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Purpose: This study aimed to investigate whether the quantitative parameters of dual-energy computed tomography (DECT) can predict the effects of chemotherapy in advanced adenocarcinoma based on the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines., Materials and Methods: A total of 90 patients (59 males, 31 females, age 61.4 ± 12.3 (23-85)) with unresectable lung adenocarcinoma (TNM stage IIIB or IV) who underwent DECT before chemotherapy were prospectively included in this study. By comparing baseline studies with the best response achieved during 1 st line chemotherapy, patients were divided into two groups according to RECIST (version 1.1) guidelines as follows; responders (CR or PR) and non-responders (SD or PD). Quantitative measurements were performed on baseline DECT, and a logistic regression model was used to evaluate predictive factors for a response to chemotherapy., Results: Among 90 patients, 38 were categorized as responders, while 52 patients were non-responders. The mean iodine concentration measurements were significantly higher in responders compared with non-responders (1.81 ± 0.51 vs 1.33 ± 0.76 mg/ml, p < 0.001). On multivariate analysis, EGFR mutation (odds ratio (OR): 3.116, 95% confidential interval (CI):1.182-8.213, p = .019) and iodine concentration (OR: 1.112, 95% CI:1.034-1.196, p = .006) were found to be significant for predicting a treatment response., Conclusions: Dual-energy CT using a quantitative analytic method based on iodine concentration measurements can be used to predict the effects of chemotherapy in patients with advanced adenocarcinoma., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Objectives: Cripto-1 (CR-1) plays a critical role in the activation of SMAD, SRC, and epithelial-to-mesenchymal transition (EMT) pathways and has been shown to be prognostic in several cancer types. In addition, we showed that CR-1 renders EGFR-mutated NSCLC cells resistant to EGFR-TKI through the activation of SRC and EMT via miR-205 downregulation. This study aimed to investigate the correlation between expression of CR-1 and miR-205 and prognosis of NSCLC patients with or without EGFR mutations., Materials and Methods: A total of 265 patients with stage I (AJCC 6th edition) radically resected NSCLC were tested for CR-1 expression and EGFR mutations by immunohistochemistry and miR-205 expression via qPCR assay., Results: CR-1 expression was evaluated with immunohistochemistry using a tissue microarray on 265 T1-2N0 surgical NSCLC samples. Of the 265 tumors, 250 (94%) expressed various levels of CR-1. A significant inverse correlation was identified between expression of miR-205 and CR-1. NSCLC patients (T1N0, n = 106) with high CR-1 expression had worse prognosis (shorter recurrence-free survival, p = .045) than those with low CR-1 expression. A similar trend was observed in NSCLC patients with normal preoperative carcinoembryonic antigen (CEA) levels (serum CEA levels <5 ng/ml; n = 179; p = .085); however, no significant correlation was found between CR-1 expression and survival rate in the T2N0 or high CEA groups. In addition, NSCLC patients with low miR-205 expression (n = 126) had poorer prognosis in terms of recurrence than those with high miR-205 expression (n = 127; p = .001)., Conclusion: High CR-1 expression is correlated with poor prognosis in NSCLC with low tumor burden and may be used to select high-risk patients for adjuvant chemotherapy in early NSCLC. Moreover, low miR-205 expression likely related to high CR-1 expression could be a prognostic marker for patients with NSCLC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Although treatment of BRAF V600E-mutant non-small cell lung cancer (NSCLC(V600E)) with GSK2118436 has shown an encouraging efficacy, most patients develop resistance. To investigate the mechanisms of acquired resistance to GSK2118436 in NSCLC(V600E), we established GSK2118436-resistant (GSR) cells by exposing MV522 NSCLC(V600E) to increasing GSK2118436 concentrations. GSR cells displayed activated EGFR-RAS-CRAF signaling with upregulated EGFR ligands and sustained activation of ERK1/2, but not MEK1/2, in the presence of GSK2118436. Treatment of GSR cells with GSK2118436 enhanced EGFR-mediated RAS activity, leading to the formation of BRAF-CRAF dimers and transactivation of CRAF. Interestingly, sustained activation of ERK1/2 was partly dependent on receptor-interacting protein kinase-2 (RIP2) activity, but not on MEK1/2 activity. Combined BRAF and EGFR inhibition blocked reactivation of ERK signaling and improved efficacy in vitro and in vivo Our findings support the evaluation of combined BRAF and EGFR inhibition in NSCLC(V600E) with acquired resistance to BRAF inhibitors. Mol Cancer Ther; 15(7); 1627-36. ©2016 AACR., (©2016 American Association for Cancer Research.)

