scholarly journals PATH-18. CSF-DERIVED CIRCULATING TUMOR DNA REFLECTS DISEASE COURSE AND CLONAL EVOLUTION IN MEDULLOBLASTOMA

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi146-vi147
Author(s):  
Anthony P Y Liu ◽  
Rahul Kumar ◽  
Kyle Smith ◽  
Giles Robinson ◽  
Amar Gajjar ◽  
...  
Keyword(s):  
Clonal Evolution ◽  
Disease Status ◽  
Pediatric Brain Tumors ◽  
Circulating Tumor Dna ◽  
Tumor Evolution ◽  
Longitudinal Assessment ◽  
Primary Tumors ◽  
Suboptimal Outcome ◽  
Dismal Prognosis ◽  
Tumor Dna

Abstract Medulloblastoma (MB) is the most common malignant brain tumor in young children. A multi-modal approach comprises standard of care, and recent advances in molecular studies have identified clinically relevant subgroups. Nonetheless, 30% of MB patients relapse or progress, conferring dismal prognosis. Such suboptimal outcome is partly due to a lack of sensitive biomarkers for response-adapted personalization of treatment and relapse prediction. Circulating tumor DNA has been shown to correlate with disease status in a variety of adult cancers, but studies in pediatric brain tumors, including medulloblastoma, are scarce. Here, we aim to evaluate the utility of profiling cell-free DNA (cfDNA) derived from longitudinally-banked cerebrospinal fluid (CSF) samples collected from children with MB enrolled in two prospective, multi-center trials (SJMB03 and SJMB12, estimated sample size of 100 patients, including 50 with subsequent progression). cfDNA was extracted, quantified, and analyzed for size distribution from pre-centrifuged CSF serially banked during the course of treatment and follow-up. Low-pass whole genome sequencing (LP-WGS) enabled detection of chromosomal and focal copy number alterations (CNAs). CNAs detected in cfDNA were compared against known somatic changes in corresponding primary tumors. Detectability of tumor-specific CNAs in cfDNA was then correlated with tumor burden and patient outcome. Pilot analysis showed presence of arm level and/or focal CNAs in cfDNA from 80% of CSF samples in 20 children with metastatic MB, and longitudinal assessment revealed correlation with clinical course throughout treatment with radiotherapy and chemotherapy. Further comparison of tumor and longitudinal cfDNA derived CNAs revealed divergent genomic alterations implicating potential oncogenic mechanisms underlying treatment failure and recurrence. Our study performed on a large prospective series of MB trial patients substantiates the utility of CSF derived cfDNA as an actionable biomarker in high-risk MB patients while also facilitating understanding of tumor evolution and heterogeneity.

scholarly journals MBRS-20. CSF-DERIVED CIRCULATING TUMOR DNA AS A BIOMARKER FOR DISEASE PROGRESSION AND TUMOR EVOLUTION IN MEDULLOBLASTOMA

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii401-iii402
Author(s):  
Anthony Pak-Yin Liu ◽  
Rahul Kumar ◽  
Smith Kyle ◽  
Leena Paul ◽  
Murali Chintagumpala ◽  
...  
Keyword(s):  
Copy Number Variants ◽  
Pediatric Brain Tumors ◽  
Circulating Tumor Dna ◽  
Tumor Evolution ◽  
Chi Square ◽  
Therapeutic Trials ◽  
Low Coverage ◽  
Pediatric Brain ◽  
Matched Primary Tumor ◽  
Tumor Dna

Abstract BACKGROUND Cell-free DNA (cfDNA) profiling has been shown to carry utility as a clinically relevant biomarker in a variety of cancers, but studies in pediatric brain tumors, including medulloblastoma, are scarce. We hereby evaluated the actionability of profiling cfDNA from cerebrospinal fluid (CSF) based on a multi-institutional cohort of children with medulloblastoma. METHODS 103 children aged ≥ 3 years with medulloblastoma harboring chromosomal aneuploidy enrolled on two prospective therapeutic trials were included. cfDNA was extracted from CSF obtained longitudinally, and profiled by low-coverage whole-genome sequencing (lcWGS) for annotating copy-number variants (CNVs). cfDNA-derived CNVs were compared against patient-matched primary tumor-derived CNVs and correlated with outcome. cfDNA profiles at diagnosis and relapse were compared to evaluate tumor evolution. RESULTS Tumor-derived somatic CNVs were detected in 72% of baseline cfDNA samples, with higher detection rate in samples from patients with metastatic disease than those without (90% versus 50%, chi-square p=0.001). Longitudinal profiling of cfDNA revealed correlation between CNV detectability and clinical course, with detection of tumor-derived CNVs in cfDNA samples predating radiographic progression for ≥ 3 months in 62% of relapsing patients. Presence of cfDNA-derived CNVs in CSF collected during chemotherapy and at the end of therapy was significantly associated with inferior PFS (log-rank p<0.0001 for both time-points). Comparison of CNV profiles from cfDNA at baseline and relapse revealed molecular divergence in a subset of patients. CONCLUSION These results carry major implications and supports the incorporation of cfDNA profiling in upcoming medulloblastoma protocols for more sensitive and accurate disease monitoring and personalization of treatment.

