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  • American Society of Clinical Oncology (ASCO)  (34)
  • 1
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    CDH1 -mutated clinically advanced urothelial bladder cancer (UBC): A genomic landscape and real-world clinical outcome study (RWCOS).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 6_suppl ( 2023-02-20), p. 564-564
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 564-564
    Abstract: 564 Background: CDH1 mutated UBCs are characterized by plasmacytoid histology and are associated with an aggressive clinical course at the time of diagnosis. Methods: Cohort 1: 6,676 clinically advanced UBC patients (pts) underwent comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA), microsatellite instability (MSI), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH, high ≥16%). Predominant genetic ancestry was determined using a SNP-based approach and classified as one of the 5 categories: African (AFR), European (EUR), Central and South American (AMR), South Asian (SAS), or East Asian (EAS). Cohort 2: 586 UBC pts underwent a RWCOS using the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine urothelial clinico-genomic database (FH-FMI CGDB). The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care) Jan 2011-Apr 2022. Differences in real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by Cox proportional hazard models. Results: Cohort 1: 217 (3.3%) of UBC had a CDH1 short variant (SV) mutation with 65.2% featuring plasmacytoid histology. When compared with CDH1 wild-type (WT) UBC, the CDH1-mutated UBC had similar age, gender, and genetic ancestry. The CDH1-mutated UBC featured a higher frequency of MSI (2.7% vs 0.8%; p=.002), mean TMB (14.8 vs 9.9 mut/Mb p 〈 .0001), RB1 GA (52.5% vs 20.3%; p 〈 .0001), PTEN GA (9.2% vs 4.3%; p=.006) and PIK3CA GA (29.5% vs 21.8%; p=.02), but less gLOH high (6.8% vs 15.9%; p=.009), CDKN2A loss (12.4% vs 38.3%; p 〈 .0001), MTAP loss (10.1% vs 25.1%; p 〈 .0001) and FGFR3 GA (9.7% vs 18.1%; p=.002). TP53 GA were similar (62.3% vs 60.3%). Cohort 2: 22 (3.7%) featured CDH1 mutations. Compared with the CDH1 WT pts, the age, gender, ethnicity and ECOG status were similar. Evaluation of the RWCOS showed that CDH1 mutation was associated with less favorable outcomes for 270 UBC pts treated with immune checkpoint inhibitors (ICPI) including rwPFS (2.8 vs 3.5 months; p=.096) and rwOS (3.3 vs 9.5 months; p=.03). Similar comparisons for 316 UBC pts treated with chemotherapy showed no significant adverse impact of CDH1 mutation status on either rwPFS (7.9 vs 6.2 months) and rwOS (13.4 vs 13.4 months). Conclusions: In addition to its classic association with plasmacytoid histology, CDH1-mutated UBC features a unique CGP pattern including higher MSI and TMB status and activating GA in the MTOR pathway while harboring a lower FGFR3 GA frequency. RWCOS further supports that CDH1 mutation predicts resistance to ICPI-based treatments but does not impact responsiveness to chemotherapy. These results further support that CGP has the potential to customize the treatment and improve outcomes for UBC patients based on the determination of their genomic signatures.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.6_suppl.564
    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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  • 2
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    Vulvar Squamous Cell Carcinoma: Comprehensive Genomic Profiling of HPV+ Versus HPV– Forms Reveals Distinct Sets of Potentially Actionable Molecular Targets
    American Society of Clinical Oncology (ASCO) ; 2020
    In:  JCO Precision Oncology , No. 4 ( 2020-11), p. 647-661
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 4 ( 2020-11), p. 647-661
