ALK Mutations Research Articles

Cost-effectiveness of adjuvant atezolizumab versus best supportive care in the treatment of patients with resectable early-stage non-small cell lung cancer and overexpression of PD-L1

AimsTo assess the cost-effectiveness of adjuvant atezolizumab in the treatment of early-stage NSCLC patients (stage II–IIIA) with expression PD-L1 ≥ 50% without mutations in EGFR or ALK rearrangements in Spain.Materials and methodsA 5-states Markov model (DFS, locoregional recurrence, 1 L-metastatic recurrence, 2 L-metastatic recurrence, and death states) was adapted to the Spanish setting. Demographic characteristics of the hypothetical cohort, transition probabilities from the DFS state, and safety parameters were obtained from IMpower010 study (GO29527). Transition probabilities from locoregional and metastatic health states were obtained from the literature. The usual clinical practice in Spain (use of health resources, management of the disease, etc.) was obtained from a previous analysis carried out by the authors of this study. A societal perspective was considered so both direct and indirect costs were included (expressed in € of 2021). A lifetime horizon was used, so costs and health outcomes were discounted at 3% per year. Sensitivity analyses were performed to evaluate uncertainty.ResultsOver a lifetime horizon, treatment with adjuvant atezolizumab provided greater effectiveness (+2.61 life years [LY] and +1.95 quality-adjusted life years [QALY]) and higher cost (€+22,538) than BSC. The incremental cost-effectiveness ratio (ICER) and incremental cost-utility ratios (ICUR) of the analysis were €8,625/LY gained and €11,583/QALY gained, respectively. Robustness of these base-case results was confirmed by the sensitivity analyses performed. In the probabilistic sensitivity analysis, 90% of the simulations performed showed that adjuvant atezolizumab is cost-effective versus BSC, considering a threshold of €30,000/QALY.ConclusionsOur results showed that adjuvant treatment with atezolizumab in patients with early-stage resected NSCLC with overexpression of PD-L1 and without EGFR and ALK mutations is cost-effective versus BSC as the ICERs and ICURs obtained are below the cost-effectiveness thresholds commonly considered in Spain, thus offering a new treatment alternative for these patients.

ALK Gene Mutation and ALK Protein Expression in Advanced Neuroblastoma and the Potential Value in Risk Stratification in Fine-Needle Aspiration Biopsy Samples.

The protein ALK is targeted for therapy in neuroblastoma, and ALK mutation confers a poor prognosis. We evaluated ALK in a cohort of patients with advanced neuroblastoma diagnosed by fine-needle aspiration biopsy (FNAB). Fifty-four cases of neuroblastoma were evaluated for ALK protein expression by immunocytochemistry and ALK gene mutation by next-generation sequencing. MYCN amplification by fluorescence in situ hybridization, International Neuroblastoma Risk Group (INRG) staging, and risk assignment was performed, and patients were managed accordingly. All parameters were correlated with overall survival (OS). ALK protein showed cytoplasmic expression in 65% cases and did not correlate with MYCN amplification (P = .35), INRG groups (P = .52), and OS (P = .2); however, ALK-positive, poorly differentiated neuroblastoma showed better prognosis (P = .02). ALK negativity was associated with poor outcome by Cox proportional hazard model (hazard ratio, 2.36). Two patients showed ALK gene F1174L mutation with 8% and 54% allele frequency and high ALK protein expression; they died of disease 1 and 17 months following diagnosis, respectively. A novel IDH1 exon 4 mutation was also detected. ALK expression is a promising prognostic and predictive marker in advanced neuroblastoma that can be evaluated in cell blocks from FNAB samples along with traditional prognostic parameters. ALK gene mutation confers a poor prognosis for patients with this disease.

