Course Of Non-small Cell Lung Cancer Research Articles

Investigating treatment response and immune profile in association with pattern identification in NSCLC patients scheduled for immune checkpoint inhibitor monotherapy (HARMONY study)

Immune checkpoint inhibitors (ICI) considerably improve overall survival of advanced nonsmall cell lung cancer (NSCLC) patients. However, it has certain limitations, such as low response rates. Although programmed death-ligand 1 (PD-L1) expression is currently used as a representative predictive biomarker, it cannot robustly predict response; thus, identifying other dynamic biomarkers to ensure better selection of patients susceptible for ICI therapy is required. Pattern identification is a diagnostic system used in oriental medicine and is performed through collecting and analyzing a series of symptoms and characteristic signs. We intended to analyze the association between survival, treatment response, and immune profile evaluated on every visit according to different pattern identifications and determine how pattern identification changes during the course of NSCLC treated with ICI. Across 10 academic hospitals, 200 patients diagnosed with stage Ⅲb-Ⅳ NSCLC and scheduled for ICI monotherapy (pembrolizumab or atezolizumab) as second-line or more treatment following platinum-based first-line treatment for NSCLC will be recruited. Throughout the study, participants are expected to exhibit different immune profiles according to pattern identification in association with treatment response and survival. The primary endpoint is progression-free survival (PFS), while secondary endpoints are overall survival (OS), objective response rate (ORR), and immune profile, all of which will be analyzed in association with pattern identification. Approximately 10 mL blood samples will be obtained from each patient. Results from the analysis of immune cells and cytokines will be analyzed together with pattern identification. Results from the analysis of differences in survival, treatment response, and immune profile, together with pattern identification for NSCLC patients during ICI therapy, will have significant scientific and medical contributions, and will provide comprehensive data to identify pattern identification-based immune biomarkers for predicting survival and treatment response of ICI therapy for NSCLC patients. Ethical approval has been obtained from the medical ethics committees of 10 academic hospitals. All amendments to the research protocol were submitted and approved. This trial is registered in Clinical Research Information Service (CRIS) of the Republic of Korea with the number KCT0005173. Registration date: July 22, 2020 (version 3.0).

EGFR gene aberrations in non-small cell lung cancer patients in the Crimea Republic.

e20514 Background: Non-small cell lung cancer (NSCLC) accounts for 85% of all lung cancers and remains the most commonly diagnosed human neoplasm with a poor prognosis. Significantly improving the clinical course of NSCLC, EGFR tyrosine kinase inhibitors are effective only against tumors carrying activating mutations in the EGFR gene, and their frequency varies depending on the patient population. The aim of the study was to analyze a retrospective group of Crimean patients with advanced NSCLC for the presence of EGFR gene aberrations and association with clinical outcome. Methods: We used DNA samples from FFPE blocks of tumor and non-tumor tissues of 72 European-type patients (aged 46-78 years, median 64 years, 82% - men, 18% - women) diagnosed with lung cancer (T1-1aN0-2M0-1, stage I-IV). The relative copy number of the EGFR gene was assessed by RT-qPCR using GAPDH and B2M as reference genes. Mutations (9 deletions in exon 19, L858R, T790M, L861Q, G719S/A/C, 3 insertions in exon 20, S768I) in the EGFR gene were determined using the Therascreen EGFR RGQ PCR Kit (Qiagen, Germany). Results: For Crimean population patients, the squamous subtype of NSCLC was more common (57%). EGFR copy number evaluation in patients with adenocarcinoma showed locus amplification in 9 patients (30%), no loss of copy number was recorded. In the squamous cell carcinoma group, locus amplification prevailed in 25 of 42 samples (59.6%) and a decrease in copy number was noted in 4 samples (9.5%). Differences in the frequency of aberrant changes in the relative copy number of EGFR in adenocarcinoma and squamous cell lung cancer groups were statistically significant (χ2 = 11.04 at p = 0.003). The activating mutation frequency in adenocarcinoma samples was 9.7% (ex19del), which was lower than the frequency recorded in European adenocarcinoma patient populations (14.4%, p = 0.036). No EGFR mutations were found in cases of squamous cell lung cancer. The presence of mutations and/or changes in EGFR copy number were associated with shorter overall survival in patients who did not receive targeted and immune therapy (p = 0.034). Conclusions: The ex19del activating mutation of the EGFR gene frequency in adenocarcinoma samples was 9.7%. A more frequent EGFR alteration was detected when assessing the locus copy number in the tumor relative to the non-tumor tissue: changes were recorded for 30% of adenocarcinoma cases and 69.1% of squamous cell lung cancer.

