Circulating tumor (ct)-DNA alterations in patients with testicular germ tumors.

e16063 Background: Testicular germ cell tumors (GCT) infrequently harbor somatic mutations. ctDNA assay allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution of resistance. To our knowledge, ctDNA genomic alterations observed in in testicular GCTs have not been heretofore described. We report ctDNA profiling of patients (pts) with testicular GCTs. Methods: 31 Pts with testicular GCTs from multiple institutions in the United States that underwent ctDNA analysis using the Guardant360 platform were eligible. Two patients had one serial ctDNA sample. De-identified demographic data were collected in addition to data for ctDNA alterations. Guardant360 is a CLIA-certified ctDNA panel that assesses single nucleotide variant and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants reported at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or found in OncoKB were considered pathogenic. Results: Of 31 patients with testicular GCTs, 162 ctDNA alterations were detected in 26 patients (84%) across 41 genes (Table). A median number of 3 alterations (range 1-19) was detected per sample. Among the 162 alterations, 88 were believed to be pathogenic and detectable in 20 patients (65%). 12/31 pts (39%) were documented to be post systemic therapy. The median age was 38 years (range 20-61). The most common pathogenic somatic alterations were KRAS (n = 12/88, 14%), CCND2 (n = 8/88, 9%), MET (n = 8/88, 9%), CDK6 (n = 7/88, 8%), TP53 (n = 6/88, 7%), and RAF1 (n = 5/88, 6%). In 2 patients with serial samples, 5 novel pathogenic alterations were detected in the second sample including FGFR2, APC, CDK6, RAF1, and MAPK1. Conclusions: ctDNA alterations were frequently detected in resistant testicular GCTs and appear similar to alterations previously described in tumor tissue analyses of testicular GCTs. Given that ctDNA offers a non-invasive means of profiling tumor DNA, further development of this promising modality is warranted to determine it's relevance in clinical practice. [Table: see text]

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Circulating tumor (ct)-DNA alterations in patients with testicular germ cell tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.6_suppl.415 ◽

2020 ◽

Vol 38 (6_suppl) ◽

pp. 415-415

Author(s):

Archana Agarwal ◽

Amin Nassar ◽

Rebecca Nagy ◽

Catherine Curran ◽

Sarah Abou Alaiwi ◽

...

Keyword(s):

Germ Cell ◽

Somatic Mutations ◽

Demographic Data ◽

Germ Cell Tumors ◽

Testicular Germ Cell Tumors ◽

Testicular Germ Cell ◽

The Usa ◽

Evolution Of Resistance ◽

Dna Alterations ◽

Ctdna Analysis

415 Background: Testicular germ cell tumors (GCT) infrequently harbor somatic mutations. ctDNA assessment allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution of resistance. We report ctDNA profiling of patients (pts) with testicular GCTs. Methods: 40 patients (pts) with advanced testicular GCTs from multiple institutions in the USA that underwent ctDNA analysis using the Guardant (G)-360 platform were eligible and a total of 48 samples were collected. 36 pts had one sample, 3 pts had 2 samples, 1 pt had 6 samples. De-identified demographic data were collected in addition to data for ctDNA alterations. G360 employed a CLIA-certified ctDNA panel that assessed single nucleotide variant and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants reported at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or found in OncoKB were considered pathogenic. Results: Of 40 patients with testicular GCTs, 13pts (33%) were post systemic therapy. The median age was 36 years (range 20-61). 199 ctDNA alterations were detected in 35 patients (87.5%) across 41 genes. Among the 199 alterations, 102 were believed to be pathogenic and detectable in 26 samples from 25 pts (62.5) (%). The most common pathogenic somatic alterations were KRAS (n = 16/102, 16%), TP53 (n = 16/102, 16%), CCND2 (n = 9/102, 9%), CDK6 (n = 9/102, 9%), MET (n = 9/102, 9%), and RAF1 (n = 6/102, 6%). Conclusions: ctDNA alterations were frequently detected in resistant testicular GCTs and appear similar to alterations previously described in tumor tissue analyses of testicular GCTs. Given that ctDNA offers a non-invasive means of profiling tumor DNA, further development of this promising modality is warranted to study the evolution of resistance to cisplatin-based chemotherapy and new potentially actionable alterations.

