METex14 ctDNA Dynamics & Resistance Mechanisms Detected in Liquid Biopsy (LBx) From Patients (pts) With METex14 Skipping NSCLC Treated With Tepotinib

2022 ◽  
Vol 112 (2) ◽  
pp. e13-e14
Author(s):  
P. Paik ◽  
R. O'Hara ◽  
R. Veillon ◽  
E. Felip ◽  
A. Cortot ◽  
...  
2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 6557-6557
Author(s):  
Charles Abbott ◽  
Nikita Bedi ◽  
Simo V Zhang ◽  
Robin Li ◽  
Rachel Pyke ◽  
...  

6557 Background: The reduced scope, and number of genes profiled by typical liquid biopsy panels can result in missed biomarkers including neoantigens, which may change with treatment, as well as potentially undetected resistance mechanisms and pathways beyond the scope of targets typically captured by panels. To address these limitations, we used a whole-exome scale liquid biopsy monitoring platform, NeXT Liquid Biopsy, to analyze head and neck squamous cell carcinoma (HNSCC) patients that have received anti-PD1 therapy. Presently, we sought to (1) monitor neoantigen changes in cfDNA as a complement to tumor biopsy-derived neoantigens, (2) compare the impact of tumor escape mechanisms, including HLA-LOH, on neoantigens identified in tissue and cfDNA and (3) to identify novel biological signatures that combine information from both solid tumor and liquid biopsies. Methods: Pre- and post-intervention matched normal, tumor and plasma samples were collected from a cohort of 12 patients with HNSCC. Following baseline sample collection all patients received a single dose of nivolumab, followed by resection approximately one month later when feasible, or a second biopsy where resection was impractical. Solid tumor and matched normal samples were profiled using ImmunoID NeXT, an augmented exome/transcriptome platform and analysis pipeline. Exome-scale somatic variants were identified in cfDNA from plasma samples using the NeXT Liquid Biopsy platform. Data from these two platforms were compared with corresponding clinical findings. Results: Concordant somatic events were detected between plasma and tumor at pre- and post-treatment timepoints. Neoantigens predicted to arise from these somatic events were reduced in solid tumor post-treatment, but increased in cfDNA, when compared to pre-treatment timepoints. HLA LOH was identified in a number of subjects, likely resulting in reduced neoepitope presentation in those cases. Immune cell infiltration increased in the tumor following treatment, with no changes to the CD8+/Treg cell ratio, suggesting consistent immunoregulation. Conclusions: Exome-wide neoantigen burden was reliably predicted from cfDNA, providing additional insight complementing data from solid tumor. Analyzing HLA LOH, and neoantigen burden from both solid and liquid biopsies together over the course of treatment creates a more comprehensive profile of therapeutic response and resistance mechanisms in HNSCC patients missed with typical liquid biopsy panels.


Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2247
Author(s):  
Lilli Hofmann ◽  
Katja Sallinger ◽  
Christoph Haudum ◽  
Maria Smolle ◽  
Ellen Heitzer ◽  
...  

Novel androgen receptor (AR) signaling inhibitors have improved the treatment of castration-resistant prostate cancer (CRPC). Nonetheless, the effect of these drugs is often time-limited and eventually most patients become resistant due to various AR alterations. Although liquid biopsy approaches are powerful tools for early detection of such therapy resistances, most assays investigate only a single resistance mechanism. In combination with the typically low abundance of circulating biomarkers, liquid biopsy assays are therefore informative only in a subset of patients. In this pilot study, we aimed to increase overall sensitivity for tumor-related information by combining three liquid biopsy approaches into a multi-analyte approach. In a cohort of 19 CRPC patients, we (1) enumerated and characterized circulating tumor cells (CTCs) by mRNA-based in situ padlock probe analysis, (2) used RT-qPCR to detect cancer-associated transcripts (e.g., AR and AR-splice variant 7) in lysed whole blood, and (3) conducted shallow whole-genome plasma sequencing to detect AR amplification. Although 44–53% of patient samples were informative for each assay, a combination of all three approaches led to improved diagnostic sensitivity, providing tumor-related information in 89% of patients. Additionally, distinct resistance mechanisms co-occurred in two patients, further reinforcing the implementation of multi-analyte liquid biopsy approaches.


