EGFR-mutant Lung Adenocarcinoma Research Articles

Osimertinib as neoadjuvant therapy in patients with EGFR-mutant resectable stage II-IIIB lung adenocarcinoma (NEOS): A multicenter, single-arm, open-label phase 2b trial

ObjectivesOsimertinib, a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), has been approved for EGFR-mutant non-small-cell lung cancer (NSCLC). We aimed to evaluate the efficacy and safety of neoadjuvant osimertinib in patients with EGFR-mutant resectable locally advanced NSCLC. Materials and MethodsThis single-arm, phase 2b trial (ChiCTR1800016948) was conducted at six centers in mainland China. Patients with a measurable stage IIA-IIIB (T3-4 N2) lung adenocarcinoma and EGFR exon 19 and/or 21 mutations were enrolled. The patients were treated with osimertinib 80 mg orally once per day for six weeks, followed by surgical resection. The primary endpoint was the objective response rate (ORR) assessed according to the Response Evaluation Criteria In Solid Tumors version 1.1. ResultsBetween October 17, 2018, and June 08, 2021, 88 patients were screened for eligibility. Forty patients were enrolled and treated with neoadjuvant osimertinib therapy. The ORR was 71.1 % (27/38) (95 % confidence interval: 55.2–83.0) in 38 patients who completed the 6-week osimertinib treatment. Thirty-two patients underwent surgery, and 30 (93.8 %) underwent successful R0 resection. Thirty (75.0 %) of 40 patients had treatment-related adverse events during neoadjuvant treatment, and three (7.5 %) had treatment-related adverse events of grade 3. The most common treatment-related adverse events were rash (n = 20 [50 %]), diarrhea (n = 12 [30 %]), and oral ulceration (n = 12 [30 %]). ConclusionsThe third-generation EGFR TKI osimertinib, with satisfying efficacy and acceptable safety profile, could be a promising neoadjuvant therapy in patients with resectable EGFR-mutant NSCLC.

Effect of EGFR-TKIs combined with craniocerebral radiotherapy on the prognosis of EGFR-mutant lung adenocarcinoma patients with brain metastasis: A propensity-score matched analysis.

Epidermal growth factor receptor (EGFR)-mutant lung cancers are associated with a high risk of developing brain metastases (BM). Craniocerebral radiotherapy is a cornerstone for the treatment of BM, and EGFR-TKIs act on craniocerebral metastases". However, whether EGFR-TKIs combined with craniocerebral radiotherapy can further increase the efficacy and improve the prognosis of patients is unclear. This study aimed to evaluate the difference in efficacy between targeted-therapy alone and targeted-therapy combined with radiotherapy in EGFR-mutant lung adenocarcinoma patients with BM. A total of 291 patients with advanced non-small cell lung cancer (NSCLC) and EGFR mutations were enrolled in this retrospective cohort study. Propensity score matching (PSM) was conducted using a nearest-neighbor algorithm (1:1) to adjust for demographic and clinical covariates. Patients were divided into two groups: EGFR-TKIs alone and EGFR-TKIs combined with craniocerebral radiotherapy. Intracranial progression-free survival (iPFS) and overall survival (OS) were calculated. Kaplan-Meier analysis was used to compare iPFS and OS between the two groups. Brain radiotherapy included WBRT, local radiotherapy, and WBRT+Boost. The median age at diagnosis was 54 years (range: 28-81 years). Most patients were female (55.9%) and non-smokers (75.5%). Fifty-one pairs of patients were matched using PSM. The median iPFS for EGFR-TKIs alone (n=37) and EGFR-TKIs+craniocerebral radiotherapy (n=24) was 8.9 and 14.7 months, respectively. The median OS for EGFR-TKIs alone (n=52) and EGFR-TKIs+craniocerebral radiotherapy (n=52) was 32.1 and 45.3 months, respectively. In EGFR-mutant lung adenocarcinoma patients with BM, targeted therapy combined with craniocerebral radiotherapy is an optimal treatment.

Brief Report: Combination of Osimertinib and Dacomitinib to Mitigate Primary and Acquired Resistance in EGFR-Mutant Lung Adenocarcinomas.