Rare driver alterations in nonsmall cell lung cancer: novel targeted drugs.

The current review presents clinically relevant driver alterations in nonsmall cell lung cancer (NSCLC) and the targeted treatments currently available for clinical use as well as those in clinical trials and advanced stages of drug development. Mesenchymal-epithelial transition factor, human epidermal growth factor receptor 2, proto-oncogene B-RAF (BRAF), proto-oncogene tyrosine-protein kinase ROS (ROS1), rearranged during transfection (RET) and neurotrophic tyrosine kinase are rare genetic driver alterations, each present in a small subset of patients with NSCLC. Treatments targeting BRAF, ROS1, RET and neurotrophic tyrosine kinase are approved in Europe, and promising treatments targeting mesenchymal-epithelial transition factor and human epidermal growth factor receptor 2 are available in clinical trials and compassionate use programs. The response rates, duration of response and tolerability observed in trials of targeted drugs in this setting are presented in detail here. While rare driver alterations are, by definition, rare, their recognition can change the course of NSCLC for those patients affected. Targeted treatments for many rare driver alterations are well tolerated and effective. Screening for molecular changes in advanced NSCLC should include screening for rare drivers, and patients should be directed to clinical trials in setting where treatment of the driver alterations is not otherwise available.

Downregulation of hsa-microRNA-204-5p and identification of its potential regulatory network in non-small cell lung cancer: RT-qPCR, bioinformatic- and meta-analyses

BackgroundPulmonary malignant neoplasms have a high worldwide morbidity and mortality, so the study of these malignancies using microRNAs (miRNAs) has attracted great interest and enthusiasm. The aim of this study was to determine the clinical effect of hsa-microRNA-204-5p (miR-204-5p) and its underlying molecular mechanisms in non-small cell lung cancer (NSCLC).MethodsExpression of miR-204-5p was investigated by real-time quantitative PCR (RT-qPCR). After data mining from public online repositories, several integrative assessment methods, including receiver operating characteristic (ROC) curves, hazard ratios (HR) with 95% confidence intervals (95% CI), and comprehensive meta-analyses, were conducted to explore the expression and clinical utility of miR-204-5p. The potential objects regulated and controlled by miR-204-5p in the course of NSCLC were identified by estimated target prediction and analysis. The regulatory network of miR-204-5p, with its target genes and transcription factors (TFs), was structured from database evidence and literature references.ResultsThe expression of miR-204-5p was downregulated in NSCLC, and the downtrend was related to gender, histological type, vascular invasion, tumor size, clinicopathologic grade and lymph node metastasis (P<0.05). MiR-204-5p was useful in prognosis, but was deemed unsuitable at present as an auxiliary diagnostic or prognostic risk factor for NSCLC due to the lack of statistical significance in meta-analyses and absence of large-scale investigations. Gene enrichment and annotation analyses identified miR-204-5p candidate targets that took part in various genetic activities and biological functions. The predicted TFs, like MAX, MYC, and RUNX1, interfered in regulatory networks involving miR-204-5p and its predicted hub genes, though a modulatory loop or axis of the miRNA-TF-gene that was out of range with shortage in database prediction, experimental proof and literature confirmation.ConclusionsThe frequently observed decrease in miR-204-5p was helpful for NSCLC diagnosis. The estimated target genes and TFs contributed to the anti-oncogene effects of miR-204-5p.

