Correlation of circulating tumor DNA (ctDNA), tissue-based genomic profiling and clinical efficacy in the biomarker directed Ph1b trial in metastatic bladder cancer (BISCAY).

4553 Background: BISCAY is a biomarker-directed Ph1b multi-arm platform study exploring the combination of targeted therapies with anti-PD-L1, Durvalumab, in advanced urothelial cancer. Methods: Next generation sequencing (NGS) of tumour tissue samples from > 380 patients(pts) was performed using the FoundationOne assay alongside IHC for PD-L1. ct DNA from pts enrolled in trial modules at treatment initiation was profiled using the Guardant Health OMNI platform assessing a panel of 500 genes. For a subset of pts, serial plasma samples were also analysed to monitor early signs of response vs. resistance and changes in ct DNA dynamics using a bespoke NGS panel of 10 genes. Results: To date 149 pts have been actively enrolled across 7 different biomarker selected and unselected treatment modules. Across all screened pts the most prevalent genomic alterations in tumour tissue were TERT promoter (65%), TP53 (59%), KMT2D 21%, KDM6A 21%, with the most common CNV CDKN2A/ B loss (32 %). All enrolled pts tested had detectable ctDNA in plasma. Similar genomic alterations, both frequency and type, were detected in both plasma ctDNA and tumour tissue with high concordance for module specific biomarkers used for patient allocation (80% (8/10) for ATM, BRCA1 and 2). Alterations in putative biomarkers predictive of response to anti-PD-L1, such as HRR/MMR alterations and high bTMB levels ( > 20mut/Mb) were observed in22% and 40% patient plasma samples, respectively. Correlations between biomarkers across modules treatment efficacy have been explored. Conclusions: All pts with advanced bladder cancer enrolled on BISCAY who were plasma profiled had detectable ctDNA; frequencies of genomic alterations (in both tumour tissue and plasma) were comparable to prior published data sets. ctDNA may be an attractive alternative to tissue-based NGS, providing comprehensive dynamic snapshots of genomic landscapes at the start and during therapy, and warrants further prospective investigation in trials.

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PATH-06. ASSESSMENT OF CIRCULATING TUMOR DNA IN CEREBROSPINAL FLUID BY WHOLE EXOME SEQUENCING TO DETECT GENOMIC ALTERATIONS OF GLIOBLASTOMA

Neuro-Oncology ◽

10.1093/neuonc/noaa215.688 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii165-ii165

Author(s):

Hao Duan ◽

Zhenqiang He ◽

Zhenghe Chen ◽

Yonggao Mou

Keyword(s):

Cerebrospinal Fluid ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Tumor Tissue ◽

Circulating Tumor Dna ◽

Genomic Alterations ◽

Tissue Samples ◽

Whole Exome ◽

Resected Tumor ◽

Tumor Dna

Abstract Cerebrospinal fluid (CSF) has been demonstrated as a better source of circulating tumor DNA (ctDNA) than plasma for brain tumors. However, it is unclear whether whole exome sequencing (WES) is qualified for detection of ctDNA in CSF. The aim of this study was to determine if assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma. CSFs of ten glioblastoma patients were collected pre-operatively at the Department of Neurosurgery, Sun Yat-sen University Cancer Center. ctDNA in CSF and genome DNA in the resected tumor were extracted and subjected to WES. The identified glioblastoma-associated mutations from ctDNA in CSF and genome DNA in the resected tumor were compared. Due to the ctDNA in CSF was unqualified for exome sequencing for one patient, nine patients were included into the final analysis. More glioblastoma-associated mutations tended to be detected in CSF comparing with the corresponding tumor tissue samples (3.56±0.75 vs. 2.22±0.32, P=0.097), while the statistical significance was limited by the small sample size. The average mutation frequencies were similar in CSF and tumor tissue samples (74.12% ± 6.03% vs. 73.83% ± 5.95%, P = 0.924). The R132H mutation of isocitrate dehydrogenase 1 and the G34V mutation of H3F3A which had been reported in the pathological diagnoses were also detected from ctDNA in CSF by WES. Patients who received temozolomide chemotherapy previously or those whose tumor involved subventricular zone tended to harbor more mutations in their CSF. Assessment of ctDNA in CSF by WES is a feasible approach to detect genomic alterations of glioblastoma, which may provide useful information for the decision of treatment strategy.

