Correlation analysis between driver gene mutation and clinicopathological features in lung adenocarcinoma based on real-world cumulative clinical data.

Background: Driver genes are essential predictors of targeted therapeutic efficacy. Detecting driver gene mutations in lung adenocarcinoma (LUAD) patients can help to screen for targeted drugs and improve patient survival benefits. This study aims to investigate the mutation characterization of driver genes and their correlation with clinicopathological features in LUAD. Methods: A total of 440 LUAD patients were selected from Sir Run Run Shaw Hospital between July 2019 and September 2022. Postoperative tissue specimens were analyzed for gene mutations using next-generation sequencing technology, focusing, including epidermal growth factor receptor EGFR, ALK, ROS1, RET, KRAS, MET, BRAF, HER2, PIK3CA and NRAS. At the same time, clinicopathological data were collected and organized for multidimensional correlation analysis. Results: Of 440 LUAD patients, driver gene mutations were not detected in 48 patients. The proportion of patients with driver gene mutations was as high as 89.09%. The top three driver genetic mutations were EGFR, KRAS, and MET. Sixty-nine types of EGFR mutations were detected and distributed in the protein tyrosine kinase catalytic domain (56, 81.16%), Furin-like cysteine-rich region (9, 13.04%), receptor binding domain (3, 4.35%), and EGFR transmembrane domain (1, 1.45%). Single gene locus mutation occurred in 343 LUAD patients, but the mutation gene types covered all tested genes. Our findings showed that EGFR mutations were more commonly observed in non-smoking and female patients (P<0.01), KRAS mutations were more prevalent in male patients and smokers (P<0.01), ROS1 mutations had larger tumor diameters (P<0.01) and RET mutations were more prevalent in smokers (P<0.05). Conclusions: LUAD patients exhibit diverse genetic mutations, which may co-occur simultaneously. Integrated analysis of multiple mutations is essential for accurate diagnosis and effective treatment of the disease. The use of NGS can significantly expand our understanding of gene mutations and facilitate integrated analysis of multiple gene mutations, providing critical evidence for targeted treatment methods.

Active and machine learning-enhanced discovery of new FGFR3 inhibitor, Rhapontin, through virtual screening of receptor structures and anti-cancer activity assessment.

Introduction: This study bridges traditional remedies and modern pharmacology by exploring the synergy between natural compounds and Ceritinib in treating Non-Small Cell Lung Cancer (NSCLC), aiming to enhance efficacy and reduce toxicities. Methods: Using a combined approach of computational analysis, machine learning, and experimental procedures, we identified and analyzed PD173074, Isoquercitrin, and Rhapontin as potential inhibitors of fibroblast growth factor receptor 3 (FGFR3). Machine learning algorithms guided the initial selection, followed by Quantitative Structure-Activity Relationship (QSAR) modeling and molecular dynamics simulations to evaluate the interaction dynamics and stability of Rhapontin. Physicochemical assessments further verified its drug-like properties and specificity. Results: Our experiments demonstrate that Rhapontin, when combined with Ceritinib, significantly suppresses tumor activity in NSCLC while sparing healthy cells. The molecular simulations and physicochemical evaluations confirm Rhapontin's stability and favorable interaction with FGFR3, highlighting its potential as an effective adjunct in NSCLC therapy. Discussion: The integration of natural compounds with established cancer therapies offers a promising avenue for enhancing treatment outcomes in NSCLC. By combining the ancient wisdom of natural remedies with the precision of modern science, this study contributes to evolving cancer treatment paradigms, potentially mitigating the side effects associated with current therapies.

Three subtypes of lung cancer fibroblasts define distinct therapeutic paradigms.

Cancer-associated fibroblasts (CAFs) are highly heterogeneous. With the lack of a comprehensive understanding of CAFs' functional distinctions, it remains unclear how cancer treatments could be personalized based on CAFs in a patient's tumor. We have established a living biobank of CAFs derived from biopsies of patients' non-small lung cancer (NSCLC) that encompasses a broad molecular spectrum of CAFs in clinical NSCLC. By functionally interrogating CAF heterogeneity using the same therapeutics received by patients, we identify three functional subtypes: (1) robustly protective of cancers and highly expressing HGF and FGF7; (2) moderately protective of cancers and highly expressing FGF7; and (3) those providing minimal protection. These functional differences among CAFs are governed by their intrinsic TGF-ß signaling, which suppresses HGF and FGF7 expression. This CAF functional classification correlates with patients' clinical response to targeted therapies and also associates with the tumor immune microenvironment, therefore providing an avenue to guide personalized treatment.

