Seasonal influences on the efficacy of anti-programmed cell death (ligand) 1 inhibitors in lung cancer.

BACKGROUND: Seasonal variations in systemic immunity have been reported. This study aimed to evaluate whether seasonality affects the efficacy of anticancer immunotherapy. METHODS: A total of 604 patients with lung cancer receiving single anti-programmed cell death (ligand) 1 (anti-PD-[L]1) inhibitors from two prospective observational cohorts were screened. Primary outcomes were progression-free survival (PFS) and overall survival (OS). Patients were classified into two groups according to the season when the treatment started: winter (November-February) and other seasons (March-October). Kaplan-Meier analysis and Cox proportional hazards models were fitted to evaluate the impact of seasonality on survival. For validation, propensity score matching was performed. RESULTS: A total of 484 patients with advanced non-small cell lung cancer were included. In an unmatched population, multivariable analysis demonstrated that the winter group (n = 173) had a significantly lower risk of progression or death from immunotherapy than the other group (n = 311) (PFS: hazard ratio [HR], 0.77 [95% confidence interval (CI), 0.62-0.96]; p = .018; OS: HR, 0.77 [95% CI, 0.1-0.98]; p = .032). In a propensity score-matched population, the winter group (n = 162) showed significantly longer median PFS (2.8 months [95% CI, 1.9-4.1 months] vs. 2.0 months [95% CI, 1.4-2.7 months]; p = .009) than the other group (n = 162). The winter group's median OS was also significantly longer than that of the other group (13.4 months [95% CI, 10.2-18.0 months] vs. 8.0 months [95% CI, 3.6-8.7 months]; p = .012). The trend toward longer survival in the winter group continued in subgroup analyses. CONCLUSIONS: Starting an anti-PD-(L)1 inhibitor in winter was associated with better treatment outcomes in patients with lung cancer compared to other seasons.

Proteogenomic Characterization Reveals Estrogen Signaling as a Target for Never-Smoker Lung Adenocarcinoma Patients without EGFR or ALK Alterations.

Never-smoker lung adenocarcinoma (NSLA) is prevalent in Asian populations, particularly in women. EGFR mutations and anaplastic lymphoma kinase (ALK) fusions are major genetic alterations observed in NSLA, and NSLA with these alterations have been well studied and can be treated with targeted therapies. To provide insights into the molecular profile of NSLA without EGFR and ALK alterations (NENA), we selected 141 NSLA tissues and performed proteogenomic characterization, including whole genome sequencing (WGS), transcriptomic, methylation EPIC array, total proteomic, and phosphoproteomic analyses. Forty patients with NSLA harboring EGFR and ALK alterations and seven patients with NENA with microsatellite instability were excluded. Genome analysis revealed that TP53 (25%), KRAS (22%), and SETD2 (11%) mutations and ROS1 fusions (14%) were the most frequent genetic alterations in NENA patients. Proteogenomic impact analysis revealed that STK11 and ERBB2 somatic mutations had broad effects on cancer-associated genes in NENA. DNA copy number alteration analysis identified 22 prognostic proteins that influenced transcriptomic and proteomic changes. Gene set enrichment analysis revealed estrogen signaling as the key pathway activated in NENA. Increased estrogen signaling was associated with proteogenomic alterations, such as copy number deletions in chromosomes 14 and 21, STK11 mutation, and DNA hypomethylation of LLGL2 and ST14. Finally, saracatinib, an Src inhibitor, was identified as a potential drug for targeting activated estrogen signaling in NENA and was experimentally validated in vitro. Collectively, this study enhanced our understanding of NENA NSLA by elucidating the proteogenomic landscape and proposed saracatinib as a potential treatment for this patient population that lacks effective targeted therapies. SIGNIFICANCE: The proteogenomic landscape in never-smoker lung cancer without known driver mutations reveals prognostic proteins and enhanced estrogen signaling that can be targeted as a potential therapeutic strategy to improve patient outcomes.

Drug Response of Patient-Derived Lung Cancer Cells Predicts Clinical Outcomes of Targeted Therapy.