Genomic ALK alterations in primary and relapsed neuroblastoma

BackgroundGenomic alterations of the anaplastic lymphoma kinase gene (ALK) occur recurrently in neuroblastoma, a pediatric malignancy of the sympathetic nervous system. However, information on their development over time has remained sparse.MethodsALK alterations were assessed in neuroblastomas at diagnosis and/or relapse from a total of 943 patients, covering all stages of disease. Longitudinal information on diagnostic and relapsed samples from individual patients was available in 101 and 102 cases for mutation and amplification status, respectively.ResultsAt diagnosis, ALK point mutations occurred in 10.5% of all cases, with highest frequencies in stage 4 patients <18 months. At relapse, ALK alteration frequency increased by 70%, both in high-risk and non-high-risk cases. The increase was most likely due to de novo mutations, frequently leading to R1275Q substitutions, which are sensitive to pharmacological ALK inhibition. By contrast, the frequency of ALK amplifications did not change over the course of the disease. ALK amplifications, but not mutations, were associated with poor patient outcome.ConclusionsThe considerably increased frequency of ALK mutations at relapse and their high prevalence in young stage 4 patients suggest surveying the genomic ALK status regularly in these patient cohorts, and to evaluate ALK-targeted treatment also in intermediate-risk patients.

Targeting immune cell types of tumor microenvironment to overcome resistance to PD-1/PD-L1 blockade in lung cancer.

Lung cancer is the common malignant tumor with the highest mortality rate. Lung cancer patients have achieved benefits from immunotherapy, including immune checkpoint inhibitors (ICIs) therapy. Unfortunately, cancer patients acquire adaptive immune resistance, leading to poor prognosis. Tumor microenvironment (TME) has been demonstrated to play a critical role in participating in acquired adaptive immune resistance. TME is associated with molecular heterogeneity of immunotherapy efficacy in lung cancer. In this article, we discuss how immune cell types of TME are correlated with immunotherapy in lung cancer. Moreover, we describe the efficacy of immunotherapy in driven gene mutations in lung cancer, including KRAS, TP53, EGFR, ALK, ROS1, KEAP1, ZFHX3, PTCH1, PAK7, UBE3A, TNF-α, NOTCH, LRP1B, FBXW7, and STK11. We also emphasize that modulation of immune cell types of TME could be a promising strategy for improving adaptive immune resistance in lung cancer.

Targeting polymerase θ impairs tumorigenesis and enhances radiosensitivity in lung adenocarcinoma.

Radioresistance remains a major obstacle to efficacious radiotherapy in non-small-cell lung cancer (NSCLC). DNA replication proteins are novel targets for radiosensitizers. POLQ is a DNA polymerase involved in DNA damage response and repair. We found that POLQ is overexpressed in NSCLC and is clinically correlated with high tumor stage, poor prognosis, increased tumor mutational burden, and ALK and TP5 mutation status; POLQ inhibition impaired lung tumorigenesis. Notably, POLQ expression was higher in radioresistant lung cancer cells than in wild-type cancer cells. Moreover, POLQ expression was further increased in radioresistant cells after radiation. Enhanced radioresistance is through a prolonged G2/M phase and faster repair of DNA damage, leading to reduced radiation-induced apoptosis. Novobiocin (NVB), a POLQ inhibitor, specifically targeted cancer cells. Genetic knockdown of POLQ or pharmacological inhibition by NVB decreased radioresistance in lung adenocarcinoma while causing little toxicity to normal pulmonary epithelial cells. In conclusion, POLQ is a promising and practical cancer-specific target to impair tumorigenesis and enhance radiosensitivity in NSCLC.

Single-cell next-generation sequencing of circulating tumor cells in patients with neuroblastoma.

