EGFR-mutant Adenocarcinoma Research Articles

Transformation of adenocarcinoma into small cell lung cancer as one of the mechanisms of acquired resistance to anti-EGFR tyrosine kinase inhibitors

Transformation of adenocarcinoma into small cell lung cancer (SCLC) is a rare and unique biological property of a cancer cell that is responsible for the mechanism of acquired resistance to EGFR tyrosine kinase inhibitors. There are very few clinical observations of phenotypic cellular transformation during metastatic progression of lung cancer in the literature. The aim of the work is to demonstrate clinical observation of phenotypic transformation of metastatic EGFR-mutated adenocarcinoma into small cell lung cancer with neuroendocrine differentiation during therapy with tyrosine kinase inhibitors. Case report. Due to the rarity of this biological phenomenon, we describe our own observation of the transformation of EGFR-mutated metastatic adenocarcinoma into DCLC with neuroendocrine differentiation, which occurred in a 42-year-old woman during treatment with gefitinib. Conclusions. Transformation and changes in cell phenotype during tyrosine kinase inhibitor therapy were the cause of resistance and failure of further treatment with osimertinib in the second line. It was concluded that it is necessary to consider this mechanism of resistance in clinical practice and to perform repeat biopsies during metastatic progression in patients with EGFR-mutated lung adenocarcinoma.

Abstract LB094: Assessment of minimal residual disease in lung cancer patients treated with osimertinib using liquid biopsy

Abstract Purpose: Drug tolerance has emerged as one of the major mechanisms driving resistance to targeted therapies (TT), but a comprehensive understanding of the dynamics and molecular heterogeneity underlying the adaptive drug response in patients is still lacking. Here, we used iterative liquid biopsies from osimertinib-treated lung cancer patients to monitor and characterize minimal residual disease (MRD) using both circulating tumor DNA (ctDNA) and circulating tumor cells (CTC). Experimental design: LUNG-RESIST (NCT04222335) is a prospective research study enrolling EGFR-mutant adenocarcinoma patients treated by osimertinib frontline. We collected blood samples at baseline, 1 month and every 3 months until progression. CtDNA was used to monitor the initial EGFR mutation (EGFRm) by digital PCR, and to identify new potential biomarkers of resistance by next-generation sequencing (NGS). CTC were enriched and isolated based on their size, absence of leucocyte staining and viability, to perform single-cell transcriptomic and genomic analyses. Results: 40 patients have been enrolled with a median progression-free survival (mPFS) of 14.5 months (95%CI, 8.5-24.5 months). 28/40 (70%) patients had detectable EGFRm in ctDNA at baseline, and decreased ctDNA level could be measured in 25/26 (96%) patients after 1 month of treatment, with a complete clearance in 15/26 (58%) patients. 7/11 (64%) patients without clearance at 1 month relapsed within 9 months. Clinical relapse could be anticipated 3 months ahead based on ctDNA increase for 9/20 (45%) patients. CTC-like cells have been collected at baseline and MRD (between 1 and 3 months) from respectively 31/40 (78%) and 29/40 (73%) patients, and at clinical progression for 12/22 (54%) patients who relapsed, for a total number of 1,510 cells. The number of CTC-like cells decreased after 1 month of treatment in 18/29 (62%) patients, and increased again in 7/12 (58%) patients at the time of clinical relapse. The results of NGS analyses on ctDNA and single-cell transcriptomic and genomic analyses on CTC will be presented at the congress, and should provide a better insight into the dynamics of molecular events occurring throughout the adaptive response in patients. Conclusion: We report the first molecular profiling of both ctDNA and CTC during the adaptive response to osimertinib in lung cancer patients. Monitoring the response and predicting the clinical outcome for EGFR-mutant lung cancer patients undergoing TT treatment can be done using ctDNA level as a biomarker. The isolation of CTC-like cells represents a non-invasive approach to study drug tolerance and ultimately develop new combinatory treatments to prevent relapse. Citation Format: Celia Delahaye, Anne Casanova, Estelle Clermont-Tarenchon, Aurelia Doussine, Juan-Pablo Cerapio, Anaïs Anton, Emma Devienne, Vincent Dongay, Julie Milia, Gilles Favre, Olivier Calvayrac, Anne Pradines, Julien Mazieres. Assessment of minimal residual disease in lung cancer patients treated with osimertinib using liquid biopsy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB094.