Intratumor heterogeneity leads to different responses to targeted therapies, even within patients whose tumors harbor identical driver oncogenes. This study examined clinical outcomes according to a patient-derived cell (PDC)-based drug sensitivity test in lung cancer patients treated with targeted therapies. From 487 lung cancers, 397 PDCs were established with a success rate of 82%. In 139 PDCs from advanced non-small-cell lung cancer (NSCLC) patients receiving targeted therapies, the standardized area under the curve (AUC) values for the drugs was significantly correlated with their tumor response (p = 0.002). Among 59 chemo-naive EGFR/ALK-positive NSCLC patients, the PDC non-responders showed a significantly inferior response rate (RR) and progression-free survival (PFS) for the targeted drugs than the PDC responders (RR, 25% vs. 78%, p = 0.011; median PFS, 3.4 months [95% confidence interval (CI), 2.8-4.1] vs. 11.8 months [95% CI, 6.5-17.0], p < 0.001). Of 25 EGFR-positive NSCLC patients re-challenged with EGFR inhibitors, the PDC responder showed a higher RR than the PDC non-responder (42% vs. 15%). Four patients with wild-type EGFR or uncommon EGFR-mutant NSCLC were treated with EGFR inhibitors based on their favorable PDC response to EGFR inhibitors, and two patients showed dramatic responses. Therefore, the PDC-based drug sensitivity test results were significantly associated with clinical outcomes in patients with EGFR- or ALK-positive NSCLC. It may be helpful for predicting individual heterogenous clinical outcomes beyond genomic alterations.

Tumor Microenvironment Modulation by Neoadjuvant Erlotinib Therapy and Its Clinical Impact on Operable EGFR-Mutant Non-Small Cell Lung Cancer.

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have greatly improved survival in EGFR-mutant (EGFRm) non-small cell lung cancer (NSCLC); however, their effects on the tumor microenvironment (TME) are unknown. We assessed the changes induced by neoadjuvant erlotinib therapy (NE) in the TME of operable EGFRm NSCLC. MATERIALS AND METHODS: This was a single-arm phase II trial for neoadjuvant/adjuvant erlotinib therapy in patients with stage II/IIIA EGFRm NSCLC (EGFR exon 19 deletion or L858R mutations). Patients received up to 2 cycles of NE (150 mg/day) for 4 weeks, followed by surgery and adjuvant erlotinib or vinorelbine plus cisplatin therapy depending on observed NE response. TME changes were assessed based on gene expression analysis and mutation profiling. RESULTS: A total of 26 patients were enrolled; the median age was 61, 69% were female, 88% were stage IIIA, and 62% had L858R mutation. Among 25 patients who received NE, the objective response rate was 72% (95% confidence interval [CI], 52.4 to 85.7). The median disease-free and overall survival (OS) were 17.9 (95% CI, 10.5 to 25.4) and 84.7 months (95% CI, 49.7 to 119.8), respectively. Gene set enrichment analysis in resected tissues revealed upregulation of interleukin, complement, cytokine, transforming growth factor ß, and hedgehog pathways. Patients with upregulated pathogen defense, interleukins, and T-cell function pathways at baseline exhibited partial response to NE and longer OS. Patients with upregulated cell cycle pathways at baseline exhibited stable/progressive disease after NE and shorter OS. CONCLUSION: NE modulated the TME in EGFRm NSCLC. Upregulation of immune-related pathways was associated with better outcomes.

Nivolumab after Induction Chemotherapy in Previously Treated Non-Small-Cell Lung Cancer Patients with Low PD-L1 Expression.

This study aimed to investigate whether cyclophosphamide (C) and adriamycin (A) induction therapy (IT) prior to nivolumab could enhance the efficacy of nivolumab in previously treated patients with non-squamous (NSQ) non-small-cell lung cancer (NSCLC) with less than 10% programmed death-ligand 1 (PD-L1) expression. Twenty-two enrolled patients received four cycles of CA-IT every 3 weeks. Nivolumab was given 360 mg every 3 weeks from the second cycle and 480 mg every 4 weeks after four cycles of CA-IT. The median progression-free survival (PFS) and overall survival (OS) were 2.4 months and 11.6 months, respectively. Fluorescence-activated cell sorting revealed the lowest ratio of myeloid-derived suppressor cells (MDSCs) to CD8+T-cells in the responders. Proteomic analysis identified a consistent upregulation of extracellular matrix-receptor interactions and phagosome pathways in the responders. Among the differentially expressed proteins, the transferrin receptor protein (TFRC) was higher in the responders before treatment (fold change > 1.2). TFRC validation with an independent cohort showed the prognostic significance of either OS or PFS in patients with low PD-L1 expression. In summary, CA-IT did not improve nivolumab efficacy in NSQ-NSCLCs with low PD-L1 expression; however, it induced decreasing MDSC, resulting in a durable response. Higher baseline TFRC levels predicted a favorable response to nivolumab in NSCLC with low PD-L1 expression.

