Treatment With EGFR-tyrosine Kinase Inhibitors Research Articles

Primary tumor consolidative therapy improves the outcomes of patients with advanced EGFR-mutant lung adenocarcinoma treated with first-line osimertinib.

Patients with advanced epidermal growth factor receptor (EGFR)-mutant lung adenocarcinoma (LAD) inevitably experience drug resistance following treatment with EGFR-tyrosine kinase inhibitors (TKIs). We aimed to analyze the effect of primary tumor consolidative therapy (PTCT) on patients treated with first-line osimertinib. This retrospective cohort study was conducted in patients with advanced stage III or stage IV LAD with EGFR-sensitizing mutations (exon 19 deletion or L858R mutation) with disease control after first-line osimertinib. A curative dose of primary tumor radiotherapy or primary tumor resection was classified as PTCT. We compared the progression-free survival (PFS) and overall survival (OS) of patients with and without PTCT. This study included 106 patients with a median age of 61.0 years, and of those, 42% were male and 73.6% were never-smokers. Exon 19 deletion was observed in 67.9%, 30.2% had a programmed cell death ligand 1 (PD-L1) tumor proportion score <1%, 33.0% had brain metastasis, and 40.6% had oligometastasis. In all, 53 (50%) patients underwent PTCT. Patients who underwent PTCT demonstrated significantly better PFS [30.3 (95% confidence interval (CI), 24.1-36.4) versus 18.2 (95% CI, 16.1-20.2) months; p = 0.005] and OS [not reached versus 36.7 (95% CI, 32.5-40.9) months; p = 0.005] than patients who did not. A multivariate analysis showed that PTCT was an independent factor associated with better PFS [hazard ratio (HR), 0.22; 95% CI, 0.10-0.49; p < 0.001] and OS [HR, 0.10; 95% CI, 0.01-0.82; p = 0.032]. The PFS benefits of PTCT were consistent across subgroups, and the HR tended to be lower in patients aged <65 years, males, smokers, stage IVB disease, L858R, PD-L1 expression ⩾1%, non-oligometastasis, and brain metastasis. Of the patients with advanced EGFR-mutant LAD, those who underwent PTCT had a significantly better survival outcome than those who did not. The survival benefits were consistent across different subgroups.

Immunotherapy-based combination strategies for treatment of EGFR-TKI-resistant non-small-cell lung cancer.

The rapid development of molecular targeted therapybrings hope to patients with advanced non-small-cell lung cancer (NSCLC). However, drug resistance inevitably occurs during treatment with EGFR-tyrosine kinase inhibitors (TKIs). Osimertinib, a third-generation EGFR-TKI, shows a favorable prognosis in T790M-positive NSCLC. Unfortunately, acquired resistance is still a challenge for both patients and clinicians. There is still no consensus on the optimal treatment. PD-1 and its ligand receptor 1 (PD-L1) inhibitors have yielded great progress, especially in patients with no actionable mutations. In this review, the authors take stock of the relationship between EGFR mutations and PD-L1 expression and summarize the important clinical studies on immunotherapy-inhibitor-based treatment in patients withEGFR-TKI-resistant NSCLC.

Impact of neutrophil-to-lymphocyte ratio in patients with EGFR-mutant NSCLC treated with tyrosine kinase inhibitors.

Background Exon 19 deletion and L858R point mutation in exon 21 of the epidermal growth factor receptor (EGFR) are the most commonly encountered mutations in patients with non-small cell lung cancer (NSCLC) and predict better clinical outcomes following treatment with EGFR-tyrosine kinase inhibitors (TKIs). The inflammatory indicator neutrophil-to-lymphocyte ratio (NLR) in peripheral blood serves as a predictive factor for NSCLC patients treated with chemotherapy. Here, we aimed to evaluate the correlation between NLR and clinical efficacy of EGFR-TKIs in NSCLC patients harboring EGFR mutations. Methods We retrospectively collected information of 205 patients with advanced NSCLC harboring exon 19 deletion or L858R point mutation and receiving gefitinib or erlotinib. The clinical outcomes in the NSCLC patients were evaluated based on NLR level before EGFR-TKI therapy. Results The optimal cut-off value for NLR was 3.55. The response rates in the low-NLR and high-NLR groups were 69.2% and 51.5%, respectively. The median progression-free survival (PFS) in the low-NLR and high-NLR groups were 15.7months and 6.7months, respectively. The median overall survival (OS) in the low-NLR and high-NLR groups were 37.6months and 19.2months, respectively. The multivariate analysis identified performance status (PS), NLR, stage, and smoking status as independent predictors of PFS. Moreover, the PS and NLR were identified as independent predictors of OS. Conclusions NLR was a significant predictor of clinical efficacy and OS in NSCLC patients harboring EGFR mutations treated with gefitinib or erlotinib.