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A pilot study reveals the potential of miR-31-3p and miR-196a-5p as non-invasive biomarkers in advanced laryngeal cancer

Folia Medica ◽

10.3897/folmed.63.e55346 ◽

2021 ◽

Vol 63 (3) ◽

pp. 355-364

Author(s):

Silva Garo Kyurkchiyan ◽

Todor Miroslavov Popov ◽

Felitsiya Shakola ◽

Julian Rangachev ◽

Vanyo Ivanov Mitev ◽

...

Keyword(s):

Laryngeal Squamous Cell Carcinoma ◽

Tumour Tissue ◽

Control Group ◽

Plasma Samples ◽

Tissue Samples ◽

Non Invasive ◽

Laboratory Techniques ◽

Laryngeal Tumour ◽

Fresh Frozen ◽

Spss Software

Introduction: Recently, miRNAs have become popular molecules used as non-invasive biomarkers in cancer diseases. Aim: The aim of the study was to explore the expression of four miRNAs isoforms: miR-31-3p, miR-196a-5p, miR-210-3p and miR-424-5p in plasma and tissue samples from patients with advanced laryngeal squamous cell carcinoma (LSCC) and healthy controls. Materials and methods: Fresh-frozen tumour and normal laryngeal tissue as well as plasma samples were obtained from 22 patients diagnosed with advanced LSCC. The control group included plasma samples from 21 cancer-free volunteers. Total RNA (including miRNAs) extraction, reverse transcription and real time qPCR were the laboratory techniques used in the study. The obtained results were analyzed using SPSS software v. 23. Results: We found that miR-31-3p, miR-196a-5p, and miR-210-3p levels were significantly elevated in laryngeal tumour tissue, but only the levels of miR-31-3p and miR-196a-5p were significantly upregulated in the plasma LSCC target group. Positive correlation was obtained for miR-31-3p (rs=0.443, p=0.039) and miR-196a-5p (rs=0.548; p=0.008) between plasma and adjacent tumour tissue LSCC samples. ROC analyses were used to evaluate the discriminative power of both miRNAs alone and in combination. The combination of miR-31-3p and miR-196a-5p showed best results with AUC=0.978 (95% CI: 0.945–1.000, p<0.001) with 100% sensitivity and 81% specificity at cut-off: RQ=2.99. Conclusions: Based on this miR-31-3p and miR-196a-5p are proposed as potential biomarkers for validation in larger LSCC group and could be included in a non-invasive miRNAs set for detection of advanced LSCC.

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Genomic alterations in appendiceal carcinoma using circulating DNA.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.658 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 658-658

Author(s):

Walid Labib Shaib ◽

Ali Roberts ◽

Mehmet Akce ◽

Christina Wu ◽

Olatunji B. Alese ◽

...

Keyword(s):

