Comparison of the Predictive Power of a Combination versus Individual Biomarker Testing in Non–Small Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Since tumor mutational burden (TMB) and gene expression profiling (GEP) have complementary effects, they may have improved predictive power when used in combination. Here, we investigated the ability of TMB and GEP to predict the immunotherapy response in patients with non–small cell lung cancer (NSCLC) and assessed if this combination can improve predictive power compared to that when used individually. @*Materials and Methods@#This retrospective cohort study included 30 patients with NSCLC who received immune checkpoint inhibitors (ICI) therapy at the Seoul National University Bundang Hospital. programmed cell death-ligand-1 (PD-L1) protein expression was assessed using immunohistochemistry, and TMB was measured by targeted deep sequencing. Gene expression was determined using NanoString nCounter analysis for the PanCancer IO360 panel, and enrichment analysis were performed. @*Results@#Eleven patients (36.7%) showed a durable clinical benefit (DCB), whereas 19 (63.3%) showed no durable benefit (NDB). TMB and enrichment scores (ES) showed significant differences between the DCB and NDB groups (p=0.044 and p=0.017, respectively); however, no significant correlations were observed among TMB, ES, and PD-L1. ES was the best single biomarker for predicting DCB (area under the curve [AUC], 0.794), followed by TMB (AUC, 0.679) and PD-L1 (AUC, 0.622). TMB and ES showed the highest AUC (0.837) among other combinations (AUC [TMB and PD-L1], 0.777; AUC [PD-L1 and ES], 0.763) and was similar to that of all biomarkers used together (0.832). @*Conclusion@#The combination of TMB and ES may be an effective predictive tool to identify patients with NSCLC patients who would possibly benefit from ICI therapies.

Genetic Alterations in Preinvasive Lung Synchronous Lesions / Journal of the Korean Cancer Association, 대한암학회지

Purpose@#Despite advances in treatment, lung cancer remains the leading cause of cancer mortality. This study aimed to characterise genome-wide tumorigenesis events and to understand the hypothesis of the multistep carcinogenesis of lung adenocarcinoma (LUAD) @*Materials and Methods@#We conducted multiregion whole-exome sequencing of LUAD with synchronous atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ, or minimally invasive adenocarcinoma of 19 samples from three patients to characterize genome-wide tumorigenesis events and validate the hypothesis of the multistep carcinogenesis of LUAD. We identified potential pathogenic mutations preserved in preinvasive lesions and supplemented the finding by allelic variant level from RNA sequencing. @*Results@#Overall, independent mutational profiles were observed per patient and between patients. Some shared mutations including epidermal growth factor receptor (EGFR , p.L858R) were present across synchronous lesions. @*Conclusion@#Here, we show that there are driver gene mutations in AAH, and they may exacerbate as a sequence in a histological continuum, supporting the Darwinian evolution model of cancer genome. The intertumoral and intratumoral heterogeneity of synchronous LUAD implies that multi-biomarker strategies might be necessary for appropriate treatment.

Antineutrophil Cytoplasmic Antibodies Negative Microscopic Polyangiitis With Initial Pulmonary Manifestation

Microscopic polyangiitis (MPA) is a small vessel vasculitides mostly associated with anti-neutrophil cytoplasmic antibodies (ANCA). The kidney is the most commonly affected organ in MPA. We report the case of a 9-year-old girl with ANCA-negative MPA who initially presented with respiratory symptoms, including cough, sputum, and dyspnea. Based on her symptoms, atypical pneumonia was suspected. Also, childhood interstitial lung disease was considered based on findings seen on chest CT. Despite initial improvement of symptoms with oral corticosteroid therapy, dyspnea with initiation of corticosteroid tapering was noted. A final diagnosis of MPA was made after lung biopsy. ANCA was negative in both the initial and repeat blood tests. Oral cyclophosphamide and prednisolone treatments led to full remission. Since then, the patient has been treated with low dose prednisolone and azathioprine for maintenance. A good treatment response was achieved and her clinical symptoms, pulmonary functions, and radiologic findings have since improved. Thus, early and precise diagnosis of MPA is crucial for remission induction and prevention of symptom relapse.

