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• HER2 forms heterodimers with EGFR in cell lines without HER2 amplification. • HER2-EGFR heterodimers are abundant in cell lines with EGFR mutations. • HER2 is rapidly internalized as a result of its heterodimerization with EGFR. • HER2 is efficiently transferred to lysosomes in cells with EGFR mutations. • T-DM1 shows high cytotoxic efficacy in cells with EGFR mutations. Human epidermal growth factor receptor 2 (HER2) forms homodimers and is retained at the surface of cancer cells positive for HER2 amplification. The dimerization, internalization, and intracellular trafficking of HER2 in cancer cells without HER2 amplification have remained uncharacterized, however. HER2 homodimers and heterodimers were detected in various cell lines with the use of an in situ proximity ligation assay. The effects of wild-type or mutant forms of epidermal growth factor receptor (EGFR) on intracellular trafficking of HER2 were examined by live-cell imaging. The sensitivity of cell lines without HER2 amplification to ado-trastuzumab emtansine (T-DM1), an anti-HER2 (trastuzumab)–cytotoxic drug conjugate (ADC) was also investigated. HER2 preferentially formed heterodimers with EGFR rather than homodimers and was rapidly internalized together with EGFR in cells without HER2 amplification. HER2-EGFR heterodimers were more abundant and HER2 was more efficiently transferred to lysosomes in such cells with than in those without EGFR activating mutations. T-DM1 showed a high cytotoxic efficacy in the cells with EGFR mutations, suggesting that mutant forms of EGFR promote the transfer of HER2-bound T-DM1 to lysosomes through efficient formation of HER2-EGFR heterodimers. Our findings reveal that HER2 trafficking is affected by EGFR, especially by mutant forms of the receptor, and they provide a rationale for the use of HER2-targeting ADCs in the treatment of EGFR -mutated lung cancer. [ABSTRACT FROM AUTHOR]

Summary: Lung cancer is a major cause of cancer-related death in the developed countries and the overall survival rate has still an extremely poor. Although cigarette smoking is the main cause of lung cancer, not all smokers develop lung cancer, and a fraction of lifelong non-smokers will die from lung cancer. Genetic host factors have recently been implicated to account for some of the observed differences in lung cancer susceptibility. Various DNA alterations can be caused by exposure to environmental and endogenous carcinogens. Most of these alterations, if not repaired, may result in genetic instability, mutagenesis and cell death. DNA repair mechanisms are important for maintaining DNA integrity and preventing carcinogenesis. Recent genetic association studies on lung cancer risk have focused on identifying effects of single nucleotide polymorphisms (SNPs) in candidate genes, among which DNA repair genes are increasingly studied. Genetic variations in DNA repair genes are thought to modulate DNA repair capacity and are suggested to be related to lung cancer risk. We identified a sufficient number of epidemiologic studies on lung cancer to conduct a meta-analysis for genetic polymorphisms in nucleotide base repair (BER) pathway, focusing on 8-oxoguanine DNA glycosylase 1, X-ray cross-complementing group 1 (XRCC1) and apurinic/apyrimidinic endonuclease 1. The 399Gln/Gln genotype of the XRCC1 Arg399Gln polymorphism was associated with an increased risk of lung cancer among Asians (OR=1.34, 95% CI=1.16–1.54) but not among Caucasians. Little evidence of associations has been found between other BER genes and lung cancer risk. Considering the data available, it can be conjectured that if there is any risk association between single SNP and lung cancer, this risk increase/decrease will probably be minimal. Advances in identification of new polymorphisms and in high-throughput genotyping techniques will facilitate analysis of multiple genes in multiple DNA repair pathways. Therefore, it is likely that the defining feature of future epidemiologic studies will be the simultaneous analysis of large samples of cases and controls. [Copyright &y& Elsevier]

• In situ proximity ligation assay was applied to detect Her1 homo- and heterodimers. • Dimers were detected in non–small cell lung cancer (NSCLC) cell lines and tumors. • EGFR inhibitor treatment depleted homodimers more than heterodimers in NSCLC cells. • NSCLC patients with a high hetero-/homodimer ratio had a poor outcome on osimertinib. The epidermal growth factor receptor (EGFR, also known as Her1) is a member of the human epidermal growth factor receptor (HER) family of proteins and a target of tyrosine kinase inhibitors (TKIs) in the treatment of non–small cell lung cancer (NSCLC) positive for activating mutations of EGFR. Signal transduction by HER family proteins is dependent on their homo- or heterodimerization, but little is known of the relation between the relative proportions of such dimers of Her1 and sensitivity to EGFR-TKIs. We here investigated the feasibility of assessing this relation with the in situ proximity ligation assay (PLA) technique, which is able to detect the interaction of two proteins of interest when they are in close proximity. In situ PLA was applied to detect Her1 homodimers and Her1 heterodimers in NSCLC cell lines and tissue specimens positive for EGFR activating mutations. In situ PLA allowed visualization and quantitative assessment of Her1 homodimers as well as of Her1 heterodimers with Her2, Her3, or Her4 not only in NSCLC cell lines but also in NSCLC tissue specimens obtained from various anatomic sites and by different collection methods. Treatment of NSCLC cell lines with EGFR-TKIs resulted in a decrease in the number of Her1 dimers, with the effect on homodimers being greater than that on heterodimers. A high ratio of Her1 heterodimers to homodimers was associated with poor progression-free survival in NSCLC patients treated with osimertinib. In situ PLA allows the detection of HER family dimers in NSCLC tissue, and quantitative assessment of Her1 homo- and heterodimers may prove informative for prediction of the response of NSCLC patients to EGFR-TKI treatment. [ABSTRACT FROM AUTHOR]