Concentrations of SP-A and HSP70 are associated with polarization of macrophages in pleural effusions of non-small cell lung cancer

Damage-associated molecular pattern (DAMP) molecules can initiate an immune response through Toll-like receptors (TLRs). DAMPs are released from cells as a response to the extracellular danger and can be by-products of tissue damage. In cancer microenvironment necrotic cells release debris which has potency to become DAMPs. Non-small cell lung cancer (NSCLC) is often accompanied by pleural effusion (PE), which contains a variety of DAMPs. Surfactant protein A (SP-A) and heat shock protein 70 (Hsp70) are important DAMPs in the respiratory tract.The aim of this study was to determine a correlation between SP-A or Hsp70 and development of PE in the course of NSCLC. Moreover, we aimed to determine relationships between DAMPs and certain humoral factors associated with formation and persistence of PE as well as pleural-residing macrophages. In 34 PE samples, we estimated concentration of SP-A, Hsp70, IL-6, IL-18, G-CSF, M-CSF, SCF, SDF1α, VEGF as well as the fraction of macrophages and their pattern of polarization.We have found correlations between the concentration of the SP-A and Hsp70 and the percentage of PE-derived macrophages, also between concentrations of SP-A and Hsp70, and cytokines which participate in inflammation and processes involved in remodeling of extracellular matrix (ECM). Our data indicate an important role of SP-A during the development of PE associated with NSCLC. We suggest that measurement of concentration level of SP-A can be helpful in the course of diagnosis of malignant PE associated with NSCLC.

Potential paraneoplastic syndromes and selected autoimmune conditions in patients with non-small cell lung cancer and small cell lung cancer: A population-based cohort study.

BackgroundLittle is known about the occurrence and distribution of types of paraneoplastic syndromes (PNS) in patients with lung cancer. Identification of autoimmune PNS is particularly important for discerning them from immune-related adverse events of novel immunotherapies. We estimated the occurrence of PNS among patients with lung cancer and compared it with that in the general population.MethodsIn this registry-based cohort study in Denmark, we identified all patients with incident primary lung cancer between 1997 and 2010, and in a general-population comparison cohort matched on calendar time, sex, age, and residence. Among patients with non-small cell lung cancer (NSCLC) and small-cell lung cancer (SCLC), we estimated prevalence of potential PNS and selected autoimmune conditions and compared their incidence rates with those of equivalent conditions in the general population cohort, using hazard ratios (HRs) adjusted for baseline comorbidity.ResultsThere were 35,319 patients with NSCLC and 6,711 patients with SCLC. The incidence rates per 1000 person-years (95% confidence interval) of any potential PNS or selected autoimmune disorders were 135.4 (131.9–139.1) among NSCLC patients and 237.3 (224.4–250.5) among SCLC patients. Adjusted HRs for any potential PNS or selected autoimmune disorders were 4.8 (4.7–5.0) for NSCLC and 8.2 (7.6–8.8) for SCLC.ConclusionIncidence rate of any potential PNS or selected autoimmune disorders among patients with lung cancer was greater than that in the general population and was greater after SCLC than after NSCLC.ImpactThese results provide context to discerning PNS from adverse effects of novel immunotherapies during the clinical course of NSCLC and SCLC.

Percentages of NKT cells in the tissues of patients with non-small cell lung cancer who underwent surgical treatment.

IntroductionNatural killer T (NKT) cells are involved in the antitumor response by direct cytotoxicity and indirectly through activation of effector cells. Recent studies have shown a relationship between the number and function of NKT cells and clinical outcomes. NKT cells seem to represent a promising tool for immunotherapy of cancer.The aim of the studyThe aim of the study was to evaluate the distribution of NKT cells in peripheral blood, lymph nodes and tumor tissue of non-small cell lung cancer (NSCLC) patients, as well as development of the most efficient set of cytokines stimulating differentiation of NKT cells.Material and methodsWe evaluated the percentage of iNKT+CD3+ cells in the tissues collected from patients with NSCLC. For the generation of NKT cells, we cultured cells isolated from the blood of 20 healthy donors and from the tissues of 4 NSCLC patients. Cells were stimulated with α-GalCer in combinations with cytokines.ResultsWe noted significant differences in the percentages of NKT cells in the patients’ tissues. The highest percentage of these cells was observed in the tumor tissue and the lowest in the lymph nodes. In vitro, in healthy donors all α-GalCer-cytokine combinations were effective in stimulation of NKT cells’ proliferation. NKT cells’ proliferation was the most efficiently stimulated by α-GalCer+IL-2+IL-7 and α-GalCer+IL-2+IFN-γ.ConclusionsOur results suggest that in the course of NSCLC, NKT cells migrate to the primary tumor and accumulate therein. All tested combinations of α-GalCer and cytokines were capable of generation of NKT cells in vitro.