scholarly journals The mutational landscape of spinal chordomas and their sensitive detection using circulating tumor DNA

2020 ◽  
Author(s):  
Austin K Mattox ◽  
Beibei Yang ◽  
Christopher Douville ◽  
Sheng-fu Lo ◽  
Daniel Sciubba ◽  
...  
Keyword(s):  
Clinical Status ◽  
Spinal Column ◽  
Disease Recurrence ◽  
The United States ◽  
Circulating Tumor Dna ◽  
Blood Draw ◽  
Primary Tumors ◽  
Whole Exome ◽  
Tumor Dna

Abstract Background Chordomas are the most common primary spinal column malignancy in the United States. The aim of this study was to determine whether chordomas may be detected by evaluating mutations in circulating tumor DNA (ctDNA). Methods 32 patients with a biopsy-confirmed diagnosis of chordoma had blood drawn pre-operatively and/or at follow up appointments. Mutations in the primary tumor were identified by whole exome sequencing and liquid biopsy by ddPCR and/or RACE-Seq was used to detect one or more of these mutations in plasma ctDNA at concurrent or later time points. Results 87.1% of patients were ctDNA positive at the time of initial blood draw (p < 0.001). Follow up blood draws in twenty of the patients suggest that ctDNA levels may reflect the clinical status of the disease. Patients with positive ctDNA levels were more likely to have greater mutant allele frequencies in their primary tumors (p = 0.004) and undergo radiotherapy (p = 0.02), and the presence of ctDNA may correlate with response to systemic chemotherapy and/or disease recurrence. Conclusions Detection of ctDNA mutations may allow for the detection and monitoring of disease progression for chordomas.

scholarly journals Circulating tumor DNA reveals genetics, clonal evolution, and residual disease in classical Hodgkin lymphoma

Blood ◽  
2018 ◽  
Vol 131 (22) ◽  
pp. 2413-2425 ◽  
Author(s):  
Valeria Spina ◽  
Alessio Bruscaggin ◽  
Annarosa Cuccaro ◽  
Maurizio Martini ◽  
Martina Di Trani ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Residual Disease ◽  
Clonal Evolution ◽  
Circulating Tumor Dna ◽  
Classical Hodgkin Lymphoma ◽  
Key Points ◽  
Tumor Dna

Key Points ctDNA is as an easily accessible source of tumor DNA for cHL genotyping. ctDNA is a radiation-free tool to track residual disease in cHL.

Concordance of Genomic Variants in Matched Primary Breast Cancer, Metastatic Tumor, and Circulating Tumor DNA: The MIRROR Study

2019 ◽  
pp. 1-16 ◽  
Author(s):  
Fernando Moreno ◽  
Javier Gayarre ◽  
Sara López-Tarruella ◽  
María del Monte-Millán ◽  
Antonio C. Picornell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Primary Tumor ◽  
Metastatic Breast ◽  
Metastatic Tumor ◽  
Circulating Tumor Dna ◽  
Primary Tumors ◽  
Genomic Variants ◽  
Ctdna Analysis ◽  
Tumor Dna