Achievement of pathological complete response with osimertinib for EGFR-mutated lung adenocarcinoma

BackgroundTyrosine-kinase inhibitors (TKIs) of epidermal growth factor receptor (EGFR) usually provide a potent anti-tumor efficacy with robust radiographic response for non-small cell lung cancer (NSCLC) harboring activating mutations in the EGFR gene. However, first-generation EGFR-TKIs may provide only modest pathological response in the majority of EGFR-mutated NSCLC. Here, we present a case of EGFR-mutated adenocarcinoma in which a pathological complete response was revealed in histological specimens obtained during conversion surgery following systemic treatment using a third-generation EGFR-TKI.Case presentationA 61-year-old Japanese man was admitted to our hospital for salvage surgery. Four months prior to the admission, he had been diagnosed with unresectable adenocarcinoma (clinical stage IIIA/T4N1MO) originating from the right lower lobe. Chest computed tomography had revealed a 3.4-cm tumor and enlarged hilar nodes that invaded into the left atrium through the lower pulmonary vein. An activating EGFR-mutation (L858R) had been detected in the tumor specimen. Osimertinib monotherapy had provided a dramatic radiographic response. The patient was diagnosed with potentially resectable disease after 4 months’ osimertinib treatment and was referred to our hospital. Complete resection with right lower lobectomy and combined resection of the left atrium was achieved. Pathological examination showed no viable tumor cells in the resected specimens. Postoperative course was uneventful. The patient is alive without tumor recurrence at 2 years after surgery.ConclusionsPathological complete response was achieved with systemic treatment with osimertinib prior to surgery. Conversion surgery after osimertinib treatment may be safe and effective for NSCLC harboring activating EGFR-mutations.

Establishment and characterization of BMC-PDC-019: a novel patient-derived cell line of EGFR-mutant pulmonary adenocarcinoma transformed into small-cell lung cancer.

Transformed small-cell lung cancer (tSCLC) from EGFR-mutant adenocarcinoma is a rare and aggressive form of lung cancer that can occur when the tumor develops resistance to EGFR targeted therapy and the cancer cells acquire additional genomic alterations that cause them to transform into SCLC. Treatment for tSCLC has not been established yet, and chemotherapy regimens for de novo SCLC are mostly recommended. However, these treatments showed disappointing outcome, and novel anti-cancer agents and immunological approaches are currently being developed. The patient-derived cell line is a critical tool for pre-clinical and translational research, but cell line models for tSCLC are not publicly available from cell banks. The aim of this study was to establish and characterize a novel cell line for tSCLC. Using a lymph-node biopsy tissue from a 58-year-old female patient, whose tumor was EGFR-mutant lung adenocarcinoma progressed on afatinib, we successfully established a cell line, named BMC-PDC-019. The tumor sample and cell line showed a typical expression of SCLC markers, such as CD56 and synaptophysin. The population doubling-time of BMC-PDC-019 cells was 48h. We examined a range of proliferation-inhibiting effects of anti-cancer drugs currently used for de novo SCLC, using BMC-PDC-019 cells. We concluded that BMC-PDC-019 would be a useful tool for pre-clinical and translational research.

Differential Prognostic Value of Vascular Invasion in Resected Lung Adenocarcinomas According to Epidermal Growth Factor Receptor Mutational Status

BackgroundIt is unclear whether all patients with stage IB to IIIA epidermal growth factor receptor (EGFR)-mutant adenocarcinoma should receive adjuvant osimertinib. We investigated the prognostic value of vascular invasion for risk stratification according to EGFR mutational status. Materials and MethodsThis retrospective study evaluated patients with stage IB to IIIA lung adenocarcinoma resected between 2011 and 2016 at a tertiary care center. The study outcome was overall survival (OS). The prognostic value of vascular invasion was analyzed using the adjusted log-rank test and multivariable Cox regression with clinico-pathological factors as covariates. A sensitivity analysis, which included the presence of ground-glass opacity on CT scans as an additional covariate, and subgroup analyses according to the pathological stage were performed. ResultsIn total, 272 patients were included (146 women; median age, 66 years [interquartile range: 58, 72 years]; 128 EGFR-mutant adenocarcinomas). The 5-year OS rate was 90.8% (95% CI: 84.0%, 98.1%) in EGFR-mutant, vascular invasion-absent lung adenocarcinomas, which was higher than in other subgroups (P < .05). Vascular invasion was an independent, negative prognostic factor in EGFR-mutant lung adenocarcinomas (adjusted log-rank test, P = .02; adjusted hazard ratio, 3.01; 95% CI: 1.30, 7.02; P = .01). However, the prognosis of EGFR wild-type adenocarcinomas was not associated with the presence of vascular invasion (adjusted log-rank test, P = .95; adjusted hazard ratio, 1.32; 95% CI: 0.74, 2.34; P = .35). Similar results were observed in the sensitivity analysis and subgroup analyses. ConclusionsVascular invasion-absent, EGFR-mutant, resected lung adenocarcinomas showed a very good prognosis, and vascular invasion had a differential prognostic value according to EGFR mutational status.

