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

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.

Identifying genomic alterations in small cell lung cancer using the liquid biopsy of bronchial washing fluid.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e21098-e21098
Author(s):  
Jinfang Zhai ◽  
Songyan Han ◽  
Qinxiang Guo ◽  
Binbin Shan ◽  
Jing Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Tumor Tissue ◽  
Small Cell ◽  
Plasma Samples ◽  
Small Cell Lung ◽  
Tissue Samples ◽  
Bronchial Washing ◽  
Treatment Naïve

e21098 Background: With the rapid development of cancer genomics, the precision medicine of small cell lung cancer (SCLC) is emerging. However, there are limitations to the clinical use of tumor tissue and peripheral blood biopsies. The main purpose of this study was to evaluate the potential use of bronchial washing fluid (BWF) in the liquid biopsy of SCLC. Methods: Twenty-one SCLC patients diagnosed in 2019 were enrolled in this study. BWF (separated as supernatant and precipitate), treatment-naive plasma and tumor tissue samples were collected from all of patients and subjected to next-generation sequencing (NGS) using a 1021-gene panel. The concordance rates of genomic profiling using NGS in these four types of samples were evaluated. Results: Of these 21 patients, 20 BWF supernatant (BWFs) samples, 21 BWF precipitate (BWFp) samples, 21 tumor tissue samples and 20 plasma samples were successfully tested. The detectability of somatic mutations was 100% for BWFs, BWFp and tumor tissues, and only one plasma was absent with any mutation. Matched tumor tissue, BWFs, BWFp and plasma samples were subsistent for 19 patients. For these patients, 204 genomic alterations were identified in tissue samples, of which 189 (92.6%), 175 (85.5%) and 163 (79.9%) alterations were detected in the matched BWFs, BWFp and plasma samples, respectively. Moreover, tumor mutation burden (TMB) was also calculated. Compared with the proportion of TMB-H samples in tissue samples counting 61.9% (13/21), 60% (12/20) of BWFs samples and 52.38 % (11/21) of BWFp samples were TMB-H (defined as more than or equal to 9 mutations per megabase), which was a molecular biomarker that can be used in immunotherapy efficacy prediction. The TMBs of BWFs, BWFp and treatment-naive plasma samples all had strong correlation with that of tissue samples. The TMB of BWFs had the strongest correlation (Pearson r = 0.9512, p < 0.0001), and the TMB of treatment-naive plasma had relatively lower correlation (Pearson r = 0.8782, p < 0.0001) compared with those of BWFs (Pearson r = 0.936, p < 0.0001) and BWFp (Pearson r = 0.8782, p < 0.0001). Conclusions: For SCLC patients, the liquid biopsy of BWF showed high potential to identify DNA alterations and calculate TMB grades, which suggested that genomic analysis of BWF liquid biopsy may have clinical value in predicting the effectiveness of targeted therapy and immunotherapy. It can be widely used in routine clinical practice.

Association of PFS with levels of pretreatment lactate dehydrogenase in patients with EML4-ALK rearrangement non-small cell lung cancer treated with ALK tyrosine kinase inhibitor.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20513-e20513
Author(s):  
Hongge Liang ◽  
Di Ma ◽  
Yan Xu ◽  
Jing Zhao ◽  
Minjiang Chen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lactate Dehydrogenase ◽  
Small Cell Lung Cancer ◽  
Progression Free Survival ◽  
Small Cell ◽  
Post Treatment ◽  
Small Cell Lung ◽  
Alk Rearrangement ◽  
Free Survival ◽  
Pre Treatment