Circulating tumor cells (CTCs) derived from any tumor tissue could contribute to metastasis and resistance to cancer treatments. In this study, we performed single-cell next-generation sequencing of CTCs and evaluated their usefulness for characterizing tumor biology and the mechanisms of metastasis in neuroblastomas (NB). We aimed to isolate CTCs from10 patients with NB at diagnosis before any treatments and four patients at relapse. GD2+ CD90+ CD45- CD235a- DAPI- cells were isolated as neuroblastoma CTCs using fluorescence-activated cell sorting. In five patients with advanced stages (M stage), DNA and RNA sequencing of CTCs at single-cell level were performed. NB CTCs were isolated from eight of the 10 patients at diagnosis and three of the four patients at relapse. More CTCs could be isolated from patients with advanced stages. In one patient, ALK mutation (p.F1174L), was identified in both tumor tissue and a CTC. In patients with MYCN amplification, this gene was amplified in 12 of 13 CTCs. Using single-cell RNA sequencing, angiogenesis-related and cell cycle-related genes together with CCND1 and TUBA1A genes were found to be upregulated in CTCs. In one patient, CTCs were divided into two subgroups showing different gene expression profiles. In one subgroup, cell cycle-related and proliferation-related genes were differentially upregulated compared with the other group. In conclusion, next-generation sequencing of CTCs at single-cell level might help to characterize the tumor biology and the mechanisms of metastasis in NB.

PP01.09 Genotypic Characteristics and Resistance Mutations in Advanced ALK+ NSCLC: The ALK-PATHFINDER Study

ALK rearrangements occur in approximately 5% of advanced non-small cell lung cancer (NSCLC) patients. The current standard initial therapy is a second-generation ALK tyrosine kinase inhibitor (TKI), such as alectinib or brigatinib, which has shown great improvements in response rates, progression-free survival and overall survival. However, most patients relapse due to acquired resistance mechanisms including secondary mutations in ALK kinase domain, such as G1202R and I1171N. Indeed, ALK mutations are more frequent in patients treated with second generation inhibitors than with first-generation (53-54% under alectinib or ceritinib, 71% under brigatinib vs. 20% under crizotinib). In addition, the optimal sequence of ALK inhibitors has not been established yet, but the selection of the most suitable subsequent line according to ALK resistance mutations must be a key strategic approach for the therapeutic decision-making process for these patients.

Acquired L1196M ALK mutation in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma during alectinib administration.

Acquired L1196M ALK mutation in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma during alectinib administration.

Cost-effectiveness of atezolizumab versus pembrolizumab as first-line treatment in PD-L1-positive advanced non-small-cell lung cancer in Spain

BackgroundAtezolizumab has recently been approved for first-line treatment of high PD-L1 expression metastatic Non-Small-Cell Lung Cancer (NSCLC) patients with no EGFR or ALK mutations, on the basis of the IMpower110 trial. This study aims to estimate the cost-effectiveness of atezolizumab compared with pembrolizumab among these patients in Spanish settings, based on the results of the two cut-offs of the IMpower110 study.MethodsA three-state partitioned-survival model was adapted to Spanish settings to calculate health outcomes and costs over a lifetime horizon. Clinical data for atezolizumab were collected from the interim and the exploratory results (data cut-off: Sept’18 and Feb’20, respectively) of the IMpower110 trial while a network meta-analysis was used to model pembrolizumab treatment. Utility data were collected from the trial. Direct medical costs were considered based on resources identified by experts. Costs and outcomes were discounted at 3% per year. Health outcomes were expressed as cost per Life Year (LY) and cost per Quality-Adjusted Life Year (QALY). Both deterministic and probabilistic sensitivity analyses were performed to assess the robustness of results.ResultsOver a lifetime horizon, the incremental results showed that atezolizumab generated similar health outcomes (LYs and QALYs) to pembrolizumab, with minimal differences depending on the cut-off used (+ 0.70 and + 0.42 LYs and QALYs with Sept’18 cut-off and − 0.80 and − 0.72 LYs and QALYs with Feb’20 cut-off). However, for both cut-offs, atezolizumab produced meaningfully less costs than pembrolizumab (€ − 54,261 with Sept’18 cut-off and € − 81,907 with Feb’20 cut-off). The sensitivity analyses carried out confirmed the robustness of the base-case results.ConclusionsThe cost-effectiveness analysis, comparing the two cut-off of IMpower110, shows that atezolizumab provides similar health gains to pembrolizumab but at a lower cost for the first-line treatment of metastasic NSCLC patients in Spain.

Dishevelled Segment Polarity Protein 3: A Novel Prognosis-related Marker in Pan-driver-gene-negative Lung Adenocarcinoma.