Abstract 3886: Analysis of concomitant genetic alterations in advanced EGFR-mutated lung adenocarcinoma by targeted NGS: A multicenter prospective and real world study

Abstract Background:The response of 1st-line EGFR-TKI treatment in advanced EGFR-mutated lung adenocarcinoma patients are highly effective, but its sustainability and clinical course are quite variable from patient to patient. In this study, we investigated the clinical impact of concomitant genetic mutations analyzed by targeted NGS on PFS and acquired resistance in advanced EGFR-mutated lung adenocarcinoma patients. Methods: Eighty-five advanced NSCLC patients harboring EGFR mutations were enrolled prospectively in multi-centers from 2019 to 2022 (NCT04122833). We performed the targeted next generation sequencing on 324 cancer-related genes by Foundation One CDx with pre-treated tumor samples. First- or second-generation EGFR-TKIs(gefitinib, afatinib, or erlotinib) were administered in 1st-line setting. After the progression, tissue re-biopsy or plasma liquid biopsy (FoundationOne Liquid CDx) for NGS if tissue biopsy is difficult or risk was performed. Results: Of the 85 patients (70.6% of female, 65.8% of nonsmoker, 56.4% of E19del and 38.8% of E21 L858R mutation), 50 patients experienced a disease progression in November, 2022. The median PFS was 20 months (95 %CI: 15.2-24.8). The most frequent co-mutations were TP53 (47.1%), CDKN2A/B loss (34.1%), MTAP loss (20%), NKX2-1amp(15.3%), MDM2amp (14.1%), RMB10, CCNE/CCND1 amp, NFKB1 amp (11.8%) and CDK4/6 amp (10.6%). Patients with TP53, CDK4/6 amp and MYC amp were independently associated with shorter PFS. In a multivariate analysis, tumors with copy number alterations such as CDK4/6 amp or Myc amp were also independently associated with shorter PFS. However, the CDKN2A/2B loss, MTAP loss, and MDM amp were not related with the PFS. In the number of co-mutations, patients harboring ≥5 co-mutations identified by NGS had shorter median PFS than patients with 0-1 or 2-4 co-mutations. (mPFS 0-1: 2-4: ≥5 co-mutations=35: 18: 9.3 months, p&amp;lt;0.001). At progression, 22 patients harbored an acquired T790M mutation (25.8%). Before TKI treatment, patients with CDKN2A/B loss, MTP loss or CCND/CCNE1 amp in pretreatment tumor have more acquired T790M mutation after progression significantly (p&amp;lt;0.05) Conclusion: We have demonstrated that concomitant mutations detected by targeted NGS analysis provide significant impact on the drug response and clinical course of advanced EGFR-mutated adenocarcinoma patients treated by 1st-line EGFR-TKIs. It is suggested that targeted NGS along with PCR-based detection will be necessary for precision medicine-based individualized practice of 1st-line EGFR-TKI-based combination treatment. Citation Format: In Ae Kim, Seung Joon Kim, Sung Yong Lee, Chang Min Choi, Jae Cheol Lee, Tae Won Jang, Seung Hun Jang, Chan Kwon Park, Wan Seop Kim, Jae Young Hur, Hee Joung Kim, Young Whan Kim, Key Young Lee. Analysis of concomitant genetic alterations in advanced EGFR-mutated lung adenocarcinoma by targeted NGS: A multicenter prospective and real world study. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3886.

Risk Factors for Recurrence of Stage I Epidermal Growth Factor Receptor Mutated Lung Adenocarcinoma

BackgroundWe aimed to clarify the risk factors for postoperative recurrence in patients with epidermal growth factor receptor (EGFR)-mutated stage I lung adenocarcinoma, using EGFR wild-type adenocarcinoma as a comparator, to select optimal candidates for adjuvant therapy with EGFR tyrosine kinase inhibitor (TKI). MethodsData of patients with pathologic stage I EGFR-mutated (n = 713) and wild-type (n = 673) adenocarcinoma who did not receive adjuvant therapy were retrospectively analyzed. The cumulative incidence of recurrence (CIR) was estimated using Gray’s method, and multivariable Fine-Gray competing risk models identified independent risk factors associated with recurrence. ResultsThe CIR did not differ significantly between patients with EGFR-mutated and wild-type adenocarcinoma (P = .32). Multivariable analysis revealed that greater size (cm) of invasive tumor (hazard ratio 1.539; 95% CI, 1.077-2.201), lymphovascular invasion (hazard ratio 5.180; 95% CI, 2.208-12.15), pleural invasion (hazard ratio 3.388; 95% CI, 1.524-7.533), and high-grade histologic subtype (hazard ratio 4.295; 95% CI, 1.539-11.99) were independent risk factors for recurrence in patients with EGFR-mutated adenocarcinoma. The 5-year CIR was significantly higher among patients with these factors (tumor size greater than 2 cm, 15.9%; lymphovascular invasion, 26.9%; pleural invasion, 39.3%; and high-grade subtype, 44.4%) than among patients without them (4.4%, 2.2%, 3.9%, and 5%, respectively; P < .001). For patients with EGFR wild-type adenocarcinoma, independent risk factors for recurrence were invasive tumor size, lymphovascular invasion, and pleural invasion, but not histologic subtypes. ConclusionsEven for patients with EGFR-mutated stage I lung adenocarcinoma, recurrence risk is stratified. Adjuvant therapy may be considered if they have high-risk factors for recurrence.

