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  • 1
    Online Resource
    Online Resource
    Molecular profiling of aggressive variant urothelial carcinoma.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 7_suppl ( 2019-03-01), p. 378-378
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 7_suppl ( 2019-03-01), p. 378-378
    Abstract: 378 Background: The WHO recognizes multiple variant histologies of urothelial carcinoma (vUC), many of which have been associated with poor outcomes compared with urothelial carcinoma (UC). We aimed to explore molecular differences between aggressive vUC and UC. Methods: 23 micropapillary (MP), 16 plasmacytoid (P), 23 sarcomatoid (S), 7 nested (N), 6 clear cell (CC), and 2 giant cell (GC) vUC specimens were tested between 2012 to 2018 via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing (next generation sequencing [NGS]), gene amplification (CISH or NGS), and protein expression (immunohistochemistry [IHC] ). Findings were compared to 435 control UC specimens using the Chi-square test. Results: 84% of samples were from primary tumor. Alterations identified are summarized in Table 1, and are notable for high rates of TP53 mutations across histologic subtypes, varying rates of RB1, ERBB2 and FGFR mutations, and overall low rates of DNA damage repair (DDR) mutations (29 genes reported) except in S. There were more ARID1A mutations detected in MP than UC (100% [3 specimens] v. 41.3%, p=0.044), and more CDH1 mutations in P than UC (50% [4 specimens] v. 2%, p 〈 0.001). CISH ERBB2 (HER2) amplification was seen in 27.3% MP compared with only 10.4% in UC (p=0.005). Compared to UC, PD-L1 IHC (SP142 assay) was positive ( 〉 5%) in a high proportion of S (55.6%, p=0.002) but in a lower proportion of other vUC (e.g. absent in P). Tumor mutational burden (TMB) was high in a lower proportion of vUC: 18.4% UC vs. 14.3% MP, 0% P, 16.7% S. Conclusions: Aggressive variant histology UCs have a differential profile of molecular aberrations compared to UC, with notable differences in potential targets such as HER2 and DDR genes as well as immunotherapy biomarkers. Further studies are needed to confirm these findings, and may support therapy development for these rare, aggressive UC subtypes. Aberrations (%) in Variant Histology UC. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.7_suppl.378
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 2
    Online Resource
    Online Resource
    Molecular profiles of small cell bladder and prostate cancer and comparisons with small cell lung cancer.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 6_suppl ( 2018-02-20), p. 264-264
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 6_suppl ( 2018-02-20), p. 264-264
    Abstract: 264 Background: Small cell bladder cancer (SCBC) and small cell prostate cancer (SCPC) are rare and aggressive cancers. Standard therapy remains a platinum agent combined with etoposide, with few options after recurrence. Advances in molecular genomics and drug development have altered our approach to cancer. These same novel approaches may alter how we approach SCBC and SCPC. The purpose of this study is to identify potential targets and compare molecular profiles of SCBC and SCPC to SCLC. Methods: In total, 21 SCBC and 19 SCPC were identified from a de-identified database (Caris Life Sciences). Specimens were evaluated for genetic aberrations (Sanger or next generation sequencing [NGS], ISH) and/or protein expression (immunohistochemistry [IHC] ). Comparisons were made against a de-identified cohort of SCLC (n = 428). Results: Pathogenic/presumed pathogenic mutations in SCBC were found in TP53 (91.7%, 11/12), RB1 (18.2%, 2/11), PTEN (8.3%, 1/12), EGFR (7.7%, 1/13), and PIK3CA (7.1%, 1/14). SCPC genetic aberrations were detected in TP53 (72.7%, 8/11) and RB1 (25.0%, 2/8). No carcinomas in this cohort had a high mutational burden or MSI-high status (0%, 0/7). Amplified genes found in SCBC included DDR2 (50%, 1/2) and EGFR (25.0%, 1/4). In SCPC, gene amplification was found in AKT2 (20%, 1/5), CCNE1 (20%, 1/5), FGFR1 (20%, 1/5), and MYC (20%, 1/5). The highest protein expression rates in SCBC involved MRP1 (100%, 5/5), TOP2A (94.1%, 16/17), and RRM1 (81.3%, 13/16). The highest protein expression rates in SCPC were MRP1 (100%, 6/6), TUBB3 (100%, 9/9), and TOP2A (94.4%, 17/18). Comparisons between SCBC and SCPC with SCLC revealed more similarities than differences. Significant differences were found in RRM1 by IHC between SCBC and SCLC. Also, significant differences were found between SCPC and SCLC in AR and PTEN by IHC. Conclusions: Comparisons of GU small cell carcinomas reveal similarities to SCLC. Both TP53 and RB1 mutations were found in both SCBC and SCPC. Amplification in genes CCNE1 and FGFR1, frequently identified in SCLC, were also found in SCPC. The high protein expression in biomarkers like MRP1 may explain the poor response to cytotoxic chemotherapy. Prospective studies are urgently needed.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.6_suppl.264
    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
    Online Resource
    Online Resource
    Non-urothelial bladder cancer: Genomic alterations and patient outcomes.
