02, respectively) after pre-operative RT whereas homologous recombination (p=0.06) and mismatch repair (p=0.08) were not significantly different between pre-treatment and irradiated tissues. Several metabolic-associated pathways were impacted by pre-operative RT including increased glycogen metabolism (p=0.008) and a NADH-NADPH conversion (p=0.001) signature indicative of RT-induced oxidative damage. Consistent upregulation of transcriptomic features associated with increased angiogenesis (p=0.0012) and stromal remodeling (p=0.0008) was observed in irradiated samples. Conclusions: Paired transcriptomic analysis following pre-operative RT demonstrated differential upregulation of specific DDR pathways including NHEJ and NER and metabolic alterations related to oxidative stress and glycogen metabolism. AR activity signatures were decreased in response to pre-operative RT.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
    detail.hit.zdb_id: 2005181-5
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  • 10
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 6_suppl ( 2022-02-20), p. 267-267
    Abstract: 267 Background: We previously reported the results of a Phase 2 study showing that a high proportion (59%) of men with PC being followed on AS will have a negative post-treatment biopsy after 90 days of apalutamide (Schweizer, et al. SUO Annual Meeting 2020). In order to identify candidate biomarkers for response, we conducted transcriptional profiling of tumor tissue obtained from men enrolled to the aforementioned trial. Methods: We analyzed FFPE tissue obtained from men enrolled to a Phase II study testing 90-days of apalutamide. Transcript profiles were assessed using Affymetrix Microarrays (Decipher Biosciences, Inc). Differences in signaling pathways were assessed between samples at baseline, day (D) 91 (post-treatment) and at D365. We also assessed differences in signaling pathways between patients that did vs. did not have a response (i.e. negative vs. persistent cancer on surveillance biopsy) at D91, which was the primary endpoint of the study. All comparisons were made using a Wilcoxon signed rank test unless otherwise indicated. Results: Samples from 22 subjects who completed 3-months of apalutamide and subsequently underwent post-treatment biopsy were available for analysis. From 19 Baseline and 15 post-treatment tissue samples, 25 passed pathology quality control (N = 12 at baseline, N = 8 at D91 and N = 5 at D365). Principal component analysis revealed distinct transcriptional profiles between tumor samples analyzed at baseline vs. D91. Surprisingly, D365 specimens still demonstrated a distinct profile compared to both baseline and D91 samples. Pathway analysis revealed up-regulation of angiogenesis signaling at D91 (P 〈 0.01) and D365 (P = 0.03) compared to baseline. As expected, estrogen (P 〈 0.01) and androgen receptor (P = 0.02) signaling were significantly lower at D91; however, only estrogen signaling was persistently suppressed at D365 (P = 0.03). Basal pathway signatures and markers associated with inflammatory response were also significantly upregulated at D91. There were no significant differences in Gleason grade group (GG) between responders and non-responders: 8/15 (53%) with GG1 vs. 5/7 (71%) with GG2 (Fisher’s exact P = 0.648). Decipher (P = 0.01) and Cuzick (P = 0.03) risk classifiers revealed an enrichment for responses in those with higher risk disease at baseline. There was also an enrichment for responses in those with higher nucleotide excision repair signature (P = 0.03) and those with signatures associated with TP53 mutations (P = 0.02). Conclusions: We observed significant transcriptional changes following 90 days of apalutamide, with evidence of persistent differences up to one year after enrollment. Higher baseline risk score was associated with improved responses to apalutamide treatment. Prospective studies evaluating the benefit of apalutamide in men on AS with higher risk transcriptional profiles are warranted. Clinical trial information: NCT02721979.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2022
    detail.hit.zdb_id: 2005181-5
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