Search

Simple Summary: We investigated the prevalence of genetic alterations and their association with epidermal growth factor receptor (EGFR) mutations and prognosis in early-stage non-small cell lung cancer (NSCLC) after curative resection. The results showed that the prevalence of EGFR mutations, anaplastic lymphoma kinase (ALK) rearrangements, and ROS proto-oncogene 1 (ROS1) fusion were 43.0%, 5.7%, and 1.6%, respectively. Patients with EGFR-mutant NSCLC had a higher risk of recurrence than those without EGFR mutations. Additionally, EGFR mutations were related to a high proportion of distant metastases and a higher risk of central nervous system recurrence. A definitive surgical resection is the preferred treatment for early-stage non-small cell lung cancer (NSCLC). Research on genetic alterations, including epidermal growth factor receptor (EGFR) mutations, in early-stage NSCLC remains insufficient. We investigated the prevalence of genetic alterations in early-stage NSCLC and the association between EGFR mutations and recurrence after a complete resection. Between January 2019 and December 2021, 659 patients with NSCLC who underwent curative surgical resections at a single regional cancer center in Korea were recruited. We retrospectively compared the clinical and pathological data between the recurrence and non-recurrence groups. Among the 659 enrolled cases, the median age was 65.86 years old and the most common histology was adenocarcinoma (74.5%), followed by squamous cell carcinoma (21.7%). The prevalence of EGFR mutations was 43% (194/451). Among them, L858R point mutations and exon 19 deletions were 52.3% and 42%, respectively. Anaplastic lymphoma kinase (ALK) rearrangement was found in 5.7% of patients (26/453) and ROS proto-oncogene 1 (ROS1) fusion was found in 1.6% (7/441). The recurrence rate for the entire population was 19.7%. In the multivariate analysis, the presence of EGFR mutations (hazard ratio (HR): 2.698; 95% CI: 1.458–4.993; p = 0.002), stage II (HR: 2.614; 95% CI: 1.29–5.295; p = 0.008) or III disease (HR: 9.537; 95% CI: 4.825–18.852; p < 0.001) (vs. stage I disease), and the presence of a pathologic solid type (HR: 2.598; 95% CI: 1.405–4.803; p = 0.002) were associated with recurrence. Among the recurrence group, 86.5% of the patients with EGFR mutations experienced distant metastases compared with only 66.7% of the wild type (p = 0.016), with no significant difference in median disease-free survival (52.21 months vs. not reached; p = 0.983). In conclusion, adjuvant or neoadjuvant targeted therapy could be considered more actively because EGFR mutations were identified as an independent risk factor for recurrence and were associated with systemic recurrence. Further studies on perioperative therapy for other genetic alterations are necessary. [ABSTRACT FROM AUTHOR]

Background: The aim of this study was to investigate the characteristics and clinical outcomes of patients with nonsmoking small cell lung cancer (SCLC) using a nationwide registry in Korea.Methods: The Korean Association for Lung Cancer developed a registry in cooperation with the Korean Central Cancer Registry (KCCR) and surveyed approximately 10% of recorded lung cancer cases.Results: From 2014 to 2016, the KCCR registered 1,043 patients newly diagnosed with SCLC among a total of 8,110 lung cancer patients. In subgroup analysis, Kaplan meier survival analysis showed that the overall survival (OS) was significantly shorter in the nonsmoking subgroup than the ever-smoking subgroup of SCLC patients with extensive disease (6.99 vs. 9.68 months; P = 0.016). Among SCLC patients with limited disease, OS was also shorter in the nonsmoking subgroup, without statistical significance (19.4 vs. 23.5 months; P = 0.247). In a multivariate analysis using a Cox regression model, never smoking was not associated with shorter OS, but older age, extensive stage, poor performance status (Eastern Cooperative Oncology Group grade ≥ 2), male sex, no prophylactic cranial irradiation, and no active treatment (chemotherapy and/or radiotherapy) were associated with poor prognosis.Conclusion: This evaluation of an unbiased nationwide survey dataset revealed that a significant proportion of Korean SCLC patients were never-smokers. No history of smoking appeared to be a significant prognostic factor according to the univariate analysis but was confirmed to be statistically insignificant through a multivariate analysis of the total population. Reasons for a poor prognosis may include the possibility that a high rate of the elderly population is composed of nonsmokers who did not receive active treatment. [ABSTRACT FROM AUTHOR]