Primary and acquired resistance to osimertinib remain significant challenges for patients with EGFR-mutant lung cancers. Acquired EGFR alterations such as EGFR T790M or C797S mediate resistance to EGFR tyrosine kinase inhibitors (TKI) and combination therapy with dual EGFR TKIs may prevent or reverse on-target resistance. We conducted two prospective, phase I/II trials assessing combination osimertinib and dacomitinib to address on-target resistance in the primary and acquired resistance settings. In the initial therapy study, patients received dacomitinib and osimertinib in combination as initial therapy. In the acquired resistance trial, dacomitinib with or without osimertinib was administered to patients with EGFR-mutant lung cancers with disease progression on osimertinib alone and evidence of an acquired EGFR second-site mutation. Cutaneous toxicities occurred in 93% (any grade) of patients and diarrhea in 72% (any grade) with the combination. As initial therapy, the overall response to the combination was 73% [95% confidence interval (CI), 50%-88%]. No acquired secondary alterations in EGFR were observed in any patients at progression. In the acquired resistance setting, the overall response was 14% (95% CI, 1%-58%). We observed no acquired secondary EGFR alterations with dual inhibition of EGFR as up-front treatment, but this regimen was associated with greater toxicity. The combination was not effective in reversing acquired resistance after development of a second-site acquired EGFR alteration. Our study highlights the need to develop better strategies to address on-target resistance in patients with EGFR-mutant lung cancers.

PP01.62 Therapeutic Potential of Folate Conjugated Actinonin Encapsulated Human Serum Albumin Nanoformulation against Lung Adenocarcinoma Model

The ‘immune cold’ K-ras and EGFR mutant lung adenocarcinoma (LUAD) requires novel targets and chemotherapeutics as these tumors are immunotherapy non-responsive. Moreover, the ligand shedding pathway mediated by ADAM17 ultimately initiates EGFR/ERK signaling responsible for neoplastic behavior. Interestingly, ADAM17 has been reported to be inhibited by actinonin, a hydroxamate which also inhibits the mitochondrial peptide deformylase which is essential for mitochondrial translation initiation. The mitochondrial translation inhibition induces cellular apoptosis in multiple cancer cell lines, lung and renal in vivo xenograft models. Disappointingly, actinonin is a broad spectrum metalloprotease inhibitor and its free form administration poses a threat to biological tissue homeostasis. This in turn makes it a double edged sword. Therefore, this study was designed to evaluate anti-proliferative efficacy of folate receptor targeted human serum albumin (HSA) nanoformulation of actinonin against murine LUAD.

The efficacy of neoadjuvant EGFR-TKI therapy combined with radical surgery for stage IIIB lung adenocarcinoma harboring EGFR mutations: A retrospective analysis based on single center.

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) could provide survival benefits for locally advanced EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC). However, the role of radical surgery for EGFR-TKI treated stage IIIB EGFRm NSCLC remains controversial. This study attempted to assess the feasibility of neoadjuvant EGFR-TKI followed by radical surgery for stage IIIB EGFRm NSCLC. Between 2013 and 2020, EGFRm lung adenocarcinoma (LUAD) patients in clinical stage IIIB undergoing neoadjuvant EGFR-TKI followed by surgery (T-S-Arm) and EGFR-TKI alone (T-Arm) were reviewed retrospectively in Shanghai Pulmonary Hospital (SPH). The chi-square test, Student's t-test or Fisher's exact test was performed for analysis of baseline characteristics. Progression-free survival (PFS) was estimated using the Kaplan-Meier analysis. Multivariate Cox regression analysis was used to identify independent predictors of progression. A total of 43 patients were divided into T-S-Arm (n = 21) and T-Arm (n = 22). Patients were well-balanced between the two arms. The majority of patients were female (n = 25, 58.1%), non-smokers (n = 35, 81.4%), first-generation of EGFR-TKI treatment (n = 39, 90.7%), and exon 19 deletions (19-DEL) (n = 26, 60.5%). The median diagnostic age was 63.0 years [interquartile range (IQR), 54.0-67.5 years). At the cut-off date with June 30th 2022, median follow-up time was 28 months (IQR, 20-39 months). Neoadjuvant EGFR-TKI treatment followed by radical surgery could significantly improve the median PFS compared with patients underwent EGFR-TKI alone (23.0 months vs 14.5 months, P = 0.002). Multivariate Cox regression analysis demonstrated that radical surgery (T-S-Arm vs. T-Arm, HR: 0.406; 95% CI: 0.207-0.793, P = 0.027) was the only independent predictor for disease progression. The stratified analysis demonstrated patients with N2 disease could benefit from radical surgery (HR, 0.258; 95% CI, 0.107-0.618), especially for patients harboring L858R mutation (HR, 0.188; 95% CI, 0.059-0.604). For stage IIIB EGFRm NSCLC patients, the prognosis might be improved by neoadjuvant EGFR-TKI followed by radical surgery versus EGFR-TKI alone, especially for those with N2 disease and harboring L858R mutation.

MMP11 is associated with the immune response and immune microenvironment in EGFR-mutant lung adenocarcinoma.