    Abstract: Vulvar squamous cell carcinoma (vSCC) encompasses two predominant variants: one associated with detectable high-risk strains of human papillomavirus (hrHPV) and a second form often occurring in the context of chronic dermatitis in postmenopausal women. Genomic assessment of a large-scale cohort of patients with aggressive vSCC may identify distinct mutational signatures. MATERIALS AND METHODS Tumor samples from a total of 280 patients with vSCC underwent hybridization capture with analysis of up to 406 cancer-related genes. Human papillomavirus (HPV) sequences were detected by de novo assembly of nonhuman sequencing reads and aligned to the RefSeq database. Immunohistochemistry for programmed death-ligand 1 (PD-L1) was assessed. RESULTS One hundred two of 280 vSCCs (36%) contained hrHPV sequences, predominantly HPV 16 (88%). The HPV-positive (HPV+) group was significantly younger (median age, 59 v 64 years; P = .001). Compared with HPV-negative (HPV–) vSCCs, HPV+ tumors showed more frequent pathogenic alterations in PIK3CA (31% v 16%; P = .004), PTEN (14% v 2%; P 〈 .0001), EP300 (14% v 1%; P 〈 .0001), STK11 (14% v 1%; P 〈 .0001), AR (5% v 0%; P = .006), and FBXW7 (10% v 3%; P = .03). In contrast, HPV– vSCCs showed more alterations in TP53 (83% v 6%; P 〈 .0001), TERTp (71% v 9%; P 〈 .0001), CDKN2A (55% v 2%; P 〈 .0001), CCND1 amplification (22% v 2%; P 〈 .0001), FAT1 (25% v 4%; P 〈 .0001), NOTCH1 (19% v 6%; P = .002), and EGFR amplification (11% v 0%; P 〈 .0001), as well as a higher rate of 9p24.1 ( PDL1/PDL2) amplification (5% v 1%) and PD-L1 immunohistochemistry high-positive tumor staining (33% v 9%; P = .04). CONCLUSION Comprehensive molecular profiles of vSCC vary considerably with hrHPV status and may inform patient selection into clinical trials. Sixty-one percent of HPV+ vSCCs had a pathogenic alteration in the PI3K/mTOR pathway, whereas HPV– vSCCs showed alterations in TP53, TERTp, CDKN2A, CCND1, and EGFR, and biomarkers associated with responsiveness to immunotherapy.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.19.00406
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2020
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  • 3
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    BRE12-158: A Postneoadjuvant, Randomized Phase II Trial of Personalized Therapy Versus Treatment of Physician's Choice for Patients With Residual Triple-Negative Breast Cancer
    American Society of Clinical Oncology (ASCO) ; 2022
    In:  Journal of Clinical Oncology Vol. 40, No. 4 ( 2022-02-01), p. 345-355
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 40, No. 4 ( 2022-02-01), p. 345-355
    Abstract: Patients with triple-negative breast cancer (TNBC) with residual disease after neoadjuvant chemotherapy (NAC) have high risk of recurrence with prior data suggesting improved outcomes with capecitabine. Targeted agents have demonstrated activity across multiple cancer types. BRE12-158 was a phase II, multicenter trial that randomly allocated patients with TNBC with residual disease after NAC to genomically directed therapy versus treatment of physician choice (TPC). PATIENTS AND METHODS From March 2014 to December 2018, 193 patients were enrolled. Residual tumors were sequenced using a next-generation sequencing test. A molecular tumor board adjudicated all results. Patients were randomly allocated to four cycles of genomically directed therapy (arm A) versus TPC (arm B). Patients without a target were assigned to arm B. Primary end point was 2-year disease-free survival (DFS) among randomly assigned patients. Secondary/exploratory end points included distant disease-free survival, overall survival, toxicity assessment, time-based evolution of therapy, and drug-specific outcomes. RESULTS One hundred ninety-three patients were randomly allocated or were assigned to arm B. The estimated 2-year DFS for the randomized population only was 56.6% (95% CI, 0.45 to 0.70) for arm A versus 62.4% (95% CI, 0.52 to 0.75) for arm B. No difference was seen in DFS, distant disease-free survival, or overall survival for the entire or randomized populations. There was increased uptake of capecitabine for TPC over time. Patients randomly allocated later had less distant recurrences. Circulating tumor DNA status remained a significant predictor of outcome with some patients demonstrating clearance with postneoadjuvant therapy. CONCLUSION Genomically directed therapy was not superior to TPC for patients with residual TNBC after NAC. Capecitabine should remain the standard of care; however, the activity of other agents in this setting provides rationale for testing optimal combinations to improve outcomes. Circulating tumor DNA should be considered a standard covariate for trials in this setting.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.21.01657