Molecular Subtypes and Tumor Microenvironment Characteristics of Small-Cell Lung Cancer Associated with Platinum-Resistance.

Although molecular subtypes of small-cell lung cancer (SCLC) have been proposed, their clinical relevance and therapeutic implications are not fully understood. Thus, we aimed to refine molecular subtypes and to uncover therapeutic targets. We classified the subtypes based on gene expression (n = 81) and validated them in our samples (n = 87). Non-SCLC samples were compared with SCLC subtypes to identify the early development stage of SCLC. Single-cell transcriptome analysis was applied to dissect the TME of bulk samples. Finally, to overcome platinum resistance, we performed drug screening of patient-derived cells and cell lines. Four subtypes were identified: the ASCL1+ (SCLC-A) subtype identified as TP53/RB-mutated non-SCLC representing the early development stage of SCLC; the immune activation (SCLC-I) subtype, showing high CD8+/PD-L1+ T-cell infiltration and endothelial-to-mesenchymal transition (EndMT); the NEUROD1 (SCLC-N) subtype, which showed neurotransmission process; and the POU2F3+ (SCLC-P) subtype with epithelial-to-mesenchymal transition (EMT). EndMT was associated with the worst prognosis. While SCLC-A/N exhibited platinum sensitivity, the EndMT signal of SCLC-I conferred platinum resistance. A BET inhibitor suppressed the aggressive angiogenesis phenotype of SCLC-I. We revealed that EndMT development contributed to a poor outcome in SCLC-I. Moreover, heterogenous TME development facilitated platinum resistance. BET inhibitors are novel candidates for overcoming platinum resistance.

Prediction Models for Mediastinal Metastasis and Its Detection by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Potentially Operable Non-Small Cell Lung Cancer: A Prospective Study.

BACKGROUND: Prediction models for mediastinal metastasis and its detection by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) have not been developed using a prospective cohort of potentially operable patients with non-small cell lung cancer (NSCLC). RESEARCH QUESTION: Can mediastinal metastasis and its detection by EBUS-TBNA be predicted with prediction models in NSCLC? STUDY DESIGN AND METHODS: For the prospective development cohort, 589 potentially operable patients with NSCLC were evaluated (July 2016-June 2019) from five Korean teaching hospitals. Mediastinal staging was performed using EBUS-TBNA (with or without the transesophageal approach). Surgery was performed for patients without clinical N (cN) 2-3 disease by endoscopic staging. The prediction model for lung cancer staging-mediastinal metastasis (PLUS-M) and a model for mediastinal metastasis detection by EBUS-TBNA (PLUS-E) were developed using multivariable logistic regression analyses. Validation was performed using a retrospective cohort (n = 309) from a different period (June 2019-August 2021). RESULTS: The prevalence of mediastinal metastasis diagnosed by EBUS-TBNA or surgery and the sensitivity of EBUS-TBNA in the development cohort were 35.3% and 87.0%, respectively. In PLUS-M, younger age (< 60 years and 60-70 years compared with ≥ 70 years), nonsquamous histology (adenocarcinoma and others), central tumor location, tumor size (> 3-5 cm), cN1 or cN2-3 stage by CT, and cN1 or cN2-3 stage by PET-CT were significant risk factors for N2-3 disease. Areas under the receiver operating characteristic curve (AUCs) for PLUS-M and PLUS-E were 0.876 (95% CI, 0.845-0.906) and 0.889 (95% CI, 0.859-0.918), respectively. Model fit was good (PLUS-M: Hosmer-Lemeshow P = .658, Brier score = 0.129; PLUS-E: Hosmer-Lemeshow P = .569, Brier score = 0.118). In the validation cohort, PLUS-M (AUC, 0.859 [95% CI, 0.817-0.902], Hosmer-Lemeshow P = .609, Brier score = 0.144) and PLUS-E (AUC, 0.900 [95% CI, 0.865-0.936], Hosmer-Lemeshow P = .361, Brier score = 0.112) showed good discrimination ability and calibration. INTERPRETATION: PLUS-M and PLUS-E can be used effectively for decision-making for invasive mediastinal staging in NSCLC. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02991924; URL: www. CLINICALTRIALS: gov.