High expression of matrix metalloproteinase-11 (MMP11) is associated with various tumors and immune microenvironments. Conversely, poor response to immunotherapy in epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LUAD) patients is closely related to the characteristics of immune microenvironment. The Cancer Genome Atlas (TCGA)-LUAD database and our gathered clinical LUAD samples were used to examine the relationship between MMP11 expression and EGFR mutation. Then the correlation between MMP11 and immune response and the difference of immune cell infiltration in different groups were analyzed. Compared the differences in the immune microenvironment between the MMP11-positive and MMP11-negative expression groups using immunohistochemistry (IHC) and multiplex immunohistochemistry. The expression of MMP11 in samples with exon 19 deletions, exon 21 L858R or de novo exon 20 T790M mutations was higher than wild type, but there was no difference between the samples with uncommon mutation and the wild-type. The high MMP11 expression group had a higher Tumor Immune Dysfunction and Exclusion (TIDE) score. Pathways associated with enrichment in the extracellular matrix (ECM) were the main biological functions of differential genes between the high and low MMP11 groups. The IHC score of MMP11 in the EGFR-mutant group was higher than in the EGFR-wild group. In TCGA-LUAD, the high MMP11 group had a lower proportion of T cell CD8+ and NK cells activated. In the clinical samples, the infiltration levels of T cell CD8+ and NK cells in the tumor parenchyma of EGFR-mutant LUAD was lower in the MMP11-positive than in the MMP11-negative group. The expression levels of tumor cell PD-L1 were higher in the MMP11-positive expression group than in the MMP11-negative expression group, and the proportion of PD1+CD8+ T cells infiltrated was reduced in the MMP11-positive group compared to the MMP11-negative group. High expression of MMP11 was associated with EGFR mutations. Patients with EGFR-mutant LUAD with high expression of MMP11 responded poorly to immunotherapy, and the percentage of T cell CD8+ and NK cells in immune cell infiltration was lower in MMP11. Consequently, MMP11 is related to the immunological microenvironment of EGFR-mutant lung adenocarcinoma, which may be a predictor of possible immunotherapeutic response.

CBX5 loss drives EGFR inhibitor resistance and results in therapeutically actionable vulnerabilities in lung cancer

Although epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFRi) are approved for treating EGFR-mutant lung adenocarcinoma (LUAD), emergence of acquired resistance limits their clinical benefits. Several mechanisms for acquired resistance to EGFRi in LUAD have been identified; however, the molecular basis for this resistance remains unknown in ~30% of LUAD. Chromatin and DNA modifiers and their regulators play important roles in determining response to anticancer therapies. Therefore, to identify nongenetic mechanisms of EGFRi resistance in LUAD, we performed an epigenome-wide shRNA screen targeting 363 human epigenetic regulator genes. This screen identified loss of the transcriptional repressor chromobox homolog 5 (CBX5) as a driver of EGFRi resistance in EGFR-mutant LUAD. Loss of CBX5 confers resistance to multiple EGFRi in both cell culture and mice. We found that CBX5 loss in EGFR-mutant LUAD cells leads to increased expression of the transcription factor E2F1, which in turn stimulates expression of the antiapoptotic gene BIRC5 (survivin). This E2F1-mediated upregulation of BIRC5 in CBX5-knockdown LUAD cells attenuates apoptosis induction following EGFRi treatment. Consistent with these results, knockdown of E2F1 or BIRC5 partly rescues CBX5-knockdown-induced EGFRi resistance in cell culture and mice. EGFRi-resistant LUAD cell lines show reduced CBX5 expression compared to parental lines; however, bromo- and extra-terminal (BET)-domain inhibitors (BETi) restore CBX5 expression in these cells and sensitize them to EGFRi/BETi combination therapy. Similarly, treatment with a BIRC5 inhibitor suppresses growth of EGFRi-resistant LUAD cells. Collectively, these studies identify CBX5 loss as a driver of EGFRi resistance and reveal therapeutic opportunities for treating EGFRi-resistant LUAD.

Expression of Concern: A Histopathological Feature of EGFR-Mutated Lung Adenocarcinomas with Highly Malignant Potential - An Implication of Micropapillary Element.

Expression of Concern: A Histopathological Feature of EGFR-Mutated Lung Adenocarcinomas with Highly Malignant Potential - An Implication of Micropapillary Element.