Purpose: In this study, we aimed to investigate the potential prognostic molecular marker in patients with "pan-driver-gene-negative" lung adenocarcinoma (PDGN-LUAD). LUAD patients who were negative for mutations in EGFR, KRAS, BRAF, HER2, MET, ALK, RET and ROS1 were identified as PDGN-LUAD. Methods: In the screening phase, we profiled the mRNA expression levels in 52 paired PDGN-LUAD tumor tissues and adjacent normal tissues using a genome-wide microarray, and the results revealed that the expression level of dishevelled segment polarity protein 3 (DVL3) was higher in PDGN-LUAD tumor tissues than in normal lung tissues. Then, we enrolled 626 PDGN-LUAD patients from three independent hospital centers and divided them into a training cohort, an internal validation cohort and two external validation cohorts. In the training cohort, tissue microarrays (TMAs) were used to confirm the protein expression level of DVL3. Statistical methods were applied to explore the prognostic role of DVL3. Results: The results indicated that the level of DVL3 could be used to classify patients with PDGN-LUAD in the training cohort into a high-risk group (high expression level of DVL3) and a low-risk group (low expression level of DVL3). In the training cohort, high-risk patients had shorter overall survival (OS) times (hazard ratio [HR] 2.27; 95% CI, 1.57-2.97; p<0.001) than low-risk patients. In the validation phase, the performance of DVL3 as a prognostic marker was successfully validated in the internal and external cohorts. Conclusions: In conclusion, DVL3 is an important prognostic indicator for PDGN-LUAD and may provide new insights into the treatment of PDGN-LUAD.

Oncogenic driver mutations in Vietnamese patients with lung adenocarcinoma

Mutation profiles of oncogenes play essential roles in cancer therapy, but data on the prevalence of lung cancer oncogenic driver mutations in Vietnamese patients are limited. This study aims to evaluate the mutation status of EGFR, ALK, ROS1, RET and MET and analyze the association of gene mutations with clinicopathological characteristics of lung adenocarcinoma. Of the 179 lung adenocarcinoma tissues, EGFR, ALK, ROS1, RET and MET mutation frequencies were 44.6; 7.9; 3.0; 3.0 and 2.0 percent, respectively. EGFR, ALK, ROS1 and RET alterations tended to be higher in females. Moreover, rearrangements of ALK, ROS and RET were more prevalent in younger lung adenocarcinoma, but skipping at exon 14 MET was more frequent in male and older patients. Stages III and IV seem to accumulate more ALK, RET and MET abnormalities. These findings identified the variation of frequencies of Vietnamese lung adenocarcinoma with different clinicopathological characteristics and established the pioneer data for oncogenic diver mutation of lung cancer in Vietnam.

Tumor PD-L1 expression and molecular profiling are not associated with immune checkpoint inhibitor-induced thyroid dysfunction in advanced NSCLC patients.

Background: Immune-checkpoint inhibitors (ICIs) have revolutionized the treatment of advanced non-small cell lung cancer (NSCLC), however are frequently associated with thyroid immune-related adverse events (IRAEs). We investigated the association between patient characteristics, tumor PD-L1 expression and molecular profile with the development of thyroid IRAEs in NSCLC patients. Methods: Single center, retrospective study including 107 NSCLC patients treated with PD-1/PD-L1 inhibitors from April 2016 to July 2020. All patients were euthyroid at baseline with at least two TSH measurements post-treatment initiation. The primary outcome was the difference in tumor PD-L1 expression in patients who developed any thyroid IRAEs versus those who remained euthyroid. Additional outcomes included development of overt thyroid dysfunction, the association of specific molecular alterations with thyroid IRAEs, and onset of thyroid IRAEs as a function of tumor PD-L1 expression. Results: Overall, 37 (34.6%) patients developed any thyroid dysfunction and 18 (16.8%) developed overt thyroid dysfunction. Tumor PD-L1 staining intensity was not associated with thyroid IRAEs. TP53 mutation was less likely to be associated with any thyroid dysfunction (p < 0.05) and no association was found between EGFR, ROS, ALK or KRAS mutations. There was no association between PD-L1 expression and time to develop thyroid IRAEs. Conclusion: PD-L1 expression is not associated with the development of thyroid dysfunction in advanced NSCLC patients treated with ICIs, suggesting that thyroid IRAEs are unrelated to tumor PD-L1 expression.