• Cytotoxic chemotherapy and EGFR-TKI osimertinib induced prominent cell surface expression of CRT (ecto-CRT) in six NSCLC cell lines. • Systemic anticancer therapies-triggered ecto-CRT expression in NSCLC cells was positively correlated with extent of apoptosis. • Increased plasma levels of soluble CRT in advanced NSCLC patients treated with systemic anticancer therapies may serve as an indicator of ICD. Synergistic anticancer efficacy of combination treatment with immune checkpoint inhibitors (ICIs) and platinum-based chemotherapy in patients with advanced non–small cell lung cancer (NSCLC) may be attributable in part to the phenomenon of immunogenic cell death (ICD), which is characterized by the release of damage-associated molecular patterns (DAMPs) from dying tumor cells. The ability of cytotoxic chemotherapeutic agents and molecularly targeted drugs such as epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) to induce DAMPs during the treatment of NSCLC has remained unclear, however. We investigated the ability of seven cytotoxic chemotherapeutic agents and the third-generation EGFR-TKI osimertinib to induce translocation of the DAMP calreticulin to the cell surface in multiple NSCLC cell lines. The plasma concentration of soluble CRT in advanced NSCLC patients treated with cytotoxic chemotherapy or osimertinib was measured. Antimetabolites and microtubule inhibitors induced expression of CRT at the cell surface (ecto-CRT) to a greater extent than did platinum agents in six NSCLC cell lines, exhibiting higher up-regulation of phosphorylation of eukaryotic initiation factor-2α (eIF2α). Ecto-CRT expression was positively correlated with apoptosis induction in NSCLC cells treated with these various chemotherapeutic agents. The drug-induced up-regulation of ecto-CRT in NSCLC cells was attenuated by the pan-caspase inhibitor Z-VAD-FMK. Osimertinib similarly increased ecto-CRT expression in association with apoptosis induction in five EGFR -mutated NSCLC cell lines. Furthermore, the plasma concentration of soluble CRT in 16 NSCLC patients treated with single-agent pemetrexed or docetaxel and in nine EGFR -mutated NSCLC patients treated with osimertinib was increased after treatment onset. Our findings indicate that antimetabolites, microtubule inhibitors, and osimertinib are effective inducers both of CRT exposure in NSCLC cell lines and of soluble CRT release in patients with advanced NSCLC, suggesting that these agents might prove effective for promotion of antitumor immunity in combination immunotherapy. [ABSTRACT FROM AUTHOR]

• We performed IHC analysis of ASCL1 and NEUROD1 expression in SCLC clinical samples. • The expression pattern of ASCL1 and NEUROD1 differs between LD- and ED-SCLC. • NEUROD1 expression is higher in ED-SCLC than that in LD-SCLC. • NEUROD1 promotes the migration of SCLC cells in vitro. • NEUROD1 might thus contribute to metastasis in ED-SCLC. Small cell lung cancer (SCLC) manifests high-grade neuroendocrine features, and the transcription factors ASCL1 and NEUROD1 play an important role in the survival and growth as well as contribute to the heterogeneity of SCLC cells. The relative abundance of ASCL1 and NEUROD1 mRNAs differs among human SCLC cell lines, but the expression pattern of the encoded proteins in clinical SCLC specimens and its relation to clinicopathologic characteristics of patients have been unclear. We retrospectively analyzed tumor specimens collected from 95 previously untreated SCLC patients between June 1988 and December 2017 for ASCL1 and NEUROD1 expression by immunohistochemical staining. We also examined the effects of overexpression or depletion of NEUROD1 on cell migration in SCLC cell lines. Overall survival did not differ significantly between SCLC patients with a high or low expression score for ASCL1 or NEUROD1 in their tumor samples. The staining score for NEUROD1 was significantly higher in extensive-disease (ED) samples than in limited-disease (LD) samples (median of 160 versus 80 out of a maximum of 300, P = 0.0389), and the proportion of tumors with an ASCL1highNEUROD1low phenotype was smaller for ED-SCLC. Overexpression or depletion of NEUROD1 in SCLC cell lines promoted or attenuated cell migratory activity, respectively. Our clinical and experimental data indicate that the expression of NEUROD1 is increased in ED-SCLC and promotes the migration of SCLC cells. NEUROD1 might thus contribute to metastasis in ED-SCLC. [ABSTRACT FROM AUTHOR]