THORACIC CT-SCAN WITH EGFR MUTATIONS IN PULMONARY ADENOCARCINOMA PATIENTS WITH PULMONARY METASTASES AT DR. MOEWARDI HOSPITAL, SURAKARTA, INDONESIA

Highlights The thoracic CT scan can be an alternative evaluation before administering EGFR-targeting medicine to patients. EGFR is now a therapeutic target for lung cancer. Abstract Background: EGFR mutation is one of the molecular markers associated with prognosis and therapy in lung adenocarcinoma patients, including with lung metastases. The predominant imaging modality for assessing lung cancer is a chest CT scan, which correlates with prognosis. Objective: This study aimed to explore the association between characteristics of lung adenocarcinoma based on chest CT-Scan and EGFR mutation in lung adenocarcinoma with lung metastases. Material and Method: This study involved 65 lung adenocarcinoma patients in Dr. Moewardi Hospital, Surakarta, Indonesia, from January 2018-December 2020. Result: Chest CT-Scan and EGFR mutation were assessed in all subjects. EGFR mutation was found in 32 (49.8%) subjects. The risk of EGFR mutation was found to be higher in patients with lung adenocarcinoma who had lung metastases in a peripheral location (OR=11.56; 95%CI 3.57-37.33; p<0.001), tumor size <4 cm (OR=8.00; 95%CI 2.64-24.22; p<0.001), and semi-solid density (OR=5.21; 95%CI 1.79-15.19; p=0.002). Conclusion: EGFR mutation is associated with tumor location, size, and thickness based on chest CT-Scan in lung adenocarcinoma with lung metastases patients.

Utilisation Patterns and Treatment Outcomes of EGFR-Tyrosine Kinase Inhibitors in EGFR-mutant Advanced Lung Carcinoma in the Pakistani-Asian Population: A Real-world Data Study.

Data on the utilisation of epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitors (TKIs) and their clinical outcomes in a heterogeneous Pakistani-Asian population have not been previously reported. This manuscript presents the first account of the clinical outcomes of EFGR-TKIs in EGFR-mutant lung adenocarcinoma among Pakistani-Asians. A real-world data study was conducted on all advanced lung cancer patients harbouring EGFR-mutations from the cancer registry of Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan. We identified three different patterns of the use of EGFR-TKIs (Groups 1, 2 and 3) that reflect the ground realities of cancer care and delivery in Pakistan. We also noted a significant proportion of patients (Group 4) without access to EGFR TKIs. We compared the objective response rates (ORR), progression-free survival (PFS) and overall survival (OS) of each of the four groups and reported their toxicity profile. Within the limitations of a retrospective analysis, we saw differences in the frequency of EGFR mutations in this population. However, response rates and long-term outcomes of EGFR TKI therapy were comparable with the existing data. The overall use of EGFR TKIs led to a superior outcome in ORR, PFS and OS compared to chemotherapy alone; (77.8% vs. 50.0%, 16.3 vs. 10.7 months; P = 0.099; 85.6 vs. 25.9 months, respectively; P = 0.13). Except for modest differences, EGFR-mutant advanced lung adenocarcinoma outcomes among Pakistani-Asians are comparable to those of other populations.

Evolutionary Analysis of TCGA Data Using Over- and Under- Mutated Genes Identify Key Molecular Pathways and Cellular Functions in Lung Cancer Subtypes.

We identify critical conserved and mutated genes through a theoretical model linking a gene’s fitness contribution to its observed mutational frequency in a clinical cohort. “Passenger” gene mutations do not alter fitness and have mutational frequencies determined by gene size and the mutation rate. Driver mutations, which increase fitness (and proliferation), are observed more frequently than expected. Non-synonymous mutations in essential genes reduce fitness and are eliminated by natural selection resulting in lower prevalence than expected. We apply this “evolutionary triage” principle to TCGA data from EGFR-mutant, KRAS-mutant, and NEK (non-EGFR/KRAS) lung adenocarcinomas. We find frequent overlap of evolutionarily selected non-synonymous gene mutations among the subtypes suggesting enrichment for adaptations to common local tissue selection forces. Overlap of conserved genes in the LUAD subtypes is rare suggesting negative evolutionary selection is strongly dependent on initiating mutational events during carcinogenesis. Highly expressed genes are more likely to be conserved and significant changes in expression (>20% increased/decreased) are common in genes with evolutionarily selected mutations but not in conserved genes. EGFR-mut cancers have fewer average mutations (89) than KRAS-mut (228) and NEK (313). Subtype-specific variation in conserved and mutated genes identify critical molecular components in cell signaling, extracellular matrix remodeling, and membrane transporters. These findings demonstrate subtype-specific patterns of co-adaptations between the defining driver mutation and somatically conserved genes as well as novel insights into epigenetic versus genetic contributions to cancer evolution.

