scholarly journals Primary resistance mechanisms revealed in Asian TKI-sensitizing EGFR mutations NSCLC patient populations

2018 ◽  
Vol 29 ◽  
pp. ix150-ix151
Author(s):  
Q.-X. Zhang ◽  
C. Xu ◽  
W.-X. Wang ◽  
W. Zhuang ◽  
Z.-B. Song ◽  
...  
Keyword(s):  
Nsclc Patient ◽  
Resistance Mechanisms ◽  
Egfr Mutations ◽  
Primary Resistance

scholarly journals Peptide-Affinity Precipitation of Extracellular Vesicles and Cell-Free DNA Improves Sequencing Performance for the Detection of Pathogenic Mutations in Lung Cancer Patient Plasma

2020 ◽  
Vol 21 (23) ◽  
pp. 9083
Author(s):  
Catherine Taylor ◽  
Simi Chacko ◽  
Michelle Davey ◽  
Jacynthe Lacroix ◽  
Alexander MacPherson ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Extracellular Vesicles ◽  
Liquid Biopsy ◽  
Nsclc Patient ◽  
Egfr Mutations ◽  
Single Nucleotide Variants ◽  
Cell Free Dna ◽  
Free Dna ◽  
Nsclc Patients ◽  
Peptide Affinity

Liquid biopsy is a minimally-invasive diagnostic method that may improve access to molecular profiling for non-small cell lung cancer (NSCLC) patients. Although cell-free DNA (cf-DNA) isolation from plasma is the standard liquid biopsy method for detecting DNA mutations in cancer patients, the sensitivity can be highly variable. Vn96 is a peptide with an affinity for both extracellular vesicles (EVs) and circulating cf-DNA. In this study, we evaluated whether peptide-affinity (PA) precipitation of EVs and cf-DNA from NSCLC patient plasma improves the sensitivity of single nucleotide variants (SNVs) detection and compared observed SNVs with those reported in the matched tissue biopsy. NSCLC patient plasma was subjected to either PA precipitation or cell-free methods and total nucleic acid (TNA) was extracted; SNVs were then detected by next-generation sequencing (NGS). PA led to increased recovery of DNA as well as an improvement in NGS sequencing parameters when compared to cf-TNA. Reduced concordance with tissue was observed in PA-TNA (62%) compared to cf-TNA (81%), mainly due to identification of SNVs in PA-TNA that were not observed in tissue. EGFR mutations were detected in PA-TNA with 83% sensitivity and 100% specificity. In conclusion, PA-TNA may improve the detection limits of low-abundance alleles using NGS.

scholarly journals The Resistance Mechanisms of Checkpoint Inhibitors in Solid Tumors

Biomolecules ◽  
2020 ◽  
Vol 10 (5) ◽  
pp. 666 ◽  
Author(s):  
Evangelos Koustas ◽  
Panagiotis Sarantis ◽  
Athanasios G. Papavassiliou ◽  
Michalis V. Karamouzis
Keyword(s):  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Resistance Mechanisms ◽  
Epigenetic Alterations ◽  
Primary Resistance ◽  
Cellular Processes ◽  
Mutational Burden ◽  
Number Of Patients ◽  
Tumor Mutational Burden

The emergence of cancer immunotherapy has already shown some remarkable results, having changed the treatment strategy in clinical practice for solid tumors. Despite these promising long-term responses, patients seem to lack the ability to respond to immune checkpoint inhibitors, thus demonstrating a primary resistance to immunotherapy. Moreover, a significant number of patients who initially respond to treatment eventually acquire resistance to immunotherapy. Both resistance mechanisms are a result of a complex interaction among different molecules, pathways, and cellular processes. Several resistance mechanisms, such as tumor microenvironment modification, autophagy, genetic and epigenetic alterations, tumor mutational burden, neo-antigens, and modulation of gut microbiota have already been identified, while more continue to be uncovered. In this review, we discuss the latest milestones in the field of immunotherapy, resistance mechanisms against this type of therapy as well as putative therapeutic strategies to overcome resistance in solid tumors.

