Regulation of fatty acid synthase on tumor and progress in the development of related therapies.

ABSTRACT: Fatty acid synthase (FASN) is an essential molecule in lipid metabolic pathways, which are crucial for cancer-related studies. Recent studies have focused on a comprehensive understanding of the novel and important regulatory effects of FASN on malignant biological behavior and immune-cell infiltration, which are closely related to tumor occurrence and development, immune escape, and immune response. FASN-targeting antitumor treatment strategies are being developed. Therefore, in this review, we focused on the effects of FASN on tumor and immune-cell infiltration and reviewed the progress of related anti-tumor therapy development.

Epidermal growth factor receptor compound and concomitant mutations: advances in precision treatment strategies.

ABSTRACT: Epidermal growth factor receptor ( EGFR ) mutations are common oncogenic driver mutations in patients with non-small cell lung cancer (NSCLC). The application of EGFR-tyrosine kinase inhibitors (TKIs) is beneficial for patients with advanced and early-stage NSCLC. With the development of next-generation sequencing technology, numerous patients have been found to have more than one genetic mutation in addition to a single EGFR mutation; however, the efficacy of conventional EGFR-TKIs and the optimal treatments for such patients remain largely unknown. Thus, we review the incidence, prognosis, and current treatment regimens of EGFR compound mutations and EGFR concomitant mutations to provide treatment recommendations and guidance for patients with these mutations.

Mitochondrial immune regulation and anti-tumor immunotherapy strategies targeting mitochondria.

Cancer cells adapt to increasing energy and biosynthetic demands by reprogramming their metabolic pathways. Mitochondria are important organelles for the metabolic reprogramming of tumor cells. In addition to supplying energy, they play crucial roles in the survival, immune evasion, tumor progression, and treatment resistance of the hypoxic tumor microenvironment (TME) in cancer cells. With the development of the life sciences, scientists have gained an in-depth understanding of immunity, metabolism, and cancer, and numerous studies have emphasized that mitochondria are essential for tumor immune escape and the regulation of immune cell metabolism and activation. Moreover, recent evidence suggests that targeting the mitochondria-related pathway with anticancer drugs can initiate the killing of cancer cells by increasing the ability of cancer cells to be recognized by immune cells, tumor antigen presentation ability, and the anti-tumor function of immune cells. This review discusses the effects of mitochondrial morphology and function on the phenotype and function of immune cells under normal and TME conditions, the effects of mitochondrial changes in tumors and microenvironments on tumor immune escape and immune cell function, and finally focuses on the recent research progress and future challenges of novel anti-tumor immunotherapy strategies targeting mitochondria.

Therapeutic strategies targeting metabolic characteristics of cancer cells.

Metabolic reprogramming is one of the important characteristics of cancer and is a key process leading to malignant proliferation, tumor development and treatment resistance. A variety of therapeutic drugs targeting metabolic reaction enzymes, transport receptors, and special metabolic processes have been developed. In this review, we investigate the characteristics of multiple metabolic changes in cancer cells, including glycolytic pathways, lipid metabolism, and glutamine metabolism changes, describe how these changes promote tumor development and tumor resistance, and summarize the progress and challenges of therapeutic strategies targeting various links of tumor metabolism in combination with current study data.

Precision targeted therapy for EGFR mutation-positive NSCLC: Dilemmas and coping strategies.

The most common driver gene mutation in patients with non-small-cell lung cancer (NSCLC) is an epidermal growth factor receptor (EGFR) mutation. With the introduction of EGFR-tyrosine kinase inhibitors, the treatment prospects and prognosis of NSCLC patients with EGFR-sensitive mutations have significantly improved. Nonetheless, therapies targeting NSCLC are still associated with a risk of primary or secondary nonclassical drug resistance mutations. In recent years, the research and methodology have led to the continuous discovery of new drugs and drug resistance targets. These explorations have also resulted in continuously discovering new drugs. Consequently, rapid advancements have been made to overcome NSCLC drug resistance. This study aimed to review the current dilemma of targeted therapy for EGFR mutation-positive NSCLC and the coping strategies for these difficulties.

Potential new applications of immunotherapy for neuroendocrine neoplasms: immune landscape, current status and future perspectives.

