Addition of selpercatinib to overcome osimertinib resistance in non-small cell lung cancer (NSCLC) with acquired RET fusion detected in ctDNA at very low allele frequency.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3046-3046
Author(s):  
Leeseul Kim ◽  
Young Kwang Chae ◽  
Chan Mi Jung ◽  
Alice Daeun Lee ◽  
Emma Yu
Keyword(s):  
Allele Frequency ◽  
Treatment Regimen ◽  
Brain Mri ◽  
Acquired Resistance ◽  
Egfr Inhibitors ◽  
Variant Allele ◽  
Leptomeningeal Disease ◽  
Precision Oncology ◽  
Variant Allele Frequency ◽  
Nsclc Patients

3046 Background: Osimertinib, a highly selective third generation EGFR tyrosine kinase inhibitor (TKI) became the standard front-line therapy for EGFR-mutant NSCLC. However, therapeutic options are limited for TKI resistance which commonly occurs. Therefore, overcoming acquired resistance to osimertinib remains an important high unmet need in the field of precision oncology. Herein, we present the first case of advanced adenocarcinoma of the lung that showed notable response with the addition of selpercatinib after acquired resistance to osimertinib monotherapy. Methods: Case presentation. Results: A 37-year-old woman with stage IVB adenocarcinoma of lung with osseous, hepatic and brain metastases initially received one cycle of carboplatin, pemetrexed and pembrolizumab. Based on the EGFR exon19 deletion detected from ctDNA NGS assay (Guardant 360) [variant allele frequency (VAF) 62.7%], the treatment regimen was changed to osimertinib monotherapy (80mg PO daily). Bevacizumab was empirically added given CNS involvement. She maintained overall stable disease for 10 months before subsequent CT showed disease progression. The treatment regimen was switched to atezolizumab, bevacizumab, paclitaxel and carboplatin combination therapy. She tolerated 6 cycles of the regimen in 4 month before a subsequent brain MRI revealed progression of the metastatic brain disease with new leptomeningeal disease. Whole brain radiotherapy was performed and decision was made to start combination TKI treatment of selpercatinib (120mg BID) added to the osimertinib (80mg daily) monotherapy based on her repeat ctDNA NGS assay result showing concurrent acquired CCDC6RET fusion (VAF 0.05%) and EGFR exon 19 deletion (VAF 10.0%). The 6 week follow-up CT demonstrated significant decrease in the largest lung mass (33.95*24.22mm->32.50*16.07mm). Repeat ctDNA NGS assay at one week after selpercatinib use showed disappearance of RET fusion and significant decrease in EGFR clone (VAF 10.0% to 0.05%). Conclusions: It has been reported that co-occurring RET fusions in NSCLC patients with EGFR mutations may contribute to acquired resistance to EGFR inhibitors. Several successful cases of cabozantinib, a non-selective RET inhibitor, or pralsetinib, a selective RET inhibitor combined with EGFR inhibitor, have been reported to aid in overcoming the acquired resistance to EGFR inhibitors. To date, there has been no report of clinical benefit in adding a RET inhibitor based on ctDNA detection of RET fusion with minute variant allele frequency. We for the first time report the case of overcoming acquired resistance to osimertinib by adding selpercatinib, a selective RET inhibitor in NSCLC patients with acquired RET fusion detected in ctDNA at VAF of 0.05%.

scholarly journals 138P The impact of variant allele frequency in EGFR mutated NSCLC patients on targeted therapy

2021 ◽  
Vol 16 (4) ◽  
pp. S772
Author(s):  
A. Addeo ◽  
A. Friedlaender ◽  
M. Chevallier ◽  
C. De Vito ◽  
P. Tsantoulis
Keyword(s):  
Targeted Therapy ◽  
Allele Frequency ◽  
Variant Allele ◽  
Variant Allele Frequency ◽  
Nsclc Patients ◽  
The Impact ◽  
Egfr Mutated

scholarly journals Examination of the predicted prevalence of Gitelman syndrome by ethnicity based on genome databases

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Atsushi Kondo ◽  
China Nagano ◽  
Shinya Ishiko ◽  
Takashi Omori ◽  
Yuya Aoto ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Carrier Frequency ◽  
Japanese Population ◽  
Autosomal Recessive ◽  
Disease Prevalence ◽  
Gitelman Syndrome ◽  
Variant Allele ◽  
Variant Allele Frequency ◽  
Genome Databases ◽  
Heterozygous Carriers

