scholarly journals High Circulating Sonic Hedgehog Protein Is Associated With Poor Outcome in EGFR-Mutated Advanced NSCLC Treated With Tyrosine Kinase Inhibitors

2021 ◽  
Vol 11 ◽  
Author(s):  
Paul Takam Kamga ◽  
Aurélie Swalduz ◽  
Adrien Costantini ◽  
Catherine Julié ◽  
Jean-François Emile ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Sonic Hedgehog ◽  
Advanced Nsclc ◽  
Plasma Samples ◽  
Shh Pathway ◽  
Poor Outcome ◽  
Nsclc Patients ◽  
Tumor Biopsies ◽  
Egfr Mutated ◽  
Egfr Tki

IntroductionGrowing preclinical evidence has suggested that the Sonic hedgehog (Shh) pathway is involved in resistance to tyrosine kinase inhibitor (TKI) therapy for EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC). However, little is known concerning the prognostic value of this pathway in this context.Materials and MethodsWe investigated the relationship between plasma levels of Shh and EGFRm NSCLC patients’ outcome with EGFR TKIs. We included 74 consecutive patients from two institutions with EGFRm advanced NSCLC treated by EGFR TKI as first-line therapy. Plasma samples were collected longitudinally for each patient and were analyzed for the expression of Shh using an ELISA assay. The activation of the Shh–Gli1 pathway was assessed through immunohistochemistry (IHC) of Gli1 and RT-qPCR analysis of the transcripts of Gli1 target genes in 14 available tumor biopsies collected at diagnosis (baseline).ResultsAmong the 74 patients, only 61 had baseline (diagnosis) plasma samples, while only 49 patients had plasma samples at the first evaluation. Shh protein was detectable in all samples at diagnosis (n = 61, mean = 1,041.2 ± 252.5 pg/ml). Among the 14 available tumor biopsies, nuclear expression of Gli1 was observed in 57.1% (8/14) of patients’ biopsies. Shh was significantly (p < 0.05) enriched in youth (age < 68), male, nonsmokers, patients with a PS > 1, and patients presenting more than 2 metastatic sites and L858R mutation. Higher levels of Shh correlated with poor objective response to TKI, shorter progression-free survival (PFS), and T790M-independent mechanism of resistance. In addition, the rise of plasma Shh levels along the treatment was associated with the emergence of drug resistance in patients presenting an initial good therapy response.ConclusionThese data support that higher levels of plasma Shh at diagnosis and increased levels of Shh along the course of the disease are related to the emergence of TKI resistance and poor outcome for EGFR-TKI therapy, suggesting that Shh levels could stand both as a prognostic and as a resistance biomarker for the management of EGFR-mutated NSCLC patients treated with EGFR-TKI.

scholarly journals Detection of EGFR Activating and Resistance Mutations by Droplet Digital PCR in Sputum of EGFR-Mutated NSCLC Patients

2021 ◽  
Vol 15 ◽  
pp. 117955492199307
Author(s):  
Klaus Hackner ◽  
Anna Buder ◽  
Maximilian J Hochmair ◽  
Matthaeus Strieder ◽  
Christina Grech ◽  
...  
Keyword(s):  
Stable Disease ◽  
Progressive Disease ◽  
Kinase Inhibitor ◽  
Diagnostic Yield ◽  
Resistance Mutation ◽  
Egfr Mutations ◽  
Plasma Samples ◽  
Percent Agreement ◽  
Nsclc Patients ◽  
Egfr Mutated