PURPOSE Genetic heterogeneity between primary tumors and their metastatic lesions has been documented in several breast cancer studies. However, the selection of therapy for patients with metastatic breast cancer and the search for biomarkers for targeted therapy are often based on findings from the primary tumor, mainly because of the difficulty of distant metastasis core biopsies. New methods for monitoring genomic changes in metastatic breast cancer are needed (ie, circulating tumor DNA [ctDNA] genomic analysis). The objectives of this study were to assess the concordance of genomic variants between primary and metastatic tumor tissues and the sensitivity of plasma ctDNA analysis to identify variants detected in tumor biopsies. PATIENTS AND METHODS Next-generation sequencing technology was used to assess the genomic mutation profile of a panel of 54 cancer genes in matched samples of primary tumor, metastatic tumor, and plasma from 40 patients with metastatic breast cancer. RESULTS Using Ion Torrent technology (ThermoFisher Scientific, Waltham, MA), we identified 110 variants that were common to the primary and metastatic tumors. ctDNA analysis had a sensitivity of 0.972 in detecting variants present in both primary and metastatic tissues. In addition, we identified 13 variants in metastatic tissue and ctDNA not present in primary tumor. CONCLUSION We identified genomic variants present in metastatic biopsies and plasma ctDNA that were not present in the primary tumor. Deep sequencing of plasma ctDNA detected most DNA variants previously identified in matched primary and metastatic tissues. ctDNA might aid in therapy selection and in the search for biomarkers for drug development in metastatic breast cancer.

Quantifying the evolution of tumor architecture using serial circulating tumor DNA.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 600-600
Author(s):  
Jason Henry ◽  
Jonathan M. Loree ◽  
John H. Strickler ◽  
Kanwal Pratap Singh Raghav ◽  
Van K. Morris ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Limit Of Detection ◽  
Circulating Tumor Dna ◽  
Tumor Evolution ◽  
Disease Course ◽  
Serial Sampling ◽  
Blood Specimens ◽  
Serial Samples ◽  
Tumor Dna ◽  
Over Time

600 Background: There is limited data regarding changes in the genomic landscape in individual patients over time as serial tissue biopsy has risk and is of uncertain clinical benefit. The advent of circulating tumor DNA (ctDNA) allows for safe and repeated molecular sampling with the potential to investigate evolution of tumor architecture over the disease course. Methods: From 5/15 to 12/17, 116 patients with metastatic CRC had between three to 12 blood specimens taken over the treatment course. Plasma was tested using targeted NGS assay (Guardant360, Guardant Health, 68 gene). To account for variations in the amount of ctDNA in serial samples, a window of evaluable allele frequency was established for each patient as the fold change between the max allele frequency (mAF) and limit of detection for serial samples with the lowest mAF. Mutations not falling within this window were excluded from analysis. Substantial treatment induced selective pressure (SP) was defined as a decrease in the mutant mAF of > 50% in patients with at least an initial mAF of 1%. Results: 116 patients with a total of 317 serial blood samples were evaluable after accounting for ctDNA variations over time. Specimens were collected a median of 12 months apart, with a median of three specimens per patient. Thirteen patients (11%) did not have any changes in mutations on serial sampling, however the remainder of patients gained an average of 1.1 mutations per time point (mut/tp), and lost 1.0 mut/tp. 31% of patients demonstrated evidence of substantial treatment-induced SP. These patients were more likely to demonstrate a change in clonal architecture of the tumor (46% greater rate than those without SP, P = 0.04), predominantly through gain of new clones. In contrast, clonal hematopoiesis alterations that may be induced by chemotherapy, such as JAK2V617F, were neither gained or lost. Conclusions: After correction for variations over time in the total amount of ctDNA in circulation, we identify numerous changes in tumor architecture with serial sampling. For the first time in colorectal cancer we demonstrate that when treatment-induced SP is applied the rate of tumor evolution is increased, demonstrating potential value of monitoring changes in tumor architecture over the disease course.

The landscape of genomic alterations detected in serial circulating tumor DNA (ctDNA) in clinical progressive metastatic breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1084-1084
Author(s):  
Saya Jacob ◽  
Andrew A. Davis ◽  
Lorenzo Gerratana ◽  
Ami N. Shah ◽  
Neelima Katam ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Metastatic Breast ◽  
Circulating Tumor Dna ◽  
Wilcoxon Test ◽  
Bone Lesions ◽  
Tumor Evolution ◽  
Longitudinal Assessment ◽  
Clinical Progression ◽  
The Impact