AbstractGitelman syndrome is an autosomal recessive inherited salt-losing tubulopathy. It has a prevalence of around 1 in 40,000 people, and heterozygous carriers are estimated at approximately 1%, although the exact prevalence is unknown. We estimated the predicted prevalence of Gitelman syndrome based on multiple genome databases, HGVD and jMorp for the Japanese population and gnomAD for other ethnicities, and included all 274 pathogenic missense or nonsense variants registered in HGMD Professional. The frequencies of all these alleles were summed to calculate the total variant allele frequency in SLC12A3. The carrier frequency and the disease prevalence were assumed to be twice and the square of the total allele frequency, respectively, according to the Hardy–Weinberg principle. In the Japanese population, the total carrier frequencies were 0.0948 (9.5%) and 0.0868 (8.7%) and the calculated prevalence was 0.00225 (2.3 in 1000 people) and 0.00188 (1.9 in 1000 people) in HGVD and jMorp, respectively. Other ethnicities showed a prevalence varying from 0.000012 to 0.00083. These findings indicate that the prevalence of Gitelman syndrome in the Japanese population is higher than expected and that some other ethnicities also have a higher prevalence than has previously been considered.

Abstract 569: Correlation of variant allele frequency and mean tumor molecules with tumor burden in patients with solid tumors

2021 ◽  
Author(s):  
Antony Tin ◽  
Vasily Aushev ◽  
Ekaterina Kalashnikova ◽  
Raheleh Salari ◽  
Svetalana Shchegrova ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Allele Frequency ◽  
Tumor Burden ◽  
Variant Allele ◽  
Variant Allele Frequency

scholarly journals Variant allele frequency enrichment analysis in vitro reveals sonic hedgehog pathway to impede sustained temozolomide response in GBM

2015 ◽  
Vol 5 (1) ◽  
Author(s):  
Nidhan K. Biswas ◽  
Vikas Chandra ◽  
Neeta Sarkar-Roy ◽  
Tapojyoti Das ◽  
Rabindra N. Bhattacharya ◽  
...  
Keyword(s):  
Allele Frequency ◽  
Sonic Hedgehog ◽  
Enrichment Analysis ◽  
Hedgehog Pathway ◽  
Variant Allele ◽  
Sonic Hedgehog Pathway ◽  
Variant Allele Frequency

scholarly journals Clone decomposition based on mutation signatures provides novel insights into mutational processes

2021 ◽  
Author(s):  
Taro Matsutani ◽  
Michiaki Hamada
Keyword(s):  
Allele Frequency ◽  
Tumor Heterogeneity ◽  
Cytidine Deaminase ◽  
Lymphocytic Leukemia ◽  
Variant Allele ◽  
Variant Allele Frequency ◽  
Coding Regions ◽  
Activation Induced Cytidine Deaminase ◽  
Almost All ◽  
Mutational Processes

Intra-tumor heterogeneity is a phenomenon in which mutation profiles differ from cell to cell within the same tumor and is observed in almost all tumors. Understanding intra-tumor heterogeneity is essential from the clinical perspective. Numerous methods have been developed to predict this phenomenon based on variant allele frequency. Among the methods, CloneSig models the variant allele frequency and mutation signatures simultaneously and provides an accurate clone decomposition. However, this method has limitations in terms of clone number selection and modeling. We propose SigTracer, a novel hierarchical Bayesian approach for analyzing intra-tumor heterogeneity based on mutation signatures to tackle these issues. We show that SigTracer predicts more reasonable clone decompositions than the existing methods that use artificial data that mimic cancer genomes. We applied SigTracer to whole-genome sequences of blood cancer samples. The results were consistent with past findings that single base substitutions caused by a specific signature (previously reported as SBS9) related to the activation-induced cytidine deaminase intensively lie within immunoglobulin-coding regions for chronic lymphocytic leukemia samples. Furthermore, we showed that this signature mutates regions responsible for cell-cell adhesion. Accurate assignments of mutations to signatures by SigTracer can provide novel insights into signature origins and mutational processes.