Low Frequency ◽

Circulating Tumor Dna ◽

Plasma Samples ◽

Single Nucleotide Variants ◽

Liquid Biopsies ◽

Genomic Alterations ◽

Synonymous Mutations ◽

Molecular Alterations ◽

Uncertain Significance ◽

Brca1 Brca2

658 Background: Appendiceal cancers (AC) comprise around 0.5% of all gastrointestinal neoplasia. The genomic landscape of AC has not been well studied. The yield of circulating tumor DNA (ctDNA) from the plasma of patients with AC has not been reported. The aim of this study is to confirm the feasibility of NGS using ctDNA and characterize common alternations in the genomic profile of AC. Methods: The molecular alterations in 372 plasma samples from 303 patients with AC using clinical-grade NGS of ctDNA (Guardant 360) across multiple institutions, was evaluated. The test detects single nucleotide variants in 54 -73 genes, copy number amplifications, fusions, and indels in selected genes. Results: A total of 303 AC patients were evaluated; 169 female (56%). Median age was 56.8 (range: 25-83). ctDNA NGS testing was done on 372 plasma samples; 48 patients had testing performed twice, 9 three times, and 1 was tested four times. Genomic alterations were defined in 207 (55.6%) samples with a total of 288 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. TP53 associated genes were most commonly altered (n = 96, 33.3%), followed by KRAS (n = 41, 14.2%), APC (n = 19, 6.6%), EGFR (n = 15, 5.2%), BRAF (n = 13, 4.5%), NF1 (n = 13, 4.5%), MYC (n = 9, 3.1%), GNAS (n = 8, 2.7%), PI3CA (n = 7, 2.4%), MET (n = 6, 2.08%), ATM in 6 (1.6%). Other genomic alterations of low frequency, but clinically relevant: AR (n = 4, 1.39%), TERT (n = 4, 1.39%), ERBB2 (n = 4, 1.39%), SMAD4 (n = 3, 1.04%), CDK4 (n = 2, 0.69%), NRAS (n = 2, 0.69%), FGFR1 (n = 2, 0.69%), FGFR2 (n = 2, 0.69%), PTEN (n = 2, 0.69%), RB1 (n = 2, 0.69%), and CDK6, CDKN2A, BRCA1, BRCA2, JAK2, IDH2, MAPK, NTRK1, CDH1, ARID1A, and PDGFRA were all reported once. Conclusions: Evaluation of ctDNA was feasible among individuals with AC. The frequency of genomic alterations in ctDNA testing is similar to those previously reported in tissue NGS. Liquid biopsies are non-invasive methods that can provide personalized options for targeted therapies in patients with AC.

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Genomic Profiling of Blood-Derived Circulating Tumor DNA from Patients with Advanced Biliary Tract Cancer

Pathology & Oncology Research ◽

10.3389/pore.2021.1609879 ◽

2021 ◽

Vol 27 ◽

Author(s):

Chen Chen ◽

Tao Wang ◽

Mengmei Yang ◽

Jia Song ◽

Mengli Huang ◽

...

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Circulating Tumor Dna ◽

Chinese Patients ◽

Ras Signaling ◽

Genomic Alterations ◽

Tissue Samples ◽

Genomic Changes ◽

Tract Cancer ◽

Tumor Dna

Background: Biliary tract cancer is a highly lethal malignancy with poor clinical outcome. Accumulating evidence indicates targeted therapeutics may provide new hope for improving treatment response in BTC, hence better understanding the genomic profile is particularly important. Since tumor tissue may not be available for some patients, a complementary method is urgently needed. Circulating tumor DNA (ctDNA) provides a noninvasive means for detecting genomic alterations, and has been regarded as a promising tool to guide clinical therapies.Methods: Next-generation sequencing of 150 cancer-related genes was used to detect gene alterations in blood-derived ctDNA from 154 Chinese patients with BTC. Genomic alterations were analyzed and compared with an internal tissue genomic database and TCGA database.Results: 94.8% patients had at least one change detected in their ctDNA. The median maximum somatic allele frequency was 6.47% (ranging 0.1–34.8%). TP53 and KRAS were the most often mutated genes. The frequencies of single nucleotide variation in commonly mutated genes in ctDNA were similar to those detected in tissue samples, TP53 (35.1 vs. 40.4%) and KRAS (20.1 vs. 22.6%). Pathway analysis revealed that mutated genes were mapped to several key pathways including PI3K-Akt, p53, ErbB and Ras signaling pathway. In addition, patients harboring LRP1B, TP53, and ErbB family mutations presented significantly higher tumor mutation burden.Conclusions: These findings demonstrated that ctDNA testing by NGS was feasible in revealing genomic changes and could be a viable alternative to tissue biopsy in patients with metastatic BTC.

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Changes in circulating tumor DNA levels are associated with treatment response and progression-free survival in relapse/refractory DLBCL subjects.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.7546 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 7546-7546

Author(s):

Alexander F. Lovejoy ◽

Hai Lin ◽

Ehsan Tabari ◽

Seng Lor Saelee ◽

David Matthew Kurtz ◽

...