Objectives: To evaluate whether the selection of first-line chemotherapy based on ERCC1 and RRM1 mRNA expression levels would improve clinical outcomes in advanced non-small cell lung cancer (NSCLC) patients., Materials and Methods: Eligible patients were randomly assigned 1:1 to the experimental and control arms; the experimental arm received gemcitabine/carboplatin (GC) if ERCC1 and RRM1 expression was low, gemcitabine/vinorelbine (GV) if ERCC1 was high and RRM1 was low, docetaxel/carboplatin (DC) if ERCC1 was low and RRM1 was high, and docetaxel/vinorelbine (DV) if both were high. In the control arm, patients received DC., Results: This study was prematurely terminated after the futility analysis of 43 progression-free survival (PFS) events. A total of 55 patients (n = 26 in the experimental arm, n = 29 in the control arm) were evaluable for efficacy and toxicity. Nineteen (73.1%) patients were assigned to receive GC, 0 (0.0%) to GV, 4 (15.4%) to DC, and 3 (11.5%) to DV in the experimental arm. The overall response rates were 42.3 and 48.3% in the experimental and control arms, respectively, which were not statistically different (P = 0.657). The median PFS was 5.2 months in the experimental arm and 5.4 months in the control arm (P = 0.286). The median overall survival was 17.4 months in the experimental arm and 12.6 months in the control arm (P = 0.638). The occurrence of grade 3 or higher neutropenia (69.2 vs. 93.1%, P = 0.035) and febrile neutropenia (3.8 vs. 24.1%, P = 0.054) was more common in the control arm., Conclusion: ERCC1 and RRM1 mRNA expression-based chemotherapy did not improve clinical outcomes in advanced NSCLC (NCT01648517).

RET rearrangement is a newly identified oncogenic mutation in lung adenocarcinoma (LADC). Activity of dovitinib (TKI258), a potent inhibitor of FGFR, VEGFR, and PDGFR, in RET-rearranged LADC has not been reported. The aims of the study are to explore antitumor effects and mechanisms of acquired resistance of dovitinib in RET-rearranged LADC. Using structural modeling and in vitro analysis, we demonstrated that dovitinib induced cell-cycle arrest at G0-G1 phase and apoptosis by selective inhibition of RET kinase activity and ERK1/2 signaling in RET-rearranged LC-2/ad cells. Strong antitumor effect of dovitinib was observed in an LC-2/ad tumor xenograft model. To identify the acquired resistance mechanisms to dovitinib, LC-2/ad cells were exposed to increasing concentrations of dovitinib to generate LC-2/ad DR cells. Gene-set enrichment analysis of gene expression and phosphor-kinase revealed that Src, a central gene in focal adhesion, was activated in LC-2/ad DR cells. Saracatinib, an src kinase inhibitor, suppressed ERK1/2 phosphorylation and growth of LC-2/ad DR cells. Taken together, these findings suggest that dovitinib can be a potential therapeutic option for RET-rearranged LADC, in which acquired resistance to dovitinib can be overcome by targeting Src., (©2015 American Association for Cancer Research.)

Objectives: Fibroblast growth factor receptor 1 (FGFR1) plays a critical role in many human cancers. We tried to identify the frequency of FGFR1 amplifications among Korean patients with small cell lung cancer (SCLC). Additionally, we examined the clinical significance of FGFR1 amplifications for overall survival (OS) and progression-free survival (PFS) among SCLC patients who received standard chemotherapies., Materials and Methods: Tumor tissues from 158 Korean patients diagnosed with SCLC from September 2009 to February 2013 were collected and analyzed using an FGFR1 FISH assay with a probe that hybridized to chromosome region 8p12-8p11.23 (Abbott Molecular, Abbott Park, IL)., Results and Conclusion: FGFR1 amplification was detected in three patients (1.9%) harboring extensive disease (ED). A multivariate analysis showed that among the patients with ED, FGFR1 amplification was associated with shorter disease-free survival to first-line chemotherapy with etoposide plus cisplatin or carboplatin (hazard ratio [HR]=7.1; 95% confidence interval [CI]=2.0-25.4; P=0.003). The median overall survival time of the patients with ED was 8.2 and 10.2 months among patients with and without FGFR1 amplification, respectively (P=0.37). Although FGFR1 amplification is rare in SCLC compared to non-small cell lung cancer or other malignancies with squamous histology, it is associated with poor survival following standard chemotherapy in SCLC. Further studies in large cohorts of patients with SCLC are needed to verify these results. Our results imply that FGFR1 may be a potential therapeutic target in SCLC and it could be confirmed in a clinical trial., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