A Multicenter Two-arm, Phase II Trial Assessing the Safety and Efficacy of First-line Lazertinib and Locally Ablative Radiotherapy in Patients With Synchronous Oligo-metastatic EGFR-mutant Non-small Cell Lung Cancer (ABLATE, KCSG-LU21-11)

BackgroundThe current standard treatment of advanced non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation is upfront EGFR targeted therapy. However, patients invariably experience disease progression at primary tumors or metastatic sites. Adding stereotactic body radiation therapy (SBRT) to systemic therapy can improve progression-free survival (PFS) and overall survival (OS). This multicenter, 2-arm, phase II study aims to evaluate the efficacy and safety of lazertinib, a third generation EGFR tyrosine kinase inhibitor, combined with upfront locally ablative radiotherapy in EGFR-mutant NSCLC patients with synchronous oligometastatic disease (ClinicalTrials.gov: NCT05167851). Patients and MethodsKey inclusion criteria are biopsy-proven EGFR-mutated adenocarcinoma with synchronous, oligometastatic (≤5 metastases) NSCLC. Patients will be randomized 1:1 to receive lazertinib or lazertinib + SBRT to the primary tumor and metastatic sites. The primary endpoint is PFS according to RECIST: Response Evaluation Criteria in Solid Tumor version 1.1, and the secondary endpoints are OS, objective response rate, and safety. ResultsPatient enrolment began in January 2021 and is ongoing at 7 sites in the Republic of Korea. ConclusionThis trial will provide valuable information on the efficacy and safety of lazertinib in combination with SBRT in patients with synchronous, oligometastatic EGFR-mutant NSCLC.

Exosomes from EGFR-Mutated Adenocarcinoma Induce a Hybrid EMT and MMP9-Dependant Tumor Invasion.

Simple SummaryExosomes, a class of extra cellular nano-sized vesicles (EVs), and their contents have gained attention as potential sources of information on tumor detection and regulatory drivers of tumor progression and metastasis. We report that exosomes from serum of patients with Epidermal Growth Factor Receptor (EGFR) -mutated non-small cell lung cancer (NSCLC) induce invasion by promoting hybrid EMT. We depict exosomes as valuable actors of metastasis formation and establishment of pre-metastatic niche. Patients with an EGFR mutation are prone to metastatic recurrence. Exosomes should therefore be strongly considered as key players in cancer relapse but also as major actors in the establishment of the pre-metastatic niche.Exosomes, a class of extra cellular nano-sized vesicles (EVs), and their contents have gained attention as potential sources of information on tumor detection and regulatory drivers of tumor progression and metastasis. The effect of exosomes isolated from patients with an Epidermal Growth Factor Receptor (EGFR)-mutated adenocarcinoma on the promotion of epithelial–mesenchymal transition (EMT) and invasion were examined. Exosomes derived from serum of patients with EGFR-mutated non-small cell lung cancer (NSCLC) mediate the activation of the Phosphoinositide 3-kinase (PI3K)/AKT/ mammalian target of rapamycin (mTOR) pathway and induce an invasion through the up-regulation of matrix metalloproteinase-9 (MMP-9) in A549 cells. We observed a significant increase in the expression of vimentin, a mesenchymal marker, while retaining the epithelial characteristics, as evidenced by the unaltered levels of E-cadherin and Epithelial cell adhesion molecule (EPCAM). We also observed an increase of nuclear factor erythroid 2-related factor 2 (NFR2) and P-cadherin expression, markers of hybrid EMT. Exosomes derived from EGFR-mutated adenocarcinoma serum could be a potential mediator of hybrid EMT and tumor invasion. Understanding how cancerous cells communicate and interact with their environment via exosomes will improve our understanding of lung cancer progression and metastasis formation.

Abstract 958: Exosomes from EGFR-mutated adenocarcinoma induce a hybrid EMT and MMP9-dependant tumour invasion