Gefitinib as neoadjuvant therapy for resectable stage II-IIIA non-small cell lung cancer: A phase II study.

INTRODUCTION: Currently, limited data on tyrosine kinase inhibitors as neoadjuvant therapy exist. This prospective study aimed to investigate the efficacy and safety of preoperative gefitinib in patients with stage II-IIIA operable non-small cell lung cancer (NSCLC). METHODS: This was a single-arm, phase II trial performed in the Shanghai Cancer Center. Between August 2013 and October 2015, patients with operable stage II-IIIA NSCLC with epidermal growth factor receptor (EGFR) exon 19 deletion or exon 21 L858R mutation were enrolled. Patients were treated with preoperative gefitinib (250 mg once daily for 42 days), followed by surgical resection. The primary endpoint was objective response rate (ORR); secondary endpoints were the rate of major pathologic response (MPR), disease-free survival (DFS), overall survival, and adverse events (AEs). ORR was defined as the proportion of patients achieving complete response or partial response radiologically. MPR was defined as no more than 10% viable tumor. RESULTS: Of the 35 eligible patients, 33 were considered as intention-to-treat population. ORR, the primary endpoint, was 54.5% (95% confidence interval [CI], 37.7-70.7), and the rate of MPR was 24.2% (95% CI, 11.9-40.4). Median DFS was 33.5 months (95% CI, 19.7-47.3); median overall survival was not reached. Skin toxicity (24/35,68.6%) and gastrointestinal symptoms (17/35,48.6%) were the most common AEs; no patients reported grade 3 or 4 AEs. After surgery, 4 patients experienced chylothorax (4/33,12.1%). Patients with MPR had a prolonged survival compared with those without (DFS, P = .019). CONCLUSIONS: Neoadjuvant therapy with gefitinib in patients with stage II-IIIA NSCLC is safe and may be a viable treatment for patients whose tumors have EGFR mutations. Patients with MPR were associated with improved survival.

Genomic and immune profiling of pre-invasive lung adenocarcinoma.

Adenocarcinoma in situ and minimally invasive adenocarcinoma are the pre-invasive forms of lung adenocarcinoma. The genomic and immune profiles of these lesions are poorly understood. Here we report exome and transcriptome sequencing of 98 lung adenocarcinoma precursor lesions and 99 invasive adenocarcinomas. We have identified EGFR, RBM10, BRAF, ERBB2, TP53, KRAS, MAP2K1 and MET as significantly mutated genes in the pre/minimally invasive group. Classes of genome alterations that increase in frequency during the progression to malignancy are revealed. These include mutations in TP53, arm-level copy number alterations, and HLA loss of heterozygosity. Immune infiltration is correlated with copy number alterations of chromosome arm 6p, suggesting a link between arm-level events and the tumor immune environment.

Heterogeneity and Coexistence of T790M and T790 Wild-Type Resistant Subclones Drive Mixed Response to Third-Generation Epidermal Growth Factor Receptor Inhibitors in Lung Cancer.

PURPOSE: Third-generation epidermal growth factor receptor (EGFR) inhibitors like nazartinib are active against EGFR mutation-positive lung cancers with T790M-mediated acquired resistance to initial anti-EGFR treatment, but some patients have mixed responses. METHODS: Multiple serial tumor and liquid biopsies were obtained from two patients before, during, and after treatment with nazartinib. Next-generation sequencing and droplet digital polymerase chain reaction were performed to assess heterogeneity and clonal dynamics. RESULTS: We observed the simultaneous emergence of T790M-dependent and -independent clones in both patients. Serial plasma droplet digital polymerase chain reaction illustrated shifts in relative clonal abundance in response to various systemic therapies, confirming a molecular basis for the clinical mixed radiographic responses observed. CONCLUSION: Heterogeneous responses to treatment targeting a solitary resistance mechanism can be explained by coexistent tumor subclones harboring distinct genetic signatures. Serial liquid biopsies offer an opportunity to monitor clonal dynamics and the emergence of resistance and may represent a useful tool to guide therapeutic strategies.