• dNLR is a novel serum inflammatory marker. • dNLR is calculated from white blood cell concentration and neutrophil count. • dNLR was associated with treatment response in NSCLC treated with anti-PD-1 drugs. • dNLR was an independent prognostic factor in NSCLC treated with anti-PD-1 drugs. • dNLR might be the most important factor for the efficacy of anti-PD-1 therapy. Several serum markers have been associated with treatment response and clinical outcome in non-small cell lung cancer (NSCLC) patients treated with immune checkpoint inhibitors. We performed univariate and multivariate analyses on 226 patients with advanced or recurrent NSCLC treated with anti-programmed cell death-1 (PD-1) therapy. The cut-off values for body mass index (BMI), albumin (Alb), and serum inflammatory markers were determined by receiver operating characteristic curve analyses. Tumor response was assessed by computed tomography according to the Response Evaluation Criteria in Solid Tumors, version 1.1. BMI ≥ 19.1 kg/m2 and derived neutrophil-lymphocyte ratio (dNLR) < 2.79 were independent predictors of overall response, and Alb ≥ 3.5 g/dL and dNLR < 2.79 were independent predictors of disease control. Analyses of survival revealed that Alb < 3.5 g/dL, dNLR ≥ 2.79, lymphocyte-monocyte ratio < 2.12, and red blood cell distribution width ≥ 15.9 % were independent predictors of both progression-free and overall survival. Moreover, these markers tended to have a strong impact on survival, especially among patients with programmed cell death-ligand 1 tumor proportion score ≥ 50 %. dNLR might be the most important factor for predicting the efficacy in NSCLC patients treated with anti-PD-1 therapy. [ABSTRACT FROM AUTHOR]

• We performed a study to observe patients developing PE under αPD-1 therapy. • Some of patients could receive clinical benefit by continuing αPD-1 therapy. • αPD-1 therapy upregulated immune checkpoint proteins on T lymphocytes in PE. • Analyses of T lymphocytes in PE may predict response to αPD-1 therapy. Pleural effusion (PE) occasionally develops in cancer patients during treatment with antibodies to programmed cell death–1 (PD-1) or to its ligand PD-L1 (hereafter, αPD-1 therapy). Such effusion often contains infiltrated mononuclear cells, although the types of immune cell present as well as the outcome of such patients have remained unclear. We performed a multi-institutional, observational study to examine the clinical outcome of patients who develop PE after the onset of αPD-1 therapy. We compared the immune cell profiles and the immune status of lymphocytes in PE as determined by flow cytometry between nine patients who developed effusion during αPD-1 therapy (αPD-1 group) and 15 patients who developed PE during treatment with other anticancer agents (control group). Most mononuclear cells in PE were lymphocytes in both the αPD-1 and control groups. The frequency of both CD4+ and CD8+ T lymphocytes expressing the immune checkpoint proteins TIM-3 or TIGIT as well as that of CD8+ T lymphocytes expressing PD-L1 were increased in the αPD-1 group compared with the control group. αPD-1 therapy continued for a substantial period after the emergence of PE in six of the nine patients in the αPD-1 group, and the frequency of CD4+ T lymphocytes in PE expressing the immune checkpoint protein LAG-3 or the cytokine interkeukin-17 was lower for these patients than for those who did not receive a sustained treatment benefit. Our results suggest a clinical benefit of continuing αPD-1 therapy in some patients who develop PE. We found that infiltrating T lymphocytes in PE manifest a more exhausted phenotype during αPD-1 therapy than during treatment with other cancer drugs, with subpopulations of these cells characterized by specific immune checkpoint protein and cytokine expression profiles possibly contributing to the antitumor immune response. [ABSTRACT FROM AUTHOR]

Highlights • Whether antinuclear antibodies (ANA) affect PD-1 inhibitor treatment is unclear. • We examined the safety and efficacy of such treatment in NSCLC patients with ANA. • Immune-related adverse events did not differ between patients with or without ANA. • Progression-free and overall survival were shorter in patients positive for ANA. Abstract Objectives To examine the possible effects of antinuclear antibodies (ANA) on the safety and efficacy of programmed cell death–1 (PD-1) inhibitors in patients with advanced non–small cell lung cancer (NSCLC). Patients and methods Clinical data including ANA status were reviewed retrospectively for patients with advanced NSCLC who received monotherapy with a PD-1 inhibitor. Results Of the 83 patients analyzed, 18 (21.7%) were positive for ANA. The incidence of immune-related adverse events (irAEs) did not differ significantly between patients with ANA (6/18, 33.3%) and those negative for ANA (21/65, 32.3%), although it tended to increase as the ANA titer increased. Progression-free survival (2.9 versus 3.8 months, p = 0.03) and overall survival (11.6 versus 15.8 months, p = 0.03) were significantly shorter in patients positive for ANA than in those without ANA. Conclusion PD-1 inhibitors can be administered safely in advanced NSCLC patients positive for ANA without obvious exacerbation of autoimmune disease, although patients with a high titer of such antibodies may warrant close monitoring. However, the presence of ANA might be associated with a poor outcome of such treatment. [ABSTRACT FROM AUTHOR]