A Randomized Phase II Study of Irinotecan Plus Cisplatin with or without Simvastatin in Ever-Smokers with Extended Disease Small Cell Lung Cancer.

PURPOSE: This study evaluated whether an addition of simvastatin to chemotherapy improves survival in ever-smokers with extensive disease (ED)-small cell lung cancer (SCLC). Materials and Methods: This is an open-label randomized phase II study conducted in National Cancer Center (Goyang, Korea). Chemonaive patients with ED-SCLC, smoking history (≥ 100 cigarettes lifetime), and Eastern Cooperative Oncology Group performance status of ≤ 2 were eligible. Patients were randomized to receive irinotecan plus cisplatin alone or with simvastatin (40 mg once daily orally) for a maximum of six cycles. Primary endpoint was the the 1-year survival rate. RESULTS: Between September 16, 2011, and September 9, 2021, 125 patients were randomly assigned to the simvastatin (n=62) or control (n=63) groups. The median smoking pack year was 40 years. There was no significant difference in the 1-year survival rate between the simvastatin and control groups (53.2% vs. 58.7%, p=0.535). The median progression-free survival and overall survival between the simvastatin arm vs. the control groups were 6.3 months vs. 6.4 months (p=0.686), and 14.4 months vs. 15.2 months, respectively (p=0.749). The incidence of grade 3-4 adverse events was 62.9% in the simvastatin group and 61.9% in the control group. In the exploratory analysis of lipid profiles, patients with hypertriglyceridemia had significantly higher 1-year survival rates than those with normal triglyceride levels (80.0% vs. 52.7%, p=0.046). CONCLUSION: Addition of simvastatin to chemotherapy provided no survival benefit in ever-smokers with ED-SCLC. Hypertriglyceridemia may be associated with better prognosis in these patient population.

A randomized Phase 2 study to compare erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation.

BACKGROUND: This study evaluated whether an addition of bevacizumab to erlotinib improves clinical outcomes in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). METHODS: This is an open-label, multicenter, randomized Phase 2 study in South Korea. Chemonaïve patients with Stage IIIB/IV NSCLC with EGFR 19 deletion or L858R mutation were eligible. Asymptomatic brain metastasis (BM) was enrolled without local treatment. Patients received either erlotinib plus bevacizumab or erlotinib. RESULTS: Between December 2016 and March 2019, 127 patients were randomly assigned to receive erlotinib plus bevacizumab (n = 64) or erlotinib (n = 63). Fifty-nine (46.5%) patients had baseline BM. Fewer patients in the erlotinib plus bevacizumab arm received radiotherapy for BM than in the erlotinib arm (10.3% vs. 40.0%). A trend toward longer progression-free survival (PFS) was observed in the erlotinib plus bevacizumab arm compared with the erlotinib alone arm; however, it was not statistically significant (median PFS, 17.5 months vs. 12.4 months; hazard ratio [HR], 0.74; 95% CI, 0.51-1.08; p = .119). The unplanned subgroup analysis showed a longer PFS with erlotinib plus bevacizumab in patients with BM (median PFS, 18.6 months vs. 10.3 months; HR, 0.54; 95% CI, 0.31-0.95; p = .032). Grade 3 or worse adverse events occurred in 56.6% of the erlotinib plus bevacizumab arm and 20.6% of the erlotinib arm. CONCLUSIONS: Although it was not statistically significant, a trend to improvement in PFS was observed in patients with erlotinib plus bevacizumab compared to erlotinib alone. PLAIN LANGUAGE SUMMARY: A randomized Phase 2 study compared erlotinib with or without bevacizumab in previously untreated patients with advanced non-small cell lung cancer with EGFR mutation. The erlotinib plus bevacizumab failed to improve median progression-free survival compared with the erlotinib alone. However, the progression-free survival benefit from erlotinib plus bevacizumab was found in patients with brain metastasis with no severe hemorrhagic adverse effects.

Usefulness of BRAF VE1 immunohistochemistry in non-small cell lung cancers: a multi-institutional study by 15 pathologists in Korea.