Prevalence, clinical and molecular characteristics of early stage EGFR-mutated lung cancer in a real-life West-European cohort: Implications for adjuvant therapy

ObjectivesThe landmark ADAURA study recently demonstrated a significant disease-free survival benefit of adjuvant osimertinib in patients with resected EGFR-mutated lung adenocarcinoma. However, data on prevalence rates and stage distribution of EGFR mutations in non-small cell lung cancer in Western populations are limited since upfront EGFR testing in early stage lung adenocarcinoma is not common practice. Here, we present a unique, real-world, unselected cohort of lung adenocarcinoma to aid in providing a rationale for routine testing of early stage lung cancers for EGFR mutations in the West-European population. Material and methodsWe performed routine unbiased testing of all cases, regardless of TNM stage, with targeted next-generation sequencing on 486 lung adenocarcinoma cases between 01- January 2014 and 01 February 2020. Clinical and pathological data, including co-mutations and morphology, were collected. EGFR-mutated cases were compared to KRAS-mutated cases to investigate EGFR-specific characteristics. ResultsIn total, 53 of 486 lung adenocarcinomas (11%) harboured an EGFR mutation. In early stages (stage 0-IIIA), the prevalence was 13%, versus 9% in stage IIIB-IV. Nine out of 130 (7%) stage IB-IIIA patients fit the ADAURA criteria. Early stage cases harboured more L858R mutations (p = 0.02), fewer exon 20 insertions (p = 0.048), fewer TP53 co-mutations (p = 0.007), and were more frequently never smokers (p = 0.04) compared to late stage cases with EGFR mutations. The KRAS-mutated cases were distributed more evenly across TNM stages compared to the EGFR-mutated cases. ConclusionAs (neo-)adjuvant targeted therapy regimes enter the field of lung cancer treatment, molecular analysis of early stage non-small cell lung cancer becomes relevant. Testing for EGFR mutations in early stage lung adenocarcinoma holds a substantial yield in our population, as our number needed to test ratio for adjuvant osimertinib was 14.4. The observed differences between early and late stage disease warrant further analysis to work towards better prognostic stratification and more personalised treatment.

Abstract B016: A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons

Abstract Lung cancer is the leading cause of cancer-related death worldwide and affects over 2 million people each year. In lung adenocarcinoma (LUAD), somatic activating mutations of epidermal growth factor receptor (EGFR) occur in approximately 15% of patients. The first-line therapy for patients with EGFR-mutant LUAD is administration of osimertinib, an EGFR tyrosine kinase inhibitor (TKI). While many patients’ tumors initially respond to osimertinib treatment, resistance inevitably develops in most cases, which is a major challenge that hinders treatment efficacy. One common mechanism of resistance to osimertinib is the amplification of oncogenes, such as MET, HER2, and RET. Despite the high prevalence of oncogene amplifications in resistant tumors, the mechanisms that control oncogene amplification and transcription are poorly understood. Recent work has shown that oncogenes are frequently amplified on extrachromosomal DNA (ecDNA), which are circularized and highly amplified DNA sequences that are present in at least 14% of human cancers. Additional studies have implicated ecDNA amplification in the acquisition of resistance to TKIs, yet the mechanisms through which ecDNA is regulated are largely unknown. In the present study, we have identified a novel epigenetic factor that promotes the acquisition of TKI resistance through the organization and transcription of oncogene amplicons, some of which occur on ecDNA. To determine whether this factor binds to DNA, we used and found that it is enriched at the promoters of amplified oncogenes. Further, we performed protein immunoprecipitation followed by mass spectrometry and identified multiple candidate interacting factors, such as histone readers and components of the cohesin machinery. Depletion of this epigenetic factor prevents the acquisition of TKI resistance and leads to reduced transcription of oncogene amplicons. Thus, we propose a novel mechanism that promotes the acquisition of TKI resistance via the spatial organization and transcription of oncogene amplicons. Citation Format: Rebecca M. Starble, Eric G. Sun, Tyler B. Jensen, Rana Gbyli, Ning Sun, Andrew Z. Xiao. A novel epigenetic factor is required for the acquisition of TKI resistance in lung adenocarcinoma via the regulation of oncogene amplicons. [abstract]. In: Proceedings of the AACR Special Conference: Cancer Epigenomics; 2022 Oct 6-8; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_2):Abstract nr B016.