Highlights • Platinum-etoposide toxicity was associated with UGT1A1 polymorphisms in SCLC patients. • Etoposide-induced nephrotoxicity was significantly associated with such polymorphisms. • Reduced etoposide glucuronidation activity of UGT1A1 variants may cause nephrotoxicity. Abstract Objectives Etoposide is a key agent in the treatment of small cell lung cancer (SCLC). Uridine diphosphate (UDP)–glucuronosyltransferase 1A1 (UGT1A1) is thought to be largely responsible for the glucuronidation of etoposide as well as that of irinotecan, suggesting that polymorphisms of UGT1A1 might be predictive of etoposide toxicity. We therefore examined the relation between UGT1A1 polymorphisms and toxicity profile during platinum-etoposide doublet therapy in SCLC patients. Materials and Methods SCLC patients who underwent platinum-etoposide doublet therapy and molecular testing for UGT1A1 genotype were reviewed for the occurrence of adverse events during treatment. Results A total of 41 SCLC patients received platinum-etoposide doublet therapy and were genotyped for UGT1A1*6 and UGT1A1*28 alleles. These alleles were detected in 15 (36.6%) patients, with the genotypes of *6/– , *6/*6 , *28/– , *28/*28 , or *6/*28 being observed in 9 (22.0%), 2 (4.9%), 2 (4.9%), 1 (2.4%), and 1 (2.4%) patients, respectively. The presence of these alleles was significantly associated with an increase in serum creatinine concentration of grade ≥2 (incidence of 66.7% for patients with the alleles versus 11.5% for those without, P < 0.001). Multivariate analysis also showed that these UGT1A1 alleles were significantly associated with therapy-induced nephrotoxicity (odds ratio of 19.30, 95% confidence interval of 2.50–149.00, P < 0.005). Although the differences did not achieve statistical significance, the incidence of other severe toxicities including febrile neutropenia was also slightly higher in patients with the UGT1A1*6 or UGT1A1*28 alleles than in those without them. Conclusion Our results reveal an association between UGT1A1 polymorphisms and toxicity of platinum-etoposide doublet therapy in SCLC patients, suggesting that close monitoring for toxicity, especially nephrotoxicity, is warranted for patients with such variant alleles receiving this treatment. [ABSTRACT FROM AUTHOR]

Highlights • Nab-paclitaxel at 50 mg/m2 in concurrent phase was determined to be the RD. • Common toxicities of grade 3 or 4 in concurrent phase was leukopenia and neutropenia. • The ORR was 76.8% and mPFS was 11.8 months in 56 patients treated at the RD. • Our results reveal encouraging feasibility and activity for this regimen. Abstract Objectives Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non–small cell lung cancer (NSCLC). Patients and methods In a phase I study, escalating doses of weekly nab-paclitaxel (40 or 50 mg/m2) were administered along with weekly carboplatin at an area under the curve (AUC) of 2 mg mL–1 min and concurrent radiotherapy with 60 Gy in 30 fractions to patients with locally advanced NSCLC. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. In a phase II study, nab-paclitaxel was administered at the recommended dose (RD) together with carboplatin and radiation. Results In the phase I study, one of six patients experienced dose-limiting toxicity (leukopenia of grade 3 requiring a second consecutive skip in the administration of weekly chemotherapy) with nab-paclitaxel at 50 mg/m2, which was therefore determined to be the RD. Fifty-six patients treated at the RD were evaluable for safety and efficacy. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). No treatment-related deaths occurred during the study period. The objective response rate was 76.8% (95% confidence interval [CI], 64.2–85.9%), median progression-free survival was 11.8 months (60% CI, 10.6–16.2 months; 95% CI, 8.2–20.8 months), and median overall survival was not reached. Conclusion Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m2 and carboplatin at an AUC of 2 in patients with locally advanced NSCLC. [ABSTRACT FROM AUTHOR]