Air embolism is a rare, fatal complication of computed tomography (CT)‐guided transthoracic needle biopsy (TTNB) of the lung. Here, we report a patient who developed an air embolism after CT‐guided TTNB, which led to ST‐elevation myocardial infarction and acute cerebral ischemia. The patient recovered completely without critical sequelae and was diagnosed with adenocarcinoma harboring activating epidermal growth factor receptor (EGFR) mutation. The patient responded to subsequent treatment with gefitinib. Key points: Signficant findings of the study: Air embolism is a rare, fatal complication of CT‐guided transthoracic lung biopsy. Only a few cases have been previously reported where myocardial and cerebral infarction occurred after TTNB, demonstrated not only on CT scan, but also electrocardiogram and electroencephalogram. What this study adds: Detection of driver gene mutation is crucial for planning lung cancer treatment. Despite the need for tissue biopsy, air embolism propagation to vital organs could result in severe end‐organ damage and multidisciplinary approaches are needed to improve initial outcomes. [ABSTRACT FROM AUTHOR]

Background: We correlated the tumor proportion score (TPS) of programmed cell death ligand 1 (PD‐L1, SP263 or 22C3) expression with the disease control rate (DCR, partial remission and stable disease), and progression free survival (PFS) after nivolumab or pembrolizumab treatment. Methods: A total of 70 case records (55 males, 15 females) of patients with non‐small cell lung cancer (NSCLC, 46 adenocarcinoma, 22 squamous cell carcinoma, and two others) were reviewed. The PD‐L1 expressions were divided into High (SP263 ≥ 30%, 22C3 ≥ 80%) and Low groups (SP263 < 30%, 22C3 < 80%). In the combined analysis, the PD‐L1 group was defined as High if either of the two stains was classified as High and defined as Low if both stains were classified as Low. Results: Among the patients treated with nivolumab (n = 37), the SP263 High group showed higher DCR compared to the SP263 Low group (52.6% vs. 11.1%, P = 0.024). In patients treated with pembrolizumab (n = 33), no significant difference in DCR and PFS according to PD‐L1 expression was observed. In the combined analysis (n = 36), patients in the PD‐L1 High group showed significantly higher DCRs than those in the PD‐L1 Low group (56.1% vs. 24.1%, P = 0.028). PFS was significantly longer in the PD‐L1 High group than in the Low group (medians 4.1 vs. 1.6 months, respectively, P = 0.04). Conclusion: A high expression level of PD‐L1 was correlated with a significantly higher DCR and longer PFS in NSCLC patients treated with nivolumab or pembrolizumab. [ABSTRACT FROM AUTHOR]

Background: We determined the clinical characteristics and predictive factors of long‐term response to pemetrexed maintenance therapy as first‐line treatment for non‐small cell lung cancer (NSCLC). Methods: A total of 950 advanced NSCLC patients received pemetrexed (500 mg/m2) plus cisplatin (60 mg/m2) (Pem‐Cis) induction chemotherapy every three weeks as first‐line treatment between January 2010 and August 2018. Patients who did not show progression after four cycles of Pem‐Cis and received at least one cycle of pemetrexed maintenance were recruited (n = 199). Results: Patients were divided into subgroups according to total cycles of pemetrexed: ≤ 10 (F10, n = 134) and > 10 (M10, n = 65). The M10 group had a higher proportion of patients with stage M1a (intrathoracic metastasis alone) and exhibited lower levels of thymidylate synthase (TS) than the F10 group (median H‐score 10.0% vs. 60.0%; P = 0.031). Further subgrouping identified extreme responders: ≤ 7 (F7, n = 101) and ≥ 20 (M20, n = 26) cycles. The M20 group showed lower mean serum CEA levels before (17.5 vs. 147.0; P = 0.099) and after (6.9 vs. 53.2; P = 0.001) Pem‐Cis treatment, and a higher incidence of normalization after Pem‐Cis (abnormal 41.7% vs. 68.5%; P = 0.015). M1a stage, normalization of CEA levels after Pem‐Cis, and lower TS H‐score were predictors of progression‐free survival in patients administered pemetrexed maintenance. Conclusion: M1a stage and lower TS expression were predictors of long‐term response to pemetrexed maintenance. CEA normalization after Pem‐Cis could be an additional surrogate marker of positive response to long‐term treatment. [ABSTRACT FROM AUTHOR]

Glutathione peroxidase 3 (GPx3), a major scavenger of reactive oxygen species (ROS) in plasma, acts as a redox signal modulator. However, the mechanism underlying GPx3-mediated suppression of cancer cell growth is unclear. The aim of this study was to identify these mechanisms with respect to lung cancer. To enhance the redox modulating properties of GPx3, lung cancer cells were subjected to serum starvation for 12 h, resulting in ROS generation in the absence of oxidant treatment. We then investigated whether suppression of tumorigenesis under conditions of oxidative stress was dependent on GPx3. The results showed that GPx3 effectively suppressed proliferation, migration, and invasion of lung cancer cells under oxidative stress. In addition, GPx3 expression led to a significant reduction in ROS production by cancer cells and induced G2/M phase arrest. We also found that inactivation of cyclin B1 significantly suppressed by nuclear factor-κB(NF-κB) inactivation in lung cancer cells was dependent on GPx3 expression. To further elucidate the mechanism(s) underlying GPx3-medited suppression of tumor proliferation, we next examined the effect of GPx3-mediated redox signaling on the ROS-MKP3-extracellular signal-regulated kinase (Erk)-NF-κB-cyclin B1 pathway and found that GPx3 strongly suppressed activation of the Erk-NF-κB-cyclin B1 signaling cascade by protecting MKP3 (an Erk-specific phosphatase) from the effects of ROS. Thus, this study demonstrates for the first time that the GPx3 suppresses proliferation of lung cancer cells by modulating redox-mediated signals. [ABSTRACT FROM AUTHOR]