Prophylactic cranial irradiation in non-small cell lung cancer patients: who might be the candidates?

ObjectivesBrain metastases (BMs) often advance the course of non-small cell lung cancer (NSCLC). We performed an observational study in order to investigate the possible correlation of selected clinical and epidemiological factors with BM appearance in patients suffering from different histological subtypes of NSCLC stage I–IV.MethodsThe study included 161 consecutive patients with NSCLC. Analyzed data included patient- and tumor-related characteristics.ResultsThirty-nine patients (24.2%) presented BMs within 12 (0–36) weeks of diagnosis. BMs decreased the mean overall survival significantly (15.6 versus 50.7 weeks, P < 0.001), with hazard ratio (95% confidence interval) 3.60 (2.42–5.35). The age of the patients with BM was significantly lower than that of the patients without BM (60.8 ± 8.9 versus 66.5 ± 8.5, P < 0.001). Patients with BM had significantly higher pack-years consumption (75.9 ± 23.9 versus 58.9 ± 31.9, P = 0.003) and larger tumor size compared with patients without BM (size in mm: 55.1 ± 20.1 versus 45.9 ± 19.3, P = 0.012). The presence of BM was also correlated with the absence of lung (P < 0.001), bone (P = 0.005), and adrenal (P = 0.046) metastases.ConclusionYounger NSCLC patients with high tobacco consumption, large tumor size, and absence of metastases in other organs (lung, bones, adrenal metastases) are at high risk of BM appearance during the course of NSCLC and are candidates for prophylactic cranial irradiation early in the course of the disease.

Prophylactic cranial irradiation in non-small cell lung cancer patients: who might be the candidates?

Prophylactic cranial irradiation in non-small cell lung cancer patients: who might be the candidates? Charalampos Dimitropoulos1, Georgios Hillas2, Sofia Nikolakopoulou2, Ioanna Kostara2, Konstantinos Sagris2, Fotis Vlastos2, Manos Alchanatis319th Respiratory Medicine Department; 2Department of Respiratory and Critical Care Medicine, Research Unit; 3University of Athens, 1st Respiratory Medicine Department, University of Athens Medical School, “Sotiria” Chest Diseases Hospital, Athens, GreeceObjectives: Brain metastases (BMs) often advance the course of non-small cell lung cancer (NSCLC). We performed an observational study in order to investigate the possible correlation of selected clinical and epidemiological factors with BM appearance in patients suffering from different histological subtypes of NSCLC stage I–IV.Methods: The study included 161 consecutive patients with NSCLC. Analyzed data included patient- and tumor-related characteristics.Results: Thirty-nine patients (24.2%) presented BMs within 12 (0–36) weeks of diagnosis. BMs decreased the mean overall survival significantly (15.6 versus 50.7 weeks, P < 0.001), with hazard ratio (95% confidence interval) 3.60 (2.42–5.35). The age of the patients with BM was significantly lower than that of the patients without BM (60.8 ± 8.9 versus 66.5 ± 8.5, P < 0.001). Patients with BM had significantly higher pack-years consumption (75.9 ± 23.9 versus 58.9 ± 31.9, P = 0.003) and larger tumor size compared with patients without BM (size in mm: 55.1 ± 20.1 versus 45.9 ± 19.3, P = 0.012). The presence of BM was also correlated with the absence of lung (P < 0.001), bone (P = 0.005), and adrenal (P = 0.046) metastases.Conclusion: Younger NSCLC patients with high tobacco consumption, large tumor size, and absence of metastases in other organs (lung, bones, adrenal metastases) are at high risk of BM appearance during the course of NSCLC and are candidates for prophylactic cranial irradiation early in the course of the disease.Keywords: NSCLC, brain metastases, clinical and epidemiological factors, PCI