PD-L1 Testing in Non-small Cell Lung Cancer: Past, Present, and Future

Blockade of the programmed cell death-1 (PD-1) axis has already been established as an effective treatment of non-small cell lung cancer. Immunohistochemistry (IHC) for programmed death-ligand 1 (PD-L1) protein is the only available biomarker that can guide treatment with immune checkpoint inhibitors in non-small cell lung cancer. Because each PD-1/PD-L1 blockade was approved together with a specific PD-L1 IHC assay used in the clinical trials, pathologists have been challenged with performing various assays with a limited sample. To provide a more unified understanding of this, several cross-validation studies between platforms have been performed and showed consistent results. However, the interchangeability of assays may be limited in practice because of the risk of misclassification of patients for the treatment. Furthermore, several issues, including the temporal and spatial heterogeneity of PD-L1 expression in the tumor, and the potential for cytology specimens to be used as an alternative to tissue samples for PD-L1 testing, have still not been resolved. In the future, one of the main aims of immunotherapy research should be to find a novel predictive biomarker for PD-1 blockade therapy and a way to combine it with PD-L1 IHC and other tests.

Human Leukocyte Antigen Class I and Programmed Death-Ligand 1 Coexpression Is an Independent Poor Prognostic Factor in Adenocarcinoma of the Lung

BACKGROUND: Both human leukocyte antigen (HLA) class I and programmed death-ligand 1 (PD-L1) molecules are known to play important roles in cancer immunity. In this study, we evaluated HLA class I expression in resected adenocarcinoma of the lung, and investigated its prognostic impact in correlation with PD-L1 expression. METHODS: HLA class I and PD-L1 expression was evaluated by immunohistochemistry in a total of 403 resected lung adenocarcinomas using tissue microarray. Correlations between the expression of HLA class I/PD-L1 and clinicopathologic features and prognostic significance were analyzed. RESULTS: HLA class I expression was reduced in 91.6% of adenocarcinoma, and more frequently reduced in patients with younger age, absence of vascular invasion, and low pathologic stage (p = .033, p = .007, and p = .012, respectively). Positive PD-L1 expression in tumor cells was 16.1% (1% cut-off), and associated with poor differentiation, presence of vascular invasion and nodal metastasis (p < .001, p = .002, and p = .032, respectively). On survival analysis, HLA class I or PD-L1 expression alone did not show any statistical significance. On the integrated analysis, HLA class I (+)/PD-L1 (+) subgroup showed a significantly shorter overall survival than other groups (p = .001). Multivariate analysis revealed that coexpression of HLA class I and PD-L1 was an independent poor prognostic factor of lung adenocarcinoma. (p < .001; hazard ratio, 6.106; 95% confidence interval, 2.260 to 16.501). CONCLUSIONS: Lung adenocarcinoma with coexpression of HLA class I and PD-L1 was associated with poor prognosis. This subgroup may evade immune attack by expressing PD-L1 protein despite HLA expression.

Clinical Significance of Pleural Attachment and Indentation of Subsolid Nodule Lung Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Lung cancers presenting as subsolid nodule commonly have peripheral location, making the cancer-pleura relationship noteworthy. We aimed to evaluate the effect of pleural attachment and/or indentation on visceral pleural invasion (VPI) and recurrence-free survival. MATERIALS AND METHODS: Patients who underwent curative resection of lung cancer as subsolid nodules from April 2007 to January 2016 were retrospectively evaluated. They were divided into four groups according to their relationship with the pleura. Clinical, radiographical, and pathological findings were analyzed. RESULTS: Among 404 patients with malignant subsolid nodule, 120 (29.7%) had neither pleural attachment nor indentation, 26 (6.4%) had attachment only, 117 (29.0%) had indentation only, and 141 (34.9%) had both. VPI was observed in nodules of 36 patients (8.9%), but absent in nonsolid nodules and in those without pleural attachment and/or indentation. Compared to subsolid nodules with concurrent pleural attachment and indentation, those with attachment only (odds ratio, 0.12; 95% confidence interval [CI], 0.02 to 0.98) and indentation only (odds ratio, 0.10; 95% CI, 0.03 to 0.31) revealed lower odds of VPI. On subgroup analysis, the size of the solid portion was associated with VPI among those with pleural attachment and indentation (p=0.021). Such high-risk features for VPI were associated with earlier lung cancer recurrence (adjusted hazard ratio, 3.31; 95% CI, 1.58 to 6.91). CONCLUSION: Concurrent pleural attachment and indentation are risk factors for VPI, and the odds increase with larger solid portion in subsolid nodules. Considering the risk of recurrence, early surgical resection could be encouraged in these patients.

