scholarly journals Alectinib-Induced Pleural and Pericardial Effusions in ALK-Positive NSCLC

2021 ◽  
pp. 1323-1327
Author(s):  
Maiken Parm Ulhoi ◽  
Boe Sandahl Sorensen ◽  
Peter Meldgaard
Keyword(s):  
Progressive Disease ◽  
Heart Function ◽  
Circulating Tumor Dna ◽  
Driver Mutations ◽  
First Line ◽  
Alk Positive ◽  
Next Generation Sequencing Ngs ◽  
Tumor Dna ◽  
Generation Sequencing ◽  
Mild Toxicity

Alectinib is the first-line targeted treatment for advanced ALK-positive non-small-cell lung cancer. Although it has a relatively mild toxicity profile, adverse events (AEs) do occur. We present a case of alectinib-induced bilateral pleural effusions and pericardial effusion that has not previously been reported. The patient developed severe dyspnea 3 months after starting alectinib. He underwent thorough clinical examination including evaluations of heart function. The heart function was normal. There was no sign of pneumonitis or progressive disease on the CT scans. Cytology samples of the pleural fluid from multiple thoracocenteses were examined and showed no malignant cells. Next-generation sequencing (NGS) analysis of circulating tumor DNA from sequential blood samples was also carried out. NGS identified no known driver mutations associated with the effusions. Hence, the effusions were suspected to be an alectinib-induced AE. Alectinib was withdrawn, and the patient commenced brigatinib. The effusions subsequently regressed.

scholarly journals Tracking the Evolution of Resistance to ALK Tyrosine Kinase Inhibitors Through Longitudinal Analysis of Circulating Tumor DNA

2018 ◽  
pp. 1-14 ◽  
Author(s):  
Ibiayi Dagogo-Jack ◽  
A. Rose Brannon ◽  
Lorin A. Ferris ◽  
Catarina D. Campbell ◽  
Jessica J. Lin ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Longitudinal Analysis ◽  
Kinase Inhibitors ◽  
Circulating Tumor Dna ◽  
Evolution Of Resistance ◽  
Alk Positive ◽  
Tumor Dna ◽  
Generation Sequencing

Purpose ALK (anaplastic lymphoma kinase) rearrangements predict for sensitivity to ALK tyrosine kinase inhibitors (TKIs); however, responses to ALK TKIs are generally short lived. Serial molecular analysis is an informative strategy used to identify genetic mediators of resistance. Although multiple studies support the clinical benefits of repeat tissue sampling, the clinical utility of longitudinal circulating tumor DNA analysis has not been established in ALK-positive lung cancer. Patients and Methods We used a 566-gene hybrid-capture next-generation sequencing assay to perform a longitudinal analysis of plasma specimens from 22 ALK-positive patients with acquired resistance to ALK TKIs to track the evolution of resistance during treatment. To determine tissue–plasma concordance, we compared plasma findings with the results of repeat biopsies. Results At disease progression, we detected an ALK fusion in plasma from 19 (86%) of 22 patients and identified ALK resistance mutations in plasma specimens from 11 patients (50%). There was 100% agreement between tissue- and plasma-detected ALK fusions. Among 16 patients for which contemporaneous plasma and tissue specimens were available, we observed 100% concordance between ALK mutation calls. ALK mutations emerged and disappeared during treatment with sequential ALK TKIs, which suggests that plasma mutation profiles were dependent on the specific TKI administered. ALK G1202R—the most frequent plasma mutation detected after progression on a second-generation TKI—was consistently suppressed during treatment with lorlatinib. Conclusion Plasma genotyping by next-generation sequencing is an effective method for detecting ALK fusions and ALK mutations in patients who experience disease progression on ALK TKIs. The correlation between plasma ALK mutations and the response to distinct ALK TKIs highlights the potential for plasma analysis to guide the selection of ALK-directed therapies.