    American Society of Clinical Oncology (ASCO) ; 2019
    In:  Journal of Clinical Oncology Vol. 37, No. 7_suppl ( 2019-03-01), p. 399-399
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 37, No. 7_suppl ( 2019-03-01), p. 399-399
    Abstract: 399 Background: Adenocarcinoma (ADA) and squamous cell carcinoma (SCC) are rare, aggressive subtypes of bladder cancer, for which no clear standard of care exists. We report on survival of pts with ADA and SCC and identify potential therapeutic targets using molecular profiling via next generation sequencing (NGS). Methods: Survival trends, demographics, pt characteristics were obtained from the Surveillance, Epidemiology, and End Results (SEER) Database. In a separate cohort, NGS results from 72 specimens (50% metastatic) were also analyzed, using either a hotspot 47 gene panel or a 592 gene assay (Caris Life Sciences, Phoenix, AZ). Results: In SEER, 235,537 cases of bladder cancer were extracted from 1988-2008, of which 3096 were SCC and 671 were ADA. 90% of pts were white, although more African-American patients (15%) were seen in those with ADA. Among all stages, median overall survival (mOS) and 5-yr survival rates were 17.9 mos and 58% for ADA and 15 mos and 37% for SCC. Via NGS testing, 43 patients (28 ADA, 15 SCC) were tested with a 47 gene panel and 29 (21 ADA, 8 SCC) with a 592 gene panel. In the 47 gene panel, among ADA pts, the highest mutation rates were TP53 (57.1%), KRAS (21.4%), SMAD4 (14.8%), PIK3CA (10.7%) and BRCA2 (7.7%). Among SCC pts, the highest mutation rates were TP53 (66.7%), PIK3CA (33.3%), HRAS (14.3%), FBXW7 (6.7%) and AKT1 (6.7%). In the 592 gene assay, the genes with the highest mutation rates in pts with ADA were TP53 (81%), SMAD4 (33.3%), KRAS (23.8%), KMT2C (11.8%), ARID1A (11.1%), BRAF (9.5%), CTNNB1 (9.5%), KMT2D (9.5%), TSC1 (9.5%), KDM6A (5.9%), CDKN2A (5%). Among SCC pts, the highest mutation rates were TP53 (75%), CDKN2A (42.9%), FGFR3 (25%), PIK3CA (25%), CIC (14.3%), KDM6A (14.3%), BRAF (12.5%), BRCA1 (12.5%), FH (12.5%), HRAS (12.5%) and KMT2D (12.5%). Only 1 pt had high TMB. Conclusions: Genomic profiling identifies differences in underlying tumor biology of bladder ADA and SCC, which on a population level are rare with poor survival. Overall, the alterations in the PIK3CA/ AKT/ mTOR and TP53 pathways are similar to what has been reported in UC. Future analyses of these malignancies should investigate the emerging actionable targets, such as TSC1, FGFR3, BRCA1/2 and BRAF.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2019.37.7_suppl.399
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2019
    detail.hit.zdb_id: 2005181-5
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  • 4
    Online Resource
    Online Resource
    Landscape of circulating tumor DNA (ctDNA) abnormalities in advanced prostate cancer (aPCa): Distinctions in African American (AA) versus Caucasian (Ca) patients.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 6_suppl ( 2021-02-20), p. 156-156
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 6_suppl ( 2021-02-20), p. 156-156
    Abstract: 156 Background: AA have substantially higher prostate cancer incidence rates, are diagnosed at a younger age and with a more advanced stage as compared to Ca. However, after adjusting for known prognostic factors, AA have an increased overall survival. We hypothesized that these differences might be due to the underlying changes in the genomic landscape which can be revealed by liquid biopsy. Methods: Real world comprehensive genomic profiling of ctDNA from aPCa patients from two institutions. The first ctDNA results as reported by Guardant 360 panel (Redwood City, CA) were included. Association between genetic mutation and gene were tested using Barnard’s test. To account for multiple testing, we used Benjamini-Hochberg’s False Discovery Rate adjustment