Chunxia Su

Epidermal growth factor receptor-tyrosine kinase inhibitor therapy is effective as first-line treatment of advanced non-small-cell lung cancer with mutated EGFR: A meta-analysis from six phase III randomized controlled trials.

Gefiinib and erlotinib are two similar small molecules of selective and reversible epidermal growth factor receptor‐tyrosine kinase inhibitors (EGFR‐TKIs), which have been approved for second‐line or third‐line indication in previously treated advanced Non‐small‐cell lung cancer (NSCLC) patients. The results of comparing the EGFR‐TKI with standard platinum‐based doublet chemotherapy as the first‐line treatment in advanced NSCLC patients with activated EGFR mutation were still controversial. A meta‐analysis was performed to derive a more precise estimation of these regimens. Finally, six eligible trials involved 1,021 patients were identified. The patients receiving EGFR‐TKI as front‐line therapy had a significantly longer progression‐free survival (PFS) than patients treated with chemotherapy [median PFS was 9.5 versus 5.9 months; hazard ratio (HR) = 0.37; 95% confidence intervals (CI) = 0.27–0.52; p < 0.001]. The overall response rate (ORR) of EGFR‐TKI was 66.60%, whereas the ORR of chemotherapy regimen was 30.62%, which was also a statistically significant favor for EGFR‐TKI [relative risk (RR) = 5.68; 95% CI = 3.17–10.18; p < 0.001]. The overall survival (OS) was numerically longer in the patients received EGFR‐TKI than patients treated by chemotherapy, although the difference did not reach a statistical significance (median OS was 30.5 vs. 23.6 months; HR = 0.94; 95% CI = 0.77–1.15; p = 0.57). Comparing with first‐line chemotherapy, treatment of EGFR‐TKI achieved a statistical significantly longer PFS, higher ORR and numerically longer OS in the advanced NSCLC patients harboring activated EGFR mutations, thus, it should be the first choice in the previously untreated NSCLC patients with activated EGFR mutation.

MiR-21 overexpression is associated with acquired resistance of EGFR-TKI in non-small cell lung cancer

BACKGROUND AND PURPOSE With the increasing use of epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) in patients with advanced non-small cell lung cancer (NSCLC), its acquired resistance has become a major clinical problem. Recent studies revealed that miR-21 was involved into the resistance of cytotoxic agents. The aim of this study was to investigate its role in the acquired resistance of NSCLC to EGFR-TKI. METHODS EGFR-TKI-sensitive human lung adenocarcinoma cell line PC9 and the acquired resistant cell line, PC9R, were used. Lentiviral vectors were used to infect PC9 or PC9R to regulate the miR-21 expression. The expression of targeted proteins PTEN and PDCD4 was controlled by RNA interference. MicroRNA array, RT-PCR and TaqMan MicroRNA Assays were used to detect miR-21 expression. The MTT and Annexin V assays were used to determine proliferation and apoptosis. Western Blot and immunohistochemistry were used to analyze target protein expression (PTEN, PDCD4, Akt, p-Akt). We also constructed PC9R xenograft tumor model to observe the relationship between miR-21 and EGFR-TKI resistance in vivo and validated it in the clinical serum specimens of NSCLC patients treated with EGFR-TKI. RESULT MiR-21 was overexpressed in the EGFR-TKI resistant cell line PC9R relative to PC9. The level of miR-21 was reversely correlated with the expression of PTEN and PDCD4 and positive correlated with PI3K/Akt pathway. Inhibiting miR-21 with lentivirus vector induces apoptosis in PC9R cell line and inhibiting miR-21with ASO suppressed tumor growth in nude mice treated with EGFR-TKI. Furthermore, serum miR-21 expression in NSCLC patients treated with EGFR-TKI was significantly higher at the time of acquiring resistance than at baseline (p<0.01). CONCLUSION miR-21 is involved in acquired resistance of EGFR-TKI in NSCLC, which is mediated by down-regulating PTEN and PDCD4 and activating PI3K/Akt pathway.