Clinical Significance of Complex Glandular Patterns in Lung Adenocarcinoma: Clinicopathologic and Molecular Study in a Large Series of Cases.

OBJECTIVES: To explore whether complex glandular patterns (CGPs) have a potential role in the clinical management of patients with lung adenocarcinoma. METHODS: We included 356 patients with lung adenocarcinoma with available clinicopathologic information, gene mutations, and clinical outcomes for analysis. RESULTS: We identified 54 (15.2%) CGP-predominant cases. The CGPs were associated with ALK rearrangement and HER2 mutation. Survival analysis showed that the clinical outcome of CGP-predominant patients was worse than that for acinar-predominant patients (overall survival [OS], 66.4 vs 90.3 months, P < .01; recurrence-free survival [RFS], 50.1 vs 73.1 months, P = .022) but was comparable with solid-predominant subtype tumors (OS, 66.4 vs 67.8 months, P = .558; RFS, 50.1 vs 41.3 months, P = .258). In particular, the coexistence of the cribriform and fused gland pattern was associated with the poorest survival, with a death risk increased by 2.25-fold (hazard ratio, 3.25; 95% confidence interval, 1.35-7.86, P = .009). CONCLUSIONS: Our results provide new insight into the potential role of CGPs in clinical management and will be beneficial for treatment decision making in patients with lung adenocarcinoma.

Extended Right Thoracic Approach Compared With Limited Left Thoracic Approach for Patients With Middle and Lower Esophageal Squamous Cell Carcinoma: Three-year Survival of a Prospective, Randomized, Open-label Trial.

OBJECTIVE: To investigate whether survival is improved by using the right thoracic approach (extended lymphadenectomy) compared with the left thoracic approach (limited lymphadenectomy) for esophageal cancer. BACKGROUND: The optimal surgical technique for esophageal cancer remains unclear. METHODS: Between May 2010 and July 2012, 300 patients with middle and lower thoracic esophageal carcinoma were randomized to receive esophagectomy through either the right or left thoracic approach. Of these, 286 patients with squamous cell carcinoma determined by postoperative pathology were included in this analysis. Disease-free survival (DFS) and overall survival (OS) were compared between the right (n = 146) and left thoracic groups (n = 140). RESULTS: The median follow-up was 55.9 months [95% confidence interval (CI): 53.1-58.6]. The 3-year DFS rates were 62% and 52% in the right and left thoracic arms, respectively [hazard ratio (HR) 0.709; 95% CI, 0.506-0.995; P = 0.047, log-rank test]. The 3-year OS rates were 74% and 60%, respectively (HR, 0.663; 95% CI, 0.457-0.961; P = 0.029). Subgroup analyses revealed longer DFS in the right thoracic arm (vs left thoracic arm) in patients with lymph node involvement (HR, 0.632; 95% CI, 0.412-0.969, P = 0.034), but not in patients without lymph node involvement (HR, 0.757; 95% CI, 0.434-1.320, P = 0.325), and in patients with R1-2 resection margins (HR, 0.495; 95% CI, 0.290-0.848, P = 0.009), but not R0 margins (HR, 0.944; 95% CI, 0.603-1.477, P = 0.801). CONCLUSIONS: Compared with the left thoracic approach, the right thoracic approach associated with increased DFS and OS in esophageal squamous cell carcinoma patients, particularly in those with lymph node involvement and/or R1-2 resection margins.

Epithelial-to-Mesenchymal Transition Antagonizes Response to Targeted Therapies in Lung Cancer by Suppressing BIM.

Purpose: Epithelial-to-mesenchymal transition (EMT) confers resistance to a number of targeted therapies and chemotherapies. However, it has been unclear why EMT promotes resistance, thereby impairing progress to overcome it.Experimental Design: We have developed several models of EMT-mediated resistance to EGFR inhibitors (EGFRi) in EGFR-mutant lung cancers to evaluate a novel mechanism of EMT-mediated resistance.Results: We observed that mesenchymal EGFR-mutant lung cancers are resistant to EGFRi-induced apoptosis via insufficient expression of BIM, preventing cell death despite potent suppression of oncogenic signaling following EGFRi treatment. Mechanistically, we observed that the EMT transcription factor ZEB1 inhibits BIM expression by binding directly to the BIM promoter and repressing transcription. Derepression of BIM expression by depletion of ZEB1 or treatment with the BH3 mimetic ABT-263 to enhance "free" cellular BIM levels both led to resensitization of mesenchymal EGFR-mutant cancers to EGFRi. This relationship between EMT and loss of BIM is not restricted to EGFR-mutant lung cancers, as it was also observed in KRAS-mutant lung cancers and large datasets, including different cancer subtypes.Conclusions: Altogether, these data reveal a novel mechanistic link between EMT and resistance to lung cancer targeted therapies. Clin Cancer Res; 24(1); 197-208. ©2017 AACR.