Keyword(s):

Tumor Tissue ◽

Residual Disease ◽

Progression Free Survival ◽

Circulating Tumor Dna ◽

Response To Therapy ◽

P Value ◽

Molecular Response ◽

Plasma Samples ◽

Tissue Samples ◽

Tumor Dna

7546 Background: Detection of an initial molecular response to therapy in DLBCL could help differentiate patients who will relapse (30-40% of frontline subjects) from those who will not. Recent studies in DLBCL showed ability to detect residual disease and molecular response to therapy from analysis of circulating tumor DNA (ctDNA). Here we performed targeted next generation sequencing (NGS) of baseline ctDNA vs. tumor tissue, and on-treatment ctDNA samples in 32 relapse/refractory DLBCL subjects from the ROMULUS study to assess correlation of outcome with molecular response. Methods: We sequenced plasma, plasma depleted whole blood (PDWB), and tumor DNA from 32 subjects (range 2-6 samples / subject). Library preparation and NGS were performed using hybrid capture-based workflows, with a panel of ~300 kb targeting regions relevant for disease detection in DLBCL. Variants were called from tissue and plasma data, and PDWB data were used to filter out non-tumor specific variants. Results: 83% of variants detected in tissue (1441/1745) were found in the corresponding plasma samples, and 78% of variants detected in plasma (1441/1846) were found in corresponding tissue samples, in line with previous reports. To follow ctDNA changes with treatment, tumor-specific variants were determined from tissue or cycle 1 day 1 (C1D1) plasma samples. These variants were then monitored in C1D1 and later timepoints, with similar ctDNA levels based on variants determined from C1D1 plasma or tissue (R2=0.99). Change in ctDNA levels from C1D1 to C2D1 separated subjects that responded from subjects that progressed (Wilcoxon p-value: 9.39×10-4). Subjects that showed a 10-fold or higher drop in ctDNA levels between C1D1 and C2D1 had significantly longer PFS than those with a smaller ctDNA fold change (HR: 8.06; p=0.0008). Conclusions: This study showed that tumor-specific variants can be identified in baseline plasma with similar performance as from tumor tissue, and that monitoring molecular response as an early change in ctDNA levels after one cycle of treatment correlated with outcomes in this DLBCL study. Clinical trial information: NCT01691898.

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Concordance of Genomic Alterations between Circulating Tumor DNA and Matched Tumor Tissue in Chinese Patients with Breast Cancer

Journal of Oncology ◽

10.1155/2020/4259293 ◽

2020 ◽

Vol 2020 ◽

pp. 1-8 ◽

Cited By ~ 1

Author(s):

Bing Xu ◽

Guangyu Shan ◽

Qixi Wu ◽

Weiwei Li ◽

Hongjiang Wang ◽

...

Keyword(s):

Breast Cancer ◽

Circulating Tumor Dna ◽

Concordance Rate ◽

Chinese Patients ◽

Genomic Alteration ◽

Single Nucleotide Variants ◽

Genomic Alterations ◽

Tissue Samples ◽

Wilcoxon Rank Sum Test ◽

Tumor Dna

Purpose. Circulating tumor DNA (ctDNA) served as a noninvasive method with less side effects using peripheral blood. Given the studies on concordance rate between liquid and solid biopsies in Chinese breast cancer (BC) patients were limited, we sought to examine the concordance rate of different kinds of genomic alterations between paired tissue biopsies and ctDNA samples in Chinese BC cohorts. Materials and Methods. In this study, we analyzed the genomic alteration profiles of 81 solid BC samples and 41 liquid BC samples. The concordance across 136 genes was evaluated. Results. The median mutation counts per sample in 41 ctDNA samples was higher than the median in 81 tissue samples (p=0.0254; Wilcoxon rank sum test). For mutation at the protein-coding level, 39.0% (16/41) samples had at least one concordant mutation in two biopsies. 20.0% tissue-derived mutations could be detected via ctDNA-based sequencing, whereas 11.7% ctDNA-derived mutations could be found in paired tissues. At gene amplification level, the overall concordant rate was 68.3% (28/41). The concordant rate at gene level for each patient ranged from 83.8% (114/136) to 99.3% (135/136). And, the mean level of variant allele frequency (VAF) for concordant mutations in ctDNA was statistically higher than that for the discordant ones (p<0.001; Wilcoxon rank sum test). Across five representative genes, the overall sensitivity and specificity were 49.0% and 85.9%, respectively. Conclusion. Our results indicated that ctDNA could provide complementary information on genetic characterizations in detecting single nucleotide variants (SNVs) and insertions and deletions (InDels).