e20513 Background: We performed a retrospective analysis to investigate the association between the lactate dehydrogenase (LDH) levels and progression-free survival (PFS) in patients with echinoderm microtubule-associated protein-like 4-anaplasticlymphoma kinase (EML4-ALK) rearrangement non-small cell lung cancer (NSCLC) receiving treatment with crizotinib. Methods: Advanced NSCLC patients with EML4-ALK rearrangement receiving treatment with crizotinib were enrolled at Peking Union Medical College and Cancer Hospital Chinese Academy of Medical Sciences between January 2007 and January 2016. Pre-treatment or post-treatment serum LDH levels were analyzed with progression-free survival (PFS) and patients’ clinical parameters. Results: Overall, 212 patients were studied. Kaplan-Meier univariate analysis showed that elevated pre-treatment LDH level (7.9 vs. 14.1 months, P = 0.004) were associated with PFS, while the mean value of post-treatment LDH level (14.3 vs. 13.3 months, P = 0.970) were not associated with PFS. Coxproportional hazards model also identified that pre-treatment LDH level (hazard ratio [HR] = 1.841, 95% confidence interval [CI] 1.062-3.190, P = 0.030) was associated with the PFS. Logistic regression analysis showed that post-treatment LDH level was associated with creatine kinase(OR = 6.712, 95% CI 3.395-13.273, P < 0.01), CKMB (OR = 6.297, 95% CI 2.953-13.427, P < 0.01), and hemoglobin(OR = 4.163, 1.741-9.956, P = 0.001). Conclusions: An elevated pre-treatment serum LDH level ( > 250U/L) is significantly associated with shorter PFS in patients with EML4-ALK rearrangement NSCLC. Post-treatment elevated serum LDH level is associated with multiple factors including muscle damage and anemia, rather than PFS.

Validation of proteomic classifier for clinical benefit from erlotinib as first line treatment for advanced non-small cell lung cancer (ECOG 3503)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7508-7508
Author(s):  
B. J. Solomon ◽  
H. Roder ◽  
R. Robert ◽  
F. Taguchi ◽  
J. Brahmer ◽  
...  
Keyword(s):  
Mass Spectrometry ◽  
Lung Cancer ◽  
Clinical Benefit ◽  
Small Cell ◽  
Plasma Samples ◽  
Time To Progression ◽  
Small Cell Lung ◽  
First Line ◽  
Pre Treatment ◽  
Nsclc Patients

7508 Background: In this study we tested the ability of our serum mass spectrometry classifier of clinical benefit from gefitinib to classify pre-treatment sera and plasma samples from non-small cell lung cancer (NSCLC) patients treated first line with erlotinib in ECOG E3503. Methods: Pretreatment serum and plasma samples were available from 73 of the 96 previously untreated advanced NSCLC patients treated with single agent erlotinib on ECOG protocol 3503, 13 subjects had only serum samples, and 10 had only plasma samples. All of these samples analyzed in replicate by MALDI mass spectrometry (MS). A prediction algorithm we established based on a training cohort of 139 patients treated second or third line with gefitinib was used to classify these patients for survival and time to progression, and results obtained from serum and plasma were compared when both were available Results: We found that the signals for the 8 distinct mass-to-charge (m/z) features used in our classifier were highly concordant between serum and plasma samples from the same patient, and that there was no difference in the classification of the patients between serum and plasma when both were available. Therefore we classified all 96 patients using serum if available, and plasma if not. The classification algorithm very successfully classified patients into groups with good and poor survival (median survival of 306 days vs 107 days, p = 0.0007). With the available follow-up, the time to progression was also statistically significant in this group (p = 0.007, data not shown). In a Cox multivariate analysis including the most significant univariate parameters PS (0 vs. 1 vs 2), number of involved sites (=3 vs >3) and prior weight loss (<5% vs = 5%), the MALDI MS classification algorithm retained independent significance at p = 0.03, with a hazard ratio of 0.53. Conclusions: This multi-institutional ECOG study demonstrates that MALDI MS can assist in the pre-treatment selection of a subgroup of NSCLC patients who are likely to show improved survival after treatment with first line erlotinib. No significant financial relationships to disclose.

Longitudinal evaluation of EGFR mutation in plasma for non-small cell lung cancer patients with front-line chemotherapy

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8099-8099
Author(s):  
B. Hua ◽  
J. Zhao ◽  
S. H. Wang ◽  
L. Yang ◽  
J. C. Duan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cancer Patients ◽  
Egfr Mutation ◽  
Small Cell ◽  
Post Treatment ◽  
Wild Type ◽  
Small Cell Lung ◽  
Mutant Type ◽  
Lung Cancer Patients ◽  
Pre Treatment