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Circulating tumor (ct)-DNA alterations in urothelial/bladder cancer (UC/BC): Updates on a dynamic genomic landscape.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.4534 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 4534-4534 ◽

Cited By ~ 2

Author(s):

Petros Grivas ◽

Rebecca J Nagy ◽

Gregory Russell Pond ◽

Sumati Gupta ◽

Jue Wang ◽

...

Keyword(s):

Tumor Tissue ◽

Clonal Evolution ◽

Median Number ◽

Cancer Genes ◽

Genomic Landscape ◽

Urothelial Bladder ◽

Dna Alterations ◽

New Gene ◽

Ctdna Analysis ◽

Serial Samples

4534 Background: Cell-free ctDNA may be potentially actionable, may have prognostic/predictive role and evolve after therapy. We updated our analysis of our retrospective study to shed light on UC/BC biology. Methods: Patients (pts) with UC/BC with ctDNA analysis for potentially actionable alterations using Guardant360 were identified. A 70-gene ctDNA next generation sequencing panel from a CLIA-licensed, CAP-accredited laboratory (Guardant Health, Inc.) offers complete exon sequencing for 29 cancer genes, critical exons in 39 genes and amplifications (16 genes), fusions (6 genes) and indels (3 genes) harvested from 10 mL of peripheral blood. Descriptive statistics were used. Results: There were 246 pts with 276 samples. At least 1 alteration was detected in 249 (90%) samples. Median age at time of ctDNA collection was 67 years (39-85), 78% men, median number of alterations per sample was 3.5 (1-35) most pts had MIBC. In MIBC pts, the most common alterations at the 1st ctDNA sample were in TP53 (52%), PI3KCA (18%) ARID1A (17%), FGFR2 (15%), MET & NF1 (14%), EGFR (13%), BRAF (12%), FGFR3 (11%), RAF1 (10%), BRCA1 & CCNE1 (9%). In MIBC pts, the most common genes with increased copy number were RAF1 & CCNE1 (8%), ERBB2 & PI3KCA (7%), EGFR, BRAF, FGFR1, MYC (each 5%), MET (4%), KRAS (3%). Most common altered pathways included TP53 signaling (56%), RAS/RAF/MEK/ERK (51%), RTK (48%), cell cycle (38%), FGFR family (34%), DNA damage response (25%), PI3KCA/AKT/mTOR (23%) and chromatin remodeling (17%). Interestingly, FGFR3 and RAS alterations were mutually exclusive in most cases, but each may co-occur with TP53alterations. 54 serial ctDNA samples from 24 pts (18 pts with 2 samples; 6 pts with 3 samples) revealed persistent, lost and new gene alterations. Conclusions: ctDNA was detected in 90% of pts and alterations were similar to those previously seen in UC tumor tissue. Tumor heterogeneity, interim therapy, genomic instability and clonal evolution can explain differences in serial samples. Correlation assessment with prior therapies and outcomes is being pursued to inform trial designs. Prospective validation, assessment of ctDNA concordance with tumor tissue DNA, and evaluation of clinical utility is warranted.

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Genomic landscape of circulating tumor (ct)-DNA alterations in patients with penile cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e16027 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e16027-e16027

Author(s):

Archana Agarwal ◽

Amin Nassar ◽

Rebecca Nagy ◽

Catherine Curran ◽

Sarah Abou Alaiwi ◽

...

Keyword(s):