Abstract Exosomes are a class of extra cellular vesicles (EVs), with a multi vesicular endosomal origin, that are released by all cell types, with sizes ranging from 30-150nm and a lipid bilayer membrane. Recent studies document that tumour cells shed exosomes at considerably higher rates, and these exosomes play critical roles in several early and late events associated with tumour development and metastasis. Thus, circulating exosomes are emerging as a new paradigm of ‘liquid biopsy’ for non-invasive cancer diagnosis. They have been reported to influence epithelial mesenchymal transition (EMT) in pathological states such as metastatic lung cancer. We successfully isolated exosomes from an Epidermal Growth Factor Receptor (EGFR) mutated cell line (HCC827) and from serum of different lung cancer patients: EGFR-mutated adenocarcinoma (N=5), wild-type adenocarcinoma (N=5), squamous (N=3) and serum of patients with no cancer (N=5) and analysed their effects on cells from an A549 cell line. By zymography, we observed that exosomes derived from the EGFR-mutated adenocarcinoma patients contains significantly more MMP-9 and pro-MMP-9 than those derived from other patients. When incubated with A549 cells, all exosomes, derived from the EGFR mutated cell line and from patients (regardless of patient origin), induced an increase in MMP2 activity. However, the increase of MMP9 activity was seen only in A549 cells treated with exosomes derived from EGFR-mutated adenocarcinoma patients and from the EGFR mutated cell line. MMPs are one of the major attributes that epithelial cells acquire after undergoing EMT. Respectively by a modified Boyden chamber assay and by wound healing assay, we showed, that EGFR-mutated exosomes treatment increases the invasive capacity (fold change of 1.7; p-value=0.0008) and the migratory capacity [CM1] of A549 and HBE4 E6/E7 cells in an MMP-9 dependant pathway. By western blot and qPCR, we observed a significant increase of vimentin expression, a mesenchymal marker while retaining the epithelial characteristics as evidenced by the unaltered levels of E-cadherin and EPCAM. EMT is not a binary process but instead, cells often exhibit a spectrum of epithelial/mesenchymal phenotype(s). Such hybrid cells can move collectively as clusters which is thought to enhance their invasive properties. By qPCR, we observed an increase of NRF2, P-cadherin and cytokeratin 14, markers of hybrid-EMT and collective migration. Our results suggest that exosomes derived from EGFR-mutated adenocarcinoma serum could be a potential mediator of hybrid-EMT and tumour invasion and may provide insights into the mechanisms of lung cancer progression and metastasis. Further studies are required to precisely delineate these mechanisms and explore novel therapeutic avenues. Citation Format: Amina Jouida, Cormac McCarhty, Aurelie Fabre, Allan Kelly, Parthiban Nadarajan, Marissa O Callaghan, Michael P. Keane. Exosomes from EGFR-mutated adenocarcinoma induce a hybrid EMT and MMP9-dependant tumour invasion [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 958.

Patient-derived organoids to predict the drug response in locally advanced or metastatic lung cancer: A real-world study.

9136 Background: Lung cancer organoids (LCOs) were expected to be the potential precision medicine approach for clinical response prediction. However, the clinical applications of both tissue and malignant serous effusions (MSE) derived LCOs were rarely reported. Our previous work demonstrated that MSE-derived LCOs maintain the genomic signature of the original tumor. In this study, we aimed to create LCOs using tissue or MSE, then validate the reliability of the model by comparing LCOs and their origin from the pathological and molecular levels. Furthermore, drug sensitivity tests of LCOs were also performed to evaluate the feasibility of LCO drug test as an approach for personalized medicine. Methods: Primary or metastatic tumor tissues were obtained from advanced lung cancer patients through core biopsy or surgically resected biopsy at the Guangdong Provincial People’s Hospital. MSEs were also collected. LCOs were generated from the obtained tissue and MSE, and the pathological features and genomic profiles were verified by analyzing the consistency with their origin. Then, the drug sensitivity scheme was formulated to follow the principles of clinical medication. In addition, proteomics analysis by 4D LC-MS/MS was also performed to analysis the molecular details of combinational therapy. Results: In our study, we generated 213 LCOs from 106 patients, mainly from MSE. The success rate to generate LCOs derived from MSE was 81.4% (131/161). The concordance rate of pathological phenotypes of LCOs samples verified by immunohistochemistry with clinical samples was 75% (63/84). In our cohort, LCO based drug sensitivity tests (LCO-DST) of targeted therapies were performed to predict the tumor response, and the AUC value of ROC analysis of osimertinib in EGFR-mutant adenocarcinoma reached 0.94(LCOs samples = 15, p= 0.0047). There were 2 patients with advanced lung adenocarcinoma, one with de novo EGFR mutation /MET amplification and the other with EGFR mutation combined with acquired RET fusion. The results of LCO based drug tests of 2 patients showed that combined targeted therapy (osimertinib plus savolitinib/cabozantinib) showed high tumor inhibition rate validated in clinical treatment and made differences. Then, 4D label-free high through-put proteomic analysis was performed in the patient with EGFR mutation and acquired RET fusion, demonstrating caspase 3 increased dramatically in combination of osimertinib and BLU-667 and the downstream proteins of EGFR and RET were down-regulated. Conclusions: LCOs derived from MSE faithfully reflected the pathological and genomic features of their original patients. The LCOs based drug test results are remarkably consistent with the tumor response. These results suggested the important prospects of LCO as an in vitro model for lung cancer precision medicine.