Effect of Platinum-Based Chemotherapy on PD-L1 Expression on Tumor Cells in Non-small Cell Lung Cancer / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Programmed death-1 (PD-1)/PD-1 ligand (PD-L1) axis blockades have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC). We assessed the effect of platinum-based chemotherapy on tumor PD-L1 expression and its clinical implications. MATERIALS AND METHODS: We used immunohistochemistry to retrospectively evaluate the percentage of tumor cells with membranous PD-L1 staining (tumor proportion score) in paired tumor specimens obtained before and after platinum-based neoadjuvant chemotherapy (NACT) in 86 patients with NSCLC. We analyzed the correlation between the change in PD-L1 tumor proportion score and clinicopathologic characteristics, response to NACT, and survival. RESULTS: The PD-L1 tumor proportion score increased in a significant proportion of patients with NSCLC after platinum-based NACT (Wilcoxon signed-rank test, p=0.002). That pattern was consistent across clinically defined subgroups except for patients with partial response to NACT. Tumors from 26 patients (30.2%) were PD-L1‒negative before NACT but PD-L1-positive after NACT, whereas the reverse pattern occurred in six patients (7%) (McNemar’s test, p < 0.001). Increase in PD-L1 tumor proportion score was significantly associated with lack of response to NACT (Fisher exact test, p=0.015). There was a tendency, albeit not statistically significant, for patients with an increase in PD-L1 tumor proportion score to have shorter survival. CONCLUSION: Tumor PD-L1 expression increased after platinum-based NACT in a significant proportion of patients with NSCLC. Increase in tumor PD-L1 expression may predict poor clinical outcome.

Osteosarcomatous Differentiation in Rebiopsy Specimens of Pulmonary Adenocarcinoma with EGFR-TKI Resistance

No abstract available.

Efficacy of Pemetrexed-based Chemotherapy in Comparison to Non-Pemetrexed-based Chemotherapy in Advanced, ALK+ Non-Small Cell Lung Cancer

PURPOSE: Previous retrospective studies suggest that anaplastic lymphoma kinase (ALK) mutation-positive (ALK+) non-small cell lung cancer (NSCLC) patients are sensitive to pemetrexed. To determine its efficacy, we retrospectively evaluated clinical outcomes of pemetrexed-based chemotherapy in patients with ALK+ NSCLC. MATERIALS AND METHODS: We identified 126 patients with advanced, ALK+ NSCLC who received first-line cytotoxic chemotherapy. We compared response, progression-free survival (PFS), and overall survival (OS) rates according to chemotherapy regimens. Furthermore, we evaluated intracranial time to tumor progression (TTP) and proportion of ALK+ cells as prognostic factors. RESULTS: Forty-eight patients received pemetrexed-based chemotherapy, while 78 received other regimens as first-line treatment. The pemetrexed-based chemotherapy group showed superior overall response (44.7% vs. 14.3%, p < 0.001) and disease control (85.1% vs. 62.3%, p=0.008) rates. The pemetrexed-based chemotherapy group also exhibited longer PFS (6.6 months vs. 3.8 months, p < 0.001); OS rates were not significantly different. The lack of exposure to second-generation ALK inhibitors and intracranial metastasis on initial diagnosis were independent negative prognostic factors of OS. Intracranial TTP was similar between the treatment groups (32.7 months vs. 35.7 months, p=0.733). Patients who harbored a greater number of ALK+ tumor cells (≥70%) showed prolonged OS on univariate analysis (not reached vs. 44.8 months, p=0.041), but not on multivariate analysis (hazard ratio: 0.19, 95% confidence interval: 0.03–1.42; p=0.106). CONCLUSION: Pemetrexed-based regimens may prolong PFS in patients with ALK+ NSCLC as a first-line treatment, but are not associated with prolonged OS. Exposure to second-generation ALK inhibitors may improve OS rates in patients with ALK+ NSCLC.