Clinical factors associated with treatment outcomes in EGFR mutant non-small cell lung cancer patients with brain metastases: a case-control observational study

BackgroundNon-small cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) mutations often develop brain metastases. Treatment with EGFR-tyrosine kinase inhibitors (TKIs) has shown the effectiveness; however, knowledge of the clinical factors associated with outcomes in NSCLC patients with EGFR mutations remains limited.MethodsTreatment-naive patients diagnosed with advanced non-squamous NSCLC with brain metastases harboring EGFR mutations and treated with an EGFR-TKI as first-line therapy were enrolled with analysis of their medical records.ResultsA total of 134 advanced NSCLC patients with brain metastases harboring EGFR mutations received an EGFR-TKI (gefitinib: 62, erlotinib: 49, and afatinib: 23) as the first-line therapy. Sixty-nine had exon 19 deletions (51.5%), and 56 (41.8%) had L858R mutations. There was no statistically significant difference in progression-free survival (PFS) and overall survival (OS) among the EGFR-TKIs. Significantly shorter OS was noted in patients with multiple brain metastases (hazard ratio [HR]: 2.43, p = 0.007), uncommon EGFR mutations (HR: 3.75, p = 0.009), and liver metastases. Thirty-eight patients (29.1%) received brain radiotherapy for brain metastases before disease progression, and had a significantly longer time until intracranial progression. However, the brain radiotherapy had no statistically significant impact on PFS or OS.ConclusionsPatients with uncommon mutations, multiple brain metastases, and concomitant liver metastases tended to have shorter OS. Brain radiotherapy could delay the time to intracranial disease progression but had no impact on survival. The different first-line EGFR-TKIs achieved similar treatment responses in terms of PFS and OS in the EGFR-mutated NSCLC patients with brain metastases.

Epidermal Growth Factor Receptor (EGFR) Pathway, Yes-Associated Protein (YAP) and the Regulation of Programmed Death-Ligand 1 (PD-L1) in Non-Small Cell Lung Cancer (NSCLC).

The epidermal growth factor receptor (EGFR) pathway is a well-studied oncogenic pathway in human non-small cell lung cancer (NSCLC). A subset of advanced NSCLC patients (15–55%) have EGFR-driven mutations and benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs). Immune checkpoint inhibitors (ICIs) targeting the PD-1/PDL-1 axis are a new anti-cancer therapy for metastatic NSCLC. The anti-PD-1/PDL-1 ICIs showed promising efficacy (~30% response rate) and improved the survival of patients with metastatic NSCLC, but the role of anti-PD-1/PDL-1 ICIs for EGFR mutant NSCLC is not clear. YAP (yes-associated protein) is the main mediator of the Hippo pathway and has been identified as promoting cancer progression, drug resistance, and metastasis in NSCLC. Here, we review recent studies that examined the correlation between the EGFR, YAP pathways, and PD-L1 and demonstrate the mechanism by which EGFR and YAP regulate PD-L1 expression in human NSCLC. About 50% of EGFR mutant NSCLC patients acquire resistance to EGFR-TKIs without known targetable secondary mutations. Targeting YAP therapy is suggested as a potential treatment for NSCLC with acquired resistance to EGFR-TKIs. Future work should focus on the efficacy of YAP inhibitors in combination with immune checkpoint PD-L1/PD-1 blockade in EGFR mutant NSCLC without targetable resistant mutations.