Background: In cases of EGFR‐tyrosine kinase inhibitor (TKI) failure, re‐biopsy may be useful to understand resistance mechanisms and guide further treatment decisions. However, performing re‐biopsy is challenging because of several hurdles. We assessed the feasibility of re‐biopsy in advanced non‐small cell lung cancer (NSCLC) patients in real‐world clinical practice. Methods: We retrospectively reviewed the clinical and pathologic data of advanced NSCLC patients who experienced disease progression after previous treatment with EGFR‐TKIs at a single tertiary hospital in Korea between January 2014 and December 2016. Re‐biopsy specimens included small biopsy, surgical tissue, or liquid‐based cytology. EGFR mutation was tested using peptide nucleic acid‐mediated clamping PCR. Results: Of the 230 NSCLC patients that experienced progression after EGFR‐TKI therapy, 105 (45.7%) underwent re‐biopsy. Re‐biopsy was successfully performed in 94 (89.5%) patients, and 11 patients were diagnosed with no malignancy. The complication rate was 8.6%, including seven cases of pneumothorax. EGFR mutation testing was performed on 75 patients using re‐biopsy specimens. Of the 57 patients who had sensitizing mutations at diagnosis, T790M mutations were found in 19 (33.3%), while 38 (66.7%) had no T790M mutation. Multivariate analysis showed that the re‐biopsy group was younger (P = 0.002) and exhibited a previous response to EGFR‐TKIs (P < 0.001). Conclusion: Re‐biopsy in advanced NSCLC is feasible in real world clinical practice, particularly in younger patients and those who achieved a previous response to EGFR‐TKIs. [ABSTRACT FROM AUTHOR]

Objectives: We aimed to evaluate the prevalence and predictive role of c-MET expression and EGFR mutation in the efficacy of erlotinib in non-small-cell lung cancer (NSCLC). Methods: We prospectively recruited 196 patients with stage IV or recurrent NSCLC treated with erlotinib after failure of first-line chemotherapy. Immunohistochemistry was used to evaluate c-MET overexpression, silver in situ hybridization (SISH) to assess gene copy number, and real-time polymerase chain reaction to detect EGFR mutations, respectively, in tumor tissue. Results: The major histologic type was adenocarcinoma (66.8%). c-MET was overexpressed in 55.8% (87/156) and dominant in females as well as non-squamous histology. Although c-MET gene amplification and high polysomy were observed in 2.0% (3/152) and 11.2% (17/152), they did not correlate with any characteristics. EGFR mutation was detected in 13.1% (20/153). The objective response rate of erlotinib was higher (61.1 vs. 3.7%, p < 0.001) and the median progression-free survival (PFS) was longer (10.2 vs. 1.9 months, p < 0.001) in EGFR-sensitizing mutations. However, c-MET positivity did not show a significant correlation with response to erlotinib or PFS. Conclusion: We reconfirmed EGFR mutation as a strong predictive marker of NSCLC. However, c-MET positivity was not associated with response or PFS, although c-MET overexpression correlated with some clinical characteristics. [ABSTRACT FROM AUTHOR]

Background Epidermal growth factor receptor ( EGFR) gene mutation is a reliable predictive factor for response to EGFR-tyrosine kinase inhibitors ( TKIs). The quantified EGFR value may also predict response and survival within an EGFR mutated group. Methods We conducted a retrospective study of 836 lung cancer patients. The patient sample was divided into two groups based on the mean delta cycle threshold (∆ Ct) value. EGFR mutation tests using peptide nucleic acid ( PNA)-mediated clamping polymerase chain reaction ( PCR) were performed. The efficiency of PCR clamping was determined by measuring the Ct value and EGFR quantification was determined by the corrected ∆ Ct value. Results EGFR mutation positivity was 30.1% and there were 235 single activating mutations. In this mutation group, the higher corrected ∆ Ct value (≥ mean value) group showed better objective response (70.9% vs. 54.9%, P = 0.022) and clinical benefit rates (86.4% vs. 68.3%, P = 0.003) than the lower group. In addition, corrected ∆ Ct values were significantly and inversely correlated with disease response ( r = −0.184, P = 0.017). In multivariate analysis, both female gender ( P = 0.014) and higher corrected Δ Ct value ( P = 0.012) were independent predictive factors for better clinical benefit rate. The higher corrected Δ Ct value group had a tendency for longer progression-free survival than the lower group ( P = 0.050). Conclusion The corrected ∆ Ct value, which refers to EGFR quantification by PNA-mediated PCR clamping, can predict better clinical response to EGFR- TKI therapy. However, further study is warranted to determine its value as a biomarker to reflect survival. [ABSTRACT FROM AUTHOR]