A high number of co-occurring genomic alterations detected by NGS is associated with worse clinical outcomes in advanced EGFR-mutant lung adenocarcinoma: Data from LATAM population

BackgroundCo-occurring genomic alterations identified downstream main oncogenic drivers have become more evident since the introduction of next-generation sequencing (NGS) analyses at diagnosis and progression. Emerging evidence has stated that co-occurring genomic alterations at diagnosis might represent de novo and primary resistance mechanisms to tyrosine kinase inhibitors (TKIs) in advanced EGFR-mutant (EGFRm) non-small lung cancer (NSCLC). In this study, we assessed the prognostic role of co-occurring genomic alterations in advanced EGFRm NSCLC. MethodsA cohort of 111 patients with advanced NSCLC harboring EGFR-sensitive mutations detected by PCR was analyzed in 5 Latin American oncological centers from January 2019 to December 2020. All eligible patients received upfront therapy with EGFR-TKI. Co-occurring genomic alterations were determined at diagnosis in every patient by the NGS (FoundationOneCDx) comprehensive platform, which evaluates 324 known cancer-related genes. ResultsEGFR exon19 deletion was the most frequent oncogenic driver mutation (60.4 %) detected by NGS. According to the NGS assay, 31 % and 68.3 % of patients had 1–2 and ≥ 3 co-occurring genomic alterations, respectively. The most frequent co-occurring genomic alterations were TP53 mutations (64.9 %) followed by CDKN2AB alterations (13.6 %), BRCA2 (13.6 %), and PTEN (12.7 %) mutations. Baseline central nervous system disease was present in 42.7 % of patients. First- or second-generation EGFR TKIs (gefitinib, afatinib, or erlotinib) were the most common treatment in 67.5 % of patients, while osimertinib was administered in 27.9 % of cases. The median PFS in all evaluated patients was 13.63 months (95 %CI: 11.79–15.52). Using ≥ 3 co-occurring alterations as the cut-off point, patients with ≥ 3 co-occurring genomic alterations showed a median PFS, of 12.7 months (95 %CI: 9.92–15.5) vs 21.3 months (95 %CI: 13.93-NR) in patients with 2 or less co-occurring genomic alterations [HR 3.06, (95 %CI: 1.55–5.48) p = 0.0001]. Also, patients with a TP53 mutation had a shorter PFS, 13.6 (95 %CI: 10.7–15.5) vs 19.2 months (95 %CI: 12.8-NR); in wild type TP53 [HR 2.01 (95 %CI: 1.18–3.74) p = 0.12]. In the multivariate analysis, the number (≥3) of concurrent genomic alterations and ECOG PS of 2 or more were related to a significant risk factor for progression [HR 2.79 (95 %CI: 1.49–5.23) p = 0.001 and HR 2.42 (95 %CI: 1.22–4.80) p = 0.011 respectively]. ConclusionEGFR-mutant NSCLC is not a single oncogene-driven disease in the majority of cases, harboring a higher number of co-occurring genomic alterations. This study finds the number of co-occurring genomic alterations and the presence of TP53 mutations as negative prognostic biomarkers, which confers potentially earlier resistance mechanisms to target therapy.

Erratum to NOTCH alteration in EGFR-mutated lung adenocarcinoma leads to histological small-cell carcinoma transformation under EGFR-TKI treatment

[This corrects the article DOI: 10.21037/tlcr-21-536.].

AZ12756122, a novel fatty acid synthase inhibitor, decreases resistance features in EGFR-TKI resistant EGFR-mutated NSCLC cell models

Different EGFR tyrosine kinase inhibitors (TKIs) have been developed for the treatment of non-small cell lung cancer (NSCLC) patients harboring sensitizing mutations in the EGFR gene. Apart from acquired secondary mutations, multiple resistance mechanisms have been reported, such as the overexpression of fatty acid synthase (FASN), a multi-functional enzyme essential for the de novo lipogenesis, or the increase of cancer stem cells, a small subpopulation within the tumor responsible for relapse, metastasis, and resistance to therapies. Hence, the purpose of this work is to evaluate the novel FASN inhibitor AZ12756122, both alone and in combination with gefitinib and osimertinib, in EGFR-mutated (EGFRm) lung adenocarcinoma cell models sensitive and resistant to EGFR-TKIs. The molecular effect of AZ12756122 (alone and in combination with EGFR-TKI) on FASN, EGFR/STAT3, Akt/mTOR, and MAPK signaling pathways was analyzed using RT-qPCR and Western blot. FASN expression was also evaluated in samples from patients with EGFRm NSCLC through immunohistochemistry. Our findings revealed that AZ12756122 caused cytotoxic effects inducing apoptosis, downregulated FASN expression and activity, decreased the activation of EGFR and Akt/mTOR pathway, and reduced cancer stem-like cells. Furthermore, the combination of AZ12756122 and osimertinib sensitized cells to EGFR-TKI, showing a synergistic effect that resulted in a reduction in the activation of EGFR, Akt/mTOR, and MAPK signaling pathways. Our study also showed that FASN+ EGFRm NSCLC patients exhibited a longer mPFS in patients who responded to EGFR-TKI treatment. In conclusion, FASN inhibition should be further studied for the treatment, alone or in combination with EGFR-TKIs, for EGFRm NSCLC patients.