Programmed Death Ligand 1 (PD-L1) Expression and its Association with Driver Mutations among Patients with Non-Small Cell Lung Cancer in a Private Tertiary Care Setting

Objective. The advent of immunotherapy has significantly changed the treatment and management of patients with advanced non-small cell lung cancer (NSCLC). Prior to initiation of immunotherapy,evaluation of programmed death ligand 1 (PD-L1) expression is required. One factor that affects PD-L1 expression in NSCLC is the presence of oncogenic driver mutations; however, little data on itsassociation is available, especially in the Philippine setting. The study aims to determine the prevalence of PD-L1 expression and its association with driver mutations among patients with non-small cell lung cancer in a private tertiary care hospital in the Philippines.Methodology. The study was undertaken for a period of two years from July 2017-July 2019 at St. Luke’s Medical Center and included 446 NSCLC samples. PD-L1 was evaluated by immunohistochemistry using 22C3 anti-PD-L1 antibody clone, EnVision FLEX visualization system on Autostainer Link 48. Patient demographics and data on driver mutation testing were recorded. Statistical analysis was performed using logistic regression.Results. PD-L1 expression was observed in 273 (61.20%) of 446 cases, 119 (61.20%) of whichdemonstrated high PD-L1 expression while 154 (34.50%) had low PD-L1 expression. There was nosignificant association between PD-L1 expression and EGFR mutation, ALK mutation, age, and gender.For histologic type, high PD-L1 expression was significantly associated with adenocarcinoma and non-small cell carcinoma, NOS.Conclusion. The overall prevalence of PD-L1 expression in non-small cell lung carcinoma is 61.20%based on the cases included. Although we did not find an association between PD-L1 expression andEGFR and ALK mutation, our study observed that ALK-mutated NSCLCs have 4.7 odds of having highPD-L1 expression, however, a higher sample size is warranted to truly determine significant association. The outcome of this study may provide help in the stratification of patients and predict those who will benefit from immunotherapy.

Retrospective analysis and a cross-sectional questionnaire survey of lung cancer concomitant with interstitial lung disease

Objective: To describe the clinical characteristics and prognosis of lung cancer concomitant with interstitial lung disease (LC-ILD), and to understand the current status of knowledge of LC-ILD by physicians in the departments related to the treatment of the disease. Methods: We conducted a retrospective analysis of in-hospitalized pathology identified lung cancer (LC) patients who were admitted to our hospital between January 2014 and December 2018. After reviewing their chest CT imagings and pathological reports, 70 patients who were concomitant with interstitial lung disease (ILD) were enrolled in our study. On the other hand, a cross-sectional survey using an online questionnaire was conducted in LC-ILD management doctors who came from 29 provincial hospitals. The perceptions of demographic features, LC characteristics and management, ILD characteristics and management, and the prognosis of LC-ILD were investigated. Results: Among the 70 enrolled LC-ILD cases, there were 52 males, and the mean age was (64.3±7.63) years (ranged from 49 years to 84 years). There were 51 patients who were older than 59 years. The most common pathological pattern of LC was adenocarcinoma. Most of them were diagnosed with LC and ILD simultaneously, and they were usually treated with chemotherapy while unresectable. There were 11 patients (15.7%) with positive EGFR or ALK mutation. Forty-five patients (64.3%) died during the follow-up, and 33 were died from LC progression. There were no significant differences between the surgical group and non-surgical group on age, pathological patterns, EGFR or ALK mutation. However, LC-ILD patients in the surgical group were diagnosed with earlier TNM classification and with better prognosis. A total of 1 014 doctors answered the questionnaire completely. In the feedback, patients aged 60 years and older (785 doctors/77.4%), and male patients (720 doctors/71%) were the predominant LC-ILD patients. Adenocarcinoma (390 doctors/38.5%), adenocarcinoma or squamous-cell cancer (SCC) (182 doctors/17.9%), and SCC (151 doctors/14.9%) were considered as the common pathological patterns of LC-ILD patients. In most doctors' feedback, the EGFR or ALK mutation was not common for LC-ILD: low (646 doctors/63.7%) or hardly (306 doctors/30.5%) positive mutation. The diagnosis of ILD was earlier than LC (506 doctors/49.9%) or there was no identified precedence of LC and ILD diagnosis (208 doctors/20.5%). Most of the doctors (693 doctors/68.3%) agreed that the vital factor for surgery or not was the severity of ILD for LC-ILD patients. There were great divergences on the treatment protocol both for the advanced LC and ILD. The patients with LC-ILD were died mostly from LC progression and ILD exacerbation (542 doctors/53.5%), followed by ILD exacerbation (237 doctors/23.4%) or LC progression (226 doctors/22.3%). Conclusions: The elderly male patients were predisposed to LC-ILD, and adenocarcinoma was the common pathological pattern. The LC-ILD patients with non-advanced LC who were performed with surgery had better prognosis. However, it is recommended to consider whether to perform surgery in combination with the severity of the ILD.