CTLA-4, CD28, and ICOS gene polymorphism associations with non-small-cell lung cancer

Polymorphisms in genes encoding CD28, ICOS, and CTLA-4 were demonstrated to be associated with susceptibility to malignancies. To the best of our knowledge, no study on this association has been performed in a Caucasian population for non-small-cell lung cancer (NSCLC). In the present work, we investigated the polymorphisms CTLA-4c.49 A> G (rs231775), CTLA-4g.319C> T (rs5742909), CTLA-4g. *642AT(8_33), CTLA- 4g.*6230G>A (CT60) (rs3087243), CTLA- 4g.*10223G>T (Jo31) (rs11571302), CD28c.17+3T> C (rs3116496), and ICOSc.1554+4GT(8_15) in 208 NSCLC patients and 326 controls. The distributions of the allele and genotype were similar in both groups for CTLA-4, CD28, and ICOS gene polymorphisms. However, we noted a tendency toward overrepresentation of individuals possessing the CTLA- 4c.49A>G[A] allele in NSCLC patients compared with controls (0.84 vs 0.79, p = 0.09). The association became significant compared with controls in women for the CTLA- 4c.49A>G[A] allele and CTLA- 4c.49A>G[AA] genotype (0.67 vs 0.54, p = 0.01, and 0.47 vs 0.30, p = 0.02; respectively). Moreover, the constellation of alleles C TLA- 4c.49A>G[A]/CT60[G]/ CD28c.17+3T>C[T]/ ICOSc.1554+4GT(8_15)[>10] increased the risk of NSCLC about 2-fold ( p = 0.002). The same constellation of alleles combined with smoking, CTLA-4g.319C> T[T], and ICOSc.1554+4GT(8_15)[>10] was associated with a decreased overall survival rate. In conclusion, the constellation of specific alleles in CTLA-4, CD28, and ICOS genes contributes to the susceptibility and clinical course of NSCLC.

Prognostic Significance of Telomerase Polymorphism in Non–Small Cell Lung Cancer

Lung cancer is the leading cause of death in oncologic patients of western countries, with very low survival rates. Telomerase main components are the catalytic subunit (hTERT) and the RNA template (hTR). A functional polymorphism in the hTERT gene was found in the promoter region (-1327T/C), and individuals homozygous for the -1327C/C genotype present shorter telomere length compared with T-carrier genotypes. Our purpose was to investigate the potential prognostic role of the hTERT functional genetic variant in non-small cell lung cancer (NSCLC) patients. We prospectively conducted a study involving 226 patients with NSCLC treated with a first-line chemotherapeutic standard protocol. A follow-up study was undertaken (median follow-up time, 26 months) to evaluate treatment response and overall survival of NSCLC patients. The hTERT -1327T/C genetic variants were analyzed by allelic discrimination with real-time PCR. Our results indicate an influence of the telomerase genetic variants in the overall survival of NSCLC patients. Cox regression analysis showed a significantly higher median estimated cumulative survival of 26.5 months in T-carrier patients, compared with that of 19.3 months in CC patients (hazard ratio, 0.52; 95% confidence interval, 0.35-0.77; P = 0.001). Telomerase functional polymorphism in the hTERT gene may contribute as a prognostic factor in NSCLC patients. Our findings indicate that hTERT genetic variants, by modulating telomere length, may confer an advantage in chemotherapy response. The assessment of telomerase genetic variants could supplement prognosis of survival in the course of NSCLC and may be a promising molecular marker of treatment response in these patients.