2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A22-A22
Author(s):  
Charles Abbott ◽  
Nikita Bedi ◽  
Jing Wang ◽  
Josette Northcott ◽  
Rachel Pyke ◽  
...  

BackgroundTypical liquid biopsy panels offer a limited understanding of tumor biology, potentially under-representing the heterogeneity of resistance in late-stage cancers. Here, diminished scope can result in undetected, therapeutically-relevant biomarkers which respond dynamically to treatment, as well as potentially missed resistance mechanisms and pathway-level events. To address the challenges associated with identifying multiple concurrent heterogeneous resistance mechanisms in individual patients, we evaluated longitudinal exome-scale tumor-informed cell-free DNA (cfDNA) data from head and neck squamous cell carcinoma (HNSCC) patients receiving anti-PD1 therapy.MethodsPre- and post-intervention matched tumor, normal and plasma samples were retrospectively obtained from 15 stage II-IV HNSCC patients. Following baseline sample collection, all patients received a single dose of nivolumab or pembrolizumab. The primary tumor was then resected approximately one month later when possible, or a second biopsy collected where resection was impractical. Paired tumor and normal samples were then profiled using ImmunoID NeXT Platform®, an augmented exome/transcriptome platform and analysis pipeline. Exome-scale cfDNA profiling of matched plasma samples was performed using the NeXT Liquid BiopsyTM platform to detect somatic variants.ResultsPatient neoantigen presentation score (NEOPSTM) rapidly and significantly contracted following therapy (p=.00098). Novel neoantigens arising post-treatment which were predicted to be presented on lost HLA alleles were significantly higher in patients with longer overall survival (p=.019). Variant detection across same-patient serial cfDNA samples revealed significantly correlated VAFs (R=.62, p<.0001) despite significant contraction of mutational burden in solid tumor (p=.0039), suggesting complex clonal/subclonal dynamics. Investigation of the evolving tumor and cfDNA subclonal architecture revealed significant association between decreasing cellular prevalence and NOTCH signaling (q=.001) and the innate immune system (q=.002), while increasing cellular prevalence was associated with p53 signalling (q=.02) and hypoxia (q=.02). These findings were complimented by transcriptomic data which showed significant enrichment of multiple immune pathways across treatment.ConclusionsWe found that immune checkpoint blockade precipitates rapid evolution of the HNSCC tumor microenvironment. By leveraging comprehensive, tumor-informed liquid biopsy data we were able to identify contracting cellular populations enriched for NOTCH pathway mutations. Longer OS following either intervention was associated with an expansion of novel neoantigens predicted to be presented by lost HLA alleles. Our results suggest that tumor-informed liquid biopsy provides a more robust understanding of therapeutic response and resistance mechanisms than that attainable with typical liquid biopsy panels alone.Ethics ApprovalThis study obtained ethics approval from Human Subjects Research at Stanford University. ID number is 40425. All participants gave informed consent prior to enrollment.


2017 ◽  
Author(s):  
Laure Sorber ◽  
Karen Zwaenepoel ◽  
An Wouters ◽  
Janssens Annelies ◽  
Birgitta Hiddinga ◽  
...  

2019 ◽  
Vol 8 (7) ◽  
pp. 998 ◽  
Author(s):  
Luigi Pasini ◽  
Paola Ulivi

The use of targeted agents and immunotherapy for the treatment of advanced non-small-cell lung cancer (NSCLC) has made it mandatory to characterize tumor tissue for patient selection. Moreover, the development of agents that are active against specific resistance mechanisms arising during treatment make it equally important to characterize the tumor tissue at progression by performing tissue re-biopsy. Given that tumor tissue is not always available for molecular characterization due to the paucity of diagnostic specimens or problems relating to the carrying out of invasive procedures, the use of liquid biopsy represents a valid approach to overcoming these difficulties. The most common material used for liquid biopsy in this setting is plasma-derived cell free DNA (cfDNA), which originates from cells undergoing apoptosis or necrosis. However, other sources of tumor material can be considered, such as extracellular vesicle (EV)-derived nucleic acids, which are actively secreted from living cells and closely correspond to tumor dynamics. In this review, we discuss the role of liquid biopsy in the therapeutic management of NSCLC with particular regard to targeted therapy and immunotherapy, and analyze the pros and cons of the different types of samples used in this context.