Treatment Effectiveness and Tolerability of Long-term Adjuvant First- and Second-Generation Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor at Different Doses in Patients With Stage IIA-IIIB Epidermal Growth Factor Receptor-Mutated Lung Adenocarcinoma: A Retrospective Study.

IntroductionFor patients with epidermal growth factor receptor (EGFR)-mutated lung cancer who undergo surgery, adjuvant tyrosine kinase inhibitor (TKI) therapy other than osimertinib is an alternative option. We aimed to discuss the long-term safety and efficacy of TKI treatment in real-world data.MethodsFrom January 2011 to May 2020, patients with stage II–III EGFR-mutated adenocarcinoma who underwent cancer resection surgery at a single center were enrolled. The primary endpoint was disease relapse, and the secondary endpoint was overall survival. In total, 30 patients were included in the study. In our study, all patients underwent complete resection using video-assisted thoracoscopic surgery. The patients were divided into a dose interruption (prolonged interval use) group and non-dose adjustment group.ResultsThe patients' pathological stages were II–III. The initial EGFR TKIs were mostly gefitinib (n = 25, 83%), and others were erlotinib (n = 3, 10%) and afatinib (n = 2, 6%). The mean disease-free survival (DFS) was 53.3 months. The 2- and 5-year DFS rate was 90.0 and 73.3%, respectively. The median TKI treatment duration in this study was 44.5 months (range, 6–133 months), which was the longest in the literature review. Of these patients, nine had dose interruption. We compared the two groups and found no treatment differences between them. There were no significant side effect potentials between both groups.ConclusionTo our knowledge, this study provides the longest experience of TKI in patients with resected EGFR mutations and also provided a dose reduction strategy (prolonged medication interval) for patients who had intolerable side effects.

Pan-Driver-Negatives versus Epidermal Growth Factor Receptor Mutants for C-Stage IA Lung Adenocarcinoma with Ground-Glass Opacity.

We aimed to verify the prognosis of epidermal growth factor receptor (EGFR) mutation of clinical (c)-stage IA lung adenocarcinoma with the ground-glass opacity (GGO) component. We evaluated 226 cases of surgically resected c-stage IA lung adenocarcinoma with GGO component. Endpoints were overall survival (OS) and recurrence-free survival (RFS). Kaplan-Meier analysis and the log-rank test were used to estimate the survival differences. Prognostic factors were assessed using the univariable and multivariable Cox proportional hazards model. Among the 226 cases, 177 cases harbored the EGFR-mutant adenocarcinoma with the GGO component. The mean duration of follow-up time was 54.4 ± 1.2 months. The 5-year OS and RFS did not differ significantly between the EGFR-mutant and wild-type groups (5-year OS 100% vs. 94.3%, hazard ratio [HR] 0.276, P = 0.168; 5-year RFS 94.7% vs. 95.7%, HR 0.873, P = 0.864). Multivariable Cox hazard model revealed that radiologically solid component size (P = 0.010) and pathological node-positive (P = 0.036) were significant predictors of an inferior RFS. EGFR-mutant was not a prognostic factor of OS and RFS for c-stage IA lung adenocarcinoma with the GGO component. Radiologically solid component size and pathological lymph node status were independent prognostic factors of worse RFS.

Prognosis of epidermal growth factor receptor-mutated stage I lung adenocarcinoma with radiologically solid features

Abstract OBJECTIVES The prognostic role of the epidermal growth factor receptor (EGFR) mutation remains controversial, especially in early-stage lung adenocarcinoma with a solid appearance. We evaluated the oncological outcomes of clinical stage I (c-stage I) radiologically invasive lung adenocarcinoma by EGFR mutation status. METHODS Between 2008 and 2013, the data from 463 surgically resected c-stage I radiologically invasive, i.e. solid-dominant lung adenocarcinomas subjected to EGFR mutant analysis, were evaluated. Oncological outcomes were assessed using multivariable Cox regression analysis. Recurrence-free survival (RFS) was estimated using Kaplan–Meier analysis and the log-rank test. RESULTS A total of 229 (49%) samples harboured the EGFR-mutant adenocarcinoma. Overall, the 5-year RFS did not differ significantly between the EGFR-mutant and EGFR wild-type groups (67.3% vs 64.9%; P = 0.639). However, among the clinical T1c/T2a tumour subset (n = 177), a multivariable Cox hazard model revealed that radiologically pure-solid tumour (P = 0.024), EGFR-mutant (P = 0.027) and pathological stage II/III (P &amp;lt; 0.001) were significant predictors of a poor RFS. Furthermore, in the c-T1c/T2a radiologically pure-solid lung adenocarcinoma subset, the EGFR-mutant group showed marginally lower 5-year RFS compared to that with the EGFR wild-type group (n = 134; 34.9% vs 53.0%; P = 0.062). Among them, multivariable Cox regression analysis revealed that EGFR mutant (P = 0.037) and pathological stage II/III (P = 0.011) were independently and significantly prognostic for worse RFS. CONCLUSIONS Among the c-stage I radiologically invasive lung adenocarcinomas, the EGFR mutation-positive type was correlated with an increased risk of recurrence in the c-T1c/T2a radiologically pure-solid tumour subset. When considering the prognostic value of EGFR mutations in early-stage lung adenocarcinoma, it is necessary to stratify them based on the presence of a ground-glass opacity component.

