Aim: To investigate potential association between administration of corticosteroids, antibiotics, probiotics, proton pump inhibitors, non-steroidal anti-inflammatory drugs (NSAID), statins and metformin and outcome in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Patients and Methods: A total of 224 patients with advanced NSCLC treated at nine comprehensive cancer centers were analyzed in this national retrospective study. Survival statistics were evaluated using Kaplan-Meier method and Cox analysis. Results: Only corticosteroid use had a significant negative effect on the objective response rate. In the univariate analysis, there was no significant effect of the studied concomitant medications on the efficacy of nivolumab. In a subsequent multifactorial analysis, a possible positive effect of the concomitant use of NSAID at the initiation of nivolumab treatment was revealed. Conclusion: The results of the present retrospective exploratory analysis underscore the importance of knowing the exact type of concomitant medication, the route of administration, the dose of medication, and the region of the ongoing study. The present data indicated a significantly higher rate of progression in patients treated with corticosteroids and the possible positive effect of NSAID use at the initiation of nivolumab treatment.Nivolumab is a human monoclonal antibody to programmed cell death protein 1 (PD1) that represents a new therapeutic option in the second-line treatment of advanced non-smallcell lung cancer (NSCLC). Improved efficacy with a more favorable adverse event profile has been documented for nivolumab compared to docetaxel in phase III trials. However, the objective response rate of nivolumab monotherapy is only about 20%, with the disease control rate 2209

Aim: To investigate potential associations between clinical and standard peripheral blood biomarkers and clinical outcome in patients with non-small cell lung cancer (NSCLC) treated with nivolumab. Patients and Methods: A total of 120 patients with advanced NSCLC treated at seven comprehensive cancer care centers were analyzed in this national retrospective study. Survival statistics were evaluated using the Kaplan-Meier method and Cox analysis. Results: Among clinical parameters, histology was significantly associated with progression-free survival. Univariate Cox-proportional hazards model indicated prognostic and predictive role of a panel of laboratory parameters reflecting chronic inflammatory pattern (elevated neutrophil count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, C-reactive protein and decrease in hemoglobin and albumin). Higher serum calcium concentration was also associated with nivolumab treatment effect. Conclusion: Tumor histology was the only clinical parameter predicting the outcome of nivolumab treatment.Among the laboratory parameters, our analysis identified a laboratory panel reflecting chronic inflammation as a potential predictive marker of nivolumab treatment.Nivolumab is a human monoclonal anti-programed cell death 1 (PD-1) therapy that represents a new therapeutic option in the second-line treatment of advanced non-small cell lung cancer (NSCLC). Improved efficacy and a more favorable adverse event profile have been documented for nivolumab compared to docetaxel in phase III studies. However, the objective response rate on nivolumab monotherapy is only about 20%, with the disease control rate reaching approximately 50% (1, 2). Therefore, many patients do not benefit from nivolumab treatment and, taking into account the cost/efficacy ratio, identification of predictive parameters that would aid identification of the most suitable candidates for this therapy remains a topic of high unmet medical need. Much effort has been made to demonstrate that programmed death-ligand 1 (PD-L1) expression on tumor cells represent, a potential biomarker of response to anti-PD1 therapy (3, 4). However, for nivolumab, this seems to hold true in nonsquamous NSCLC only, although data for other drugs, e.g. pembrolizumab, have demonstrated the predictive role of PD-L1 expression even in patients with squamous histology (5). For various reasons, PD-L1 expression is still not an ideal biomarker (6). Therefore, the search for other predictive biomarkers should continue. Several approaches 6771

Abstract. Attributing to their pathophysiological role and stability in biological samples, microRNAs (miRNAs) have the potential to become valuable predictive markers for non-small cell lung cancer (NSCLC). Samples of biopsy tissue constitute suitable material for miRNA profiling with the aim of predicting the effect of palliative chemotherapy. The present study group included 81 patients (74 males, 7 females, all smokers or former smokers) with the squamous cell carcinoma (SCC) histological subtype of NSCLC at a late stage (3B or 4). All patients received palliative chemotherapy based on platinum derivatives in combination with paclitaxel or gemcitabine. The expression of 17 selected miRNAs was measured by reverse transcription-quantitative polymerase chain reaction in tumor tissue macrodissected from formalin-fixed paraffin-embedded (FFPE) tissue samples. To predict the effect of palliative chemotherapy, the association between gene expression levels and overall survival (OS) time was analyzed. From the 17 miRNAs of interest, low expression levels of miR-342 and high expression levels of miR-34a and miR-224 were associated with a reduced OS time in subgroups of patients based on smoking status and treatment modality. Using cluster analysis, associations between combinations of miR-34a, -224 and -342 expression levels with patient survival were identified. The present study revealed that patients with the simultaneous high expression of miR-224 and -342 had a similar prognostic outcome to those with the low expression of miR-224 and -342, which was significantly reduced, compared with patients exhibiting high expression of either miR-224 or miR-342 with low expression of the other. We hypothesize that the effect of a particular miRNA is dependent on the expression level of other members of the miRNA network. This finding appears to complicate survival analyses based on individual miRNAs as markers. In conclusion, the present study provides evidence that specific miRNAs were associated with OS time, which may be candidate predictors for the effectiveness of palliative treatment in SCC lung cancer patients. This objective can be better achieved by combining more markers together than by using individual miRNAs.