Unique distribution of programmed death ligand 1 (PD-L1) expression in East Asian non-small cell lung cancer.

BACKGROUND: To determine the proportion and clinical features of programmed death ligand 1 (PD-L1) expression in East Asian non-small cell lung cancer (NSCLC). METHODS: PD-L1 expression was assessed by immunohistochemistry (IHC) and tumor proportion score (TPS) with the use of PD-L1 IHC 22C3 antibody (Dako North America) in 108 surgically resected lung squamous cell carcinomas (SCC) and 221 lung adenocarcinomas (LUADs), and was correlated with clinical variables, histologic subtypes, and common driver mutations. RESULTS: Positive PD-L1 expression was found in 37 lung SCC (37/108, 34.3%), including 15 cases with TPS ≥50% (15/108, 13.9%) and 22 cases with TPS <50% (22/108, 20.4%). In adenocarcinoma cohort, 9 cases were found PD-L1 expression positive (9/221, 4.1%), including 1 case with TPS ≥50% (1/221, 0.5%) and 8 cases with TPS <50% (8/221, 3.9%). Totally, high PD-L1 expression (TPS ≥50%) was significantly associated with male sex (P=0.026), current/ever smoking history (P=0.008) and SCC subtype (P<0.001). Positive PD-L1 expression (including TPS ≥50% and TPS <50%) in LUAD cohort was significantly associated with male sex (P=0.046), current/ever smoking history (P=0.002), mutation pan-negative status (P=0.038), solid-predominant subtype (P<0.001), large tumor size (P=0.027) and lymph node metastasis (P=0.019). No significant difference was found between PD-L1 high expression group (TPS ≥50%) and low/negative expression group in SCC cohort. CONCLUSIONS: This study revealed the unique distribution of PD-L1 expression in East Asian NSCLCs, which is largely different from Western populations. Since the high response rate of pembrolizumab in the treatment of lung cancer patients with PD-L1 TPS ≥50%, this result indicates that prospective PD-L1 expression testing in specific East Asian patients could facilitate decision making for immunotherapy.

The Histologic Classifications of Lung Adenocarcinomas Are Discriminable by Unique Lineage Backgrounds.

OBJECTIVES: Lung adenocarcinomas are a heterogeneous set of diseases with distinct genetic and histologic characteristics. Besides the discovery of oncogenic mutations and introduction of the histologic classifications (2011 International Association for the Study of Lung Cancer/American Thoracic Society/European Respiratory Society and 2015 WHO), increasing evidence has linked this intertumor heterogeneity to the lung lineage-specific pathways and lineage genes. Therefore, in this study, we assessed the gene expression of identified lung lineage genes to study their role in distinguishing lung adenocarcinoma diversities. METHODS: A total of 278 surgically resected lung adenocarcinomas were included. Each case was evaluated for genetic mutations and histologic classification. Lineage genes associated with respiratory tract differentiation (NK2 homeobox 1 gene [NKX2-1], GATA protein binding 6 gene [GATA6], foxhead box J1 gene [FOXJ1], and SAM pointed domain containing ETS transcription factor gene [SPDEF]) and stem/basal-like status (inhibitor of DNA binding 2, HLH protein gene [ID2], POU class 5 homeobox 1 gene [POU5F1], SRY-box 2 gene [SOX2], and v-myc avian myelocytomatosis viral oncogene homolog gene [MYC]) were selected. mRNA expression of these genes in each tumor sample was assessed by quantitative real-time polymerase chain reaction and normalized to paired normal lung tissue. RESULTS: Distinct lineage gene expressions were found on the basis of genetic and histologic diversities. Expression of NKX2-1, GATA6, FOXJ1, and POU5F1 exhibited a significant linear relationship across histologic subgroups that was independent of genetic mutation status. Expression levels of NKX2-1 and POU5F1 were also associated with EGFR mutation status, independent of histologic subtypes. Further analysis revealed that the overexpression of SPDEF defined longer relapse-free survivals, especially in stage I disease. CONCLUSIONS: For the first time, we showed the unique lineage backgrounds of different histologic subtypes and oncogenic mutations. Assessing this added parameter might be beneficial in discriminating intertumor heterogeneity, advancing target exploration, developing theranostic/prognostic biomarkers, and designing clinical trials.