Objectives TrkB is a receptor for brain-derived neurotrophic factor (BDNF) and is highly expressed in various cancers, with BDNF-TrkB signaling having been implicated in tumor progression and metastasis. The role of the BDNF-TrkB system in small cell lung cancer (SCLC), a neuroendocrine cancer, has remained unclear, however. We examined BDNF and TrkB expression in SCLC patients as well as the function of BDNF-TrkB signaling in SCLC cell lines. Materials and methods BDNF and TrkB expression in tumor specimens of 58 SCLC patients and 20 non–small cell lung cancer (NSCLC) patients was examined by immunohistochemistry and was scored on the basis of the distribution and intensity of staining. TrkB-overexpressing SCLC (SBC5 TrkB ) cells were established by retrovirus transduction and were examined for the effects of BDNF on intracellular signaling, cell proliferation, and cell migration in vitro. Results The staining score for TrkB in NSCLC and SCLC specimens was 2.80 ± 0.19 and 3.60 ± 0.15, respectively, whereas that for BDNF was 1.95 ± 0.32 and 2.76 ± 0.14, respectively. High levels of both TrkB and BDNF expression in SCLC tumors were significantly associated with poor overall survival in multivariate analysis (hazard ratio = 1.821, P  = 0.036). BDNF activated AKT and ERK signaling pathways in and promoted the migration of SBC5 TrkB cells, and these effects were attenuated by the pan-Trk inhibitor GNF-5837. GNF-5837 also inhibited the proliferation of SBC5 TrkB cells in the presence of BDNF. Conclusion Coexpression of BDNF and TrkB was associated with poor prognosis in SCLC patients, and BDNF promoted the migration of TrkB-overexpressing SCLC cells. TrkB is thus a potential therapeutic target for SCLC. [ABSTRACT FROM AUTHOR]

Objectives Expression of programmed cell death–ligand 1 (PD-L1) has been associated with clinical outcome of programmed cell death–1 (PD-1) pathway blockade in non–small cell lung cancer (NSCLC). The PD-L1 IHC 22C3 pharmDx assay, the only companion diagnostic for pembrolizumab therapy, has revealed that ∼30% of all NSCLCs express PD-L1 at a high level. The frequency of high PD-L1 expression in NSCLCs with known driver oncogenes has remained unclear, however. Materials and methods We retrospectively evaluated PD-L1 expression with the 22C3 assay in tumor tissue of 80 lung adenocarcinoma patients including 71 with EGFR mutations and 9 with ALK rearrangements, all of whom were treated with corresponding tyrosine kinase inhibitors (TKIs). Results Of the 80 tumors analyzed, 26 (32.5%) had a PD-L1 tumor proportion score (TPS) of 1%–49% and 9 (11.3%) had a PD-L1 TPS of ≥50%; 35 (43.8%) thus had a PD-L1 TPS of ≥1%. Of the 71 tumors with EGFR mutations, 23 (32.4%) had a PD-L1 TPS of 1%–49% and 7 (9.9%) had a PD-L1 TPS of ≥50%. A PD-L1 TPS of ≥1% was not associated with any clinical characteristic examined. Progression-free survival on initial TKI treatment was significantly poorer for patients with a PD-L1 TPS of ≥1% than for those with a PD-L1 TPS of <1% ( p  = .016). Conclusions A subset of patients with EGFR mutations or ALK rearrangements had a PD-L1 TPS of ≥50%. Prospective studies are thus warranted to examine the efficacy of PD-1/PD-L1 inhibitors in such patients. [ABSTRACT FROM AUTHOR]

Objectives Rovalpituzumab tesirine (Rova-T), an antibody-drug conjugate directed against Delta-like protein 3 (DLL3), is under development for patients with small cell lung cancer (SCLC) positive for this protein. However, the prevalence of DLL3 expression and its association with patient ethnicity and other characteristics have remained unclear. Materiais and methods Tumor samples from 63 patients with SCLC were subjected to immunohistochemical staining for DLL3. The relation of patient characteristics including sex, age, disease stage, and smoking history to DLL3 expression status was analyzed. Results and conlusions Fifty-two patients (83%) were positive for DLL3 expression, with 20 patients (32%) being positive in at least 50% of cancer cells (DLL3-high). DLL3 expression was not associated with any of the patient characteristics examined. In addition, overall survival did not differ between DLL3-high and DLL3-low patients. Our results reveal that DLL3 is expressed in tumor specimens from most patients with SCLC, and they should inform the undertaking of clinical trials of Rova-T including an ongoing phase I study (NCT03086239) in Japan as well as global phase III trials (NCT03061812 and NCT03033511). [ABSTRACT FROM AUTHOR]