    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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  • 4
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    Durable Clinical Response to Larotrectinib in an Adolescent Patient With an Undifferentiated Sarcoma Harboring an STRN - NTRK2 Fusion
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  JCO Precision Oncology , No. 2 ( 2018-11), p. 1-8
    Details
    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 2 ( 2018-11), p. 1-8
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.18.00101
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
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  • 5
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    Clinical utility of liquid-based comprehensive genomic profiling (CGP) in gastrointestinal stromal tumors (GIST).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 11541-11541
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 11541-11541
    Abstract: 11541 Background: GIST is the most common mesenchymal cancer of the digestive tract. Beyond surgery, treatment for GIST focuses largely on tyrosine kinase inhibitors (TKI), whose selection and potential resistance depend on select mutations. We present the molecular landscape of GIST utilizing tissue and liquid biopsies with emphasis on the clinical utility of liquid biopsy in advanced GIST. Methods: Liquid (FoundationOne Liquid CDx [F1LCDx]) and tissue (FoundationOne CDx) CGP was performed by hybrid capture, targeted NGS at Foundation Medicine Inc. Tissue and liquid samples from 2,198 and 147 patients, respectively, were analyzed. A cohort of 27 paired tissue and liquid samples were also evaluated. The levels of circulating tumor DNA (ctDNA) in liquid biopsies was quantified by tumor fraction (TF), with a TF algorithm incorporating aneuploidy, variant allele frequency, and canonical alterations detected on F1LCDx. Results: Tissue CGP (n = 2,198) revealed the following prevalence of primary driver alterations: KIT (77%), PDGFRA (8%), NF1 (6%), SDHA/B/C/D (SDHx, 3%) and BRAF (1%). Rates of molecular markers previously associated with worse prognosis included: CDKN2A (29%), RB1 (9%), TP53 (6%) and SETD2 (4%). 7% of cases had no reportable known pathogenic alterations in canonical GIST genes (wild-type GIST), while 2% of cases had a mutation in more than one driver. In a cohort of 147 liquid biopsies, TF was 〈 1% in 68.0%, 1-10% in 18.4%, 〉 10% in 13.6% of samples. In samples with elevated TF ( 〉 10%), the prevalence of targetable driver alterations in KIT (89%), PDGFRA (4%) , NF1 (4%) and BRAF (4%) was comparable to the tissue prevalence. In liquid, 58% (39/67) of samples with a KIT-driver mutation had a co-occurring imatinib-resistant KIT alteration. In addition, 4/147 patients (3%) were predicted to harbor a germline KIT mutation, including one patient (0.6%) with a potential imatinib-resistant KIT D820G germline mutation and another with clinical suspicion of germline KIT L576P mutation due to the presence of multiple primary GISTs, hyperplasia of myenteric plexus and dysplastic skin nevi. In paired tissue/liquid samples, liquid detected 2/2 driver mutations found in tissue when liquid TF was 〉 10%, and 5/6 in specimens with TF 〉 1%. In the overall cohort, the relative prevalence of KIT exon 9 and 11 driver alterations was comparable in tissue vs liquid, while imatinib-resistance KIT exon 13 and 17 mutations were enriched in liquid samples. Conclusions: Known driver and TKI-resistant mutations of both somatic and potential germline origin are identified in peripheral blood ctDNA of GIST patients. Liquid biopsy shows high concordance to tissue in identifying driver mutations in the presence of elevated TF and may exhibit TKI-resistant specific alterations. This study indicates that liquid biopsy may be useful in the molecular classification of GIST during the medical management of advanced GIST patients.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.11541
    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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    CDH1 -mutated clinically advanced urothelial bladder cancer (UBC): A genomic landscape and real-world clinical outcome study (RWCOS).