BACKGROUND: Next-generation sequencing (NGS) is an approved test to select patients for BRAF V600E targeted therapy in Korea. However, the high cost, long turnaround times, and the need for sophisticated equipment and skilled personnel limit the use of NGS in daily practice. Immunohistochemistry (IHC) is a rapid and relatively inexpensive assay available in most laboratories. Therefore, in this study, we evaluate the usefulness of BRAF VE1 IHC in terms of predictive value and interobserver agreement in non-small cell lung cancers (NSCLCs). METHODS: A total of 30 cases with known BRAF mutation status were selected, including 20 cases of lung adenocarcinomas, six cases of colorectal adenocarcinomas, and four cases of papillary thyroid carcinomas. IHC for BRAF V600E was carried out using the VE1 antibody. Fifteen pathologists independently scored both the staining intensity and the percentage of tumor cell staining on whole slide images. RESULTS: In the lung adenocarcinoma subset, interobserver agreement for the percentage of tumor cell staining and staining intensity was good (percentage of tumor cell staining, intraclass correlation coefficient = 0.869; staining intensity, kappa = 0.849). The interobserver agreement for the interpretation using the cutoff of 40% was almost perfect in the entire study group and the lung adenocarcinoma subset (kappa = 0.815). Sensitivity, specificity, positive predictive value, and negative predictive value of BRAF VE1 IHC were 80.0%, 90.0%, 88.9%, and 81.8%, respectively. CONCLUSIONS: BRAF VE1 IHC could be a screening test for the detection of BRAF V600E mutation in NSCLC. However, further studies are needed to optimize the protocol and to establish and validate interpretation criteria for BRAF VE1 IHC.

Long-term Survival According to N Stage Diagnosed by Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration in Non-small Cell Lung Cancer.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is the main procedure for mediastinal staging. However, long-term survival analyses according to clinical nodal stage diagnosed by EBUS-TBNA (eN stage) have not been reported. The value of EBUS-TBNA has not been assessed through an analysis of survival in false-negative EBUS-TBNA cases. RESEARCH QUESTION: What is the prognostic impact of eN stage in non-small cell lung cancer (NSCLC)? What is the survival rate in false-negative EBUS-TBNA cases? STUDY DESIGN AND METHODS: We retrospectively (January 2006 to December 2011) reviewed the medical records of patients with NSCLC who underwent EBUS-TBNA (± transesophageal approach) for initial staging (N = 1,089). Mediastinoscopy was not performed for EBUS-TBNA-negative cases. We performed 5-year survival analyses according to eN stage and treatment modality. Survival in false-negative EBUS-TBNA cases was compared with that in patients with pN0-1, including 941 non-EBUS-TBNA cases, during the same period. RESULTS: Among the 1,089 patients undergoing EBUS-TBNA (eN0-1: n = 681; eN2: n = 314; eN3: n = 94), we observed significant differences in survival between the eN stages (eN0-1 vs eN2: P < .0001; eN2 vs eN3: P = .0118; estimated 5-year overall survival [5YOS] rate: eN0-1 = 57.4%, eN2 = 23.2%, eN3 = 12.8%). Surgery cases had better survival than nonsurgery cases among patients with eN0-1 and eN2 (eN0-1/surgery vs eN0-1/no surgery: P < .0001; eN2/surgery vs eN2/no surgery: P < .0001). Among the patients with eN0-1, there were 55 false-negative cases (eN0-1/pN2-3, pN2: n = 54; pN3: n = 1). The 5YOS rates of patients with pN0, pN1, and eN0-1/pN2-3 were 76.4%, 56.0%, and 56.4%, respectively. Patients with eN0-1/pN2-3 had worse survival than patients with pN0 (P = .0061), whereas there was no significant difference compared with patients with pN1 (P = .9191). INTERPRETATION: Long-term survival significantly differed according to eN stage in NSCLC, highlighting the importance of EBUS-TBNA in NSCLC staging. False-negative EBUS-TBNA cases had favorable survival which was similar to that of patients with pN1, which may provide a rationale for performing surgery after negative EBUS-TBNA results.

Molecular biomarker testing for non-small cell lung cancer: consensus statement of the Korean Cardiopulmonary Pathology Study Group.