1084 Background: Metastatic breast cancer (MBC) is associated with genomic evolution, representing a challenge at clinical progression. While tissue and blood next-generation sequencing (NGS) allows for the baseline detection of alterations, non-invasive longitudinal assessment of ctDNA can provide a tool for monitoring tumor evolution. We characterized genomic changes using serial ctDNA testing in patients with clinical progression. Methods: Patient data was obtained under an IRB-approved protocol and ctDNA was collected at Northwestern University between 2015-2019. All ctDNA samples were analyzed using the Guardant360 NGS assay. Of 255 patients with MBC, 86 had at least two serial ctDNA collections with the second collection drawn at first progression (P1) by imaging and clinical assessment. Participants were followed until second clinical progression (P2). We analyzed type of alterations, mutant allele frequency (MAF), number of alterations (NOA), and sites of disease on imaging in close proximity to ctDNA evaluation. Matched pairs variations in MAF and NOA at P1 and P2 were tested through Wilcoxon test. Results: We identified 44 HR+, 20 HER2+ and 22 TNBC cases. Median lines of therapy were 3 (interquartile range (IQR): 1-6) for HR+, 3 (IQR: 1-5) for HER2+, and 2 (IQR: 1-4) for TNBC. The most likely alterations between baseline to P1 were TP53 (p < 0.0075), PIK3CA (p < 0.0126), AR (p < 0.0126), FGFR1 (p < 0.0455) and ESR1 (p < 0.0143). In the HR+ subset , ESR1 was statistically more likely at P1. ESR1 at P1 was also associated with development of new liver lesions (p < 0.0320). ERBB2 mutation at P1 was associated with new lung (p < 0.0050) or bone lesions (p < 0.0030). Increase in NOA was observed between baseline and P1 (p < 0.0001), P1 and P2 (p < 0.0001), and baseline to P2 (p < 0.0004). MAF was increased between baseline and P2 (p < 0.0480). Conclusions: Serial ctDNA testing identified resistance alterations ( TP53, PIK3CA, AR, ESR1, FGFR1), with some mutations indicating new sites of disease ( ESR1, ERBB2). Heterogeneity of ctDNA was significantly associated with progressive disease. Prospective evaluation of the impact of serial ctDNA testing on treatment decisions is needed to expand the role of precision medicine in MBC. [Table: see text]

Serial ctDNA tracking reveals clonal evolution dynamics in advanced urothelial carcinoma (UC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 401-401
Author(s):  
Dario Martin Villamar ◽  
Kristin Sedgwick Price ◽  
Rebecca Nagy ◽  
Scott T. Tagawa ◽  
Ana M. Molina ◽  
...  
Keyword(s):  
Clonal Evolution ◽  
Circulating Tumor Dna ◽  
Fold Change ◽  
Dynamic Monitoring ◽  
Tumor Evolution ◽  
Testing Time ◽  
Time Points ◽  
Molecular Alterations ◽  
Clinically Significant ◽  
Radiologic Progression

401 Background: UC is characterized by extensive genomic heterogeneity. Access to genomic DNA from all metastatic lesions is infeasible. Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) may recapitulate heterogeneity and offer an opportunity for continuous tracking of tumor evolution. Methods: We analyzed a cohort of advanced UC patients with serial (2 time points) ctDNA NGS using Guardant360. Restaging scans were examined to determine the relationship between ctDNA dynamics and radiologic progression. We performed whole exome sequencing (WES) of a subset of the corresponding tumors to define patterns of genomic heterogeneity. Results: NGS was performed on 214 individual ctDNA samples from 78 advanced UC patients (61 M, 17 F). A minimum of 2 serial ctDNA tests per patient (range 2-8) were collected over an average 21.5 (2-108) weeks between samples. Molecular alterations (MAs) were identified in 188 (88%) of samples with a mean of 4.3 alterations (1-31) per sample. 184 (85%) samples harbored SNVs, 30 (14%) harbored indels and 36 CNVs (17%). Most commonly mutated genes were TP53 (18%), ARID1A, NF1 (4.5% each ), EGFR (3.5%), FGFR3 (3.4%), ERBB2 and PIK3CA (3.4% each ). The most frequently amplified genes were ERRB2 and CCNE1. Serial analysis of maximum variant allele frequency (mVAF) revealed a mean 7.5-fold change between 1st and 2nd and a 6-fold change between 2nd and 3rd ctDNA samples. Interestingly, the mean rate of mVAF fold change/week was stable between serial testing time points (0.35, 0.32 p = 0.7). We observed that patients with higher initial mVAF ( > 3%) experienced a significantly larger mean fold decrease compared to patients with initial mVAF below this threshold (p = 0.008). In patients with available restaging scans timed with ctDNA testing, all patients with radiologic progression exhibited increasing mVAF (mean: 8-fold). Interestingly, ctDNA identified several clinically-significant somatic MAs not present on matching tumor WES including PIK3CA (T727R, M1043I), TP53 (Q331*, P190L), RB1 (R556*, Q257*), APC (D2527H), and BRCA2 (P2804S).WES is ongoing in more patients. Conclusions: ctDNA sequencing enables dynamic monitoring of therapy-driven clonal evolution patterns of advanced UC.

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