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Pemetrexed is an antifolate cytostatic agent targeting several folate-dependent enzymatic pathways, widely used in the treatment of locally advanced or metastatic stage non-small cell lung cancer. Aside from the non-squamous histology, there is still no available molecular biomarker predicting treatment efficacy of pemetrexed-based chemotherapy. The aim of our retrospective study was to evaluate the association of thyroid transcription factor 1 expression with outcome of a large cohort of patients with non-squamous non-small cell lung cancer treated with pemetrexed. We retrospectively analysed clinical data of 463 patients with advanced-stage non-small cell lung cancer (IIIB or IV) treated with pemetrexed-based chemotherapy. Thyroid transcription factor 1 expression was assessed using indirect immunohistochemical detection in formalin-fixed paraffin-embedded tumour tissue at the time of diagnosis. Thyroid transcription factor 1 expression was detected in the tumour tissue from 76.0% of patients, and tumours from 24.0% of patients were thyroid transcription factor 1 negative. The median progression-free survival and overall survival for patients with thyroid transcription factor 1 positive tumours were 4.8 and 11.8 months compared to 2.8 and 8.3 months for those with thyroid transcription factor 1 negative tumours (p = 0.001 and p < 0.001). The multivariable Cox proportional hazards model revealed that thyroid transcription factor 1 expression was significantly associated with progression-free survival (hazard ratio = 1.57, p < 0.001) and also with overall survival (hazard ratio = 1.73, p < 0.001). In conclusion, the results of the conducted retrospective study suggest that the thyroid transcription factor 1 expression was independently associated with progression-free survival and overall survival in patients with advanced-stage nonsquamous non-small cell lung cancer treated with pemetrexed-based chemotherapy.

Nowadays, EGFR-TKIs (epidermal growth factor receptor-tyrosine kinase inhibitors) targeted therapy is well established treatment for patients with the so-called EGFR common mutations with advanced or metastatic non-small cell lung cancer. The effi cacy for the so-called rare and especially for the very rare complex EGFR mutations is not clear. We describe a case of a 63-year-old female with metastatic non-small cell lung cancer with complex EGFR mutation (G719X + S768I) who had been treated by gefi tinib. She achieved progression free survival within eight months. Then, we discuss our case with other literature case reports. Together, it seems that described complex EGFR mutation has a relatively good sensitivity for EGFR-TKIs treatment. SouhrnCílená terapie pomocí EGFR-TKIs (epidermal growth factor receptor-tyrosine kinase inhibitors) je v současné době dobře zavedenou léčbou pro pa cienty s tzv. častými EGFR mutacemi s pokročilým nebo metastatickým nemalobuněčným karcinomem plic. Účinnost této léčby pro tzv. vzácné a obzvláště pak pro tzv. komplexní EGFR mutace není zcela jasná. V naší kazuistice popisujeme případ 63leté ženy s metastatickým nemalobuněčným karcinomem plic s komplexní EGFR mutací (G719X + S768I), která byla léčena gefi tinibem. Doba do progrese dosáhla osm měsíců. Následně diskutujeme naší kazuistiku s literárně zveřejněmými obdobnými případy. Celkově se zdá, že popisovaná komplexní mutace má relativně dobrou citlivost pro léčbu pomocí EGFR-TKIs. Klíčová slova nemalobuněčný karcinom plic -EGFR gen -EGFR protein -complex mutations -rare EGFR mutations -EGFR-TKIsThe authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy.The Editorial Board declares that the manuscript met the ICMJE "uniform requirements" for biomedical papers.Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do bi omedicínských časopisů. Redakce časopisu Klinická onkologie a nakladatelství Ambit Media, a.s. vypisuje SOUTĚŽ NA PODPORU AUTORSKÝCH TÝMŮ PUBLIKUJÍCÍCH V ZAHRANIČNÍCH ODBORNÝCH TITULECHOdměna pro vítěze: 10 000 Kč Cíl soutěže:Podpořit renomé a prestiž časopisu Klinická onkologie -ofi ciálního časopisu ČOS ČLS JEP -u domácích i zahraničních autorů, lékařů a akademických pracovníků.

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