Several cases of acquired resistance in patients with activating epidermal growth factor receptor ( EGFR) mutation have been reported. However, rare clinical cases exist of a transformation to small cell lung cancer ( SCLC) following treatment with EGFR-tyrosine kinase inhibitors ( TKIs). We report a case of non-small cell lung cancer ( NSCLC) with L858R mutation at the time of diagnosis. After failure of EGFR-TKI therapy, we performed additional histopathologic examinations. We confirmed that the patient had a histological transformation from NSCLC to SCLC. We performed chemotherapy with etoposide and cisplatin against the SCLC and radiologic findings were improved. [ABSTRACT FROM AUTHOR]

ABSTRACT Background and objective: Expression of excision repair cross-complementation group 1 (ERCC1) is recognized as a favourable prognostic marker in patients who have undergone surgical resection of non-small cell lung cancer (NSCLC). However, in patients treated with adjuvant chemotherapy after surgical resection, ERCC1 correlated with poor prognosis. Class III beta tubulin (TUBB3) is also known to be a predictive marker of the efficacy of treatment with taxanes or vinorelbine. Methods: Tumour tissues ( n = 363) from patients with surgically resected NSCLC were analysed retrospectively. Tissue sections were labelled with ERCC1- and TUBB3-specific antibodies. Using genomic DNA from 262 patients, single nucleotide polymorphisms of the ERCC1 gene (T19007C and C8092A) were genotyped by PCR-restriction fragment length polymorphism analysis. Results: Only 5.9% of patients with stage I disease (14/238) and 61.6% of patients with stages II-III disease (77/125) received adjuvant chemotherapy. Relapses were noted in 30.6% (111) of patients, and among these, 31 ultimately succumbed. The relapse rate (RR) was 24.8% for stage I disease, and 41.6% for stages II-III disease. The RR was significantly lower in ERCC1-positive (24.3%) as compared with ERCC1-negative patients (36.3%, P = 0.014) and was lower in patients with the AA/CA genotype at the ERCC1 C8092A locus (29.5%) compared with those with the CC genotype (42.1%, P = 0.034). The median disease-free survival (DFS) time was 62.3 months. DFS was significantly greater in ERCC1-positive patients (62.3 months) than in ERCC1-negative patients (48.0 months, P = 0.042). In a multivariate analysis, ERCC1 expression and the C8092A polymorphism were independent prognostic factors in patients with stage I disease who were naïve to chemotherapy. Conclusions: ERCC1 expression and the AA/CA genotype at the C8092A locus were correlated with a good prognosis in patients who had undergone surgical resection of NSCLC. [ABSTRACT FROM AUTHOR]

We aimed to examine the usefulness of serum glutathione peroxidase 3 (GPx3) as a biomarker of lung cancer recurrence after complete resection. We prospectively collected serial serum samples at the baseline, as well as 3, 6 and 12 months after surgery from complete resection cases in 2013. GPx3 levels were measured by enzyme-linked immunosorbent assay. Statistical tests including t-tests and Cox proportional hazard regression analyses were performed. Totally, 135 patients were enrolled, and 39 (28.9%) showed relapse during the median follow-up period (63.60 months; range, 0.167–81.867). The mean GPx3 change was significantly higher in the recurrence group at 6 months (0.32 ± 0.38 vs. 0.15 ± 0.29, p = 0.016) and 12 months (0.40 ± 0.37 vs. 0.13 ± 0.28, p = 0.001). The high GPx3 change group showed significantly higher 60-months recurrence rates than the low group (48.1% vs. 25.2% at 3 months, p = 0.005; 54.5% vs. 28.9% at 6 months, p = 0.018; 38.3% vs. 18.3% at 12 months, p = 0.035). High GPx3 change at 3 months were independent risk factors of recurrence (hazard ratio (HR) 3.318, 95% confidence interval (CI), 1.582–6.960, p = 0.002) and survival (HR 3.150, 95% CI, 1.301–7.628, p = 0.011). Therefore, serum GPx3 changes after surgery may be useful predictive biomarkers for recurrence in lung cancer. Larger-scale validation studies are warranted to confirm these findings. [ABSTRACT FROM AUTHOR]