Comprehensive analysis of EGFR T790M detection by ddPCR and ARMS-PCR and the effect of mutant abundance on the efficacy of osimertinib in NSCLC patients

Patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations often develop systemic disease progression during treatment with EGFR-tyrosine kinase inhibitors (TKIs). Droplet digital polymerase chain reaction (ddPCR) and amplification refractory mutation system (ARMS)-PCR are routinely applied for detection of EGFR mutations, including T790M, which is associated with TKI sensitivity. We compared the efficiency of ddPCR and ARMS-PCR in detecting T790M and explored the association between T790M abundance and osimertinib efficacy. Genomic DNA (gDNA) from tissue and cells in hydrothorax and circulating tumor DNA (ctDNA) from peripheral blood (PB), and clinicopathological data were retrospectively collected from 263 patients who visited Sun Yat-sen University Cancer Center for T790M test. Mean T790M abundance and mutant copy number of cases tested positive by both methods, i.e., the ddPCR+ARMS+ group (19.1%, 636.9), were higher than those in the ddPCR+ARMS- group (0.36%, 12.1), suggesting that ddPCR is more sensitive in detecting samples with low mutant abundance than ARMS-PCR. T790M detection rate was comparable for gDNA and ctDNA samples (44.7% vs. 37.6%, P=0.242); however, gDNA sample tended to show more T790M abundance in ddPCR analysis. T790M coexisted with L858R mutation (8/11) more than with deletions in exon 19 (19del) mutation (3/11) in TKI-naive tumors, while 19del co-occurred as often as L858R in post-TKI tumors. T790M+ patients benefited more from osimertinib and showed longer progression-free survival (PFS) (not achieved vs. 10.1 months, P=0.0399), while lower T790M abundance (<1.065%) was associated with longer PFS (not achieved vs. 8.8 months, P=0.0033). ddPCR has a higher sensitivity than ARMS-PCR, especially in detecting the less abundant T790M. Although detection rates were comparable for ctDNA and gDNA samples, the mutation abundance was higher in gDNA sample. Finally, low T790M abundance was associated with longer PFS in NSCLC patients receiving osimertinib treatment.

Cytoplasmic ERβ1 expression is associated with survival of patients with Stage IV lung adenocarcinoma and an EGFR mutation at exon 21 L858R subsequent to treatment with EGFR-TKIs.

The present study assessed whether estrogen receptor (ER)β1 is associated with the survival of patients with advanced lung adenocarcinoma, with or without mutations of the epidermal growth factor receptor (EGFR) following treatment with EGFR-tyrosine kinase inhibitors (TKIs). Pathologically confirmed stage IV lung adenocarcinomas were assessed for EGFR mutations and ERβ1 expression. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and the log-rank test. A total of 122 out of the 201 (60.7%) patients had EGFR mutations, 64 (31.8%) of which were EGFR Del19 and 58 mutations (28.9%) were EGFR exon 21 L858R mutation. The presence of EGFR mutations was significantly increased in female patients compared with male patients (P<0.001) and in non-smokers compared with smokers (P<0.001). Patients with EGFR mutations had a significantly improved PFS and OS compared with patients without EGFR mutations treated with EGFR-TKIs. Furthermore, ERβ1 expression was significantly increased in patients with EGFR mutations compared with patients without EGFR mutations (P=0.001). However, the median PFS (P=0.005) and OS (P=0.002) of patients carrying the EGFR exon 21 L858R mutation was significantly decreased in patients with tumors where ERβ1 cytoplasmic expression was high. The multivariate analysis demonstrated that ERβ1 expression was the only independent predictor of PFS (P=0.002) and OS (P=0.003) in patients carrying the EGFR exon 21 L858R mutation. The data demonstrated that ERβ1 expression may predict outcomes of patients with lung adenocarcinoma treated with EGFR-TKI.