Objectives The regulation of redox balance in cancer cells is an important factor in tumor development and chemoresistance, with oncogene activation having been shown to induce the generation of reactive oxygen species (ROS). Activating mutations of the epidermal growth factor receptor gene ( EGFR ) are oncogenic drivers in non–small cell lung cancer (NSCLC), but it has remained unknown whether ligand-independent EGFR signaling conferred by EGFR mutation triggers ROS generation in NSCLC cells. Materials and Methods HEK293T cells were transfected with an expression vector for mutant EGFR. The expression of CD44 variant (CD44v) isoforms in NSCLC cell lines was evaluated by flow cytometry. Cells were depleted of CD44v by RNA interference and assayed for ROS and glutathione (GSH) levels. The effect of CD44v on cisplatin sensitivity was evaluated in vitro with the MTS assay. Results EGFR signaling due to EGFR mutation increased ROS levels in transfected HEK293T cells. The expression of CD44v isoforms was found to be inversely correlated with basal ROS levels in EGFR mutation–positive NSCLC cell lines. Knockdown of CD44v induced depletion of intracellular GSH and increased ROS levels in EGFR- mutated NSCLC cells that express CD44v at a high level (CD44v high ). In addition, depletion of GSH by treatment with buthionine-[ S, R ]-sulfoximine induced marked accumulation of ROS and enhanced the cytotoxicity of cisplatin in CD44v high EGFR- mutated NSCLC cells but not in corresponding CD44v low cells. This enhancement of cisplatin cytotoxicity by GSH depletion was prevented by treatment with the antioxidant N -acetyl- l -cysteine. Knockdown of CD44v also enhanced cisplatin cytotoxicity in CD44v high EGFR mutation–positive NSCLC cells but not in CD44v low cells. Conclusion Our results thus implicate CD44v in redox adaptation and as a potential target for treatment in CD44v high EGFR- mutated NSCLC cells. [ABSTRACT FROM AUTHOR]

Objectives The T790M and C797S mutations of the epidermal growth factor receptor gene ( EGFR ) confer resistance to first- and third-generation EGFR tyrosine kinase inhibitors (TKIs), respectively, in patients with non–small cell lung cancer (NSCLC) harboring activating mutations of EGFR . C797S has been identified in cis or in trans with T790M in tumor specimens from patients who experienced treatment failure with first- and third-generation EGFR-TKIs. The allelic relation between T790M and activating mutations of EGFR has not been well characterized, however. We have now developed a digital polymerase chain reaction (dPCR)–based method for determination of the allelic relation between two types of EGFR mutation (T790M and either C797S or an activating mutation). Materials and Methods Seven clinical NSCLC specimens and two NSCLC cell lines harboring both an activating mutation and T790M were analyzed with this new method to identify the allelic relation between these EGFR mutations. Results The median ratio of the number of alleles positive for both an activating mutation and T790M to the number of T790M-positive alleles was 97.1% (range, 90.0–100%). Confirmatory analysis by next-generation sequencing yielded a corresponding value of 96.7% (range, 89.1–99.5%). Our dPCR method thus reliably identifies the allelic relation between two EGFR mutations in a quantitative manner. Conclusions Almost all T790M mutations were detected in cis with activating mutations of EGFR regardless of the de novo or acquired status of T790M, with cancer cells harboring T790M and activating mutations on the same allele appearing to be selected and enriched during EGFR-TKI treatment. [ABSTRACT FROM AUTHOR]

Objectives Drug-induced interstitial lung disease (ILD) is often associated with high mortality; however it is difficult to predict and manage. we examined the clinical findings and imaging characteristics of nivolumab induced ILD reported in the two phase II studies patients with recurrent or advanced non-small-cell lung cancer. Materials and methods We examined the clinical findings and imaging characteristics of all cases of ILD reported in two phase II trials of nivolumab, an anti-programmed death-1 antibody, in Japanese patients with recurrent or advanced non-small-cell lung cancer. These studies are registered with the Japan Pharmaceutical Information Center, numbers JapicCTI-132072, JapicCTI-132073. Results Eight (7.2%; two with squamous cell carcinoma, six with non-squamous cell carcinoma) of the 111 patients included in these two studies experienced ILD, and a causal relationship with nivolumab could not be ruled out in any of them. ILD of ≥grade 3 severity was found in four patients (3.6%), and ILD was considered a serious treatment-related adverse event in seven patients (6.3%). All of the patients who experienced ILD were male and had a history of smoking, with a median age of 65 years (range 52–78 years). In seven of the eight patients who experienced ILD, their events were rapidly resolving or resolved spontaneously or with steroid therapy; one patient died of respiratory failure without resolution of ILD, after docetaxel treatment was initiated following nivolumab discontinuation. Chest computed tomography images for the seven patients with resolving or resolution of ILD showed a pattern of organizing pneumonia or nonspecific interstitial pneumonia without traction bronchiectasis, while the patient who died had traction bronchiectasis. Conclusion Although the risk factors for nivolumab-induced ILD were not identified, careful monitoring including imaging examinations is important in preventing the worsening of ILD in patients receiving nivolumab. [ABSTRACT FROM AUTHOR]