scholarly journals Nongenetic Mechanisms of Drug Resistance in Melanoma

2020 ◽  
Vol 4 (1) ◽  
pp. 315-330
Author(s):  
Vito W. Rebecca ◽  
Meenhard Herlyn
Keyword(s):  
Drug Resistance ◽  
Metastatic Melanoma ◽  
Metastatic Disease ◽  
Resistance Mechanisms ◽  
Melanoma Cells ◽  
Therapeutic Strategies ◽  
Therapeutic Resistance ◽  
Primary Resistance ◽  
Future Design ◽  
The Future

Resistance to targeted and immune-based therapies limits cures in patients with metastatic melanoma. A growing number of reports have identified nongenetic primary resistance mechanisms including intrinsic microenvironment- and lineage plasticity–mediated processes serving critical functions in the persistence of disease throughout therapy. There is a temporally shifting spectrum of cellular identities fluidly occupied by therapy-persisting melanoma cells responsible for driving therapeutic resistance and metastasis. The key epigenetic, metabolic, and phenotypic reprogramming events requisite for the manifestation and maintenance of so-called persister melanoma populations remain poorly understood and underscore the need to comprehensively investigate actionable vulnerabilities. Here we attempt to integrate the field's observations on nongenetic mechanisms of drug resistance in melanoma. We postulate that the future design of therapeutic strategies specifically addressing therapy-persisting subpopulations of melanoma will improve the curative potential of therapy for patients with metastatic disease.

scholarly journals Circulating Tumour DNA Sequencing Identifies a Genetic Resistance-Gap in Colorectal Cancers with Acquired Resistance to EGFR-Antibodies and Chemotherapy

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3736
Author(s):  
Franciele H. Knebel ◽  
Louise J. Barber ◽  
Alice Newey ◽  
Dimitrios Kleftogiannis ◽  
Andrew Woolston ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Large Fraction ◽  
Single Agent ◽  
Acquired Resistance ◽  
Genetic Resistance ◽  
Resistance Mutation ◽  
Resistance Mechanisms ◽  
Wild Type ◽  
Primary Resistance ◽  
Clinical Resistance

Epidermal growth factor receptor antibodies (EGFR-Abs) confer a survival benefit in patients with RAS wild-type metastatic colorectal cancer (mCRC), but resistance invariably occurs. Previous data showed that only a minority of cancer cells harboured known genetic resistance drivers when clinical resistance to single-agent EGFR-Abs had evolved, supporting the activity of non-genetic resistance mechanisms. Here, we used error-corrected ctDNA-sequencing (ctDNA-Seq) of 40 cancer genes to identify drivers of resistance and whether a genetic resistance-gap (a lack of detectable genetic resistance mechanisms in a large fraction of the cancer cell population) also occurs in RAS wild-type mCRCs treated with a combination of EGFR-Abs and chemotherapy. We detected one MAP2K1/MEK1 mutation and one ERBB2 amplification in 2/3 patients with primary resistance and KRAS, NRAS, MAP2K1/MEK1 mutations and ERBB2 aberrations in 6/7 patients with acquired resistance. In vitro testing identified MAP2K1/MEK1 P124S as a novel driver of EGFR-Ab resistance. Mutation subclonality analyses confirmed a genetic resistance-gap in mCRCs treated with EGFR-Abs and chemotherapy, with only 13.42% of cancer cells harboring identifiable resistance drivers. Our results support the utility of ctDNA-Seq to guide treatment allocation for patients with resistance and the importance of investigating further non-canonical EGFR-Ab resistance mechanisms, such as microenvironmentally-mediated resistance. The detection of MAP2K1 mutations could inform trials of MEK-inhibitors in these tumours.

EGFR exon 20 insertion mutations: Incidence and clinicopathologic characteristics in U.S. patients with lung adenocarcinoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 10560-10560
Author(s):  
Maria E. Arcila ◽  
Khedoudja Nafa ◽  
Jamie E. Chaft ◽  
Natasha Rekhtman ◽  
Maureen Frances Zakowski ◽  
...  
Keyword(s):  
Point Mutations ◽  
Genetic Alterations ◽  
Egfr Mutations ◽  
Small Subset ◽  
Clinicopathologic Characteristics ◽  
Primary Resistance ◽  
Recurrent Point ◽  
Exon 2 ◽  
Exon 20 ◽  
Insertion Mutations