The increase in activating EGFR mutation in plasma is an early biomarker to monitor response to osimertinib: a case report

BackgroundSystemic treatment of advanced non-small cell lung cancer (NSCLC) has changed dramatically since the introduction of targeted therapies. The analysis of circulating tumor DNA (ctDNA) is a valuable approach to monitor the clonal evolution of tumors during treatment with EGFR-tyrosine kinase inhibitors (TKIs) and to detect resistance mutations.Case presentationA NSCLC patient with exon 19 deletion (ex19del) of EGFR was treated with osimertinib after multiple lines of treatment and obtained a partial response that lasted over 26 months. Blood was collected at each visit and ctDNA was extracted to monitor ex19del by digital droplet PCR. Within a few weeks from the beginning of osimertinib, ex19del disappeared from plasma but appeared again and steadily increased a few months later anticipating tumor progression. Interestingly, the change in ex19del was much more pronounced than other mutations, since T790M appeared 3 months after the increase of ex19del, and C797S was detectable a few weeks before clinical disease progression. Then the patient received cytotoxic chemotherapy, which was associated with a decrease in ex19del and disappearance of T790M and C797S; however, at disease progression, all EGFR mutations increased again in plasma together with MET amplification which was detected by NGS.ConclusionsThe measurement of ex19del changes in ctDNA is a simple and sensitive approach to monitor clinical outcome to osimertinib and, potentially, to other therapeutic interventions.

Correlation between progression-free survival, tumor burden, and circulating tumor DNA in the initial diagnosis of advanced-stage EGFR-mutated non-small cell lung cancer.

BackgroundThis study was conducted to identify whether the presence of circulating tumor DNA (ctDNA) in plasma before treatment with EGFR‐tyrosine kinase inhibitors (TKIs) is associated with clinical outcomes.MethodsFifty‐seven pairs of tissues and plasma samples were obtained from patients with NSCLC adenocarcinoma harboring activating EGFR mutations before the administration of EGFR‐TKI treatment. ctDNA mutation was identified using the PANAMutyper EGFR mutation kit. Both qualitative and quantitative analyzes of the data were performed.ResultsConcordance rates with tissue biopsy were 40.4% and 59.6% for the qualitative and quantitative methods, respectively. Bone metastasis showed a statistically significant correlation with ctDNA detection (odds ratio 3.985, 95% confidence interval [CI] 1.027–15.457; P = 0.046). Progression‐free survival (PFS) was significantly shorter in the group detected with ctDNA than in the undetected ctDNA group (median PFS 9.8 vs. 20.7 months; hazard ratio [HR] 2.30, 95% CI 1.202–4.385; P = 0.012). Detection of ctDNA before treatment with EGFR‐TKIs (HR 2.388, 95% CI 1.138–5.014; P = 0.021) and extra‐thoracic lymph node metastasis (HR 13.533, 95% CI 2.474–68.747; P = 0.002) were independently associated with PFS. Six of 11 patients (45.5%) monitored by serial sampling showed a dynamic change in ctDNA prior to disease progression.ConclusionQuantitative testing can increase the sensitivity of the ctDNA detection test. Patients with detectable ctDNA had significantly shorter PFS after receiving EGFR‐TKIs than those with undetectable ctDNA. Tumor burden may be associated with plasma ctDNA detection. A shorter PFS was associated with detection of ctDNA and extra‐thoracic lymph node metastasis. Dynamic changes in the ctDNA level may help predict clinical outcomes.

Microwave ablation with continued EGFR tyrosine kinase inhibitor therapy prolongs disease control in non-small-cell lung cancers with acquired resistance to EGFR tyrosine kinase inhibitors.

BackgroundAlthough patients with EGFR‐mutant non‐small‐cell lung cancer (NSCLC) benefit from treatment with EGFR‐tyrosine kinase inhibitors (TKIs), outcomes are limited by the eventual development of acquired resistance. We conducted a retrospective study to evaluate the efficacy and feasibility of EGFR‐TKI therapy beyond focal progression, associated with microwave ablation.MethodsPatients with metastatic EGFR‐mutant NSCLC treated with EGFR‐TKIs at our institutions from May 2012 to December 2017 were identified. Patients with single lesion progression, treated with MWA, and continually administered EGFR‐TKI therapy until further progression, were included in the study. Initial response to target therapy, median progression‐free survival (PFS1), and first progression site were recorded. The median time to progression after local therapy (PFS2) was also assessed. Overall survival was calculated from the initiation of EGFR‐TKIs to the date of final follow‐up or death.ResultsFifteen out of 205 patients (10%) satisfied the inclusion criteria. Local therapy was well tolerated, and complete ablation was performed in 11 (73.3%) patients. The median PFS1 was 9.5 months (range 6–41), and the median PFS2 was 8 months (range 3–24). The corresponding 6 and 12 month PFS rates were 73.3% and 26.7%, respectively. Median overall survival was 23 months (range 15–64).ConclusionThe longer disease control observed in our patients suggests that continuation of EGFR‐TKI beyond focal progression associated to microwave ablation is an efficacious therapeutic strategy.