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 4587-4587
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 4587-4587
    Abstract: 4587 Background: CDH1 mutated bladder cancers are characterized by plasmacytoid histology and are associated with an aggressive clinical course. Methods: Cohort 1: 6,676 clinically advanced UBC patients underwent hybrid capture based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA) as well as microsatellite instability (MSI), tumor mutational burden (TMB), and genomic loss of heterozygosity (gLOH, high ≥16%). Tumor cell PD-L1 expression was determined by immunohistochemistry (Dako 22C3). GAs were compared between CDH1 mutated and wild-type (WT) patients using Chi-square. Cohort 2: 586 UBC patients underwent a RWCOS using the de-identified Flatiron Health-Foundation Medicine urothelial clinicogenomic database. The de-identified data originated from approximately 280 US cancer clinics (~800 sites of care) between January 2011 and April 2022. Differences in real-world progression-free survival (rwPFS) and overall survival (rwOS) were evaluated by Cox proportional hazard models. Results: Cohort 1: 217 UBC patients featured a CDH1 short variant mutation with 65.2% featuring plasmacytoid histology (PLC). The PLC cohort was slightly younger, with a higher proportion of male patients, and MSI-High status. Cell-Cycle regulatory GAs were significantly higher in the non-PLC cohort, specifically CDKN2A (25.5% vs 9.7%, p=0.01) and CDKN2B (23.6% vs 5.8%, p 〈 0.01). CDH1-mutated UBCs featured a higher MSI high frequency (2.7% vs 0.8%; p=.002), mean TMB (14.8 vs 9.9mut/Mb p 〈 .0001), RB1 GA (52.5% vs 20.3%; p 〈 .0001), PTEN GA (9.2% vs 4.3%; p=.006) and PIK3CA GA (29.5% vs 21.8%; p=.02), but lower gLOH (6.8% vs 15.9%; p=.009), CDKN2A loss (12.4% vs 38.3%; p 〈 .0001), MTAP loss (10.1% vs 25.1%; p 〈 .0001), and FGFR3 GA (9.7% vs 18.1%; p=.002). TP53 GAs and PD-L1 expression levels were similar between groups. From cohort 2: 22 (3.7%) patients featured CDH1 mutations. When compared with the CDH1 WT patients, the age, gender, ethnicity and ECOG status were similar. CDH1 mutation was associated with less favorable outcomes for 270 UBC patients treated with immune checkpoint inhibitors (ICPI) including rwPFS (2.8 vs 3.5 months; p=.096) and rwOS (3.3 vs 9.5 months; p=.03). Similar comparisons for 316 UBC patients treated with chemotherapy showed no significant adverse impact of CDH1 mutation status on either rwPFS (7.9 vs 6.2 months; p=.11) and rwOS (13.4 vs 13.4 months; p=0.83). Conclusions: In addition to its classic association with PLC histology, CDH1-mutated UBC features an unique genomic landscape including higher MSI and TMB, activating GAs in the MTOR pathway, but lower frequency of FGFR3 GAs. RWCOS further supports that CDH1 mutation predicts resistance to ICPI-based treatment, but does not systemic chemotherapy. These findings support CGP to guide therapeutic approaches based on the personalized genomic signature of UBC.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.4587
    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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  • 7
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    Identification of potential germline (GL) variants by routine clinical comprehensive genomic profiling (CGP) and confirmatory GL testing in 24 tumor types.