10560 Background: Activating insertion mutations in exon 20 of EGFR are reported in a small subset of lung adenocarcinomas (ADC). In contrast to the classic EGFR mutations, they appear to confer primary resistance to currently approved EGFR tyrosine kinase inhibitors. Their incidence and clinicopathologic features are not well established. Methods: Lung ADCs (n=1500) were screened for major activating mutations in EGFR (exons 19 and 21) and KRAS (exon 2). Negative cases were tested for EGFR exon 20 insertions by a PCR-based sizing assay. Extended testing for additional recurrent point mutations in EGFR, KRAS, BRAF, NRAS, PIK3CA, MEK1 and AKT was performed in all cases by Sequenom mass spectrometry. A subset of cases was also tested for ALK rearrangements by FISH. Results: We identified 32cases withEGFRexon 20 insertions, accounting for 11% of all EGFR mutations. EGFRexon 20 insertions were mutually exclusive with the other genetic alterations tested except for PIK3CA mutations. The incidence was higher among never-smokers (p<0.0001) but there was no association with sex, ethnic origin or stage at diagnosis. Insertions were 3, 6, 9 or 12bp; 9bp insertions were most common (50%, 16/32). Morphologically, 90% of tumors were moderate to poorly differentiated with a predominant mixed ADC phenotype. Conclusions: EGFR exon 20 testing may identify a unique subset of EGFR mutant lung ADCs which is significantly larger than previously reported, making this the third most common type of EGFR mutation after exon 19 deletions and L858R. This population could potentially benefit from alternate targeted therapies, many of which are currently in clinical development.

Blood-based genomic profiling of circulating cell-free tumor DNA (ctDNA) in 1397 patients (pts) with colorectal cancer (CRC).

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 584-584
Author(s):  
John H. Strickler ◽  
Kimberly C. Banks ◽  
Rebecca J Nagy ◽  
Richard B. Lanman ◽  
AmirAli Talasaz ◽  
...  
Keyword(s):  
Acquired Resistance ◽  
Jak2 V617f ◽  
Resistance Mechanisms ◽  
The Body ◽  
Egfr Mutations ◽  
Genomic Alteration ◽  
Genomic Profiling ◽  
Single Nucleotide Variants ◽  
Genomic Alterations ◽  
Clinical Potential

584 Background: ctDNA is shed into the bloodstream by tumor cells throughout the body, offering a non-invasive means of genomic testing, and a way to detect heterogeneous, subclonal genomic alterations present in distinct tumor lesions within an individual pt. However, a broad comparison of mutation prevalence in CRC ctDNA versus CRC tumor tissue has not yet been performed. Methods: ctDNA from 1397 CRC pts was analyzed using a CLIA-certified digital sequencing assay (Guardant360, Guardant Health) capable of detecting single nucleotide variants (SNV) in up to 70 genes, as well as selected insertions/deletions, amplifications, and fusions. Subclonal mutations were defined as mutations with mutant allele fractions (MAF) ≤ 50% of the greatest somatic MAF in the sample. Frequencies of mutations detected were compared to two large tissue-based sequencing databases (TCGA and NHS/HPS). Results: 1500/1772 (85%) tests had at least one genomic alteration (1397 unique pts). The most common SNV mutations included TP53 (62%), APC (47%), KRAS (39%), PIK3CA (17%), EGFR (11%), SMAD4 (11%), and BRAF (11%); these frequencies were comparable to rates in TCGA and NHS/HPS. In contrast, EGFR extracellular domain (ECD) mutations (42 pts) and JAK2 V617F mutations (16 pts) detected in ctDNA were not seen in tissue sequencing, reflecting acquired resistance to EGFR antibodies and clonal hematopoiesis of indeterminate clinical potential, respectively. 88% of pts with ECD mutations had at least one additional non-ECD resistance alteration detected in ctDNA (range 1-9, median 2.6), including KRAS, NRAS, BRAF, MAP2K1, MET and ERBB2. EGFR mutations were most likely to be detected as subclonal (86%), while mutations most likely to be clonal included KRAS (71%), TP53 (65%), BRAF (65%), and APC(63%). In 84 pts with serial monitoring, 87% had either gain (61%) or loss (63%) of clones over time. Conclusions: Blood-based genomic profiling can effectively detect common genomic alterations in CRC at comparable frequencies as observed in tissue and provide novel insights into tumor clonality and clonal dynamics. Clinical trials to target EGFR ECD mutations may be limited by the multiplicity of resistance mechanisms in each pt.