Penile Cancer ◽

Demographic Data ◽

Tumor Biology ◽

The United States ◽

Median Number ◽

Hpv Infection ◽

Single Nucleotide Variants ◽

Genomic Alterations ◽

Her Family ◽

Platinum Based Chemotherapy

e16027 Background: Penile cancer is a rare disease associated with HPV infection and is known to harbor recurrent somatic genomic alterations in the ERBB (HER)-family, CDKN2A, TP53, NOTCH1 and PIK3CA. ctDNA assay allows the noninvasive genomic profiling of malignancies and may assist with understanding molecular evolution of resistance. To our knowledge, the genomic alterations observed in ctDNA for penile cancer have not been described before. We report ctDNA profiling of patients with advanced penile cancer. Methods: Sixteen pts with metastatic penile cancer from multiple institutions in the United States that underwent ctDNA analysis using the Guardant360 platform were eligible. Three patients had at least one serial ctDNA sample. De-identified demographic data were collected. Guardant 360 is CLIA-certified ctDNA panel that assesses single nucleotide variants and copy number alterations in 68 to 73 genes for potentially actionable genomic alterations. Variants seen at least 3 times in the Catalogue of Somatic Mutations in Cancer (COSMIC) database or reported in OncoKB were considered pathogenic. Results: The median age was 64 years (range 40-77). 4 pts (25%) were documented to be post platinum-based chemotherapy. The median number of ctDNA alterations detected per sample was 2 (range 0-6). Overall, genomic alterations were detected in 15/16 patients (94%) across 21 genes (table 1). Alterations were most frequently detected in TP53 (9/16, 56%), CDKN2A (5/16, 31%), TERT promoter (5/16, 31%), PIK3CA (3/16, 19%) and ERBB2 (3/16, 19%). In 3 patients with serial samples, 9 novel pathogenic alterations were detected in the second sample including ATM, CDKN2A, ARID1A, CCND1, CDK6, EGFR, PDGFRA, PIK3CA, and SMAD4. Conclusions: ctDNA alterations in patients with advanced penile cancer were frequently detected with similar prevalences to previously described tumor tissue analyses. New alterations observed on serial ctDNA assays may provide insights regarding tumor biology and inform drug development. [Table: see text]

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Outcomes of IDH1/2 mutant AML patients treated with IDH1/2 inhibitors: A single institutional experience.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e19010 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e19010-e19010

Author(s):

Constantine Nick Logothetis ◽

Chetasi Talati ◽

Gregoire Calon ◽

Nathan P Horvat ◽

Virginia Olivia Volpe ◽

...

Keyword(s):

Adverse Events ◽

Somatic Mutations ◽

Demographic Data ◽

Response Duration ◽

Initial Response ◽

Median Number ◽

Resistance Mechanisms ◽

Overall Response ◽

Line Therapy ◽

Number Of Patients

e19010 Background: Recent studies showed that IDH1/2 are frequently mutated in AML and that aberrant 2-HG elevation driven by the mutant IDH1/2 proteins plays a pivotal role in AML development. Subsequent clinical trials of IDH1/2 inhibitors demonstrated promising outcomes in IDH1/2mut AML patients. In this single institutional retrospective study, we explored the efficacy and safety outcomes of IDH1/2mut AML patients treated with Ivosidenib or Enasidenib. Methods: We retrospectively identified AML patients who had IDH1/2 somatic mutations based on NGS assessments. Clinical and demographic data were extracted from the medical records. Statistical analyses were performed using GraphPad Prism (v.7.03) and SPSS (v.24.0). Results: A total of 43 ( IDH1mut, n = 12; IDH2mut, n = 33; both IDH1/2mut, n = 2) patients were included in the study. Median age at AML diagnosis was 67.6 (24.2-83.3) years and 24 (55.8%) patients were male. Eighteen (42%) patients had secondary AML and 13 (34.2%), 17 (44.7%), and 8 (21.1%) patients had favorable, intermediate, and adverse risk, respectively. A total of 23 (53.5%) and 9 (20.9%) patients received intensive chemotherapy and hypomethylating agents as their 1st line therapy. One patient received Enasidenib as the 1st line therapy and the rest of the patients had relapsed/refractory disease prior to IDH1/2 inhibitor therapy. Median number of treatment prior to IDH1/2 inhibitors was 4 (0-8). The median duration of IDH1/2 inhibitor treatment was 3.2 (0.2-31.6) months ( IDH1 mut, 2.5 [0.7-13.5]; IDH2 mut, 3.4 [0.2-31.6]). Treatment response was assessed in 38 patients and 18 had overall response (CR, n = 7 [18.4%]; PR, n = 11 [28.9%]). Among these, 13 patients had concurrent somatic mutations in FLT3, KRAS, NRAS, or PTPN11. The overall response rate in these patients was not statistically different compared to patients who did not have these mutations (38.5% vs. 40%, p > 0.05). The median PFS was 3.9 (0.4-14.7) months ( IDH1 mut, 5.6 [1.7-11.5] vs. IDH2 mut, 3.7 [0.4-14.7], p > 0.05) and median OS was 7.6 (0.4-44.1) months. The most common reason for IDH1/2 inhibitor discontinuation was disease progression (n = 21) followed by adverse events (n = 3) and allogeneic transplant (n = 2). The adverse events were assessed in 41 patients and the most common adverse events were differentiation syndrome ( IDH1 mut, n = 3; IDH2 mut, n = 5) and leukocytosis ( IDH1 mut, n = 4; IDH2 mut, n = 4) followed by hepatic toxicity ( IDH2 mut n = 7), and QTc prolongation ( IDH1 mut, n = 3). Conclusions: Our study indicates that IDH1/2 inhibitors remain a reasonable option for the refractory/relapsed IDH1/2mut AML. However, significant number of patients failed to show any response and many of the patients who showed initial response had short response duration. These findings warrant further studies to identify underlying resistance mechanisms of IDH1/2 inhibitors and the optimal combination therapeutic strategies.