The majority of non-small cell lung cancer (NSCLC) patients harbor EGFR-activating mutations that can be therapeutically targeted by EGFR tyrosine kinase inhibitors (EGFR-TKI), such as erlotinib and gefitinib. Unfortunately, a subset of patients with EGFR mutations are refractory to EGFR-TKIs. Resistance to EGFR inhibitors reportedly involves SRC activation and induction of epithelial-to-mesenchymal transition (EMT). Here, we have demonstrated that overexpression of CRIPTO1, an EGF-CFC protein family member, renders EGFR-TKI-sensitive and EGFR-mutated NSCLC cells resistant to erlotinib in culture and in murine xenograft models. Furthermore, tumors from NSCLC patients with EGFR-activating mutations that were intrinsically resistant to EGFR-TKIs expressed higher levels of CRIPTO1 compared with tumors from patients that were sensitive to EGFR-TKIs. Primary NSCLC cells derived from a patient with EGFR-mutated NSCLC that was intrinsically erlotinib resistant were CRIPTO1 positive, but gained erlotinib sensitivity upon loss of CRIPTO1 expression during culture. CRIPTO1 activated SRC and ZEB1 to promote EMT via microRNA-205 (miR-205) downregulation. While miR-205 depletion induced erlotinib resistance, miR-205 overexpression inhibited CRIPTO1-dependent ZEB1 and SRC activation, restoring erlotinib sensitivity. CRIPTO1-induced erlotinib resistance was directly mediated through SRC but not ZEB1; therefore, cotargeting EGFR and SRC synergistically attenuated growth of erlotinib-resistant, CRIPTO1-positive, EGFR-mutated NSCLC cells in vitro and in vivo, suggesting that this combination may overcome intrinsic EGFR-inhibitor resistance in patients with CRIPTO1-positive, EGFR-mutated NSCLC.

Background: We retrospectively compared adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided and empirical chemotherapies for unresectable non-small cell lung cancer (NSCLC) in this case-control study., Patients and Methods: Unresectable NSCLC patients receiving ATP-CRA-guided platinum-based doublets as first-line therapy were enrolled as cases (n=27; 14 platinum-sensitive and 13 platinum-resistant patients). Performance status, stage, and chemotherapeutic regimen-matched patients receiving empirical chemotherapy were selected from the retrospective database as controls (n=93) in a case to control ratio of approximately 1:3., Results: Response rate and survival (progression-free; overall) in both groups were not significantly different. However, the platinum-sensitive subgroup by ATP-CRA showed a higher response rate than the empirical group (71 versus 38%; p=0.023) with a trend toward longer progression-free survival (8.7 versus 4.8 months for platinum-sensitive versus empirical; p=0.223) and overall survival (not reached versus 12.6 months for platinum-sensitive versus empirical for p=0.134)., Conclusion: ATP-CRA may be helpful in selecting platinum-responsive patients in unresectable NSCLC. We consider that nonplatinum doublets in platinum-resistant patients by ATP-CRA may be a more adapted approach than platinum-based doublets in future clinical trials.