Objectives We performed an open-label, multicenter, single-arm phase II study (UMIN ID 000010532) to prospectively evaluate the efficacy and safety of nab-paclitaxel for previously treated patients with advanced non–small cell lung cancer (NSCLC). Methods Patients with advanced NSCLC who experienced failure of prior platinum-doublet chemotherapy received weekly nab-paclitaxel (100 mg/m 2 ) on days 1, 8, and 15 of a 21-day cycle until disease progression or the development of unacceptable toxicity. The primary end point of the study was objective response rate (ORR). Results Forty-one patients were enrolled between September 2013 and April 2015. The ORR was 31.7% (90% confidence interval, 19.3%–44.1%), which met the primary objective of the study. Median progression-free survival was 4.9 months (95% confidence interval, 2.4–7.4 months) and median overall survival was 13.0 (95% confidence interval, 8.0–18.0 months) months. The median number of treatment cycles was four (range, 1–17) over the entire study period, and the median dose intensity was 89.1 mg/m 2 per week. Hematologic toxicities of grade 3 or 4 included neutropenia (19.5%) and leukopenia (17.1%), with no cases of febrile neutropenia being observed. Individual nonhematologic toxicities of grade 3 or higher occurred with a frequency of <5%. Conclusion Weekly nab-paclitaxel was associated with acceptable toxicity and a favorable ORR in previously treated patients with advanced NSCLC. Our results justify the undertaking of a phase III trial comparing nab-paclitaxel with docetaxel in this patient population. [ABSTRACT FROM AUTHOR]

Objectives The combination use of gefitinib and epidermal growth factor receptor (EGFR) testing is a standard first-line therapy for patients with non-small cell lung cancer (NSCLC). Here, we examined the cost-effectiveness of this approach in Japan. Materials and methods Our analysis compared the ‘EGFR testing strategy’, in which EGFR mutation testing was performed before treatment and patients with EGFR mutations received gefitinib while those without mutations received standard chemotherapy, to the ‘no-testing strategy,’ in which genetic testing was not conducted and all patients were treated with standard chemotherapy. A three-state Markov model was constructed to predict expected costs and outcomes for each strategy. We included only direct medical costs from the healthcare payer's perspective. Outcomes in the model were based on those reported in the Iressa Pan-Asia Study (IPASS). The incremental cost-effectiveness ratio (ICER) was calculated using quality-adjusted life-years (QALYs) gained. Sensitivity and scenario analyses were conducted. Results The incremental cost and effectiveness per patient of the ‘EGFR testing strategy’ compared to the ‘no-testing strategy’ was estimated to be approximately JP¥122,000 (US$1180; US$1 = JP¥104 as of February 2014) and 0.036 QALYs. The ICER was then calculated to be around JP¥3.38 million (US$32,500) per QALY gained. These results suggest that the ‘EGFR testing strategy’ is cost-effective compared with the ‘no-testing strategy’ when JP¥5.0 million to 6.0 million per QALY gained is considered an acceptable threshold. These results were supported by the sensitivity and scenario analyses. Conclusion The combination use of gefitinib and EGFR testing can be considered a cost-effective first-line therapy compared to chemotherapy such as carboplatin–paclitaxel for the treatment for NSCLC in Japan. [ABSTRACT FROM AUTHOR]

Abstract: Objective: The clinicopathological characteristics and surgical results of young lung cancer patients were investigated. Materials and methods: Seven hundred and four (6.0%) patients with lung cancer, aged up to 50 years, were enrolled from among the 11,663 patients registered in the Japanese Lung Cancer Registry Study 2004, and their clinical data were compared with those of 10,959 patients older than 50 years. This epidemiological study is based on the single year registration of surgically treated patients in the major institutes in Japan. Results: The 5-year overall survival rate (5Y-OS) and the 5-year lung cancer-related survival rate was 79.2%/69.0% (p <0.001) and 81.3%/76.6% (p =0.005) in the young/old groups, respectively. In the young/old groups, lobectomy and pneumonectomy was performed in 76.9%/78.0% and 5.7%/3.2%, respectively; adjuvant therapies were given preoperatively in 10.4%/4.7% (p <0.001) and postoperatively in 31.4%/24.5% (p <0.001). The proportions of patients with p-stage IIIA (18.2%) and adenocarcinoma histology (78.7%) were higher in the young group. The 5Y-OS was 94.8%/86.2% for p-stage IA (p <0.001), 87.0%/73.2% for p-stage IB (p =0.001), 61.0%/61.6% for p-stage IIA (p =0.595), 71.0%/48.4% for p-stage IIB (p =0.003), 49.6%/39.4% for p-stage IIIA (p =0.020), and 80.0%/24.8% for p-stage IIIB (p =0.012); it was 83.5%/80.7% for females (p =0.106) and 75.1%/62.3% for males (p <0.001) in the young/old groups. The postoperative survival was significantly better with all operative procedures in the young group. The 5Y-OS after recurrence was 17.9%/13.4% in the young/old groups (p =0.016). In the young group, the 5Y-OS was better in females (83.5%) than in males (75.1%, p =0.002), and for patients with adenocarcinoma (80.3%) than for those with squamous cell carcinoma (68.5%, p =0.013). Age up to 50 years was identified as an independent better prognostic factor on multivariate analysis. Conclusions: The postoperative survival in lung cancer patients aged up to 50 years was better than that in patients older than 50 years. [Copyright &y& Elsevier]