8099 Background: To investigate longitudinally epidermal growth factor receptor (EGFR) mutation status in the plasma of pre- and post-chemotherapy for patients with advanced non-small cell lung cancer. Methods: Total of 153 advanced lung cancer patients were included in this study. Plasma samples in pre- and post-chemotherapy ( 2 cycles after) were collected. The DNA concentration was determined by real-time PCR. The EGFR exon 19 and 21 were amplified by mutant-enriched PCR and detected by denaturing high performance liquid chromatograph (DHPLC). The associations between EGFR mutation, DNA level and chemotherapeutic response were analyzed. Results: Among the 153 pts, EGFR mutation were detected 41.2% (63/153) and 27.4% (42/153) in plasma of pre-and post-chemotherapy, respectively. The objective response rate was 31.4% (48/153) and the circulating DNA level trend to decrease after chemotherapy in PR group but increase in PD group (p=0.012). 25 and 73 cases showed consistent EGFR mutation and wild-type status in pre-treatment and post-treatment plasma, respectively. Among 38 patients with change from pre-treatment EGFR mutant-type to post-treatment wild-type status, 11 gained PR, 12 SD and 15 PD. While for 17 patients with change from pre-treatment EGFR wild-type to post-treatment mutant-type, PR, SD and PD were 8, 7 and 2, respectively. The change to mutant-type in post-treatment plasma were found to be significantly higher in PR and disease control than PD(P=0.047, P=0.042). Conclusions: The data indicated that chemotherapy could not only affect the DNA concentration but also change the EGFR mutation detection in plasma for pts with advanced NSCLC. Reason for EGFR mutation change related with response of chemotherapy deserves further study. No significant financial relationships to disclose.

scholarly journals Blood-Based Liquid Biopsy for Comprehensive Cancer Genomic Profiling Using Next-Generation Sequencing: An Emerging Paradigm for Non-invasive Cancer Detection and Management in Dogs

2021 ◽  
Vol 8 ◽  
Author(s):  
Kristina M. Kruglyak ◽  
Jason Chibuk ◽  
Lisa McLennan ◽  
Prachi Nakashe ◽  
Gilberto E. Hernandez ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Liquid Biopsy ◽  
Tumor Tissue ◽  
Genomic Profiling ◽  
Next Generation ◽  
Blood Draw ◽  
Genomic Alterations ◽  
Tissue Samples ◽  
Non Invasive ◽  
Generation Sequencing

This proof-of-concept study demonstrates that blood-based liquid biopsy using next generation sequencing of cell-free DNA can non-invasively detect multiple classes of genomic alterations in dogs with cancer, including alterations that originate from spatially separated tumor sites. Eleven dogs with a variety of confirmed cancer diagnoses (including localized and disseminated disease) who were scheduled for surgical resection, and five presumably cancer-free dogs, were enrolled. Blood was collected from each subject, and multiple spatially separated tumor tissue samples were collected during surgery from 9 of the cancer subjects. All samples were analyzed using an advanced prototype of a novel liquid biopsy test designed to non-invasively interrogate multiple classes of genomic alterations for the detection, characterization, and management of cancer in dogs. In five of the nine cancer patients with matched tumor and plasma samples, pre-surgical liquid biopsy testing identified genomic alterations, including single nucleotide variants and copy number variants, that matched alterations independently detected in corresponding tumor tissue samples. Importantly, the pre-surgical liquid biopsy test detected alterations observed in spatially separated tissue samples from the same subject, demonstrating the potential of blood-based testing for comprehensive genomic profiling of heterogeneous tumors. Among the three patients with post-surgical blood samples, genomic alterations remained detectable in one patient with incomplete tumor resection, suggesting utility for non-invasive detection of minimal residual disease following curative-intent treatment. Liquid biopsy allows for non-invasive profiling of cancer-associated genomic alterations with a simple blood draw and has potential to overcome the limitations of tissue-based testing posed by tissue-level genomic heterogeneity.

scholarly journals C-reactive protein reduction post treatment is associated with improved survival in atezolizumab (anti-PD-L1) treated non-small cell lung cancer patients

PLoS ONE ◽  
2021 ◽  
Vol 16 (2) ◽  
pp. e0246486
Author(s):  
Namrata S. Patil ◽  
Wei Zou ◽  
Simonetta Mocci ◽  
Alan Sandler ◽  
Marcus Ballinger ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Small Cell ◽  
Post Treatment ◽  
Phase Iii ◽  
C Reactive Protein ◽  
Small Cell Lung ◽  
Reactive Protein ◽  
Pre Treatment ◽  
Serum Crp