Combination Strategies Using EGFR-TKi in NSCLC Therapy: Learning from the Gap between Pre-Clinical Results and Clinical Outcomes.

Although epidermal growth factor receptor (EGFR) inhibitors have been used to treat non-small cell lung cancer (NSCLC) for decades with great success in patients with EGFR mutations, acquired resistance inevitably occurs after long-term exposure. More recently, combination therapy has emerged as a promising strategy to overcome this issue. Several experiments have been carried out to evaluate the synergism of combination therapy both in vitro and in vivo. Additionally, many clinical studies have been carried out to investigate the feasibility of treatment with EGFR-tyrosine kinase inhibitors (TKi) combined with other NSCLC treatments, including radiotherapy, cytotoxic chemotherapies, targeted therapies, and emerging immunotherapies. However, a significant gap still exists when applying pre-clinical results to clinical scenarios, which hinders the development and use of these strategies. This article is a literature review analysing the rationalities and controversies in the transition from pre-clinical investigation to clinical practice associated with various combination strategies. It also highlights clues and challenges regarding future combination therapeutic options in NSCLC treatment.

EGFR T790M Detection in Circulating Tumor DNA from Non-small Cell Lung Cancer Patients Using the PNA-LNA Clamp Method.

To evaluate the utility of plasma circulating tumor DNA (ctDNA) using the peptide nucleic acid-locked nucleic acid (PNA-LNA) clamp method to detect epidermal growth factor receptor (EGFR) mutations in non-small cell lung cancer (NSCLC) patients who had progressed under treatment with EGFR-tyrosine kinase inhibitors (TKIs). Blood samples were collected from patients with EGFR mutation-positive NSCLC who had progressed on EGFR-TKIs between March 2016 and August 2016 at the Kyoto University Hospital. Extracted ctDNA was analyzed using the PNA-LNA clamp method. In eligible patients, tissue re-biopsy was also performed and EGFR mutation status was compared between tissue and plasma samples. Thirty-one patients were enrolled in this study. Known activating EGFR mutations and the T790M mutation were detected in 18 (58%) and 5 patients (16%), respectively. Twenty-five patients underwent tissue re-biopsy. Adequate samples for mutation analysis were obtained from 21 patients and 10 patients were found to be tissue T790M-positive. Among these 10 patients, 4 patients were positive for T790M in plasma ctDNA (sensitivity 40% and specificity 100%). All patients with T790M-positive plasma ctDNA responded to osimertinib. Sensitivity of the PNA-LNA clamp method in detecting the plasma EGFR T790M mutation was moderate with elevated, however, specificity. Plasma EGFR T790M testing may be adequate for the initial step; however, tissue re-biopsy should be considered for plasma T790M-negative patients because of its high false-negative rate.

P3.02b-063 Analysis of Survival in EGFR-Mutation-Positive Advanced Non-Small-Cell Lung Cancer Patients with Miliary Pulmonary Metastasis: Topic: EGFR Clinical