across all tests to determine thresholds for false discovery rates. Same analysis was performed using a Bayesian Network Machine learning approach. Results: Overall, 361 patients with aPCa (81 AA and 280 Ca) were included in the analysis. Pathogenic genomic alterations were found in 87.0% of the cases, more frequently TP53 (42.4%), AR (34.1%), PIK3CA (13.9%), BRAF (12.7%), NF1 (10.8%) and MYC (10.0%). Targetable alterations of interest included DNA repair genes [BRCA 2 (7.8%), BRCA 1 (4.4%), ATM (6.4%), CDK12 (2.2%)], PIK3CA/mTOR/AKT (19.1%), PTEN (3.3%) and NTRK (1.9%). MSI-high was found in 4 patients. AA as compared to Ca had a significantly higher prevalence of CDK12 (20.7% vs. 3.8%, p=0.016) and GNA11 mutations (3.7% vs. 0.4%, p=0.0225). BayesNet analysis also supported these results (table). Conclusions: In this dataset, liquid biopsy of ctDNA was useful for genetic characterization of aPCa and reveal differences in the molecular phenotype of AA and Ca in aPCa with potential clinical implications. These findings support ongoing research on the clinical utility of non-invasive genotyping and therapeutic response monitoring with a focus on AA population. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.6_suppl.156
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
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  • 5
    Online Resource
    Online Resource
    Real-world prevalence of homologous recombination repair gene ( BRCA1/2 and ATM ) mutations (HRRm) in patients (pts) with advanced prostate cancer (aPC) as detected by comprehensive genomic profiling (CGP) of circulating cell-free DNA (cfDNA).
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 6_suppl ( 2021-02-20), p. 256-256
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 6_suppl ( 2021-02-20), p. 256-256
    Abstract: 256 Background: PARP inhibitors, olaparib and rucaparib recently improved survival outcomes (in the Profound and Triton-2 trials) in pts with aPC harboring HRRm. Notably, ~35% of pts screened for the PROfound trial did not meet eligibility solely due to the lack of adequate quality/quantity of tumor tissue required for CGP (De Bono, NEJM, 2020). cfDNA analysis non-invasively assesses tumor-derived genomic alterations. We evaluated the prevalence of HRRm in a real-world aPC population, who had commercially available cfDNA assay results available. Methods: cfDNA based CGP (using a clinically-validated 73- to 74-gene panel i.e. Guardant360 or G360) from consecutive aPC pts between 11/2016–8/2020 were used for detection of HRRm. Frameshift and nonsense mutations were included as pathogenic. Variants of unknown significance were excluded. In this unmatched study, the prevalence of each HRRm was compared with those reported in literature using the chi square test. Results: cfDNA CGP from 7701 aPC pts were available for interrogation of BRCA1/BRCA2 mutations, & from 4671 aPC pts for ATM mutations. Prevalence of BRCA1 and 2 as detected by cfDNA was similar to historical CGP of primary tissue. Prevalence of BRCA1 was higher than historical CGP of metastatic tissue. Prevalence of ATM in cfDNA was higher than historic tumor tissue CGP but similar to prior reports from cfDNA testing (Table). Conclusions: In this large real-world population of pts with aPC undergoing routine cfDNA CGP by a CLIA certified lab, prevalence of HRRm was similar (or higher for BRCA1 and ATM) to what has been previously reported from the tumor tissue. These data provide the rationale for utilizing cfDNA CGP as a routine test for detection of HRRm in men with aPC to identify men who are candidates for PARPi. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.6_suppl.256
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
    detail.hit.zdb_id: 2005181-5
    Location Call Number Limitation Availability
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