Molecular biomarker testing is the standard of care for non-small cell lung cancer (NSCLC) patients. In 2017, the Korean Cardiopulmonary Pathology Study Group and the Korean Molecular Pathology Study Group co-published a molecular testing guideline which contained almost all known genetic changes that aid in treatment decisions or predict prognosis in patients with NSCLC. Since then there have been significant changes in targeted therapies as well as molecular testing including newly approved targeted drugs and liquid biopsy. In order to reflect these changes, the Korean Cardiopulmonary Pathology Study Group developed a consensus statement on molecular biomarker testing. This consensus statement was crafted to provide guidance on what genes should be tested, as well as methodology, samples, patient selection, reporting and quality control.

The Clinical Impact of Capmatinib in the Treatment of Advanced Non-Small Cell Lung Cancer with MET Exon 14 Skipping Mutation or Gene Amplification.

PURPOSE: Capmatinib, an oral MET kinase inhibitor, has demonstrated its efficacy against non-small cell lung cancer (NSCLC) with MET dysregulation. We investigated its clinical impact in advanced NSCLC with MET exon 14 skipping mutation (METex14) or gene amplification. MATERIALS AND METHODS: Patients who participated in the screening of a phase II study of capmatinib for advanced NSCLC were enrolled in this study. MET gene copy number (GCN), protein expression, and METex14 were analyzed and the patients' clinical outcome were retrospectively reviewed. RESULTS: A total of 72 patients were included in this analysis (group A: GCN ≥ 10 or METex14, n=14; group B: others, n=58). Among them, 13 patients were treated with capmatinib (group A, n=8; group B, n=5), and the overall response rate was 50% for group A, and 0% for group B. In all patients, the median overall survival (OS) was 20.2 months (95% confidence interval [CI], 6.9 to not applicable [NA]) for group A, and 11.3 months (95% CI, 8.2 to 20.3) for group B (p=0.457). However, within group A, median OS was 21.5 months (95% CI, 20.8 to NA) for capmatinib-treated, and 7.5 months (95% CI, 3.2 to NA) for capmatinib-untreated patients (p=0.025). Among all capmatinib-untreated patients (n=59), group A showed a trend towards worse OS to group B (median OS, 7.5 months vs. 11.3 months; p=0.123). CONCLUSION: Our data suggest that capmatinib is a new compelling treatment for NSCLC with MET GCN ≥ 10 or METex14 based on the improved survival within these patients.

A fusion of CD63-BCAR4 identified in lung adenocarcinoma promotes tumorigenicity and metastasis.

BACKGROUND: Recently, fusion variants of the breast cancer anti-oestrogen-resistance 4 (BCAR4) gene were recurrently discovered in lung adenocarcinoma from the genome-wide studies. However, the functional characterisation of BCAR4 fusion has not been investigated. METHODS: Based on the analysis of RNA-sequencing data, we identified a fusion transcript of CD63-BCAR4 in a Korean patient with lung adenocarcinoma who did not harbour any known activating mutations in EGFR and KRAS genes. To investigate the oncogenic effect of CD63-BCAR4, in vitro and in vivo animal experiments were performed. RESULTS: In vitro experiments showed strongly enhanced cell migration and proliferation by the exogenous expression of CD63-BCAR4 protein in bronchial epithelial cells. Cell migration was notably reduced after knockdown of BCAR4 fusion by small-interfering RNA. The tumorigenic and metastatic capability of the CD63-BCAR4 fusion was confirmed by using the mouse xenograft model. Fusion-overexpressed cells result in metastasis to the liver and lung as well as the primary tumours after subcutaneous injection into mice. Cyclin D1, MMP1, Slug and mesenchymal markers were significantly increased after CD63-BCAR4 overexpression in the in vitro and in vivo experiments. CONCLUSIONS: Taken together, our results suggest a newly identified fusion gene, CD63-BCAR4 as a potential novel oncogene in lung adenocarcinoma.

Phase II Study of Pemetrexed as a Salvage Chemotherapy for Thymidylate Synthase-Low Squamous Cell Lung Cancer.