Lung Cancer in Non-Smokers: Clinicopathological and Survival Differences from Smokers.

Background Lung cancer in non-smokers is a clinically distinct entity based on unique epidemiology, clinicopathology, genetics, treatment response, and outcome. Data from Indian centres are scarce. The objective of this study was to compare the frequency, clinical characteristics, driver mutations, and survival of non-smoking and smoking lung cancer patients treated at a tertiary cancer centre in North India. Methodology Two years of data on 724 consecutive lung cancer patients were assessed. Clinical, demographics, smoking history, and EGFR and ALK mutation test results were collected. Descriptive and inferential statistics were applied. Survival analysis was performed using the Kaplan-Meier method. Results Non-smokers comprised 40.9% of the study sample. Non-smokers were more likely than smokers to experience disease onset at a younger age (P = 0.004) and metastasis (P < 0.001).The tumor histology showed significant differences (P < 0.001), with non-smokers more likely to be diagnosed with adenocarcinoma (77.4%), while squamous and small cell histologies were commonly found among smokers (37.6% and 13.8%, respectively). The EGFR mutation and ALK rearrangement rates in the cohort were 23.3% and 10.1%, respectively, and were more frequent in non-smoking patients. Overall, 10-year survival was 7%, with a significantly better survival rate of non-smokers than smokers (median survival time of 15.13 vs10.17 months; P = 0.012). Conclusions About four out of 10 patients diagnosed with lung cancer at our centre were non-smokers. They were more often young, diagnosed at an advanced stage, with predominantly adenocarcinoma histology, and had a threefold higher frequency of EGFR mutations than smokers. In our cohort, non-smokers appear to be a targetable group with better survival than smokers.

IMMUNOTHERAPY AS NOVEL TREATMENT OF LUNG CANCER: A SYSTEMATIC REVIEW

Lung cancer is the top cause of cancer-related fatalities in both men and women around the world, and the second most commonly diagnosed cancer in both men and women. For many patients, traditional chemotherapy (CT) fails to give long-term benefit. Moreover, newer medicines targeting activating mutations in EGFR or ALK have shown increased response rates over CT in the minority of patients with these mutations; however, the majority of patients do not have actionable mutations and will not benefit from targeted therapies. In addition, several combinations of chemotherapeutic medicines with the angiogenesis inhibitor bevacizumab have provided only minor additional benefits. However, immunotherapy using checkpoint inhibitors has shown to have a lot of potential in the treatment of advanced non-SCLC (NSCLC) in recent trials. These new medications encourage the host immune system to recognize tumor cells as foreign invaders and halting their growth. They help alleviate immune system suppression, which allows tumor development to be tolerated. In checkpoint immunotherapy, humanized monoclonal antibodies targeting checkpoint signals such as programmed cell death receptor (PD-1) and programmed cell death ligand are employed (PD-L1). The immune system can be triggered to fight the tumor by inhibiting these receptors and signals. Immunotherapy for advanced lung cancer has created a new paradigm of therapeutic options, with increased survival and response rates and a less severe but distinct side profile when compared to CT. The PD-1 inhibitors nivolumab and pembrolizumab, as well as the PD-L1 inhibitor atezolizumab, have been approved by regulatory authorities for the treatment of advanced NSCLC. Hence, the current review article focuses on the role of immunotherapy, newer agents used for checkpoint inhibitors in lung cancer, their epidemiology, risk factors, side-effect profiles, therapeutic indications, and their mechanism of action for the successful treatment of lung cancer.