Background: A Phase II trial of irinotecan and cisplatin (IP) with early concurrent radiotherapy was performed in limited-disease small-cell lung cancer (LD-SCLC) to evaluate the efficacy and toxicity., Methods: For untreated LD-SCLC patients, irinotecan (60 mg/m2, Days 1, 8, and 15) and cisplatin (40 mg/m2, Days 1 and 8) were repeated every 4 weeks for a maximum of 6 cycles. Thoracic radiotherapy of 1.8 Gy/day was begun on Day 1 of the second chemotherapy cycle, up to a total of 45 to 54 Gy. Prophylactic cranial irradiation (30 Gy in 10 fractions) was performed on patients with a complete response (CR)., Results: Thirty-three LD-SCLC patients were enrolled. The median age was 60 years and 31 patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1. Twelve (36.4%) patients had N3 disease. The response rate was 87.9%, with a CR rate of 45.5%. At a median follow-up period of 27 months the median progression-free survival (PFS) and overall survival (OS) were 14.4 and 26.1 months, respectively, with 2-year PFS and OS rates of 26.8% and 54.9%. The dominating toxicity was neutropenia, with grade 3-5 of 81.8%. The most common grade 3-5 nonhematologic toxicities were diarrhea (21.2%), anorexia (21.2%), and fatigue (21.2%). Grade 3-5 radiation esophagitis and pneumonitis occurred in 18.2% and 9.1% of patients, respectively. There were 2 treatment-related deaths from sepsis and radiation pneumonitis., Conclusions: IP with early concurrent radiotherapy was effective and tolerable in untreated LD-SCLC., (Copyright (c) 2007 American Cancer Society)

Background: The study investigated correlations between adenosine triphosphate / chemotherapy response assay (ATP-CRA) and clinical outcomes after ATP-CRA-guided platinum-based chemotherapy for unresectable nonsmall-cell lung cancer (NSCLC)., Methods: The authors performed an in vitro chemosensitivity test, ATP-CRA, to evaluate the chemosensitivities of anticancer drugs such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, and vinorelbine for chemonaive, unresectable NSCLC. The cell death rate was determined by measuring the intracellular ATP levels of drug-exposed cells compared with untreated controls. A sensitive drug was defined as a drug producing 30% or more reduction in ATP compared with untreated controls. Assay-guided platinum-based 2-drug chemotherapy was given to patients with pathologically confirmed NSCLC., Results: Thirty-four patients were enrolled. Thirty tumor specimens were obtained by bronchoscopic biopsies and 4 obtained surgically. The median age was 61 years and 27 patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. The response rate was 43.8%. At a median follow-up period of 16.9 months, the median progression-free and overall survivals were 3.6 and 11.2 months, respectively. Patients were dichotomized into the platinum-sensitive (S; 20 patients) and resistant (R; 14 patients) groups. The positive/negative predictive values were 61.1% and 78.6% with a predictive accuracy of 68.8%. Although without significant differences in pretreatment parameters, the S-group showed better clinical response (P=.036), longer progression-free survival (P=.060), and longer overall survival (P=.025)., Conclusions: Despite using bronchoscopic biopsied specimens, ATP-CRA and clinical outcomes correlated well after assay-guided platinum-based 2-drug chemotherapy for unresectable NSCLC. There was a favorable response and survival in the platinum-sensitive vs resistant groups., (Copyright (c) 2007 American Cancer Society)

Purpose: Irinotecan plus cisplatin has been previously documented to be effective in the treatment of extensive-disease small cell lung cancer (ED-SCLC). This study was undertaken to investigate the efficacy and feasibility of combination chemotherapy of irinotecan and carboplatin in previously untreated ED-SCLC., Patients and Methods: From December 2002 to October 2005, 39 patients with previously untreated ED-SCLC were enrolled. Patients were treated with irinotecan (50mg/m(2) IV on days 1, 8, and 15) and carboplatin (target AUC=5 IV on day 1) every 4 weeks for up to six cycles., Results: Thirty-four patients (87.2%) were male and the median age was 65 years. ECOG performance status was 0-1 in 20 (51.3%) patients and 2 in 19 (48.7%) patients. The median number of chemotherapy cycles was six (range: 1-6 cycles). Thirty-five patients were assessable for response evaluation. The overall response rate was 69.2% (1 CR, 26 PR) under the intent-to-treat analysis. After a median follow-up of 22.7 months, the median time to progression was 6.4 months (95% confidence interval [CI]: 5.7-7.1 months) and median overall survival was 11.0 months (95% CI: 9.9-12.0 months). The estimated 1-year survival rate was 42.5%. In terms of toxicities, Grade 3/4 neutropenia and thrombocytopenia occurred in eight (25.6%) and five (15.4%) patients, respectively. Grade 3/4 non-hematologic toxicities included diarrhea (10.3%), anorexia (7.7%), infection (10.3%), and neutropenic fever (12.8%). There was one treatment-related death due to superimposed infection on the broncho-pleural fistula., Conclusion: The combination chemotherapy of irinotecan and carboplatin was effective and tolerable in previously untreated ED-SCLC patients.