Background: Proof of the T790M resistance mutation is mandatory if patients with EGFR-mutated non-small cell lung cancer (NSCLC) progress under first- or second-generation tyrosine kinase inhibitor therapy. In addition to rebiopsy, analysis of plasma circulating tumor DNA is used to detect T790M resistance mutation. We studied whether sputum is another feasible specimen for detection of EGFR mutations. Methods: Twenty-eight patients with advanced EGFR-mutated NSCLC were included during stable and/or progressive disease. The initial activating EGFR mutations (exon 19 deletions or L858R mutations) at stable disease and at progressive disease (together with T790M) were assessed in simultaneously collected plasma and sputum samples and detected by droplet digital polymerase chain reaction (ddPCR). Results: Activating EGFR mutations were detected in 47% of the plasma samples and 41% of sputum samples during stable disease, and in 57% of plasma samples and 64% of sputum samples during progressive disease. T790M was detected in 44% of the plasma samples and 66% of the sputum samples at progressive disease. In ddPCR T790M-negative results for both specimens (plasma and sputum), negativity was confirmed by rebiopsy in 5 samples. Concordance rate of plasma and sputum for T790M was 0.86, with a positive percent agreement of 1.0 and a negative percent agreement of 0.80. Conclusions: We demonstrated that EGFR mutation analysis with ddPCR is feasible in sputum samples. Combination of plasma and sputum analyses for detection of T790M in NSCLC patients with progressive disease increases the diagnostic yield compared with molecular plasma analysis alone.

scholarly journals Clinical and Molecular Features of Epidermal Growth Factor Receptor (EGFR) Mutation Positive Non-Small-Cell Lung Cancer (NSCLC) Patients Treated with Tyrosine Kinase Inhibitors (TKIs): Predictive and Prognostic Role of Co-Mutations

Cancers ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 2425
Author(s):  
Paolo Bironzo ◽  
Maria Lucia Reale ◽  
Tessa Sperone ◽  
Fabrizio Tabbò ◽  
Andrea Caglio ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Growth Factor Receptor ◽  
Epidermal Growth ◽  
Nsclc Patients

Background: Tyrosine kinase inhibitors (TKIs) show variable efficacy in epidermal growth factor receptor mutation-positive (EGFR+) NSCLC patients, even in patients harbouring the same mutation. Co-alterations may predict different outcomes to TKIs. Methods: We retrospectively analysed all consecutive EGFR+ advanced NSCLC treated with first-line TKIs at our Institutions. NGS with a 22 genes clinical panel was performed on diagnostic specimens. PD-L1 expression was also evaluated. Results: Of the 106 analysed specimens, 59 showed concomitant pathogenic mutations. No differences in OS (mOS 22.8 vs. 29.5 months; p = 0.088), PFS (mPFS 10.9 vs. 11.2 months; p = 0.415) and ORR (55.9% vs. 68.1%; p = 0.202) were observed comparing patients without and with co-alterations. Subgroup analysis by EGFR mutation type and TKIs generation (1st/2nd vs. 3rd) did not show any difference too. No correlations of PD-L1 expression levels by co-mutational status were found. Significant associations with presence of co-alterations and younger age (p = 0.018) and baseline lymph nodes metastases (p = 0.032) were observed. Patients without concomitant alterations had a significant higher risk of bone progression (26.5% vs. 3.3%, p = 0.011). Conclusions: Pathogenic co-alterations does not seem to predict survival nor efficacy of EGFR TKIs in previously untreated advanced NSCLC.

Emergence of RET rearrangement co-existing with activated EGFR mutation in EGFR -mutated NSCLC patients who had progressed on first- or second-generation EGFR TKI

Lung Cancer ◽  
2015 ◽  
Vol 89 (3) ◽  
pp. 357-359 ◽  
Author(s):  
Samuel J. Klempner ◽  
Lyudmila A. Bazhenova ◽  
Fadi S. Braiteh ◽  
Petros G. Nikolinakos ◽  
Kyle Gowen ◽  
...  
Keyword(s):  
Second Generation ◽  
Egfr Mutation ◽  
Ret Rearrangement ◽  
Nsclc Patients ◽  
Egfr Mutated ◽  
Egfr Tki

scholarly journals Efficacy and Acquired Resistance of EGFR-TKI Combined with Chemotherapy as First-Line Treatment for Chinese Patients with Advanced Non-Small Cell Lung Cancer in a Real-world Setting

2020 ◽  
Author(s):  
Qianqian Wang ◽  
Wen Gao ◽  
Fangyan Gao ◽  
Shidai Jin ◽  
Tianyu Qu ◽  
...  
Keyword(s):  
Egfr Mutation ◽  
Advanced Nsclc ◽  
Acquired Resistance ◽  
Small Cell ◽  
Combination Group ◽  
Monotherapy Group ◽  
Small Cell Lung ◽  
T790m Mutation ◽  
Nsclc Patients ◽  
Egfr Tki