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  Journal of Clinical Oncology Vol. 39, No. 15_suppl ( 2021-05-20), p. 10596-10596
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 39, No. 15_suppl ( 2021-05-20), p. 10596-10596
    Abstract: 10596 Background: Tumor CGP may identify both somatic and GL variants, though confirmatory testing is required to verify which variants originate from the GL. Studies have shown CGP can identify patients who both do and do not meet criteria for genetic counseling (GC). Ideally, improved annotation from tumor CGP could more appropriately direct GC referrals. We explore how a computational algorithm might be used to influence GC and confirmatory GL testing for variants in inherited cancer predisposition genes. Methods: 849 patients from the Aurora Oncology Precision Medicine Program who had routine hybrid-capture based CGP by Foundation Medicine from 8/2018-8/2020 were eligible. A previously published algorithm, SGZ (Sun et al PMID 29415044) which incorporates allele frequency, aneuploidy, and admixed copy number modeling was used to predict whether each single nucleotide variant (SNV) was GL or somatic. SGZ predictions for SNVs in 24 actionable inherited cancer predisposition genes were available to Aurora for review as part of standard screening to identify appropriate GC referrals. For patients who had GL testing, variants in genes on both assays were compared. Results: 76 pathogenic (P) or likely pathogenic (LP) variants predicted to be GL by SGZ were detected in 73/849 (9%) patients: ATM (7), BAP1 (2), BRCA1 (13), BRCA2 (8), BRIP1 (1), CHEK2 (18), FH (0), FLCN (2), MLH1 (1), MSH2 (0), MSH6 (3), MUTYH (12), PALB2 (3), PMS2 (1), POLE (0), RAD51C (1), RAD51D (0), RET (1), SDHA/B/C/D (0,0,0,0), TSC2 (0), and VHL (3). 27/73 (37%) patients had GL testing. 25/26 (96%) variants were confirmed to be GL in origin and 1 additional variant was detected by CGP in a region not interrogated by the GL assay: ATM (2/2), BRCA1 (6/6), BRCA2 (2/2), BRIP1 (1/1), CHEK2 (9/9), FLCN (0*/1), MSH6 (1/1), MUTYH (2/2), PALB2 (1/1), RAD51C (1/1), and VHL (0/1). Variants were confirmed in bladder, breast, CRC, glioma, NSCLC, ovary, pancreas, prostate, sarcoma, and gastric cancer. The VHL variant was discordant in a leiomyosarcoma. Conclusions: We identified the potential real-world clinical impact of computationally screening solid tumor patients undergoing routine CGP for potential P/LP GL variants. Predicting GL results with SGZ for 24 inherited cancer predisposition genes was highly concordant with confirmatory GL testing independent of tumor type. CGP annotations can facilitate GC referral and GL testing for at-risk patients, particularly in tumor types which may not typically meet guidelines for GL testing.[Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2021.39.15_suppl.10596
    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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  • 8
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    Penile squamous cell carcinoma (PSCC) with elevated tumor mutational burden (TMB): A genomic landscape study.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 6_suppl ( 2023-02-20), p. 4-4
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 6_suppl ( 2023-02-20), p. 4-4
    Abstract: 4 Background: TMB has emerged as a major biomarker of efficacy in immune checkpoint inhibitor (ICPI) therapies in the neoadjuvant, adjuvant and metastatic disease setting in a wide variety of malignancies, but not in PSCC. Methods: 397 clinically advanced (local major recurrence and/or metastatic disease) PSCC underwent hybrid capture-based comprehensive genomic profiling (CGP) to evaluate all classes of genomic alterations (GA). Tumor mutational burden (TMB) was determined on up to 1.1 Mb of sequenced DNA and microsatellite instability (MSI) was determined on up to 114 loci. Trinucleotide