MET exon 14 skipping defines a unique molecular class of non-small cell lung cancer.

PURPOSE: Recurrent MET exon 14 splicing has been revealed in lung cancers and is a promising therapeutic target. Because we have limited knowledge about the natural history of MET mutant tumors, the current study was aiming to determine the clinical and pathological characteristics in non-small cell lung cancers (NSCLC). RESULTS: Twenty-three patients (1.3%) were positive for MET exon 14 skipping. Patients with MET exon 14 skipping displayed unique characteristics: female, non-smokers, earlier pathology stage and older age. MET exon 14 skipping indicated an early event as other drivers in lung cancer, while MET copy number gain was more likely a late event in lung cancer. Overall survival (OS) of patients harboring MET exon 14 skipping was longer than patients with KRAS mutation. Almost four-fifths of the lung tumors with MET exon 14 skipping had EGFR and/or HER2 gene copy number gains. EGFR inhibitor showed moderate antitumor activity in treatment of a patient harboring MET exon 14 skipping. PATIENTS AND METHODS: From October 2007 to June 2013, we screened 1770 patients with NSCLC and correlated MET status with clinical pathologic characteristics and mutations in EGFR, KRAS, BRAF, HER2, and ALK. Quantitative Real-Time PCR was used to detect MET gene copy number gain. Immunohistochemistry (IHC) was also performed to screen MET exon 14 skipping. Clinicopathological characteristics and survival information were analyzed. CONCLUSIONS: MET exon 14 skipping was detected in 1.3% (23/1770) of the Chinese patients with NSCLC. MET exon 14 skipping defined a new molecular subset of NSCLC with identifiable clinical characteristics. The therapeutic EGFR inhibitors might be an alternative treatment for patients with MET mutant NSCLC.

Clinical and genetic features of lung squamous cell cancer in never-smokers.

To evaluate the importance of specific driver mutations to the development and outcome of lung squamous cell cancer (SQCC) in never-smokers, we assessed the clinicopathological characteristics and outcomes of 597 patients who underwent complete resection of SQCCs. In total, 88 (14.7%) never-smokers and 509 (85.3%) ever-smokers were compared. The never-smokers included more females (42.05% vs. 1.57%, P < 0.001) and more often had a personal history of malignant disease (9.09% vs. 2.36%, P = 0.003). The tumors of never-smokers were more often poorly differentiated (70.45% vs. 53.24%, P = 0.010) and more often contained oncogenic mutations (21.05% vs 11.05%, P = 0.023), particularly EGFR mutations (13.16% vs 3.40%, P = 0.001). Never-smokers also tended to have poorer OS than smokers. Our results suggest lung SQCCs in never-smokers are a subtype distinct from SQCCs occurring in smokers.

Tumor cells can follow distinct evolutionary paths to become resistant to epidermal growth factor receptor inhibition.

Although mechanisms of acquired resistance of epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancers to EGFR inhibitors have been identified, little is known about how resistant clones evolve during drug therapy. Here we observe that acquired resistance caused by the EGFR(T790M) gatekeeper mutation can occur either by selection of pre-existing EGFR(T790M)-positive clones or via genetic evolution of initially EGFR(T790M)-negative drug-tolerant cells. The path to resistance impacts the biology of the resistant clone, as those that evolved from drug-tolerant cells had a diminished apoptotic response to third-generation EGFR inhibitors that target EGFR(T790M); treatment with navitoclax, an inhibitor of the anti-apoptotic factors BCL-xL and BCL-2 restored sensitivity. We corroborated these findings using cultures derived directly from EGFR inhibitor-resistant patient tumors. These findings provide evidence that clinically relevant drug-resistant cancer cells can both pre-exist and evolve from drug-tolerant cells, and they point to therapeutic opportunities to prevent or overcome resistance in the clinic.