PURPOSE: Squamous cell carcinomas (SqCC) of the lung often express high levels of thymidylate synthase (TS), which is associated with primary resistance to pemetrexed. We explored the efficacy of pemetrexed in a selected population of patients with lung SqCC with low TS expression. MATERIALS AND METHODS: In this single-arm phase II trial, we enrolled 32 previously-treated patients with advanced lung SqCC exhibiting low immunohistochemical staining for TS (i.e., in 10% or less of tumor cells). The primary endpoint was 12-week progression-free survival (PFS) rate. RESULTS: Of 32 patients, eight patients (25%) had an Eastern Cooperative Oncology Group performance status of 2, and seven patients (22%) had previously received three or more lines of chemotherapy. The disease control rate from pemetrexed treatment was 30%, and no objective response was observed. The 12-week PFS rate was 24.5% (95% confidence interval [CI], 13.0 to 46.1). Median PFS was 1.3 months (95% CI, 1.3 to 2.7), and median overall survival was 11.8 months (95% CI, 8.1 to not applicable). Most of adverse events were grade 1 or 2. CONCLUSION: Pemetrexed demonstrated modest activity as a salvage chemotherapy in patients with advanced lung SqCC with low TS expression, although its toxicity was generally manageable.

Size and extranodal extension of metastatic lymph nodes in lung adenocarcinoma.

BACKGROUND: This study assessed the prognostic significance of metastatic lymph node size (MLNS) and extranodal extension (EN) in patients with node-positive lung adenocarcinoma (ADC). METHODS: Prognostic factors influencing survival were analyzed, including age, sex, extent of operation, T- and N-stage, size of tumor, postoperative chemotherapy, presence of EN, and MLNS (>7.0 vs. ≤7.0 mm). RESULTS: Three hundred seventy-five patients met the inclusion criteria were enrolled (mean age: 59.8±10.5 years). Increasing MLNS was significantly correlated with large tumor size (P=0.015), advanced N status (P<0.001), and presence of EN (P<0.001). In multivariable analysis, large tumor size [hazard ratio (HR) 1.135, 95% confidence interval (CI): 1.050 to 1.228, P<0.001], adjuvant chemotherapy (HR 0.582, 95% CI: 0.430 to 0.787, P<0.001), EN (HR 1.454, 95% CI: 1.029 to 2.055, P=0.034), and MLNS greater than 7 mm (HR 1.741, 95% CI: 1.238 to 2.447, P<0.001) were significant prognostic factors for survival. Patients were classified into 3 groups: Group A, MLNS ≤7.0 mm/EN (-); Group B, MLNS ≤7.0 mm/EN (+) or MLNS >7.0 mm/EN (-); and Group C, MLNS >7.0 mm/EN (+). The 5-year overall survival (OS) was 72.2%, 59.0%, and 38.5% in Groups A, B and C, respectively (P<0.001). CONCLUSIONS: The MLNS and presence of EN could provide an important prognostic implication for patients with node-positive lung ADC.

First-iGAP: A Randomized Placebo-Controlled Phase II Study of First-line Intercalated Gefitinib and Pemetrexed-Cisplatin Chemotherapy for Never-Smoker Lung Adenocarcinoma Patients.

BACKGROUND: We aimed to evaluate whether intercalated combination of EGFR tyrosine kinase inhibitor gefitinib and chemotherapy improves survival outcomes in never-smokers with advanced lung adenocarcinoma. PATIENTS AND METHODS: Never-smokers with chemo-naive stage IIIB/IV lung adenocarcinoma were randomly assigned to receive either gefitinib or placebo on days 5 to 18 of a 3-weekly cycle of pemetrexed and cisplatin. Chemotherapy was given up to 9 cycles, after which gefitinib or placebo was given daily. Patients in the placebo arm who had progression were crossed over to receive gefitinib. RESULTS: Between June 2012 and December 2014, 76 patients with median age of 58.0 years were randomized, 39 on gefitinib and 37 on the placebo arm. EGFR mutation was positive in 34 (44.7%) patients. Baseline characteristics were well balanced between the 2 arms. The gefitinib arm had a better response rate (79.5% vs. 51.4%, P = .010) and median progression-free survival (PFS) (12.4 vs. 6.7 months, hazard ratio [HR] 0.49, P = .005) than the placebo arm; however, there was no statistically significant difference in median overall survival between the 2 arms (31.8 vs. 22.9 months, HR 0.78, P = .412). The PFS benefit of intercalated use of gefitinib over placebo was more apparent for patients with EGFR-mutant tumors (13.3 vs. 7.8 months, P = .025) than those with EGFR-wild-type tumors (8.2 vs. 6.6 months, P = .063). Overall, there was no difference in the frequency of severe adverse effect between the 2 arms. CONCLUSIONS: Intercalated combination of gefitinib with pemetrexed and cisplatin was well tolerated and improved PFS in never-smoker patients with lung adenocarcinoma.