2017 ◽  
Vol 70 (9) ◽  
pp. 798-802 ◽  
Author(s):  
Eduardo Clery ◽  
Pasquale Pisapia ◽  
Salvatore Feliciano ◽  
Elena Vigliar ◽  
Antonio Marano ◽  
...  

Non-small cell lung carcinoma harbouring epidermal growth factor receptor (EGFR) mutation, usually progress after an initial response to tyrosine-kinase inhibitors (TKI). Liquid biopsy enables with a simple blood draw the accurate detection ofEGFRp.T790M mutation, the most common resistance mechanism, avoiding the more invasive tissue re-biopsy. However, in a subset of cases, resistance mechanisms are more complex featuring both genetic and morphological changes. Here we report the case of a 67 years-old woman, affected by anEGFRmutated lung adenocarcinoma and treated by TKI. At disease progression, the patient developed a morphological transition to squamous cell carcinoma in association to the arising of aPIK3CAp.E542K mutant subclone. This case illustrates that, even in the “liquid biopsy” era, cytology can have still a role by providing an overall assessment of both morphology and genetic TKI resistance mechanisms.


2018 ◽  
Author(s):  
Gad Getz ◽  
Carrie Cibulskis ◽  
Ignaty Leshchiner ◽  
Megan Hanna ◽  
Dimitri Livitz ◽  
...  

Author(s):  
Sai-Hong Ignatius Ou ◽  
Misako Nagasaka ◽  
Viola W. Zhu

Liquid biopsy has been used extensively in solid malignancies to detect actionable driver mutations, to monitor treatment response, to detect recurrence, to identify resistance mechanisms, and to prognosticate outcome. Although many liquid biopsy sequencing platforms are being used, only five test kits have received government approval. We review representative literature on these government-approved liquid biopsy kits, which are primarily used to detect EGFR mutation in lung cancer and RAS ( KRAS, NRAS, BRAF) mutations in colorectal carcinoma. Another emerging use of single-gene liquid biopsy is to detect PIK3CA mutations and to understand resistance to hormonal blockade in breast and prostate cancers. The two most commonly used next-generation sequencing (NGS) liquid biopsy tests (Guardant 360, Guardant Health; FoundationACT, Foundation Medicine Inc.) are discussed. The ability and the applicability of NGS platform to detect tumor mutation burden are also addressed. Finally, the use of circulating tumor DNA (ctDNA) to detect minimal residual disease may be the most important use of ctDNA in the setting of tumor heterogeneity. The ability to identify “shedders” and “nonshedders” of ctDNA may provide important insight into the clinicopathologic characteristics of the tumor and portend important prognostic significance regarding survival.


2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Hoai-Nghia Nguyen ◽  
Ngoc-Phuong Thi Cao ◽  
Thien-Chi Van Nguyen ◽  
Khang Nguyen Duy Le ◽  
Dat Thanh Nguyen ◽  
...  

AbstractTargeted therapy with tyrosine kinase inhibitors (TKI) provides survival benefits to a majority of patients with non-small cell lung cancer (NSCLC). However, resistance to TKI almost always develops after treatment. Although genetic and epigenetic alterations have each been shown to drive resistance to TKI in cell line models, clinical evidence for their contribution in the acquisition of resistance remains limited. Here, we employed liquid biopsy for simultaneous analysis of genetic and epigenetic changes in 122 Vietnamese NSCLC patients undergoing TKI therapy and displaying acquired resistance. We detected multiple profiles of resistance mutations in 51 patients (41.8%). Of those, genetic alterations in EGFR, particularly EGFR amplification (n = 6), showed pronounced genome instability and genome-wide hypomethylation. Interestingly, the level of hypomethylation was associated with the duration of response to TKI treatment. We also detected hypermethylation in regulatory regions of Homeobox genes which are known to be involved in tumor differentiation. In contrast, such changes were not observed in cases with MET (n = 4) and HER2 (n = 4) amplification. Thus, our study showed that liquid biopsy could provide important insights into the heterogeneity of TKI resistance mechanisms in NSCLC patients, providing essential information for prediction of resistance and selection of subsequent treatment.


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