scholarly journals Changes of the Mutational Landscape in Relapsed Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 599-599
Author(s):  
Franck Rapaport ◽  
Marc Robert de Massy ◽  
Adil al Hinai ◽  
Mathijs A. Sanders ◽  
Todd Hricik ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Allele Frequency ◽  
Combination Chemotherapy ◽  
Copy Number ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Variant Allele ◽  
Chemotherapy Treatment ◽  
Variant Allele Frequency ◽  
Acute Myeloid

Abstract Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. Unfortunately, a significant proportion of patients relapse after responding to initial treatment reflecting our poor understanding of the mechanisms mediating therapy resistance and relapse. We hypothesized that understanding the evolution of the mutational landscape between diagnosis and relapse is essential in order to identify mutational markers associated with sensitivity or resistance to treatment. To address this hypothesis we assembled a cohort of 53 clinically annotated, paired AML patient samples (diagnosis, relapse and patient-matched germline samples; mean age = 52 years). All patients achieved clinical remission after treatment with combination chemotherapy (cytarabine arabinoside and an anthracycline) during induction phase followed by consolidation chemotherapy treatment with or without a stem cell transplantation in first remission. Serial samples were collected at the time of initial diagnosis and within three months of relapse (mean time to relapse 455 days). We performed whole-exome and targeted capture followed by high-throughput sequencing. We aligned samples with BWA, recalibrated them with The Genome Analysis Toolkit (GATK) and then compiled integrated calls from substitution and indel callers (Mutect, Scalpel, Strelka, Varscan and Somatic Sniper). We performed several layers of post-processing filtering on these calls, including removing non-oncogenic mutations and previously documented non-somatic variants, and correcting for the variant allele fraction of indel calls. We filtered out the variants that were found to occur in non-copy number neutral re-arrangements using the clinically determined cytogenetic data. Furthermore, we assessed for copy number events, including loss of heterozygosity events, and for the presence and the variant allele frequency of the FLT3-ITD in our samples. We observed a median of 4.5 and 5 mutations per patient at diagnosis and relapse, respectively, with 3.5 mutations being shared by paired diagnosis and relapse samples. When limiting our analysis to genes previously shown to contribute to leukemogenesis, we found a median of 1.5 and 2 mutations per patient at diagnosis and relapse, with 1 mutation being shared. FLT3, DNMT3A, IDH2, NRAS, RUNX1 and TET2 were among the most commonly mutated genes, with a detected presence rate of 28%, 25%, 19%, 19%, 11% and 11%, respectively, in the diagnosis samples and 39%, 23%, 19%, 4%, 13% and 11% in the relapse samples. We identified significant variation in the variant allele frequency (VAF) for several of the mutations related to these genes and others, denoting variations in the cellular prevalence of the related clones after adjustment for tumor content using the mutations with the highest VAF to delineate clonal architecture. Specifically, we observed that DNMT3A, IDH2, TET2 variants are most commonly present in the bulk AML clone, and persist after treatment. WT1, GATA2 and FLT3mutations are predicted to confer relative resistance to standard combination chemotherapy treatment based on their increased VAF at relapse, whereas KRAS and NRAS subclone(s) are more sensitive to chemotherapy since their VAFs decrease following multiagent chemotherapy. Fifteen patients presented new events in leukemogenesis-related genes at relapse. Overall, our results support a model of AML as a disease with a complex mutational hierarchy and clonal architecture and provide further insight into how these change in response to standard induction therapy. Our data suggests that future efforts to develop targeted therapies with maximal clinical benefit in combination with standard induction treatments should be placed on mutated genes identified to be more strongly associated with disease relapse. Authors contributed equally: F. Rapaport and M.R. De Massy Authors contributed equally: A. al Hinai and M.A. Sanders Disclosures Guzman: Cellectis: Research Funding. Roboz:Cellectis: Research Funding; Agios, Amgen, Amphivena, Astex, AstraZeneca, Boehringer Ingelheim, Celator, Celgene, Genoptix, Janssen, Juno, MEI Pharma, MedImmune, Novartis, Onconova, Pfizer, Roche/Genentech, Sunesis, Teva: Consultancy. Melnick:Janssen: Research Funding. Levine:Qiagen: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy.

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