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Characteristics of genomic alterations in circulating tumor DNA (ctDNA) in patients (Pts) with advanced gastrointestinal (GI) cancers in nationwide large-scale ctDNA screening:SCRUM-Japan Monstar-Screen.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.106 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 106-106

Author(s):

Yoshiaki Nakamura ◽

Takao Fujisawa ◽

Shigenori Kadowaki ◽

Naoki Takahashi ◽

Masahiro Goto ◽

...

Keyword(s):

Large Scale ◽

Tumor Tissue ◽

Circulating Tumor Dna ◽

Genomic Alterations ◽

Tissue Samples ◽

Gi Cancer ◽

Oncogenic Pathways ◽

Treatment Naïve ◽

Gi Cancers ◽

Ctdna Analysis

106 Background: Analysis of ctDNA has been utilized in pts with advanced GI cancer for identification of genomic alterations for targeted therapy. However, the characteristics of ctDNA genomic alterations of GI cancers compared to non-GI cancers remains unclear. Methods: Pts with advanced solid tumors were eligible in MONSTAR-SCREEN, a nationwide ctDNA screening project in Japan. Plasma samples were analyzed by an NGS-based 70-gene ctDNA assay, FoundationOne Liquid (F1L) at a CLIA-certified and CAP-accredited laboratory since Jul 2019. For treatment-naïve pts, tumor tissue samples were analyzed by FoundationOne CDx (F1CDx), a 324-gene tissue-based panel. Results: As of Jun 18 2020, out of enrolled 540 pts with advanced solid tumor, 470 pts, consisting of 133 with advanced GI cancers (67 colorectal, 48 gastric, 14 esophageal, 2 gastrointestinal tumor (GIST) and 2 small intestinal) and 337 non-GI cancers (103 hepatobiliary and pancreatic, 70 genitourinary, 64 breast, 46 head and neck, 33 gynecologic, and 21 skin), had an available ctDNA result. Sequencing success rate was similar between GI and non-GI cancers (91.7% vs. 89.3%, P = 0.50). GI cancers had a significantly higher ctDNA level (maximum variant allele fraction) than non-GI cancers (median, 11.8% vs. 0.57%; P = 1.6E-7). The most frequently altered genes were TP53 (73%), APC (73%), KRAS (30%), BRAF (15%), and PIK3CA (12%) in colorectal cancer, TP53 (44%), KRAS (19%), PIK3CA (15%), ATM (10%), and ERBB2 (10%) in gastric cancer, and TP53 (79%), ATM (21%), ERBB2 (21%) in esophageal cancer. Mutations in genes in pathways related to RAS/RAF/MEK (39.1 % vs. 21.4 %, P = 1.8E-4), receptor tyrosine kinase (20.3% vs 11.9%, P = 0.027), p53 (66.2% vs 49.6%, P = 0.0014), and Wnt (41.4% vs 4.7%, P = 4.4E-21) were significantly enriched in GI cancers compared to non-GI cancers. Tumor tissue samples were analyzed using F1CDx for 63 treatment-naïve pts, in which 51 (31.3%) of 132 alterations identified by F1L were not detected by F1CDx. Conclusions: GI cancers had higher ctDNA levels and distinct characteristics of ctDNA genomic alterations from non-GI cancers with an enrichment in several oncogenic pathways. One-third of ctDNA alterations were detected in only ctDNA, indicating the potential of ctDNA analysis to identify heterogenous genomic alterations in advanced GI cancer. Clinical trial information: UMIN000036749.

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Molecular Characteristics and Disease Burden Metrics Determined By Next-Generation Sequencing on Circulating Tumor DNA Correlate with Progression Free Survival in Previously Untreated Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood-2019-123633 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 490-490 ◽

Cited By ~ 1

Author(s):

Ehsan Tabari ◽

Alexander F Lovejoy ◽

Hai Lin ◽

Christopher R Bolen ◽

Seng Lor Saelee ◽

...