ROS1 fusions in Chinese patients with non-small-cell lung cancer

BACKGROUND To determine the prevalence and clinicopathological features of ROS1 fusions in Chinese patients with non-small-cell lung cancer (NSCLC). METHODS Formalin-fixed and paraffin-embedded (FFPE) tissue sections from 392 patients with NSCLC were screened for ROS1 fusions by multiplex RT-PCR and all ROS1 fusions were validated by direct sequencing. The relationship between ROS1 fusions and clinicopathological features and the prognostic effect of the ROS1 fusion status on survival were analyzed. RESULTS In this study, 8 of 392 (2.0%) evaluable samples were found to harbor ROS1 fusions. Of the ROS1-positive patients, seven presented with adenocarcinoma, and one with adenosquamous carcinoma. The ratio of female to male and never smoker to smokers in a ROS1 fusion-positive group was 5:3. There was no statistically significant difference in age, sex, smoking history, histological type and pathological stage between ROS1 fusion-positive and ROS1 fusion-negative patients. ROS1 fusion-negative patients had a significantly longer survival when compared with ROS1 fusion-positive patients (P = 0.041). Lower pathological stage, younger age and ROS1 fusion-negative status were significantly associated with better prognosis on multivariate analysis. CONCLUSIONS ROS1 fusions occurred in ∼2.0% of Chinese patients with NSCLC and had no specific clinicopathological feature. ROS1 fusion-negative patients may have a better survival than ROS1 fusion-positive patients.BACKGROUND To determine the prevalence and clinicopathological features of ROS1 fusions in Chinese patients with non-small-cell lung cancer (NSCLC). METHODS Formalin-fixed and paraffin-embedded (FFPE) tissue sections from 392 patients with NSCLC were screened for ROS1 fusions by multiplex RT-PCR and all ROS1 fusions were validated by direct sequencing. The relationship between ROS1 fusions and clinicopathological features and the prognostic effect of the ROS1 fusion status on survival were analyzed. RESULTS In this study, 8 of 392 (2.0%) evaluable samples were found to harbor ROS1 fusions. Of the ROS1-positive patients, seven presented with adenocarcinoma, and one with adenosquamous carcinoma. The ratio of female to male and never smoker to smokers in a ROS1 fusion-positive group was 5:3. There was no statistically significant difference in age, sex, smoking history, histological type and pathological stage between ROS1 fusion-positive and ROS1 fusion-negative patients. ROS1 fusion-negative patients had a significantly longer survival when compared with ROS1 fusion-positive patients (P = 0.041). Lower pathological stage, younger age and ROS1 fusion-negative status were significantly associated with better prognosis on multivariate analysis. CONCLUSIONS ROS1 fusions occurred in ∼2.0% of Chinese patients with NSCLC and had no specific clinicopathological feature. ROS1 fusion-negative patients may have a better survival than ROS1 fusion-positive patients.

KIF5B‐RET fusions in Chinese patients with non–small cell lung cancer

It has been established that “ret proto‐oncogene” (RET) fusions are oncogenic drivers in non–small cell lung cancer (NSCLC). The prevalence and clinicopathologic characteristics of RET fusions in Chinese patients with NSCLC remain unclear. The objective of the current study was to determine the prevalence and clinicopathologic characteristics of KIF5B‐RET fusions (fusions of the RET and kinesin family member 5B [KIF5B] genes) in Chinese patients with NSCLC.

Association of EGFR mutation or ALK rearrangement with expression of DNA repair and synthesis genes in never-smoker women with pulmonary adenocarcinoma

Epidermal growth factor receptor (EGFR) mutation and anaplastic lymphoma kinase (ALK) rearrangement may predict the outcome of targeted drug therapy and also are associated with the efficacy of chemotherapy in patients with nonsmall cell lung cancer (NSCLC). The authors of this report investigated the relation of EGFR mutation or ALK rearrangement status and the expression of DNA repair or synthesis genes, including excision repair cross‐complementing 1 (ERCC1), ribonucleotide reductase subunit M1 (RRM1), thymidylate synthetase (TS), and breast cancer‐early onset (BRCA1), as a potential explanation for these observations.

Peripheral blood for epidermal growth factor receptor mutation detection in non-small cell lung cancer patients.