Whole Exome Sequencing Identifies Frequent Somatic Mutations in Cell-Cell Adhesion Genes in Chinese Patients with Lung Squamous Cell Carcinoma.

Lung squamous cell carcinoma (SQCC) accounts for about 30% of all lung cancer cases. Understanding of mutational landscape for this subtype of lung cancer in Chinese patients is currently limited. We performed whole exome sequencing in samples from 100 patients with lung SQCCs to search for somatic mutations and the subsequent target capture sequencing in another 98 samples for validation. We identified 20 significantly mutated genes, including TP53, CDH10, NFE2L2 and PTEN. Pathways with frequently mutated genes included those of cell-cell adhesion/Wnt/Hippo in 76%, oxidative stress response in 21%, and phosphatidylinositol-3-OH kinase in 36% of the tested tumor samples. Mutations of Chromatin regulatory factor genes were identified at a lower frequency. In functional assays, we observed that knockdown of CDH10 promoted cell proliferation, soft-agar colony formation, cell migration and cell invasion, and overexpression of CDH10 inhibited cell proliferation. This mutational landscape of lung SQCC in Chinese patients improves our current understanding of lung carcinogenesis, early diagnosis and personalized therapy.

Comprehensive investigation of oncogenic driver mutations in Chinese non-small cell lung cancer patients.

PURPOSE: To determine the frequency of driver mutations in Chinese non-small cell lung cancer (NSCLC) patients. METHODS: Comprehensive mutational analysis was performed in 1356 lung adenocarcinoma, 503 squamous cell carcinoma, 57 adenosquamous lung carcinoma, 19 large cell carcinoma and 8 sarcomatoid carcinoma. The effect of EGFR tyrosine kinase inhibitors (TKIs) on EGFR-mutated lung adenocarcinoma patients after disease recurrence was investigated. RESULTS: Mutations in EGFR kinase domain, HER2 kinase domain, KRAS, BRAF, ALK, ROS1 and RET were mutually exclusive. In lung adenocarcinoma cases "pan-negative" for the seven above-mentioned driver mutations, we also detected two oncogenic EGFR extracellular domain mutations (A289D and R324L), two HER2 extracellular and transmembrane domain mutations (S310Y and V659E), one ARAF S214C mutation and two CD74-NRG1 fusions. Six (1.2%) FGFR3 activating mutations were identified in lung squamous cell carcinoma (five S249C and one R248C). There were three (15.8%) EGFR mutations and four (21.1%) KRAS mutations in large cell carcinoma. Three (37.5%) KRAS mutations were detected in sarcomatoid carcinoma. In EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence, treatment with EGFR TKIs was an independent predictor of better overall survival (HR = 0.299, 95% CI: 0.172-0.519, P < 0.001). CONCLUSION: We determined the frequency of driver mutations in a large series of Chinese NSCLC patients. EGFR TKIs might improve the survival outcomes of EGFR-mutated lung adenocarcinoma patients who experienced disease recurrence.

Prevalence and Clinicopathological Characteristics of BRAF Mutations in Chinese Patients with Lung Adenocarcinoma.

BACKGROUND: This study was designed to identify the prevalence of BRAF mutations in Chinese patients with lung adenocarcinoma, and to reveal the association between BRAF mutations and clinicopathological characteristics in these patients. METHODS: From October 2007 to February 2013, patients with newly diagnosed primary lung adenocarcinoma were detected for mutations in BRAF, EGFR, KRAS, HER2 and ALK. Clinicopathological characteristics, including sex, age, TNM stage, tumor differentiation, smoking status, histological subtypes, and survival information were analyzed. RESULTS: Of 1358 patients with lung adenocarcinoma, 20 patients were harboring BRAF mutations, including five BRAF V600E mutations and 15 BRAF non-V600E mutations. Among these, BRAF N581I and BRAF G593S were newly reported. BRAF mutations were associated with smoking status (odds ratio 3.28; 95 % CI 1.33-8.08; p = 0.008). In patients less than 60 years of age, BRAF mutations tended to have poor differentiation in tumor samples (70.0 vs. 35.1 %; p = 0.014), and were more likely to relapse (70 vs. 28 %; p = 0.008). A significant difference was found in relapse-free survival (RFS) between BRAF mutations and other mutations, but not in overall survival. CONCLUSIONS: The prevalence of BRAF mutations in Chinese patients with lung adenocarcinoma was approximately 1.5 %. BRAF mutations were more frequent in current smokers. Patients harboring BRAF mutations had a higher rate of recurrence and worse RFS compared with other patients.