Computed Tomography Imaging Characteristics: Potential Indicators of Epidermal Growth Factor Receptor Mutation in Lung Adenocarcinoma.

The purpose of this study was to investigate the correlation between computed tomography imaging characteristics in lung adenocarcinoma and epidermal growth factor receptor (EGFR) mutations. A total of 124 patients with lung adenocarcinoma and known EGFR mutation status were collected in this retrospective study. Computed tomography quantitative parameters of each tumor, including total volume, total surface, surface-to-volume ratio (SVR), average diameter, maximum diameter, and average density, were determined using computer-aided detection software. The correlation between the EGFR mutation status and imaging characteristics was assessed. The predictive value of these imaging characteristics for EGFR mutation was calculated using the area under the receiver operating characteristic curve. Fifty-eight of 124 patients showed EGFR mutations. Patients who are female (P < 0.001) and nonsmokers (P < 0.001) and those with serum carcinoembryonic antigen (CEA) level of ≥5 (P = 0.035) were likely to have EGFR mutation. Computed tomography features including air bronchogram (P = 0.035), absence of cavitation (P = 0.010), and absence of pulmonary emphysema (P = 0.002) and quantitative parameters, such as smaller total surface (P = 0.002), smaller total volume (P = 0.001), higher SVR (P = 0.003), and smaller average diameter (P = 0.001), were associated with EGFR mutation. Logistic regression analysis revealed that the most significant independent prognostic factors of EGFR mutation for the model were nonsmoking (P = 0.035), CEA level of ≥5 (P = 0.004), presence of air bronchogram (P = 0.040), absence of cavitation (P = 0.021), and high SVR (P = 0.014). The area under the receiver operating characteristic curve, sensitivity, and specificity of the model for predicting EGFR mutation were 0.827, 75.8%, and 82.8%, respectively. EGFR-mutated adenocarcinoma showed significantly increased CEA level, presence of air bronchogram, absence of cavitation, and higher quantitative parameter SVR than those with wild-type EGFR.

Clinical characteristics of epidermal growth factor receptor-mutated advanced adenocarcinoma transformed into small-cell lung cancer

Objective: To explore the clinicopathological characteristics and genomic characteristics of four patients with epidermal growth factor receptor(EGFR)-mutated advanced adenocarcinoma transformed into small-cell lung cancer. Methods: Four cases of EGFR-mutated advanced adenocarcinoma of the lung transformed into small-cell lung cancer were studied by clinical data, pathological morphology, immunohistochemistry and gene detection. Result: EGFR-mutated adenocarcinoma of the lung was heterogeneous in clinical and genomic profiles, of ten characterized by RB1, TP53 and PIK3CA mutations. Its transformation into small-cell lung cancer was a particularly aggressive mechanism of drug resistance, but the machanisms were not clear NSE and other tumor indicators had low diagnostic value for transformation. Conclusions: EGFR-mutated adenocarcinoma of the lung transformed into small-cell lung cancer was one of the reasons for EGFR resistance with avery poor prognosis.

EGFR-Mutated Squamous Cell Lung Cancer and Its Association With Outcomes.

BackgroundThe therapeutic efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced EGFR-mutant lung squamous cell carcinoma (SCC) patients remains uncertain. Furthermore, the factors underlying the responsiveness have not been fully investigated. We therefore investigated the link between genomic profiles and EGFR-TKI efficacy.Material and MethodsWe consecutively enrolled stage IV, EGFR-mutant, and EGFR-TKI–treated patients with SCC. Patients with EGFR wild-type lung SCC and EGFR-mutant lung adenocarcinoma were consecutively enrolled as controls, and next-generation sequencing (NGS) was performed.ResultsIn total, 28 EGFR-mutant lung SCC, 41 EGFR-mutant lung adenocarcinoma, and 40 EGFR wild-type lung SCC patients were included. Among the patients with EGFR mutations, shorter progression-free survival (PFS) was observed in SCC compared to adenocarcinoma (4.6 vs. 11.0 months, P<0.001). Comparison of the genomic profiles revealed that EGFR-mutant SCC patients had similar mutation characteristics to EGFR-mutant adenocarcinoma patients, but differed from those with EGFR wild-type SCC. Further exploration of EGFR-mutant SCC revealed that mutations in CREBBP (P = 0.005), ZNF217 (P = 0.016), and the Wnt (P = 0.027) pathway were negatively associated with PFS. Mutations in GRM8 (P = 0.025) were associated with improved PFS.Conclusions EGFR-mutant lung SCC has a worse prognosis than EGFR-mutant adenocarcinoma. Mutations in other genes, such as CREBBP, ZNF217, GRM8, or Wnt that had implications on PFS raise the possibility of understanding mechanisms of resistance to EGFR-TKI in lung SCC, which will aid identification of potential beneficial subgroups of patients with EGFR-mutant SCCs receiving EGFR-TKIs.