The effect of sarcopenia on erlotinib therapy in patients with metastatic lung adenocarcinoma.

Erlotinib, a tyrosinekinase inhibitor, has been shown to improve the survival of patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer. Sarcopenia is a status with increasing importance in lung cancer, and it may predict a poor prognosis. We aimed to evaluate the impact of sarcopenia on erlotinib therapy and prognosis in patients with EGFR-mutated (exon 19 or 21 L858R) metastatic lung adenocarcinoma. Sarcopenia was defined as skeletal muscle index ≤39 cm2/m2 for women and ≤55 cm2/m2 for men. The patient characteristics, inflammation parameters, clinical and survival outcomes of the erlotinib therapy were examined according to sarcopenia status. We also analyzed the erlotinib treatment-related toxicity. Seventy-two patients were included in our retrospective study, and the mean age of the patients was 63.7 years. A total of 39 (54.2%) patients were diagnosed with sarcopenia. Patients with sarcopenia had a poor prognosis and had a shorter median progression-free survival (PFS) than patients without sarcopenia (10.5 months vs. 21.8 months, p=0.002). Sarcopenia (HR 2.08) and C-reactive protein > 6.5 mg/L (HR 2.57) were determined as independent poor prognostic factors for PFS of erlotinib therapy. Treatment-related toxicity occurred in 34.7% of patients treated with erlotinib, and sarcopenia did not significantly affect treatment-related toxicity. We also found that sarcopenia significantly affected the response to erlotinib. The expected survival outcomes may be low when erlotinib therapy is used in patients with sarcopenia and metastatic lung adenocarcinoma. This study showed that survival and clinical outcomes could be better predicted by detecting sarcopenia in patients with lung cancer using erlotinib.

The Optimal Intervention Timing of Thoracic Radiotherapy in Patients with Late-Staged EGFR Mutant Lung Adenocarcinoma

<h3>Purpose/Objective(s)</h3> Studies confirmed that thoracic radiotherapy combined with EGFR-TKIs (Epidermal Growth Factor Receptor -Tyrosine Kinase Inhibitors, EGFR-TKIs) can improve the prognosis of advanced non-small cell lung cancer patients with EGFR sensitive mutations. However, the optimal timing of radiotherapy intervention still needs to be clarified. This study aimed to investigate the effect of thoracic radiotherapy intervention on the prognosis of patients at different time points in the process of targeted therapy by analyzing the related clinical cases to provide evidence for determining the optimal therapy regimen of thoracic radiotherapy combined with EGFR TKIs. <h3>Materials/Methods</h3> Patients with EGFR mutant lung adenocarcinoma who received thoracic radiotherapy between March 2008 and June 2021 were included in present study. According to the intervention timing of thoracic radiotherapy during the course of targeted therapy, the patients were divided into two groups: radiotherapy before drug resistance and radiotherapy after drug resistance. Medical data were analyzed for thoracic progression-free survival (TPFS) and overall survival (OS). Survival curve for the two groups were determined using the Kaplan-Meier method. The hazard ratios were reported as relative risks with their corresponding 95% confidence intervals (CIs). <i>P</i> <0.05 was considered statistically significant. <h3>Results</h3> A total of 126 patients met the inclusion criteria in this retrospective study. 61 and 65 patients were divided in the groups of thoracic radiotherapy before drug resistance and after drug resistance respectively. The median TPFS and OS of the entire cohort were 16 months and 42.1 months. The median TPFS of patients with radiotherapy before EGFR-TKIs resistance was significantly longer than that of patients in another group (33.9 months vs 10.8 months, hazard ratio: 3.231, 95% confidence interval: 2.131–4.899, <i>P</i><0.05). The median OS of patients in thoracic radiotherapy before and after drug resistance groups were 53.3 and 34.4 months respectively (hazard ratio: 1.549, 95% confidence interval: 1.022–2.349, <i>P</i><0.05). <h3>Conclusion</h3> The early application of thoracic radiotherapy for the primary lesion may improve the survival of patients with advanced EGFR mutant lung adenocarcinoma.