OBJECTIVE: It is important to analyze and track Epidermal Growth Factor Receptor (EGFR) mutation status for predicting efficacy and monitoring resistance throughout EGFR-tyrosine kinase inhibitors (TKIs) treatment in non-small cell lung cancer (NSCLC) patients. The objective of this study was to determine the feasibility and predictive utility of EGFR mutation detection in peripheral blood. METHODS: Plasma, serum and tumor tissue samples from 164 NSCLC patients were assessed for EGFR mutations using Amplification Refractory Mutation System (ARMS). RESULTS: Compared with matched tumor tissue, the concordance rate of EGFR mutation status in plasma and serum was 73.6% and 66.3%, respectively. ARMS for EGFR mutation detection in blood showed low sensitivity (plasma, 48.2%; serum, 39.6%) but high specificity (plasma, 95.4%; serum, 95.5%). Treated with EGFR-TKIs, patients with EGFR mutations in blood had significantly higher objective response rate (ORR) and insignificantly longer progression-free survival (PFS) than those without mutations (ORR: plasma, 68.4% versus 38.9%, P = 0.037; serum, 75.0% versus 39.5%, P = 0.017; PFS: plasma, 7.9 months versus 6.1 months, P = 0.953; serum, 7.9 months versus 5.7 months, P = 0.889). In patients with mutant tumors, those without EGFR mutations in blood tended to have prolonged PFS than patients with mutations (19.7 months versus 11.0 months, P = 0.102). CONCLUSIONS: EGFR mutations detected in blood may be highly predictive of identical mutations in corresponding tumor, as well as showing correlations with tumor response and survival benefit from EGFR-TKIs. Therefore, blood for EGFR mutation detection may allow NSCLC patients with unavailable or insufficient tumor tissue the opportunity to benefit from personalized treatment. However, due to the high false negative rate in blood samples, analysis for EGFR mutations in tumor tissue remains the gold standard.

EGFR TKIs plus WBRT Demonstrated No Survival Benefit Other Than That of TKIs Alone in Patients with NSCLC and EGFR Mutation and Brain Metastases.

Introduction: Whether EGFR tyrosine kinase inhibitors (TKIs) plus whole brain radiation therapy (WBRT) provide a better survival benefit than EGFR TKIs alone remains undetermined in patients with NSCLC with EGFR mutation and brain metastases (BMs). Methods: A total of 230 patients with NSCLC with EGFR mutation and BM were identified. Within this group, 116 patients received EGFR TKIs alone (as first‐line therapy in 91 cases) and 51 patients received EGFR TKIs plus WBRT therapy (as first‐line treatment in 30 cases). Results: Compared with TKIs alone, EGFR TKIs plus WBRT had no superior intracranial progression‐free survival (PFS) (6.9 versus 7.4 months [p = 0.232]) and systemic PFS (7.5 versus 7.9 months [p = 0.546]) but were associated with worse overall survival (OS) (21.6 versus 26.4 months [p = 0.049]) in NSCLC with EGFR mutation and BM. Chemotherapy plus WBRT was shown to have an intracranial PFS (5.2 versus 5.9 months [p = 0.339]) and OS (10.5 versus 11.0 months [p = 0.977]) similar to those with chemotherapy alone in patients with EGFR of unknown or wild‐type status. In multivariate analysis, EGFR mutation was found to be an independent risk factor for BM (hazard ratio = 1.476, p = 0.039) and also a significant independent prognostic factor for OS in patients with NSCLC with BM (hazard ratio = 0.601, p = 0.028). Conclusions: The addition of WBRT to EGFR TKIs did not appear to have survival benefit superior to that of EGFR TKIs alone in with EGFR‐mutant NSCLC with BM. WBRT also did not bring additional benefit to chemotherapy in patients with BM and EGFR of wild‐type or unknown status.

Epithelial phenotype as a predictive marker for response to EGFR-TKIs in non-small cell lung cancer patients with wild-type EGFR.