Risk of thromboembolism in non-small-cell lung cancers patients with different oncogenic drivers, including ROS1, ALK, and EGFR mutations

Anaplastic lymphoma kinase-positive (ALK+) and ROS proto-oncogene 1 (ROS1)-positive (ROS1+) lung cancers have been reported to be associated with an elevated risk of thromboembolic events. This study aimed to assess the long-term risk of developing thromboembolism (TE) in ROS1+ lung cancer and to compare it with other oncogenic drivers in the Asian population. We retrospectively enrolled a cohort of ROS1+ lung adenocarcinoma in a medical center in Taiwan and a comparison cohort of ALK+ and epidermal growth factor receptor-positive (EGFR+) lung cancers. Venous and arterial TEs were identified throughout the cancer course, and the incidence rate was calculated. We enrolled 44 ROS1+, 98 ALK+, and 168 EGFR+ non-small-cell lung cancer (NSCLC) patients. A total of 11 (25%), 36 (36.7%), and 38 (22.6%) patients in the ROS1, ALK, and EGFR cohorts, respectively, were diagnosed with thromboembolic events throughout the follow-up course of the disease (P= 0.042). The incidence rates were 99.0, 91.9, and 82.5 events per 1000 person-years for the ROS1, ALK, and EGFR cohorts, respectively. The majority of thrombosis events in the ROS1 (91.6%) and ALK (85.4%) cohorts were venous. On the contrary, 43.2% of thromboembolic events were arterial in the EGFR cohort. A higher proportion of thromboembolic events were noted during cancer diagnosis in the ROS1 cohort (36.3%) than in the ALK (16.7%) and EGFR (10.5%) cohorts. The stage was the only clinical variable associated with thromboembolic risk. There was a significant difference in survival between patients with and without TE in the EGFR cohort, but not in the ALK and ROS1 cohorts. Although ROS1+ and ALK+ NSCLCs had a higher cumulative incidence of TE than EGFR+ NSCLC, the person-year incidence rates were similar among the three groups. EGFR-mutated NSCLC had more arterial events. Nevertheless, ALK+ lung cancer had higher venous events than EGFR-mutated lung cancer.

Analysis of molecular pathologic and clinical features of 36 patients with pulmonary sarcomatoid carcinoma

BackgroundPulmonary sarcomatoid carcinoma (PSC) is a heterogeneous disease with poor prognosis. It is essential to understand the molecular basis of its progression in order to devise novel therapeutic strategies. The aim of this study was to identify the pathological mutations in PSC through next generation sequencing technology (NGS), and provide reference for the diagnosis and molecular targeted therapy.Materials and methodsThirty-sex patients with pathologically confirmed PSC who underwent surgical tumor resection at The First Hospital of Jilin University and Jilin Cancer Hospital from June 2011 to June 2017 were enrolled. Thirteen patients were successfully followed up and detailed clinical data were obtained. NGS was performed for the exons of entire oncogenes. Kaplan–Meier method was used for the univariate analysis, and the Cox proportional risk regression model was used for multivariate analysis.ResultsA total of 19 highly frequent mutations were identified, of which the KRAS, BRCA1 and ALK mutations were significantly correlated with the overall survival (OS). Multivariate analysis showed that KRAS mutation was an independent factor affecting the OS of PSC patients.ConclusionThe KRAS mutation is an independent prognostic factor for PSC, and patients harboring the KRAS mutation had significantly shorter OS compared to patients with wild type KRAS. The characteristic mutation landscape of PSC may guide clinical targeted therapy.