Molecular Testing of Lung Cancers

Targeted therapies guided by molecular diagnostics have become a standard treatment of lung cancer. Epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements are currently used as the best predictive biomarkers for EGFR tyrosine kinase inhibitors and ALK inhibitors, respectively. Besides EGFR and ALK, the list of druggable genetic alterations has been growing, including ROS1 rearrangements, RET rearrangements, and MET alterations. In this situation, pathologists should carefully manage clinical samples for molecular testing and should do their best to quickly and accurately identify patients who will benefit from precision therapeutics. Here, we grouped molecular biomarkers of lung cancers into three categories—mutations, gene rearrangements, and amplifications—and propose expanded guidelines on molecular testing of lung cancers.

Curative Resection for Metachronous Pulmonary Metastases from Colorectal Cancer: Analysis of Survival Rates and Prognostic Factors / Journal of the Korean Cancer Association, 대한암학회지

PURPOSE: Prognostic factors in patients with pulmonary metastases (PM) from colorectal cancer (CRC) are still controversial. This study assessed oncologic outcomes and prognostic factors in patients with metachronous PM from CRC. MATERIALS AND METHODS: Between June 2003 and December 2011, 122 patients with CRC underwent curative resection of PM detected at least 4 months after CRC resection. Clinico-pathological factors selected from the prospectively maintained database were analyzed retrospectively. RESULTS: The median disease-free interval (DFI) between resection of the primary tumor and detection of PM was 22.0 months (range, 4 to 85 months). Solitary PM were detected in 77 patients (63.1%), with a median maximal tumor diameter of 12.0 mm (range, 2 to 70 mm). Of 52 patients who underwent mediastinal lymph node (LN) dissection, eight patients had LN involvement. Five-year overall survival and disease-free survival (DFS) rates after initial pulmonary metastasectomy were 66.4% and 50.9%, respectively. DFI, mediastinal LN involvement, and the number and distribution of PM were significantly prognostic factors for DFS. In multivariable analysis DFI ≥ 12 months, solitary lesion, and absence of mediastinal LN involvement were independently prognostic for DFS. Of the 122 patients, 48 patients (39.3%) developed recurrent PM a median 13.0 months after initial pulmonary metastasectomy. Recurrent DFI was independently prognostic of DFS in patients who underwent repeated pulmonary metastasectomy. CONCLUSION: There is a potential survival benefit for patients with metachronous PM from CRC who undergo pulmonary metastasectomy, even those with recurrent PM. Pulmonary metastasectomy should be considered in selected patients, particularly those with longer DFI, solitary lesions, and absence of mediastinal LN involvement.

Aquaporin 1 Is an Independent Marker of Poor Prognosis in Lung Adenocarcinoma

BACKGROUND: Aquaporin 1 (AQP1) overexpression has been shown to be associated with uncontrolled cell replication, invasion, migration, and tumor metastasis. We aimed to evaluate AQP1 expression in lung adenocarcinomas and to examine its association with clinicopathological features and prognostic significance. We also investigated the association between AQP1 overexpression and epithelial-mesenchymal transition (EMT) markers. METHODS: We examined AQP1 expression in 505 cases of surgically resected lung adenocarcinomas acquired at the Seoul National University Bundang Hospital from 2003 to 2012. Expression of AQP1 and EMT-related markers, including Ecadherin and vimentin, were analyzed by immunohistochemistry and tissue microarray. RESULTS: AQP1 overexpression was associated with several aggressive pathological parameters, including venous invasion, lymphatic invasion, and tumor recurrence. AQP1 overexpression tended to be associated with higher histological grade, advanced pathological stage, and anaplastic lymphoma kinase (ALK) translocation; however, these differences were not statistically significant. In addition, AQP1 overexpression positively correlated with loss of E-cadherin expression and acquired expression of vimentin. Lung adenocarcinoma patients with AQP1 overexpression showed shorter progression-free survival (PFS, 46.1 months vs. 56.2 months) compared to patients without AQP1 overexpression. Multivariate analysis confirmed that AQP1 overexpression was significantly associated with shorter PFS (hazard ratio, 1.429; 95% confidence interval, 1.033 to 1.977; p=.031). CONCLUSIONS: AQP1 overexpression was thereby concluded to be an independent factor of poor prognosis associated with shorter PFS in lung adenocarcinoma. These results suggested that AQP1 overexpression might be considered as a prognostic biomarker of lung adenocarcinoma.