Keyword(s):

B Cell ◽

Disease Burden ◽

Progression Free Survival ◽

B Cell Lymphoma ◽

Circulating Tumor Dna ◽

Tumor Burden ◽

Plasma Samples ◽

Tissue Samples ◽

Quantitative Pet ◽

Equity Ownership

Introduction: Due to the range of biological and molecular heterogeneity in diffuse large B-cell lymphoma (DLBCL), personalized risk stratification and treatment is a promising avenue to improving outcomes. Although most risk stratification depends primarily on clinical data (e.g. IPI), the addition of molecular, genomic or disease burden (e.g. quantitative PET imaging) features in DLBCL could help better stratify patients (pts) according to disease biology or burden. Such data are often hard to obtain in routine clinical settings; current methods remain limited by the need for tissue samples and low reproducibility in daily practice. A single method to assess such molecular markers from plasma samples could enable a standardized process. Here, we use a circulating tumor DNA (ctDNA)-based next-generation sequencing (NGS) method on pre-treatment plasma samples from first-line DLBCL pts to show prognostic correlations from molecular and disease burden assessments. Methods: We performed targeted NGS on plasma samples from 310 previously untreated DLBCL pts enrolled in the GOYA study (NCT01287741) with a custom DLBCL-specific panel using a workflow optimized for ctDNA. Cell-free DNA (cfDNA) was isolated from plasma and an average of 30.7ng (range, 0.7-50ng) of cfDNA was used. Library preparation and NGS were performed with a modified AVENIO ctDNA workflow, with a custom panel of ~314kb designed to cover regions relevant for cell-of-origin (COO) and minimal residual disease in DLBCL. Single nucleotide variants (SNVs), insertions/deletions (indels), and fusions were determined, and criteria based on publicly available data removed non-tumor specific variants. For each sample, number of tumor genome copies per mL of plasma (MMPM), a measure of tumor burden, was calculated using the allele fractions of variant calls and cfDNA mass. Variant calls from 230 pts were used to build a machine learning model to determine COO, which was tested on the remaining 80 pts. Variant and COO calls were correlated with data from corresponding tissue samples, including mutations from FoundationOne® Heme and gene expression-based COO determination from Lymph2Cx (NanoString). Variant, COO, and disease burden assessments from ctDNA NGS were also compared with clinical variables, including IPI, baseline quantitative PET imaging, and progression-free survival (PFS) data. Results: 77% of SNVs (958/1247), 63% of indels (72/115), and 74% of fusions (49/66) detected with the FoundationOne assay were detected in the plasma samples. COO calls from plasma showed 93% concordance with Lymph2Cx calls from tissue when both methods classified a sample, with 37/40 germinal center B-cell (GCB) agreeing and 17/18 non-GCB agreeing in the test set. Subsequently, correlation of various metrics from the ctDNA assay with clinical outcomes was assessed. Non-GCB pts showed a trend towards worse PFS when compared with GCB pts (hazard ratio [HR], 1.23; 95th percentile: 0.79─1.92; p=0.32). Additionally, worse PFS was observed for pts with MYC fusions (n=12; HR, 2.83; 95th percentile: 1.29─6.21; p=0.010) and TP53 SNVs or indels (n=99; HR, 1.75; 95th percentile: 1.13─2.70; p=0.031), with a similar trend for BCL2 fusions (n=31; HR, 1.96; 95th percentile: 0.94─4.07; p=0.072). Baseline MMPM was significantly correlated with total metabolic tumor volume (TMTV) as measured by PET (r=0.36; p<0.001) and sum of the product of diameters (SPD; r=0.13; p=0.022). Higher MMPM values corresponded to higher IPI scores (ANOVA p<0.001), higher likelihood of bulky disease (p=0.019), and worse PFS as a continuous variable (HR, 1.46; p=0.0006; Figure 1). In a multivariate model accounting for TMTV, MMPM was not prognostic (p=0.15), but in a model containing SPD and MMPM, both were independently prognostic (MMPM p=0.010; SPD p=0.0046), suggesting that SPD and MMPM provide complementary prognostic information. Interestingly, in this sample set, activated B-cell samples also showed a significantly higher MMPM than GCB and unclassified samples (p=0.0017). Even when considering COO and IPI in a multivariate analysis, MMPM remained correlated with PFS (HR, 1.23; p=0.079). Conclusions: We describe a single NGS-based method, which calls variants, determines COO, and assesses tumor burden from plasma. Using these results, we show that pre-treatment plasma-based molecular and tumor burden measurements in previously untreated DLBCL pts correlate with PFS. Disclosures Tabari: F. Hoffmann-La Roche: Equity Ownership; Roche Sequencing Solutions: Employment. Lovejoy:Roche Sequencing Solutions: Employment. Lin:Roche Sequencing Solutions: Employment; Veracyte: Other: Veracyte (spouse). Bolen:F. Hoffmann-La Roche: Equity Ownership; Genentech, Inc.: Employment. Saelee:Roche Sequencing Solutions: Employment. Lefkowitz:Roche Sequencing Solutions: Employment. Kurtz:Roche: Consultancy. Vitazka:Roche Sequencing Solutions: Employment. Venstrom:F. Hoffmann-La Roche Ltd: Employment. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership. Parreira:F.Hoffmann-La Roche Ltd: Employment, Equity Ownership, Honoraria. Klass:Roche Sequencing Solutions: Employment; Roche: Equity Ownership. Luong:Roche Sequencing Solutions: Employment.