mutation signatures were evaluated (Alexandrov, et al. 2013). Genome-wide loss of heterozygosity (gLOH) was determined using validated pipelines and excluding whole-arm and whole-chromosome events. TMB was categorized into three cohorts: 〈 10 mutations/Megabase [muts/Mb] (low), 10-19 muts/Mb (high), and 〉 20 muts/Mb (very high). Tumor cell PD-L1 expression was determined by IHC (Dako 22C3) and defined as tumor proportion score (TPS) 〉 1. The presence of HPV16/18 was determined by next generation sequencing (NGS). Statistical comparisons were corrected for multiple comparisons using the Bonferonni method. Results: There were 339 (85.4%) TMB low, 40 (10.1%) TMB 10-19 and 18 (4.5%) TMB very high PSCC cases in this study. The mean age of PSCC with very high TMB at 70.1 yrs was older than for TMB low at 63.4 yrs (p=.08). There were no significant differences in genomic ancestry among the 3 groups. The TMB 10-19 and TMB very high tended to feature an APOBEC genomic mutational signature more than the TMB low PSCC cases (74 and 76% vs 44%). MSI high status was absent in the TMB low PSCC, but was present in 7.5% of the TMB 10-19 and 11.8% of the TMB very high cases. gLOH levels above 16% were similar in all 3 groups and ranged from 6.2 to 9.4%. GA associated with differences in TMB status in the PSCC cases included higher PIK3CA GA in TMB 10-19 (40.0%) vs TMB low (18.3%; p=.035) and TMB very high (66.7%) vs TMB low (p=.0002). CDKN2A GA were higher in TMB low (45.7%) than in the combined TMB 10-19 + very high (25.9%; p=.049). GA in KMT2D were higher in the combined TMB 10-19 + very high (29.3%) than the TMB low PSCC (7.7%; p=0002). FGFR3 GA were similar in all 3 groups. PD-L1 expression was not significantly different among the 3 groups with TMB low (78.3%), TMB 10-19 (64.2%) and TMB very high (54.5%). HPV identification was more frequent as TMB increased: 28.3% for the TMB low, 50.0% for the TMB high and 58.8% for the TMB very high groups. Conclusions: The evaluation of PSCC by CGP based on TMB levels revels significant differences in biomarkers for the near 15% of cases that have TMB 〉 10 muts/Mb. Further study of TMB as a biomarker in ICPI-based clinical trials for advanced PSCC appear warranted.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.6_suppl.4
    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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  • 9
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    Metastatic breast cancer (MBC) with ultra-high tumor mutational burden (UHTMB): A comprehensive genomic profiling (CGP) study.
    American Society of Clinical Oncology (ASCO) ; 2023
    In:  Journal of Clinical Oncology Vol. 41, No. 16_suppl ( 2023-06-01), p. 1036-1036
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 41, No. 16_suppl ( 2023-06-01), p. 1036-1036
    Abstract: 1036 Background: Pts with MBC whose tumors feature high TMB (≥ 10 mutations/Mb) are eligible for on label immune checkpoint inhibitor (ICI) treatment. This study evaluated the genomic landscape of MBC with “Ultra high” TMB, defined at 〉 20 mutations/Mb. Methods: 2049 MBC underwent hybrid capture-based CGP to evaluate all classes of genomic alterations (GA), TMB, microsatellite instability (MSI) and trinucleotide mutational signatures. HER2 IHC results were available in a subset of pts. PD-L1 expression on immunocytes was determined by IHC (Ventana SP142). Results: 45/2049 (2.2%) of MBC were UHTMB. 45 (100%) pts had metastatic disease. 38 (84%) had documented Stage IV disease and 7 documented axillary LN metastases at the time of sequencing. Local breast tumor was used for CGP in 19 (42.2%) MBC and metastatic site biopsy was used in 26 (57.8%). When compared with 2004 non-UHTMB pts with UHTMB were older (mean 64.6 yrs vs 58.2 yrs p 〈 .0001), more often had lobular histology (40.0% vs 14.5% p 〈 .0001) and ER+ disease (86.6% vs 70.0%). Of the 35 UHTMB cases with HER2 IHC data available, 11 (31.4%%) were HER2 IHC negative (0+), 21 (60.0%) were HER2-low status (9 1+ and 12 2+/ISH negative) and 3 (8.6%) were HER2 IHC positive (3+). 