A Rare Case of Primary Tubular Adenocarcinoma of the Thymus, Enteric Immunophenotype: A Case Study and Review of the Literature

Thymic carcinomas are uncommon malignant tumors, and thymic adenocarcinomas are extremely rare. Here, we describe a case of primary thymic adenocarcinoma in a 59-year-old woman. Histological examination of the tumor revealed tubular morphology with expression of cytokeratin 20 and caudal-type homeobox 2 according to immunohistochemistry, suggesting enteric features. Extensive clinical and radiological studies excluded the possibility of an extrathymic primary tumor. A review of the literature revealed only two global cases of primary tubular adenocarcinomas of the thymus with enteric immunophenotype.

Membranous Insulin-like Growth Factor-1 Receptor (IGF1R) Expression Is Predictive of Poor Prognosis in Patients with Epidermal Growth Factor Receptor (EGFR)-Mutant Lung Adenocarcinoma

BACKGROUND: Insulin-like growth factor-1 receptor (IGF1R) is a membrane receptor-type tyrosine kinase that has attracted considerable attention as a potential therapeutic target, although its clinical significance in non-small cell lung cancer (NSCLC) is controversial. This study aimed to clarify the clinical significance of IGF1R expression in human NSCLC. METHODS: IGF1R protein expression was evaluated using immunohistochemistry in 372 patients with NSCLC who underwent curative surgical resection (146 squamous cell carcinomas [SqCCs] and 226 adenocarcinomas [ADCs]). We then analyzed correlations between expression of IGF1R and clinicopathological and molecular features and prognostic significance. RESULTS: Membranous and cytoplasmic IGF1R expression were significantly higher in SqCCs than in ADCs. In patients with SqCC, membranous IGF1R expression was associated with absence of vascular, lymphatic, and perineural invasion; lower stage; and better progression-free survival (PFS) (hazard ratio [HR], 0.586; p = .040). In patients with ADC, IGF1R expression did not have a significant prognostic value; however, in the subgroup of epidermal growth factor receptor (EGFR)-mutant ADC, membranous IGF1R expression was associated with lymphatic and perineural invasion, solid predominant histology, and higher cancer stage and was significantly associated with worse PFS (HR, 2.582; p = .009). CONCLUSIONS: Lung ADC and SqCC showed distinct IGF1R expression profiles that demonstrated prognostic significance. High membranous IGF1R expression was predictive of poor PFS in EGFR-mutant lung ADC, while it was predictive of better PFS in SqCC. These findings will help improve study design for subsequent investigations and select patients for future anti-IGF1R therapy.

Guideline Recommendations for Testing of ALK Gene Rearrangement in Lung Cancer: A Proposal of the Korean Cardiopulmonary Pathology Study Group

Rearrangement of anaplastic lymphoma kinase (ALK) gene is the best predictor of response to crizotinib, an ALK tyrosine kinase inhibitor. However, the prevalence of the ALK fusion is low, so accurate patient identification is crucial for successful treatment using ALK inhibitors. Furthermore, most patients with lung cancer present with advanced-stage disease at the time of diagnosis, so it is important for pathologists to detect ALK-rearranged patients while effectively maximizing small biopsy or cytology specimens. In this review, we propose a guideline recommendation for ALK testing approved by the Cardiopulmonary Pathology Study Group of the Korean Society of Pathologists.

In Reply: IgG4 Related Disease and Sensorineural Hearing Loss

No abstract available.

Current Issues in Lung Cancer Pathology / 한양의대학술지

Lung cancer is characterized by accumulation of oncogene activation, inactivation of tumor suppressor genes and alteration of epigenetic changes. Fortunately, the past decade has seen remarkable development in molecular pathogenesis and management of lung cancer, especially adenocarcinoma. The discovery of the biologic and therapeutic importance of acquired genetic alterations in 2 genes that encode pharmacologically targetable tyrosine kinases involved in growth factor receptor signaling, epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), has raised hope that targeted therapy will improve survival and quality of life of patients with lung cancer. Therefore, molecular testing to detect these 2 mutated genes is more important than ever and has changed the management of the patients with lung cancer and the role of pathologists. Furthermore, as most lung cancer patients present with advanced-stage disease at the time of diagnosis, it is important to detect targetable mutations using small tissue samples or cytology specimens. Here, the author summarizes the practical impact of the molecular testing of lung cancer and introduces the current knowledge of lung cancer pathology.