Miliary pulmonary metastasis of non-small-cell lung cancer (NSCLC) indicates hematogenous dissemination and is more frequent in patients harboring EGFR mutations, and dramatic responses are often observed after treatment with EGFR-tyrosine kinase inhibitors (TKI). The relevance between miliary pulmonary metastasis and EGFR mutation has been suggested; therefore, we analyzed the survival in patients with miliary pulmonary metastasis harboring EGFR mutations treated with EGFR-TKI. We retrospectively analyzed 269 patients diagnosed with advanced or recurrent NSCLC treated with EGFR-TKI between 2005 and 2015 identified from the electronic database at our hospital. OS and PFS were estimated using the Kaplan–Meier method. We analyzed the survival in all eligible patients and performed propensity score matching based on clinical characteristics. A total of 215 NSCLC patients harboring EGFR mutations and treated with EGFR-TKIs were included in the study. Patients had a median age of 61 years (38–88 years). With regard to EGFR-TKIs, gefitinib was administered in 167 patients (77.7%), erlotinib in 30 (14.0%), and afatinib in 1 (0.5%). PFS for EGFR-TKI was 12.5 months [95% confidence interval (CI) 9.6–13.8 months) and OS was 23.7 months (95% CI: 20.3–27.2). A total of 31 patients with miliary pulmonary metastasis were identified; propensity matching identified 29 patients from each group with similar clinical characteristics. PFS between miliary pulmonary metastasis and matched control groups was 8.2 months (95% CI, 5.2–5.0) vs. 14.3 months (95% CI, 9.6–30.0) (p = 0.02), and OS was 15.3 months (95% CI, 11.0–20.3 months) vs. 27.9 months (95% CI, 22.0–33.0 months) (p = 0.003). The response rates did not show any significant difference between the two groups. The prognosis of patients with advanced NSCLC harboring EGFR mutations with miliary pulmonary metastasis demonstrated significantly worse outcome compared with those without miliary pulmonary metastasis.

Retrospective study of adjuvant icotinib in postoperative lung cancer patients harboring epidermal growth factor receptor mutations.

BackgroundEpidermal growth factor receptor (EGFR) mutations occur in about 50% of Asian patients with non‐small cell lung cancer (NSCLC). Patients with advanced NSCLC and EGFR mutations derive clinical benefit from treatment with EGFR‐tyrosine kinase inhibitors (TKIs). This study assessed the efficacy and safety of adjuvant icotinib without chemotherapy in EGFR‐mutated NSCLC patients undergoing resection of stage IB–IIIA.MethodsOur retrospective study enrolled 20 patients treated with icotinib as adjuvant therapy. Survival factors were evaluated by univariate and Cox regression analysis.ResultsThe median follow‐up time was 30 months (range 24–41). At the data cut‐off, five patients (25%) had recurrence or metastasis and one patient had died of the disease. The two‐year disease‐free survival (DFS) rate was 85%. No recurrence occurred in the high‐risk stage IB subgroup during the follow‐up period. In univariate analysis, the micropapillary pattern had a statistically significant effect on DFS (P = 0.040). Multivariate logistic regression analysis showed that there was no independent predictor. Drug related adverse events (AEs) occurred in nine patients (45.0%). The most common AEs were skin‐related events and diarrhea, but were relatively mild. No grade 3 AEs or occurrences of intolerable toxicity were observed.ConclusionsIcotinib as adjuvant therapy is effective in patients harboring EGFR mutations after complete resection, with an acceptable AE profile. Further trials with larger sample sizes might confirm the efficiency of adjuvant TKI in selected patients.

Histological transformation from non-small cell to small cell lung carcinoma after treatment with epidermal growth factor receptor-tyrosine kinase inhibitor.

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.

DDX3X Induces Primary EGFR-TKI Resistance Based on Intratumor Heterogeneity in Lung Cancer Cells Harboring EGFR-Activating Mutations

The specific mechanisms how lung cancer cells harboring epidermal growth factor receptor (EGFR) activating mutations can survive treatment with EGFR-tyrosine kinase inhibitors (TKIs) until they eventually acquire treatment-resistance genetic mutations are unclear. The phenotypic diversity of cancer cells caused by genetic or epigenetic alterations (intratumor heterogeneity) confers treatment failure and may foster tumor evolution through Darwinian selection. Recently, we found DDX3X as the protein that was preferentially expressed in murine melanoma with cancer stem cell (CSC)-like phenotypes by proteome analysis. In this study, we transfected PC9, human lung cancer cells harboring EGFR exon19 deletion, with cDNA encoding DDX3X and found that DDX3X, an ATP-dependent RNA helicase, induced CSC-like phenotypes and the epithelial-mesenchymal transition (EMT) accompanied with loss of sensitivity to EGFR-TKI. DDX3X expression was associated with upregulation of Sox2 and increase of cancer cells exhibiting CSC-like phenotypes, such as anchorage-independent proliferation, strong expression of CD44, and aldehyde dehydrogenase (ALDH). The EMT with switching from E-cadherin to N-cadherin was also facilitated by DDX3X. Either ligand-independent or ligand-induced EGFR phosphorylation was inhibited in lung cancer cells that strongly expressed DDX3X. Lack of EGFR signal addiction resulted in resistance to EGFR-TKI. Moreover, we found a small nonadherent subpopulation that strongly expressed DDX3X accompanied by the same stem cell-like properties and the EMT in parental PC9 cells. The unique subpopulation lacked EGFR signaling and was highly resistant to EGFR-TKI. In conclusion, our data indicate that DDX3X may play a critical role for inducing phenotypic diversity, and that treatment targeting DDX3X may overcome primary resistance to EGFR-TKI resulting from intratumor heterogeneity.