Novel ETV1 mutation in small cell lung cancer transformation resistant to EGFR tyrosine kinase inhibitors.

e20568 Background: Non-small cell lung cancer (NSCLC) patients harboring mutations in the epidermal growth factor receptor (EGFR) gene dramatically respond to EGFR tyrosine kinase inhibitors (TKIs). However, these patients inevitably developed acquired resistance to TKIs. Among them, small cell lung cancer (SCLC) transformation is a relatively rare mechanism of resistance. However, the mechanism of SCLC transformation is largely unclear. Methods: We performed a 639 cancer-relevant gene panel to detect genetic differences of tissues before and after TKIs resistance caused by SCLC transformation. In vitro experiments were conducted to study the role of ETS variant transcription factor 1 (ETV1) on SCLC transformation and TKIs resistance. Results: We present two EGFR-mutant pulmonary adenocarcinoma (ADC) patients. One with EGFR exon 19 deletion (Ex19del) accepted first-line gefitinib treatment and then received osimertinib(AZD9291) treatment due to acquisition of EGFR-T790M mutation. A novel ETV1 mutation (p.P159S) was detected in SCLC samples after SCLC transformation when not coexisting with T790M. Another patient harbored an EGFR exon 21 mutation (p.L858R) with a long-lasting response to first-line gefitinib and then transformed to SCLC. A previously unreported ETV1 mutation (p.E462Q) was detected in SCLC tissue. In vitro, ETV1 p.E462Q and p.P159S mutations participated in neuroendocrine differentiation by inducing the expression of the neuroendocrine transcription factor, achaete-scute homolog 1 (ASCL1) and promoted H69 cells proliferation. Besides, ETV1 p.E462Q and p.P159S mutations were resistant to first-generation (gefitinib) and third-generation (osimertinib) TKIs after introducing into NCI-H358 cells. Conclusions: Novel ETV1 p.E462Q and p.P159S mutations were found in SCLC tissues of TKIs resistant patients, providing novel understanding of ETV1 involved in acquired resistance to EGFR-TKIs via SCLC transformation.

39P Tissue vs. cobas vs. DDPCR for EGFR in NSCLC: Real-world evidence from India

Background: EGFR mutant adenocarcinoma accounts for almost 33% cases of NSCLC in the Asian population. Single gene testing on tissue blocks has been the gold standard since its discovery, however owing to the inherent technical difficulties, invasive nature, difficult accessibility to the lung may limit its use in many patients. Liquid biopsy has evolved as a value added tool for early diagnosis of biomarkers in lung cancer. Various detection methods have been employed for the detection of EGFR mutation like Cobas V2 and ddPCR.

Exploring the resistance mechanisms of second-line osimertinib and their prognostic implications using next-generation sequencing in patients with non-small-cell lung cancer

IntroductionAlthough osimertinib overcomes the T790M mutation acquired after traditional epidermal growth factor receptor (EGFR) gene tyrosine kinase inhibitor (TKI) treatment, resistance to osimertinib eventually occurs. We explored resistance mechanisms of second-line osimertinib and their clinical implications by comparing next-generation sequencing (NGS) results before and after resistance acquisition. MethodsWe enrolled 34 patients with advanced EGFR-mutant adenocarcinoma whose biopsied tumour tissues were subjected to targeted NGS at the time of progression on osimertinib. For comparison, NGS was also performed on archived tumour tissues from each patient excised before osimertinib initiation. ResultsThe tumours of three patients’ were observed to have transformed to small-cell carcinoma and those of two patients to squamous cell carcinoma. Among the remaining 29 patients, T790M mutations were maintained in seven patients (24.1%), including four patients (13.8%) acquiring C797S mutations and one with MET amplification. Among the 22 patients (75.9%) with T790M loss, a variety of novel mutations were identified, including KRAS mutations, PIK3CA mutations, and RET fusion, but MET amplifications (n = 4, 18.2%) were most frequently identified variations. Progression-free survival (PFS) on osimertinib was shorter among patients with T790M loss than among those who maintained T790M (5.36 versus 13.81 months, p = 0.009), and MET-amplified patients were found to have much worse PFS among patients with T790M loss (2.10 versus 6.35 months, p = 0.01). ConclusionsLoss of the T790M mutation was associated with early resistance to osimertinib, and this was exacerbated by MET amplification. Further work is needed to fully understand the implications of each resistance mechanism.