Heterotopic Pancreas in Omphalomesenteric Duct Remnant Results in Persistent Umbilical Discharge

No abstract available.

The Correlations of Parameters Using Contrast Enhanced Ultrasonography in the Evaluation of Prostate Cancer Angiogenesis

PURPOSE: The purpose of this study is to investigate the correlations of various kinetic parameters derived from the time intensity curve in a xenograft mouse model injected with a prostate cancer model (PC-3 and LNCaP) using an ultrasound contrast agent with histopathologic parameters. MATERIALS AND METHODS: Twenty nude mice were injected with human prostate cancer cells (15 PC-3 and five LNCaP) on their hind limbs. A bolus of 500 microL (1 x 10(8) microbubbles) of second-generation US contrast agent (SonoVue) was injected into the retroorbital vein. The region of interest was drawn over the entire tumor. The time intensity curve was acquired and then fitted to a gamma variate function. The maximal intensity (A), time to peak (Tp), maximal wash-in rate (washin), washout rate (washout), area under the curve up to 50 sec (AUC50), area under the ascending slope (AUC(in)), and area under the descending slope (AUC(out)) were derived from the parameters of the gamma variate fit. Immunohistochemical staining for VEGF and CD31 was performed. Tumor volume, the area percentage of VEGF stained in a field, and the count of CD31 (microvessel density, MVD) positive vessels showed correlation with the parameters from the time intensity curve. RESULTS: No significant differences were observed between the kinetic and histopathological parameters from each group. MVD showed positive correlation with A (r=0.625, p=0.003), washin (r=0.462, p=0.040), AUC50 (r=0.604, p=0.005), and AUC(out) (r=0.587, p=0.007). Positive correlations were also observed between tumor volume and AUC50 (r=0.481, p=0.032), washin (r=0.662, p=0.001), and AUC(out) (r=0.547, p=0.012). Washout showed negative correlations with MVD (r=-0.454, p=0.044) and tumor volume (r=-0.464, p=0.039). The area percentage of VEGF did not show any correlation with calculated data from the curve. CONCLUSION: MVD showed correlations with several of the kinetic parameters. CE-US has the potential for prediction of tumor vascularity in a prostate cancer animal model.

Neuroendocrine Differentiation in Acquired Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor / 결핵및호흡기질환

BACKGROUND: Small cell lung cancer (SCLC) transformation during epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in lung cancer has been suggested as one of possible resistance mechanisms. METHODS: We evaluated whether SCLC transformation or neuroendocrine (NE) differentiation can be found in the cell line model. In addition, we also investigated its effect on responses to conventional chemotherapeutic drugs of the SCLC treatment. RESULTS: Resistant cell lines to various kinds of EGFR-TKIs such as gefitinib, erlotinib, CL-387,785 and ZD6474 with A549, PC-9 and HCC827 lung adenocarcinoma cell lines were established. Among them, two resistant cell lines, A549/GR (resistant to gefitinib) and PC-9/ZDR (resistant to ZD6474) showed increased expressions of CD56 while increased synaptophysin, Rb, p16 and poly(ADP-ribose) polymerase were found only in A549/GR in western blotting, suggesting that NE differentiation occurred in A549/GR. A549/GR cells were more sensitive to etoposide and cisplatin, chemotherapeutic drugs for SCLC, compared to parental cells. Treatment with cAMP and IBMX induced synaptophysin and chromogranin A expression in A549 cells, which also made them more sensitive to etoposide and cisplatin than parental cells. Furthermore, we found a tissue sample from a patient which showed increased expressions of CD56 and synaptophysin after development of resistance to erlotinib. CONCLUSION: NE differentiation can occur during acquisition of resistance to EGFR-TKI, leading to increased chemosensitivity.