High EGFR copy number predicts benefits from tyrosine kinase inhibitor treatment for non-small cell lung cancer patients with wild-type EGFR.

BackgroundThis study was designed to determine whether advanced non-small-cell lung cancer (NSCLC) patients with high copy number of epidermal growth factor receptor (EGFR) can benefit from treatment with EGFR-tyrosine kinase inhibitors (TKIs).MethodsEGFR gene copy number was assessed by fluorescence in situ hybridization (FISH) and EGFR mutations was tested using Luminex xTAG technology in 502 TKI-treated NSCLC patients. The association between both biomarkers and clinical benefit from EGFR-TKI were analyzed.ResultsEGFR FISH + and EGFR mutations were significantly associated with higher response rates (37.2% and 43.7%, respectively), superior progression-free survival (PFS) (FISH+, 11.2 months; hazard ratio [HR], 0.51; 95% CI, 0.42 to 0.62; p < 0.001; mutation+, 11.7 months; HR, 0.37; 95% CI, 0.31 to 0.45; p < 0.001) and overall survival (OS) (FISH+, 30.2 months; HR, 0.51; 95% CI, 0.40 to 0.65; p < 0.001; mutation+, 30.2 months; HR, 0.45; 95% CI, 0.36 to 0.58; p < 0.001). In patients with wild-type EGFR, EGFR FISH + correlated with longer PFS than EGFR FISH- status (4.4 months vs. 2.0 months; HR, 0.56; 95% CI, 0.41 to 0.75; p < 0.001), so did amplification (5.0 months vs. 2.0 months; HR, 0.43; 95% CI, 0.24 to 0.76; p = 0.003). However, FISH + had no association with improved PFS in EGFR-mutated patients (HR, 0.77; 95% CI, 0.57 to 1.03; p = 0.076).ConclusionsA combined analysis of EGFR FISH and mutation is an effective predictor of EGFR-TKI therapy. Specifically, a high EGFR copy number may predict benefit from TKIs treatment for NSCLC patients with wild-type EGFR.

EGFRPolymorphism as a Predictor of Clinical Outcome in Advanced Lung Cancer Patients Treated withEGFR-TKI

PurposeMutations in the epidermal growth factor receptor (EGFR) have been confirmed as predictors of the efficacy of treatment with EGFR-tyrosine kinase inhibitors (TKIs). We investigated whether polymorphisms of the EGFR gene were associated with clinical outcomes in non-small cell lung cancer (NSCLC) patients treated with EGFR-TKI.Materials and MethodsA polymorphic dinucleotide repeat in intron 1 [CA simple sequence repeat in intron 1(CA-SSR1)] in intron 1 and single nucleotide polymorphisms (SNP-216) in the promoter region of the EGFR gene were evaluated in 71 NSCLC patients by restriction fragment length polymorphism and DNA sequencing. The relationship between genetic polymorphisms and clinical outcomes of treatment with EGFR-TKIs was evaluated.ResultsSNP-216G/T polymorphisms were associated with the efficacy of EGFR-TKI. The response rate for the SNP-216G/T tended to be higher than that for G/G (62.5% vs. 27.4%, p=0.057). The SNP-216G/T genotype was also associated with longer progression-free survival compared with the GG genotype (16.7 months vs. 5.1 months, p=0.005). However, the length of CA-SSR1 was not associated with the efficacy of EGFR-TKI.ConclusionSNP-216G/T polymorphism was a potential predictor of clinical outcomes in NSCLC patients treated with EGFR-TKI.