Epithelial‐to‐mesenchymal transition (EMT) has profound impacts on cancer progression and also on drug resistance, including epidermal growth factor receptor tyrosine kinase inhibitors (EGFR‐TKIs). Nowadays, there is still no predictive biomarker identified for the use of EGFR‐TKIs in non‐small cell lung cancer (NSCLC) patients with wild‐type EGFR. To clarify the role of EMT phenotype as a predictive marker for EGFR‐TKI, we performed a retrospective study in 202 stage IV or recurrent NSCLC patients receiving gefitinib or erlotinib therapy from June 2008 to September 2012 in our institute. Clinical data and EGFR mutational status were collected, while epithelial, epithelial to mesenchymal, not specified or mesenchymal phenotype were classified according to EMT markers such as E‐cadherin, fibronectin, N‐cadherin and vimentin by immunohistochemistry. Epithelial phenotype was more frequently found in patients with EGFR mutation (p = 0.044). Epithelial phenotype was associated with a significantly higher objective response rate (23.5 vs. 11.1 vs. 0.0 vs. 2.4%, p = 0.011), longer progression‐free survival (4.4 vs. 1.9 vs. 1.7 vs. 1.0 months, p < 0.001) and longer overall survival (11.5 vs. 8.9 vs. 4.5 vs. 4.9 months, p < 0.001) compared to epithelial to mesenchymal, not specified and mesenchymal phenotype in the wild‐type EGFR subgroup. In the subgroup with EGFR mutation, the trend remained but without a statistically significant difference. In conclusion, epithelial phenotype was more likely expressed in patients with EGFR mutation and was associated with a better outcome in advanced NSCLC patients with wild‐type EGFR, which indicates that the EMT phenotype might be a potential marker to guide EGFR‐TKI therapy in this population.

EML4-ALK Fusion Detected by RT-PCR Confers Similar Response to Crizotinib as Detected by FISH in Patients with Advanced Non-Small-Cell Lung Cancer.

Introduction: Reverse transcriptase polymerase chain reaction (RT-PCR) assay has been proved to have high sensitivity and specificity to detect anaplastic lymphoma kinase (ALK) rearrangements. The aim of this study was to investigate the response to crizotinib in patients of advanced non–small-cell lung cancer (NSCLC) with ALK rearrangements detected by RT-PCR. Methods: Only patients with advanced NSCLC who had their ALK rearrangement status detected by RT-PCR were included in this analysis. The utility of RT-PCR and fluorescence in situ hybridization (FISH) assay were compared in patients who were treated with crizotinib based on their positive ALK rearrangements. Results: One thousand ten patients were included in this study. Among them, 104 patients were ALK RT-PCR positive and 53 of them received crizotinib treatment. Among 255 tumors simultaneously analyzed by FISH and RT-PCR, the latter successfully detected all the 25 tumors with arrangements, including two cases that were missed by FISH. The overall response rate and median progression-free survival of the 53 patients with ALK rearrangements who received crizotinib treatment were 60.4% (95% confidence interval [CI], 47.2–73.6) and 8.4 months (95% CI, 6.75–10.05), respectively, which were similar to the 21 patients detected by FISH with overall response rate of 57.1% (95% CI, 33.3–76.2; p = 0.799) and median progression-free survival of 7.4 months (95% CI, 4.43–10.38; p = 0.833) after crizotinib treatment. Interestingly, there were two patients responded to crizotinib had their ALK rearrangement detected by RT-PCR but not FISH. Conclusions: RT-PCR should be considered as an alternative/supplemental approach to detect ALK fusion oncogene in NSCLC patients who might benefit from crizotinib treatment.

Correlation of long non-coding RNA H19 expression with cisplatin-resistance and clinical outcome in lung adenocarcinoma.

The acquired drug resistance would influence the efficacy of cisplatin-based chemotherapy in non-small-cell lung cancer. The present study aimed to investigate the correlation of long non-coding RNA (lncRNA) H19 with cisplatin-resistance and clinical outcome in lung adenocarcinoma. In our study, the expression of H19 in cisplatin-resistant A549/DDP cells was unregulated. Knockdown of H19 restored the response of A549/DDP cells to cisplatin. H19-mediated chemosensitivity enhancement was associated with metastasis, induction of G0/G1 cell-cycle arrest, cell proliferation, and increased apoptosis. Furthermore, lncRNA H19 expression was significantly related to TNM stage and metastasis (P = 0.012). Overexpression of H19 was negatively correlated with cisplatin-based chemotherapy response in patients. Patients with high H19 expression exhibited a significantly shorter median progression-free survival (PFS) [4.7 months] than the low-expression patients (6.3months) [P = 0.002]. In summary, H19-mediated regulation of cisplatin resistance in human lung adenocarcinoma cells is demonstrated for the first time. H19 could potentially serve as a molecular marker to predict the clinical outcomes of lung adenocarcinoma patients.