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Identifying Genomic Alterations in Small Cell Lung Cancer Using the Liquid Biopsy of Bronchial Washing Fluid

Frontiers in Oncology ◽

10.3389/fonc.2021.647216 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jinfang Zhai ◽

Songyan Han ◽

Qinxiang Guo ◽

Binbin Shan ◽

Jing Wang ◽

...

Keyword(s):

Liquid Biopsy ◽

Tumor Tissue ◽

Small Cell ◽

Post Treatment ◽

Plasma Samples ◽

Small Cell Lung ◽

Genomic Alterations ◽

Tissue Samples ◽

Bronchial Washing ◽

Pre Treatment

Objective: With the rapid development of cancer genomics and immunomics, some new treatments of small cell lung cancer (SCLC) are emerging. However, there are limitations to the clinical use of tumor tissue. Our study aimed to evaluate the potential use of bronchial washing fluid (BWF) in the liquid biopsy of SCLC.Methods: Twenty-one extensive SCLC (ES-SCLC) patients were enrolled in this study. For all patients, four sample types, BWF supernatant (BWFs), BWF precipitate (BWFp), plasma and tumor tissue, were collected before receiving chemotherapy, and one type, plasma, was collected after chemotherapy. All samples were conducted to NGS using the 1021-gene panel. The concordance rates of genomic profiling using NGS in the four types of samples were evaluated. Multiple clinical information was analyzed for correlation.Results: We successfully tested 20 BWFs samples, 21 BWFp samples, 21 tumor tissue samples, 20 pre-treatment plasma, and 13 post-treatment plasma of these 21 patients. The detectability of somatic mutations was 100% for BWFs, BWFp, tumor tissues, and post-treatment plasma, and only one pre-treatment plasma was absent with any mutation. Matched tumor tissue, BWFs, BWFp, and pre-treatment plasma samples were subsistent for 19 patients. For these patients, 204 genomic alterations were identified in tissue samples, while 189 (92.6%), 175 (85.5%), and 163 (79.9%) alterations were detected in the matched BWFs, BWFp, and pre-treatment plasma, respectively. Moreover, we found that the three tumor markers associated with SCLC have a lower sensitivity than genomic alterations. The endocrine resistance pathway was found enriched in hyponatremia patients which may be related to the hyponatremia. The TMBs of BWF, BWFp, and pre-treatment plasma samples all had a strong correlation with that of tissue samples. Both the VAF and the MVAF of mutations in post-treatment plasma were less than those in pre-treatment plasma, which was in accordance with the evaluation of curative effect.Conclusions: For ES-SCLC patients, the liquid biopsy of BWF showed a highly potential advantage to identify DNA alterations, which suggested that genomic analysis of BWF liquid biopsy may have clinical value as a supplement for tissue and blood detection. Through the restricted validation, it can be widely used in routine clinical practice.

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