Purpose Overall survival (OS) is the most significant endpoint for evaluation of treatment benefit with checkpoint inhibitors (CPI) in cancer. We evaluated serum C-reactive protein (CRP) in non-small cell lung cancer (NSCLC) trials with atezolizumab (anti-PD-L1) as an early OS surrogate. Methods Serum from patients enrolled in randomized Phase II (n = 240) and Phase III (n = 701) trials of NSCLC patients (POPLAR, OAK) who progressed on prior-platinum chemotherapy, were analyzed for CRP levels over time. Patients were grouped by changes in CRP levels post-treatment as either increased (≥ 1.5 fold), decreased (≤ 1.5 fold) or unchanged (within +1.5 fold) relative to pre-treatment levels to assess association with progression free survival (PFS) and OS. Results Decrease in serum CRP levels at 6 weeks relative to pre-treatment were observed in patients with RECIST1.1 based complete or partial responses (CR/PR) to atezolizumab whereas patients with disease progression (PD) demonstrated an increase in CRP levels in the Phase II POPLAR study, and confirmed in the Phase III OAK study. Decrease in serum CRP as early as six weeks post treatment predicted improved PFS and OS, even in patients who were determined as stable disease (SD) in their first scan. This effect was not observed in the chemotherapy arms. Conclusion Modulation of serum CRP correlates with clinical outcome post-atezolizumab treatment. This routine lab test may provide utility in informing OS signals as early as 6 weeks post-initiation of therapy with CPIs in NSCLC.

scholarly journals Gene-Guided Treatment Decision-Making in Non-Small Cell Lung Cancer – A Systematic Review

2021 ◽  
Vol 11 ◽  
Author(s):  
Jatta Saarenheimo ◽  
Heidi Andersen ◽  
Natalja Eigeliene ◽  
Antti Jekunen
Keyword(s):  
Lung Cancer ◽  
Systematic Review ◽  
Decision Making ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Liquid Biopsy ◽  
Small Cell ◽  
Small Cell Lung ◽  
Tissue Samples ◽  
Gene Alterations

Decision-making in cancer treatment is part of clinicians’ everyday work, and it is especially challenging in non-small cell lung cancer (NSCLC) patients, for whom decisions are clearly dependent on gene alterations or the lack of them. The multimodality of treatments, involvement of gene alterations in defining systemic cancer therapies, and heterogeneous nature of tumors and their responsiveness provide extra challenges. This article reviews the existing literature to 2021 with extra effort to explore the role of genes and gene-driven therapies as part of decision-making. The process and elements in this decision-making participation are recognized and discussed comprehensively. Genetic health literacy aids are provided as a part of the review. Our systematic review, data extraction and analysis found that with current methods and broad gene panels, patients benefit from early molecular testing of liquid biopsy samples. An estimated 79% of liquid biopsy samples showed somatic mutations based on 8 original studies included in the systematic review. When both liquid biopsy samples and tissue samples are evaluated, the sensitivity to detect targetable mutations in NSCLC increases. We recommend early testing with liquid biopsy. Additional effort is needed for the logistics of obtaining and evaluating samples, and tissue samples should be saved and stored for tests that are not possible from liquid biopsy.

scholarly journals Circulating Tumor DNA Analyses as a Potential Marker of Recurrence and Effectiveness of Adjuvant Chemotherapy for Resected Non-Small-Cell Lung Cancer

2021 ◽  
Vol 10 ◽  
Author(s):  
Peng-Peng Kuang ◽  
Ning Li ◽  
Zui Liu ◽  
Tian-Yu Sun ◽  
Shu-Quan Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
High Risk ◽  
Adjuvant Chemotherapy ◽  
Small Cell Lung Cancer ◽  
Tumor Tissue ◽  
Circulating Tumor Dna ◽  
Small Cell ◽  
Plasma Samples ◽  
Small Cell Lung ◽  
Tumor Dna