Clinical outcomes of various resistance mechanisms of osimertinib in Chinese advanced non-small cell lung cancer patients.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e20530-e20530
Author(s):  
Puyuan Xing ◽  
Li Junling ◽  
Xuezhi Hao ◽  
Yuxin Mu ◽  
Shouzheng Wang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Clinical Outcomes ◽  
Cell Lung Cancer ◽  
Progression Free Survival ◽  
Resistance Mechanisms ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Kras Mutations

e20530 Background: Increasing efforts have been invested in elucidating the resistance mechanisms to osimertinib. Major resistance mechanisms include but not limited to acquired EGFR mutations, predominantly C797, mutations in bypass pathways and small cell lung cancer (SCLC) transformation. However, no study has comprehensively investigated clinical outcomes of various mechanisms of resistance. Methods: 103 T790M positive advanced Chinese non-small cell lung cancer (NSCLC) patients who progressed on 1st generation EGFR-TKI were enrolled. Targeted sequencing, using a panel consisting of 168 lung cancer related genes, was performed on paired plasma samples collected prior to osimertinib and after the development of disease progression (PD) to profile mutation spectrum. 7 patients with no mutation detected at PD were excluded from analyses. Results: Major acquired mutations included 25% EGFR mutations, predominantly C797 and L792, 16% MET amplification, 8% TP53 mutations, 4% KRAS mutations, 4% RET fusions, 4% ERBB2 amplification and 6.25% RB1 mutations. Acquired RB1 mutation may indicate the possibility of SCLC transformation. Approximately, 30% of patients with no known resistance mechanisms at PD. In this cohort, we had 61 patients with 19 deletion and 35 patients with EGFR L858R prior to the initiation of osimertinib. We revealed patients with 19del acquired more mutations ( p= 0.014) and were more likely to acquire mutations in MAP/PI3Kpathway ( p= 0.04) and TP53 at PD ( p= 0.021). On the other hand, acquired ERBB2 amplifications were only detected in L858R-mutant patients ( p= 0.047). Furthermore, 36 patients preserved T790M and 60 patients lost T790M at PD. Our data revealed patients retaining T790M, often associated with activation of bypass signaling pathways or continued EGFR activation through tertiary mutations, had a longer progression-free survival (PFS) ( p= 0.047) and overall survival (OS) ( p= 0.04) comparing to patients with T790M loss, often with diverse and EGFR-independent mechanisms. We also show that patients with acquired C797S had significantly longer PFS ( p= 0.031), while patients with acquired MET amplifications had significantly shorter PFS ( p= 0.033). Conclusions: Collectively, we revealed differential clinical outcomes associated with various resistance mechanisms, representing an important step in advancing the understanding of resistance mechanisms of osimertinib.

scholarly journals De Novo HER2 S310Y mutation associates with poor response to EGFR tyrosine kinase inhibitor in activating EGFR-mutant NSCLC patient: A case report

2019 ◽  
Vol 17 ◽  
pp. 205873921982716
Author(s):  
Fei Gao ◽  
Xiuyan Wu ◽  
Jie Wu ◽  
Yanlin Li ◽  
Zhibo Miao ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Growth Factor Receptor ◽  
Resistance Mechanisms ◽  
Primary Resistance ◽  
Epidermal Growth ◽  
Egfr Tki

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are highly effective in treating lung cancer patients with epidermal growth factor receptor (EGFR)-activating mutations. However, intrinsic resistances of tyrosine kinase inhibitor (TKI) have been reported in 20%–30% of cases. The majority of patients who have primary resistance to EGFR-TKI harbor an insertion in EGFR exon 20 and T790M mutation. Other previously described primary resistance mechanisms include MET amplification, ALK fusion, and KRAS mutation. However, other primary resistance mechanisms have not been fully investigated. Here, we present a 68-year-old Chinese never smoke female with postoperative recurrence of bone and liver metastases after 3 years of surgery, exhibiting combined EGFR and HER2 S310Y mutation by next-generation sequencing panel analysis. The patient responded to gefitinib treatment poorly and showed progressive disease with rapid growth of lung and liver metastasis. This is the first report of activated EGFR mutation patient with a HER2 S310Y mutation had progressed on EGFR-TKI. We suggest that HER2 S310Y mutation probably leads to EGFR-TKI primary resistance in EGFR-mutated NSCLC.

Sign in / Sign up

Export Citation Format

Share Document