1/3 HER2 IHC2+ cases and 2/45 (4.4%) of all UHTMB cases were positive for HER2 copy number gain on CGP. UHTMB cases had more driver GA/tumor (mean 9.8 vs 5.7 p 〈 .0001) and were less often TNBC (13.3% vs 27.0% p = .041) compared to non-UHTMB high cancers. Mutation signature analysis revealed APOBEC was predominant in UHTMB samples (82.5%); MMR signature was also observed in 10% of cases. MSI high status was significantly more frequent in UHTMB high cases (11.6% vs 0.4% p 〈 .0001). GA more frequently identified in UHTMB cases included CDH1 (45.5% vs 14.3% p 〈 .0001), PIK3CA (81.8% vs 37.9% p 〈 .0001), CDKN2A (11.4% vs 3.2% p = .017), ARID1A (25.0% vs 5.0% p 〈 .0001) and NF1 (20.5% vs 5.9% p = .0014). PD-L1 ( CD274) gene amplification (2.3% vs 1.3%) or protein expression by the Ventana SP142 assay (57.14% vs 51.10%) were not significantly different among groups. Conclusions: UHTMB MBC is a rare, yet clinically important subset of clinically advanced breast cancer driven by APOBEC mutagenesis, with high incidence of ER+ lobular histology and frequent alterations in CDH1 and PIK3CA. In addition to potential benefit from ICI based treatment, UHTMB MBC present with a high frequency of HER2-low status which may impact therapy decisions for this rare disease. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2023.41.16_suppl.1036
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2023
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  • 10
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    Genomic Profiling of Combined Hepatocellular Cholangiocarcinoma Reveals Genomics Similar to Either Hepatocellular Carcinoma or Cholangiocarcinoma
    American Society of Clinical Oncology (ASCO) ; 2021
    In:  JCO Precision Oncology , No. 5 ( 2021-11), p. 1285-1296
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    In: JCO Precision Oncology, American Society of Clinical Oncology (ASCO), , No. 5 ( 2021-11), p. 1285-1296
    Abstract: Combined hepatocellular cholangiocarcinoma (cHCC-CCA) is a rare, aggressive primary liver carcinoma, with morphologic features of both hepatocellular carcinomas (HCC) and liver cholangiocarcinomas (CCA). METHODS The genomic profiles of 4,975 CCA, 1,470 HCC, and 73 cHCC-CCA cases arising from comprehensive genomic profiling in the course of clinical care were reviewed for genomic alterations (GA), tumor mutational burden, microsatellite instability status, genomic loss of heterozygosity, chromosomal aneuploidy, genomic ancestry, and hepatitis B virus status. RESULTS In cHCC-CCA, GA were most common in TP53 (65.8%), TERT (49.3%), and PTEN (9.6%), and 24.6% cHCC-CCA harbored potentially targetable GA. Other GA were predominantly associated with either HCC or CCA, including, but not limited to, TERT, FGFR2, IDH1, and presence of hepatitis B virus. On the basis of these features, a machine learning (ML) model was trained to classify a cHCC-CCA case as CCA-like or HCC-like. Of cHCC-CCA cases, 16% (12/73) were ML-classified as CCA-like and 58% (42/73) cHCC-CCA were ML-classified as HCC-like. The ML model classified more than 70% of cHCC-CCA as CCA-like or HCC-like on the basis of genomic profiles, without additional clinico-pathologic input. CONCLUSION These findings demonstrate the use of ML for classification as based on a targeted exome panel used during routine clinical care. Classification of cHCC-CCA by genomic features alone creates insights into the biology of the disease and warrants further investigation for relevance to clinical care.
    Type of Medium: Online Resource
    ISSN: 2473-4284
    URL: Article
    DOI: 10.1200/PO.20.00397
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2021
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