Negative Thyroid Transcription Factor 1 Expression Defines an Unfavorable Subgroup of Lung Adenocarcinomas.

INTRODUCTION: Thyroid transcription factor 1 (TTF1) is a master regulator of pulmonary differentiation that is downregulated in a subset of lung adenocarcinoma, of which the clinicopathologic characteristics were not fully clarified. METHODS: One thousand forty-two lung adenocarcinoma patients who underwent surgery were investigated for clinic characteristics, histologic subtyping, and spectrum of well-identified driver mutations. TTF1 expression was correlated with these clinicopathologic factors and survival. RESULTS: Compared with TTF1 positive (TTF1+) patients, the 133 negative individuals (12.8%, TTF1-) were more likely to be male (p = 0.006) and heavy smokers (p = 0.002) who had larger tumor size (p < 0.001) and more advanced disease stage (p < 0.001). TTF1- presented more in solid and invasive mucinous-predominant carcinomas (both p < 0.001), whereas TTF1+ was identified in 100% patients with adenocarcinoma in situ, minimally invasive and lepidic-predominant adenocarcinomas. The TTF1- tumors harbored the known driver mutations in significantly low frequency compared with TTF1+ adenocarcinomas (57.8% versus 78.1%, p < 0.001), especially in epidermal growth factor receptor (EGFR) mutations (37.6% versus 60.7%, p < 0.001). There was no significant difference in recurrence-free survival between the TTF1- and TTF1+ patients, either for the whole cohort or stratified by pathologic stage, or among the driver mutation-defined subsets. However, recurrence of multiple metastases was more likely to occur in patients with TTF1- adenocarcinomas (88.1% versus 32.4%, p < 0.001). Multivariate analysis revealed that TTF1- independently predicted both poor postrecurrence survival (hazard ratio = 1.664; 95% confidence interval , 1.097-2.524; p = 0.017) and unfavorable overall survival (hazard ratio = 1.553; 95% confidence interval , 1.013-2.381; p = 0.043). CONCLUSIONS: TTF1- correlated with solid and invasive mucinous subtypes of lung adenocarcinoma and lower frequency of EGFR mutations. It defines a subgroup of lung adenocarcinomas with unfavorable outcomes.

The Allelic Context of the C797S Mutation Acquired upon Treatment with Third-Generation EGFR Inhibitors Impacts Sensitivity to Subsequent Treatment Strategies.

PURPOSE: A secondary EGFR mutation, T790M, is the most common resistance mechanism in EGFR-mutant adenocarcinomas that have progressed on erlotinib. Third-generation EGFR inhibitors capable of inhibiting mutant EGFR with T790M produce responses in nearly two thirds of patients. However, acquired resistance mechanisms in patients treated with these drugs are yet to be described. EXPERIMENTAL DESIGN: To study acquired resistance to third-generation EGFR inhibitors, T790M-positive cells derived from an erlotinib-resistant cancer were made resistant to a third-generation TKI and then characterized using cell and molecular analyses. RESULTS: Cells resistant to a third-generation TKI acquired an additional EGFR mutation, C797S, which prevented suppression of EGFR. Our results demonstrate that the allelic context in which C797S was acquired may predict responsiveness to alternative treatments. If the C797S and T790M mutations are in trans, cells will be resistant to third-generation EGFR TKIs, but will be sensitive to a combination of first- and third-generation TKIs. If the mutations are in cis, no EGFR TKIs alone or in combination can suppress activity. If C797S develops in cells wild-type for T790 (when third-generation TKIs are administered in the first-line setting), the cells are resistant to third-generation TKIs, but retain sensitivity to first-generation TKIs. CONCLUSIONS: Mutation of C797S in EGFR is a novel mechanism of acquired resistance to third-generation TKIs. The context in which the C797S develops with respect to the other EGFR alleles affects the efficacy of subsequent treatments.