The use of insulin and the effect on survival of non-small cell lung cancer patients

e22073 Background: Diabetes mellitus (DM) is one of the common morbidities in United States. Insulin therapy has been frequently used in its treatment. Some studies have postulated that activation of Insulin and Insulin-like growth factor (IGF) pathway may contribute to cancer proliferation, growth and resistance to anticancer therapies. The impact of insulin on diabetic patients with non-small cell lung cancer (NSCLC) has not been reported. Methods: 1,233 patients with NSCLC diagnosed between January 1999 and December 2004 were identified from the Tumor Registry at Henry Ford Health System. Based on inclusion criteria, data from 1,206 patients were extracted from the electronic medical records. Statistical analyses were performed between insulin and non insulin users. Results: Out of 1,206 patients, 193 patients had NSCLC and DM. Data was available from 192 patients. Sixty (31.3%) were on insulin at the time of NSCLC diagnosis and defined as insulin users, while 132 were not on insulin and defined as non- users (68.7%). Demographics, co-morbidities, disease stage at diagnosis, therapeutic interventions, and laboratory values were analyzed for overall and cancer-specific survival. More insulin users (81%) than non-users (64%) presented with advanced disease (stage ≥ 3) at diagnosis (P=0.02). Although no significant difference of Hemoglobin A1c was observed, the median survival from all causes of death was 6.5 months for insulin-users versus 9.9 months for non-users (P=0.08). When survival time was calculated from cancer-specific death, the median survival between insulin and non-insulin users was 7.2 months versus 38.7 months, respectively (P=0.002), with a hazard ratio (HR) for insulin use equals 1.91. Results from our univariable and multivariable analyses will be presented at the ASCO annual meeting in detail. Conclusions: This data indicates that the use of insulin may adversely affect the biology and clinical course of NSCLC with a tendency of advanced disease stage at diagnosis and a shorter cancer-specific survival time. Prospective study of DM with NSCLC or other cancer diagnosis will improve our understanding of this potential adverse effect on cancer biology and provide scientific rational to target IGF-pathway especially in diabetic patients. No significant financial relationships to disclose.

Loss of cables protein expression in human non–small cell lung cancer: A tissue microarray study

Loss of heterozygosity (LOH) on chromosome 18q is common in lung cancer. The genes involved in LOH on 18q in lung cancer have not been well characterized. Cables, a cyclin-dependent kinase (cdk) interacting protein, has recently been identified and mapped to human chromosome 18q11-12. Cables inhibits cell growth and suppresses tumor formation in nude mice, making it a candidate gene for 18q LOH in lung cancer. Little is known regarding Cables protein expression in human non–small cell lung cancer (NSCLC). In this study we examined Cables expression in 163 NSCLC and nonneoplastic lung specimens using tissue microarrays. Strong nuclear staining was present in normal lung and bronchial tissue. We also evaluated the Cables protein expression pattern and its correlation with histopathologic features and with clinical course of NSCLC. The results of the present study demonstrate for the first time that numerous NSCLCs (45%) lose Cables expression. Furthermore, more adenocarcinomas show a loss of this novel protein than do squamous counterparts. The relationship between tumor histology type and Cables expression appears to be statistically significant (P = 0.028). Our results suggest that Cables may be involved in the pathogenesis of NSCLC. HUM PATHOL 34:143-149. Copyright 2003, Elsevier Science (USA). All rights reserved.

Rationale for the use of chemotherapy in non-small cell lung cancer : Miller TP. Cancer Center Clinics, Arizona Cancer Center, 1515 N Campbell Ave, Tucson, AZ85724. Semin Oncol 1990;17:Suppl 7:11–13

The vast majority of patients have disseminated non-small cell lung cancer (NSCLC) at the time of diagnosis. Data from numerous studies clearly indicate that the disease is metastatic in asymptomatic patients who appear to have clinically resectable tumors. Adenocarcinoma is the histologic subtype that is most frequently metastatic, and its incidence appears to be increasing in a manner relative to other tumors. Of all of the prognostic factors, performance status appears to be most directly related to response rates. In other words, the higher the performance status, the higher the response rates. Tumor burden has been found to have an effect not only on performance status, but also on response to chemotherapy. Therefore systemic chemotherapy is urged as adjuvant treatment early in the course of NSCLC when performance status is highest and tumor burden lowest.