EGFR Mutant Lung Adenocarcinoma Showed Reduced Radiosensitivity after Acquired Resistance to EGFR TKIs

<h3>Purpose/Objective(s)</h3> Though earlier application of local radiotherapy for the primary lesion may improve the survival of patients, the timing of radiotherapy intervention for advanced EGFR mutant lung adenocarcinoma is still controversial. This study aimed to detect the difference of radiosensitivity before and after resistance and explore the related mechanism by constructing EGFR mutant lung adenocarcinoma cell lines with acquired resistance to gefitinib in vitro, so as to provide theoretical basis for determining the optimal intervention timing of radiotherapy. <h3>Materials/Methods</h3> Two lung adenocarcinoma cell lines harboring EGFR mutation-PC9 and HCC827, were used for establishment of acquired resistant cells to gefitinib. The radiosensitivity was detected using a cell counting kit. Flow cytometry was introduced to explore the cell cycle distribution and Western blot was applied to further test cell cycle and DNA repair related proteins. Soft agar assay and Western blot were performed to determine the cancer stem cell (CSC) characteristics. RT-PCR detected the expression of CSC markers. Finally, the relevant signal pathways were explored. <h3>Results</h3> The cell counting kit showed that the inhibitory activity of cells with irradiation after gefitinib resistance is weaker than that before resistance. Flow cytometry revealed that the G2/M phase proportion of PC9 and HCC827 were significantly higher than that of PC9/GR and HCC827/GR under the same irradiation dose, which is consistent with the results of western blot that the increased expression of G2/M regulatory protein, including p21, Cyclin B1, CyclinA2, pCDC2 and Myt1 were more significant increased in parental cells than resistant cells. The phosphorylated level of RAD17, ATM and CHK2 which were DNA damage repair protein were more upregulated in PC9GR and HCC827GR cells. Furthermore, GR had strong capability of sphere-forming and EMT phenotype. RT-PCR showed that the expression of many genes regulating CSC characteristics increased obviously after gefitinib resistance, including SOX2, OCT4, Nanog, Notch1, Notch3, ALDH1A1, ALDH1A3 and BMI. But the up-regulated genes in the two drug-resistant cells were not completely same. Western blot and RT-PCR showed that BMP/SMAD signal pathway was more activated in both resistant cells than that in parental cells. <h3>Conclusion</h3> Lung adenocarcinoma with EGFR mutations showed reduced radiosensitivity after acquired resistance to EGFR TKIs through obtaining CSC characteristics, which may be mediated by BMP/SMAD signal pathway.

Effect of EGFR-TKIs Combined with Cerebral Radiotherapy on Prognosis of Patients with EGFR-Mutant Lung Adenocarcinoma with Brain Metastasis

<h3>Purpose/Objective(s)</h3> Purpose: Epidermal growth factor receptor (EGFR)-mutant lung cancers have a high risk of developing brain metastases (BM). Craniocerebral radiotherapy has been considered as cornerstone for treatment of BM while BRAIN clinical trial showed that EGFR-TKI alone has effect on craniocerebral metastases. However, whether EGFR-TKI combined with radiotherapy can further increase the efficacy and improve the prognosis of patients still need to be further discussed. This retrospective study aimed to evaluate the difference in efficacy between targeted therapy alone and targeted combined radiotherapy in EGFR mutant lung adenocarcinoma patients with BM. <h3>Materials/Methods</h3> Methods and materials: 324 patients with advanced non-small cell lung cancer with EGFR mutations were enrolled in this retrospective cohort study. Propensity score matching (PSM) was conducted by using a nearest-neighbor algorithm (1:1) to adjust for demographical and clinical covariates. The patients were divided into two groups: EGFR-TKIs alone and EGFR-TKIs combined with cerebral radiotherapy. Intracranial progression-free survival (iPFS) and overall survival (OS) were calculated. Kaplan–Meier was used to compare iPFS and OS between the two groups. The brain radiotherapy contained WBRT, local radiotherapy, and WBRT+Boost. <h3>Results</h3> The median age at diagnosis was 57 (range, 23–81) years. A majority of the patients were women (57, 55.8%) and non-smokers (77, 75.5%). According to the matching results of PSM, we finally matched 51 pairs of patients. The median iPFS for EGFR-TKIs alone (n=37), EGFR-TKIs + cerebral radiotherapy (n=24) was 8.9 and 14.7 months, respectively (P=0.0334). And the median OS for EGFR-TKIs alone (n=52), EGFR-TKIs + cerebral radiotherapy (n=52) was 32.1 and 45.3 months, respectively (P=0.0106). <h3>Conclusion</h3> The present study showed that in EGFR-mutant lung adenocarcinoma patients with BM, targeted therapy combined with cerebral radiotherapy is optimal treatment mode for this subgroup of patients.