The clinical impact of family history of cancer in female never-smoker lung adenocarcinoma.

OBJECTIVES: Accumulating evidence reveals the association between the risk of never-smoker lung cancer and family history of cancer. However, the clinicogenomic effect of family history of cancer in never-smoker lung cancer remains unknown. MATERIAL AND METHODS: We screened 3,241 lung cancer patients who (a) underwent curative resection at National Cancer Center (Goyang, Korea) between 2001-2014, and (b) completed a pre-designed interview about family/smoking history at the time of diagnosis and identified 604 female never smoker lung adenocarcinoma. A positive family history of cancer [categorized as pulmonary cancer (FH-PC) or non-pulmonary cancer (FH-NPC)] was defined as a self-reported history of cancer in first-degree relatives. Survival data were followed up until January 2017. Multiplexed targeted next-generation sequencing was performed for genetic profiling. RESULTS: Of 604 patients, 29.1% (n = 176) had a FH, including 132 (21.9%) with FH-NPC and 44 (7.3%) with FH-PC. Patients with the FH-NPC had a higher proportion of young patients (≤45 years) than those without the FH-NPC (FH-NPC, FH-PC, and no FH; 13.6%, 2.3%, and 8.2%, respectively; P = 0.032). Patients with the FH-NPC had an increased risk of recurrence (hazard ratio [HR]: 1.90; 95% confidence interval [CI]: 1.40-2.56; P<0.001) and death (HR: 1.67; 95% CI: 1.18-2.37; P=0.004). In contrast, the FH-PC had no prognostic effect on recurrence (HR: 1.23; 95% CI: 0.71-2.15; P = 0.456) and death (HR: 0.93; 95% CI: 0.45-1.91; P=0.838). Among three driver oncogene alterations, EGFR mutation was significantly associated with the FH-PC (53.8%, 84.1%, and 65.8%, respectively; P = 0.016), ALK/ROS1/RET fusions was significantly associated with the FH-NPC (13.7%, 0.0%, and 5.0%, respectively; P = 0.004), but KRAS mutation was not associated with any type of the FH (13.8% vs. 6.0% vs. 7.8%, respectively; P = 0.288). CONCLUSION: The type of family history of cancer was associated with distinct clinocogenomic subtypes and prognosis of never-smoker lung adenocarcinoma.

Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration for Re-biopsy in Previously Treated Lung Cancer.

PURPOSE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is widely used for the diagnosis and staging of lung cancer. However, evidence of its usefulness for re-biopsy in treated lung cancer, especially according to the previous treatment, is limited. We evaluated the role of EBUS-TBNA for re-biopsy and its diagnostic values in patients with different treatment histories. MATERIALS AND METHODS: We reviewed the medical records of patients who underwent EBUS-TBNA for re-biopsy of suspicious recurrent or progressive lesions between January 2006 and December 2016 at the National Cancer Center in South Korea. Patients were categorized into three groups based on the previous treatment modalities: surgery, radiation, and palliation. RESULTS: Among the 367 patients (surgery, n=192; radiation, n=40; palliation, n=135) who underwent EBUS-TBNA for re-biopsy, the overall sensitivity, negative predictive value (NPV), and diagnostic accuracy of EBUS-TBNA in detecting malignancy were 95.6%, 82.7%, and 96.3%, respectively. The sensitivity was lower in the radiation group (83.3%) when compared with the surgery (95.7%, p=0.042) and palliation (97.7%, p=0.012) groups. The NPV was lower in the palliation group (50.0%) than in the surgery group (88.5%, p=0.042). The sample adequacy of EBUS-TBNA specimens was lower in the radiation group (80.3%) than in the surgery (95.4%, p < 0.001) or palliation (97.8%, p < 0.001) groups. EGFR mutation analysis was feasible in 94.6% of the 92 cases, in which mutation analysis was requested. There were no major complications. Minor complications were reported in 12 patients (3.3%). CONCLUSION: EBUS-TBNA showed high diagnostic values and high suitability for EGFR mutation analysis with regard to re-biopsy in patients with previously treated lung cancer. The sensitivity was lower in the radiation group and NPV was lower in the palliation group. The complication rate was low.