Abstract: Aurora-B is a key regulator of mitosis, and the overexpression has been detected in a variety of solid tumors. The Aurora-B overexpression has been suggested to correlate with clinical aggressiveness and aneuploidy in vitro, however, the frequency of overexpression of Aurora-B protein, the association with clinicopathologic parameters and aneuploidy remain poorly defined in non-small-cell lung cancer (NSCLC). Using 157 surgical specimens of human NSCLC, we here show that overexpression of Aurora-B proteins are significantly correlated with aneuploidy and poor outcomes in NSCLC. We examined immunohistochemical protein expression of Aurora-B, and DNA ploidy by laser scanning cytometry in 157 NSCLC cases. Aurora-B overexpression was found in 83 cases (53%) of NSCLC, and was significantly correlated with vascular invasion (p =0.012), poor differentiation (p <0.001), larger tumor size (p =0.010) and lymph node metastasis (p =0.05) and poor prognosis (p =0.011). Aneuploidy was found in 87 cases (57%), and was significantly correlated with Aurora-B overexpression (p =0.0065). Logistic multivariate analysis revealed overexpression of Aurora-B protein to be significant risk factors for aneuploidy compared with other factors. These results indicate that Aurora-B overexpression may contribute to malignant potential and increased aneuploidy in NSCLC. Thus, Aurora-B may serve as a new therapeutic target in against patients with NSCLC, although further studies will be necessary. [Copyright &y& Elsevier]

Abstract: Lung cancer is sometimes difficult to differentiate from benign lung diseases expressing nodular shadow in imaging study. We assessed the diagnostic value of two commonly used tumor markers in distinguishing primary lung cancer from benign lung disease. The serum levels of carcinoembryonic antigen (CEA) and cytokeratin 19 fragments (CYFRA 21-1) were retrospectively analyzed in 655 lung cancer patients and 237 patients with benign lung disease. The standard cut-off levels of 3.2ng/mL CEA and 3.5ng/mL CYFRA 21-1 and twice these respective levels (6.4ng/mL and 7.0ng/mL) were used. CEA and CYFRA 21-1 levels were elevated in 32% and 11% of benign lung disease patients, respectively. CEA sensitivity and specificity for lung cancer diagnosis was 69% and 68% respectively, while that for CYFRA 21-1 was 43% and 89%, respectively. Thus, the combined value for the specificity of the two tumor markers was greater than either alone. Patients were grouped depending on their hospital status, and prevalence rates were determined. The prevalence rate of lung cancer in admitted patients was 51%, the prevalence rate of lung cancer in outpatients was 12%, and the prevalence rate of lung cancer identified during health check-ups was 0.1%. Positive predictive values (PPVs) were calculated using Bayes’ theorem, and varied with the serum tumor marker and prevalence rate: PPVs of CEA [prevalence rate] were 69.2% [51%], 22.7% [12%], and 0.22% [0.1%], while PPVs of CYFRA 21-1 were 80.3% [51%], 34.8% [12%], and 0.39% [0.1%]. However, PPVs for lung cancer diagnosis at a prevalence rate of 51% were 87.3% or higher when the patient exhibited positive CEA and CYFRA 21-1, or CEA or CYFRA 21-1 levels twice the standard cut-off. Our results indicate that CEA and CYFRA 21-1 are reliable serum tumor markers for the diagnosis of lung cancer in addition to CT scans when combined or used individually at twice the standard cut-off level in high prevalence rate groups. The prevalence rate should therefore be taken into account when these serum tumor markers are used as diagnostic tools for lung cancer. [Copyright &y& Elsevier]

Abstract: High expression levels of TrkB and BDNF are associated with aggressive malignant behavior in tumor cells and a poor prognosis in patients with various types of cancer. In this study, we aimed to identify the relationship between TrkB and BDNF expression and clinicopathological variables and prognosis in non-small cell lung cancer (NSCLC). We evaluated TrkB and BDNF expression in the tumor cells of 102 NSCLC patients by immunohistochemistry. Out of all clinicopathological factors examined, only vascular invasion was significantly correlated with TrkB (P =0.010) and BDNF (P =0.015) expression. TrkB-positive tumors had significantly worse disease-free survival (P =0.0094) and overall survival (P =0.0019) than TrkB-negative tumors, and TrkB expression was an independent prognostic factor for disease-free survival (HR 3.735, 95%C.I. 1.560–11.068, P =0.002) and overall survival (HR 4.335, 95%C.I. 1.534–15.963, P =0.004) in multivariate analysis. Finally, our analysis revealed that co-expression of TrkB and BDNF conferred poorer prognosis compared with overexpression of either protein alone. Our results indicate that expression of TrkB and BDNF is associated with poor prognosis in NSCLC patients. [Copyright &y& Elsevier]

Crizotinib was the first clinically available inhibitor of the tyrosine kinase ALK, and next-generation ALK inhibitors, such as alectinib, are now under development. Although crizotinib is generally well tolerated, severe esophageal injury has been reported as a rare but serious adverse event of crizotinib therapy. We now describe the successful treatment with alectinib of a patient who developed crizotinib-induced esophageal ulceration. [ABSTRACT FROM AUTHOR]