BackgroundAlthough adjuvant chemotherapy is established for patients with non-small-cell lung cancer (NSCLC), the long-term survival remains to be improved. Postsurgical circulating tumor DNA (ctDNA) analysis of resectable NSCLC may identify patients at high risk of recurrence after adjuvant chemotherapy and facilitate personalized therapy.MethodsThis analysis included 38 patients who underwent curative-intent resection and received adjuvant chemotherapy for NSCLC. ctDNA analyses of tumor tissue, and pre- and post-operative plasma samples were performed with next-generation sequencing targeting 425 cancer-relevant genes. We define a ctDNA positive event as at least one shared mutation identified simultaneously in the plasma and tumor specimens. The primary endpoint was recurrence-free survival (RFS).ResultsAt least one somatic mutation was identified in the tumor tissue of all 38 patients. Tumor tissue-specific mutated ctDNA was detected in the preoperative plasma samples of 19 (50%) patients. ctDNA in preoperative plasma was in good accordance with that in tissue. ctDNA was detectable in the first post-operative pre-chemotherapy samples of 8 of 35 (22.9%) patients and was associated with inferior RFS (HR, 3.69; P = 0.033). ctDNA was detected in the first post-chemotherapy samples of 8 of 36 (22.2%) patients and was also associated with inferior RFS (HR, 8.76; P &lt; 0.001).ConclusionsPostoperative and post-chemotherapy ctDNA is a promising prognostic marker for resected NSCLC. ctDNA analyses may define a subgroup that remains at high risk of relapse despite standard adjuvant chemotherapy, and may help to inform intensified therapeutic strategies.

PI3K-AKT pathway alterations are revealed as a potential mechanism of chemoradiation resistance in small cell lung cancer by whole-exome sequencing.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20573-e20573
Author(s):  
Ming Chen ◽  
Ying Jin ◽  
Yamei Chen ◽  
Xiao Hu ◽  
Huarong Tang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Exome Sequencing ◽  
Small Cell ◽  
Plasma Samples ◽  
Potential Mechanism ◽  
Small Cell Lung ◽  
Whole Exome ◽  
Treatment Naïve ◽  
Pre Treatment

e20573 Background: Although small-cell lung cancer (SCLC) is sensitive to chemotherapy and radiotherapy initially, nearly all patients recur often with treatment-resistant disease. Comparing genomic profiles and clonal architecture of paired treatment-naïve and recurrent tumors may provide novel insights into mechanisms underlying recurrence and susceptibility to further treatment. Methods: Paired tumor samples procured at diagnosis and relapse were collected from 11 patients (pts) with limited-stage SCLC treated with concurrent chemoradiation (CCRT). All tissues underwent whole exome sequencing (WES). Genomic landscape including somatic mutations, somatic copy number alterations (SCNAs), and clonal architecture were compared between treatment-naïve and paired recurrent tumor samples. Baseline and paired recurrent plasma samples from another 9 pts with SCLC treated with CCRT were performed deep sequencing using a targeted panel containing 1021 cancer related genes. Results: We observed TP53 and RB1 alterations including mutations and SCNAs in the majority of treatment-naïve ( TP53 in 10 of 11, RB1 in 7 of 11 pts) and relapse samples ( TP53 in 8 of 11, RB1 in 8 of 11 pts). Tobacco exposure related mutational signature was most or second predominant in 11 pre-treatment and 9 recurrent samples, respectively. Compared with primary tumors, relapsed tumors showed significantly increased number of mutations (220 vs 210, p = 0.016). A high proportion of shared mutations between baseline and PD samples ranging from 39% to 94% was observed. More than half (n = 6) of the 11 pts had increased chromosomal instability in recurrent tumors. A total of 687 relapse-specific also called acquired mutations in 633 genes were identified, in which 158 mutations with cancer cell fraction (CCF) > 0.6. These genes were enriched in PI3K-ATK signaling pathway and covered 73% (8/11) pts. Of the 9 paired plasma samples performed by targeted sequencing, genes with specific mutations and mutations with increased CCF in relapsed plasma samples were also enriched in PI3K-ATK pathway. In vitro proliferation assay indicated that PI3K inhibitor gave rise to a marked decrease in proliferation after combined with cisplatin, implying the potential mechanism of chemoradiation resistance. The number of clones in recurrent samples was higher than that in pre-treatment samples (13 vs 12, p = 0.004), indicating that new clones emerged under the treatment and tumor heterogeneity increased. Patients characterized by weakening of the major treatment-naïve clone tended to exhibit relatively longer PFS than those with sustaining major clone in both b baseline and relapsed tumors (p = 0.034). Conclusions: PI3K-ATK pathway alterations are frequent in recurrent SCLCs, which may be a candidate resistant mechanism after chemoradiation. PFS is probably associated with clonal evolutionary pattern.

Sign in / Sign up

Export Citation Format

Share Document