Prognostic value of Beclin 1, EGFR and ALK in non-squamous non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is one of the most malignant tumors. The study was carried out to investigate the prognostic value of Beclin 1, EGFR and ALK for this cancer. Patients diagnosed with non-squamous NSCLC and admitted to our hospital from January 2011 to September 2016 were analyzed. Expression of Beclin 1 and mutation of EGFR and ALK were assessed using polymerase chain reaction (PCR) and fluorescent in situ hybridization (FISH) and analyzed for their relationship with demographic and clinical characteristics of the patients. Multivariate Cox regression models were applied to analyze the risk factors associated with survival and receiver response curves (ROC) were plotted to determine the prognostic value of Beclin 1, EGFR and ALK for patients with non-squamous NSCLC. Compared with adjacent normal tissue, Beclin 1 expression was elevated in the cancer tissue significantly; assessments of EGFR and ALK mutations showed that out of the 480 patients, 233 (48.5%) and 75 (12.6%) patients had EGFR and ALK mutations. Univariate analysis revealed that Beclin 1 level, EGFR and ALK mutations were associated with lymph node metastasis, TNM stage, tumor differentiation and prognosis, but not with gender, age and smoking status. The Kaplan–Meier survival analysis indicated that low Beclin 1 expression and positive EGFR and ALK rearrangements were associated with higher survival rate and longer progress-free survival (PFS). Multivariate Cox regression analysis showed that Beclin 1, EGFR, ALK mutations, tumor differentiation grade, TNM stage and lymph node metastasis were independently associated with PFS. ROC analysis showed that Beclin 1, EGFR and ALK were significant predictors for PFS; the areas under curve (AUC) for Beclin 1, EGFR and ALK were 0.812 (P = 0.018, cut-off value: 1.2), 0.781 (P = 0.011, cut-off value: 15%) and 0.722 (P = 0.010, cut-off value: 11%), respectively, suggesting that they have significant prognostic value for lung cancer patients. Our data indicate that Beclin 1, EGFR and ALK genes are associated with the prognosis of patients with non-squamous NSCLC. High Beclin 1 expression and negative EGFR and ALK mutations predict a poor prognosis with PFS.

Methylation of N6 adenosine-related long noncoding RNA: effects on prognosis and treatment in 'driver-gene-negative' lung adenocarcinoma.

The improvement of treatment for patients with 'driver-gene-negative' lung adenocarcinoma (LUAD) remains a critical problem to be solved. We aimed to explore the role of methylation of N6 adenosine (m6A)-related long noncoding RNA (lncRNA) in stratifying 'driver-gene-negative' LUAD risk. Patients negative for mutations in EGFR, KRAS, BRAF, HER2, MET, ALK, RET, and ROS1 were identified as 'driver-gene-negative' cases. RNA sequencing was performed in 46 paired tumors and adjacent normal tissues from patients with 'driver-gene-negative' LUAD. Twenty-three m6A regulators and relevant lncRNAs were identified using Pearson's correlation analysis. K-means cluster analysis was used to stratify patients, and a prognostic nomogram was developed. The CIBERSORT and pRRophetic algorithms were employed to quantify the immune microenvironment and chemosensitivity. We identified two clusters highly consistent with the prognosis based on their unique expression profiles for 46 m6AlncRNAs. A risk model constructed from nine m6A lncRNAs could stratify patients into high- and low-risk groups with promising predictive power (C-index=0.824), and the risk score was an independent prognostic factor. The clusters and risk models were closely related to immune characteristics and chemosensitivity. Additional pan-cancer analysis using the nine m6AlncRNAs showed that the expression of DIO3 opposite strand upstream RNA (DIO3OS) is closely related to the immune/stromal score and tumor stemness in a variety of cancers. Our results show that m6AlncRNAs are a reliable prognostic tool and can aid treatment decision-making in 'driver-gene-negative' LUAD. DIO3OS is associated with the development of various cancers and has potential clinical applications.