Comparison of tissue DNA to circulating tumor DNA in patients with brain metastases.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e13546-e13546 ◽  
Author(s):  
Tyler A. Lanman ◽  
Santosh Kesari ◽  
Sandip Pravin Patel ◽  
Lyudmila Bazhenova ◽  
Barbara A. Parker ◽  
...  
Keyword(s):  
Brain Metastases ◽  
Tumor Tissue ◽  
Late Complication ◽  
Median Number ◽  
Circulating Tumor Dna ◽  
Molecular Alterations ◽  
Dna Sampling ◽  
Next Generation Sequencing Ngs ◽  
Tumor Dna ◽  
Generation Sequencing

e13546 Background: Brain metastases are often a late complication of cancer, not easily amenable to biopsy, and may contain additional molecular alterations not found in the original tumor. We sought to analyze the concordance between tissue DNA and cell-free circulating tumor DNA (ctDNA) in patients who developed brain metastases, and determine how the ctDNA profile changed with time. Methods: We retrospectively analyzed 31 patients with brain metastases who underwent next-generation sequencing (NGS) from both ctDNA and tumor tissue DNA. Breast, lung, ovarian, renal, melanoma, and colon primaries were included (42, 32, 13, 7, 3, and 3%, respectively). Tissue DNA was from primary tumor, systemic metastasis or brain (39, 39, and 7%, respectively). A median number of five alterations was found in each tissue group. Alterations in ctDNA were compared to tumor DNA and analyzed for relative frequencies, concordance, and novel alterations. Overall survival (OS) and time between DNA sample collections was analyzed. Results: All 31 patients had detectable mutations in tumor tissue. 25 patients (80.6%) had detectable ctDNA alterations and 14 patients (45.2%) had at least one identical ctDNA alteration that was concordant with tissue DNA. The most commonly altered genes (in both ctDNA and tissue DNA) were TP53 and EGFR. Breast cancer had both the highest proportion of patients with ≥ 1 ctDNA alterations (92.3%) and the highest proportion of patients who had ≥ 1 alterations in common with tissue DNA (61.5%). 23 of the 25 patients (92%) with detectable ctDNA alterations had additional alterations not found in tissue DNA, which increased with time from tumor DNA sampling. Median time between ctDNA extraction and tissue biopsy was 6.5 months for cases with common alterations, and 12.4 months for those without common alterations. There was trend to decreased OS with increasing ctDNA burden. Conclusions: We found that ctDNA is comparable with tissue DNA sequencing in patients with brain metastases. This concordance decreases with increasing time from tissue diagnosis, reflecting the changing nature of tumor genetics and highlighting the utility of ctDNA as a feasible way to monitor changes and identify additional potentially targetable alterations.

scholarly journals Identification of Germline Cancer Predisposition Variants During Clinical Ctdna Testing

2021 ◽  
Author(s):  
Leigh Anne Stout ◽  
Nawal Kassem ◽  
Cynthia Hunter ◽  
Santosh Philips ◽  
Milan Radovich ◽  
...  
Keyword(s):  
Circulating Tumor Dna ◽  
Variant Allele Frequency ◽  
Germline Variants ◽  
Non Invasive ◽  
Invasive Method ◽  
Selection For ◽  
Ctdna Analysis ◽  
Next Generation Sequencing Ngs ◽  
Tumor Dna ◽  
Generation Sequencing

Abstract Next-generation sequencing (NGS) of circulating tumor DNA (ctDNA) is a non-invasive method to guide therapy selection for cancer patients. ctDNA variant allele frequency (VAF) is commonly reported and may aid in discerning whether a variant is germline or somatic. We report on the fidelity of VAF in ctDNA as a predictor for germline variant carriage. Two patient cohorts were studied. Cohort 1 included patients with known germline variants. Cohort 2 included patients with any variant detected by the ctDNA assay with VAF of 40–60%. In cohort 1, 36 of 91 (40%) known germline variants were identified through ctDNA analysis with a VAF of 39-87.6%. In cohort 2, 111 of 160 (69%) variants identified by ctDNA analysis with a VAF between 40–60% were found to be germline. Therefore, variants with a VAF between 40–60% should induce suspicion for germline status but should not be used as a replacement for germline testing.

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