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Racial Differences Among Boys With Testicular Germ Cell Tumors in the United States

The Journal of Urology ◽

10.1016/j.juro.2008.01.057 ◽

2008 ◽

Vol 179 (5) ◽

pp. 1961-1965 ◽

Cited By ~ 24

Author(s):

Thomas J. Walsh ◽

Benjamin J. Davies ◽

Mary S. Croughan ◽

Peter R. Carroll ◽

Paul J. Turek

Keyword(s):

United States ◽

Germ Cell ◽

Racial Differences ◽

Germ Cell Tumors ◽

The United States ◽

Testicular Germ Cell Tumors ◽

Testicular Germ Cell

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Trends in the incidence of testicular germ cell tumors in the United States

Cancer ◽

10.1002/cncr.11054 ◽

2002 ◽

Vol 97 (1) ◽

pp. 63-70 ◽

Cited By ~ 227

Author(s):

Katherine A. McGlynn ◽

Susan S. Devesa ◽

Alice J. Sigurdson ◽

Linda M. Brown ◽

Lilian Tsao ◽

...

Keyword(s):

United States ◽

Germ Cell ◽

Germ Cell Tumors ◽

The United States ◽

Testicular Germ Cell Tumors ◽

Testicular Germ Cell

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Clinical characterization of febrile neutropenia episodes in patients with testicular germ cell tumors.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e16038 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e16038-e16038

Author(s):

Angelika Bezan ◽

Florian Posch ◽

Thomas Bauernhofer ◽

Martin Pichler ◽

Joanna Szkandera ◽

...

Keyword(s):

Febrile Neutropenia ◽

Germ Cell ◽

Median Time ◽

Germ Cell Tumors ◽

Case Fatality ◽

Median Number ◽

Testicular Germ Cell Tumors ◽

Testicular Germ Cell ◽

Curative Intent ◽

Observational Cohort

e16038 Background: Febrile neutropenia (FN) is a serious complication of chemotherapy (CTX). Here, we aim to characterize the clinical course of FN in patients (pts) with testicular germ cell tumors (TGCT). Methods: 413 TGCT patients who underwent at least one cycle of CTX in adjuvant or curative intent were studied within this single-center observational cohort study. Baseline characteristics of the subpopulation with FN are reported in Table 1. Results: During a total number of 1,196 CTX cycles in 413 patients, we observed 70 episodes of febrile neutropenia (16.9%). 55 (79%) of these episodes occurred during the 1stcycle of CTX. The median time between CTX start and FN onset was 14 days [IQR: 12-15, range: 7-18]. One (1%) FN episode was fatal, and 56 patients (80%) had to be hospitalized. Median time in hospital was 7 days [IQR: 6-8, range: 3-12], and the median number of days with an absolute neutrophil count below 0.5G/L was 2 [IQR: 2-3, range: 1-7]. Twelve (20%) FN episodes occurred in the 60 pts who received primary G-CSF support. There was very little treatment delay due to FN (median: 0 days [IQR: 0-0, range: 0-7]. 3 patients (4%) developed a second FN episodes. Conclusions: This study supports prior reports that FN is a relatively frequent complication of CTX in TGCT. However, the case-fatality-rate of FN in TGCT appears to be very low. [Table: see text]

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