Abstract Background To compare the benefits and explore the cause of acquired resistance of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) and its combination with chemotherapy in advanced non-small-cell lung cancer (NSCLC) patients harboring EGFR mutation in a real-life setting.Methods This retrospective analysis included 117 advanced NSCLC patients with EGFR mutation who underwent next-generation sequencing (NGS) prior to treatment. The combination group included 50 patients who received the regimen of EGFR-TKI combined with chemotherapy, while the EGFR-TKI monotherapy group included 67 patients treated with TKI only. The primary endpoint of this study was progression-free survival (PFS); the secondary endpoints were overall survival (OS), response rate, and toxicity.Results The median PFS was significantly longer in the combination group than in the EGFR-TKI monotherapy group (19.00 months [95% CI, 14.674-23.326] vs. 11.70 months [95% CI, 10.807-12.593], p = 0.000). Subgroup analysis showed a similar trend of results. The median OS was not reached in the combination group and was 38.50 (95% CI, 35.300-41.700) months in the EGFR-TKI monotherapy group (p = 0.586). Patients in the combination group were more likely to experience adverse events, most of which showed the severity of grade 1 or 2. T790M mutation remains the main reason for acquired resistance, and the frequency of T790M mutation was similar between the two groups (p = 0.898). Conclusions Compared with EGFR-TKI monotherapy, EGFR-TKI combined with chemotherapy significantly improved PFS in advanced NSCLC patients with EGFR mutation, with acceptable toxicity.

Disease control with a second epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) after failure of a first TKI in Asian patients with non-small cell lung cancer (NSCLC)

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18104-18104
Author(s):  
A. Wong ◽  
S. W. Lim ◽  
T. M. Chin ◽  
R. Soong ◽  
R. A. Soo
Keyword(s):  
Disease Control ◽  
Advanced Nsclc ◽  
Kinase Inhibitor ◽  
Patient Characteristics ◽  
University Hospital ◽  
Bronchioloalveolar Carcinoma ◽  
Histologic Subtype ◽  
Molecular Features ◽  
Nsclc Patients ◽  
Egfr Tki

18104 Background: Asian NSCLC patients are known to have higher response rates to the EGFR TKI gefitinib (G) and erlotinib (E). Anecdotal reports suggest some activity for a second EGFR TKI after failure of the first. Methods: A retrospective review of the electronic pharmacy records, clinical and radiographic records of patients with advanced NSCLC at the National University Hospital who received both G and E in the previous 2 years was conducted. Objectives were to assess the disease control (response/stable disease) of the second TKI after failure of the first and characterize the clinical, pathological and molecular features of patients benefiting from a 2nd TKI. Results: 14 patients with advanced NSCLC who received a 2nd EGFR TKI after progression on the 1st TKI were identified. Patient characteristics: Chinese 12, female 10, and non-smokers 13. Histologic subtype: adenocarcinoma 7, bronchioloalveolar carcinoma (BAC) 3, squamous-cell carcinoma 1, NSCLC unspecified 3. 12 patients received cytotoxic chemotherapy with a median of 2 lines, (range 1–5). G and E was used as 1st/2nd/3rd/=4th line treatment in 8/2/2/2 and 0/4/2/8 patients respectively. G was used before E in 13 cases and disease control was seen in 8/14 (57%) patients. With a 2nd TKI after disease progression, disease control was seen 4/14 (28%) patients. Patient characteristics were: adenocarcinoma 3, BAC 1, all were never smokers and all received and responded to prior G. Median duration of control in these 4 patients for G was 8 (range 7–12) months, and subsequently to E was 2.5 (range 2–8) months. Disease control was associated with symptomatic improvement. Conclusion: This study documents disease control in 28% of Asian NSCLC patients treated with a second EGFR TKI after failure of a first. The molecular basis for these observations is currently being investigated. No significant financial relationships to disclose.

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