Neuroendocrine neoplasms (NENs) are a highly heterogeneous class of tumors arising from neuroendocrine cells and peptidergic neurons. After failure of first-line treatment, patients have poor prognosis and limited treatment options. Immune checkpoint inhibitors (ICIs) may be a powerful means of increasing therapeutic efficacy for such patients, but ICIs alone have low response rates and short disease control durations in most NENs and may be effective for only a portion of the population. ICIs combined with other immunotherapies, targeted therapies, or cytotoxic drugs have achieved some efficacy in patients with NENs and are worthy of further exploration to assess their benefits to the population. In addition, accumulating experimental and clinical evidence supports that the interaction between neuroendocrine and immune systems is essential to maintain homeostasis, and assessment of this broad neuroendocrine-immune correlation is essential for NEN treatment. In this review, we summarize the immune microenvironment characteristics, advances in immunotherapy, predictive biomarkers of ICI efficacy for NENs, and the effects of common endocrine hormones on the immune system, highlighting possible new application areas for this promising treatment in neglected NENs.

Targeted therapy combined with immunotherapy in patients with breast infiltrating ductal carcinoma with axillary lymph node metastasis of metaplastic SCC.

At present, the clinicopathological features, optimal treatment patterns, and prognosis of breast metaplastic squamous cell carcinoma (SCC) are not fully understood and are still controversial. Here, we report a 56-year-old female patient with breast infiltrating ductal carcinoma with axillary lymph node metastasis of metaplastic SCC admitted to our hospital. Their homology was clarified by comparing the gene mutation results of the two lesions, that is, the axillary lymph node lesion was a metastasis of breast metaplastic SCC. We treated the patient with Poly ADP-ribose Polymerase (PARP) inhibitors in combination with immune checkpoint inhibitors (ICIs) and found that she could achieve clinical benefit from the combination regimen. We reported a successful diagnosis and treatment of this rare refractory disease and reviewed the literature on the characteristics, pathogenesis, and advances in the diagnosis and treatment of breast metaplastic SCC.

Development of Immunotherapy Strategies Targeting Tumor Microenvironment Is Fiercely Ongoing.

Tumor immune microenvironment is a very complex system that is influenced by a wide range of factors; in this microenvironment, various immune cells, stromal cells, and cytokines can interact with tumor cells and jointly regulate this complex ecosystem. During tumor development, the tumor microenvironment (TME) shows the upregulation of inhibitory signals and downregulation of activating signals, which result in an immunosuppressive microenvironment and lead to tumor immune escape. In recent years, a variety of precision immunotherapy strategies have been developed to remodel the TME into a positive immune microenvironment by stimulating or restoring the inherent tumor inhibition ability of the immune system so as to improve anti-tumor therapeutic efficacy. This review focuses on immunotherapy strategies targeting the TME, including those that target the microenvironment to inhibit signaling, activate signaling, and specifically involve many new targets such as physical barriers, immune cells and their surface molecular receptors, cytokines, and metabolic factors. Furthermore, it summarizes the challenges faced while conducting research on the tumor immune microenvironment and the corresponding solutions.

Burgeoning Exploration of the Role of Natural Killer Cells in Anti-PD-1/PD-L1 Therapy.

Antibodies targeting programmed death receptor-1 (PD-1)/programmed death ligand-1 (PD-L1) have been considered breakthrough therapies for a variety of solid and hematological malignancies. Although cytotoxic T cells play an important antitumor role during checkpoint blockade, they still show a potential killing effect on tumor types showing loss of/low major histocompatibility complex (MHC) expression and/or low neoantigen load; this knowledge has shifted the focus of researchers toward mechanisms of action other than T cell-driven immune responses. Evidence suggests that the blockade of the PD-1/PD-L1 axis may also improve natural killer (NK)-cell function and activity through direct or indirect mechanisms, which enhances antitumor cytotoxic effects; although important, this topic has been neglected in previous studies. Recently, some studies have reported evidence of PD-1 and PD-L1 expression in human NK cells, performed exploration of the intrinsic mechanism by which PD-1/PD-L1 blockade enhances NK-cell responses, and made some progress. This article summarizes the recent advances regarding the expression of PD-1 and PD-L1 molecules on the surface of NK cells as well as the interaction between anti-PD-1/PD-L1 drugs and NK cells and associated molecular mechanisms in the tumor microenvironment.

Therapeutic exploration of uncommon EGFR exon 20 insertion mutations in advanced non-small cell lung cancer: breaking through brambles and thorns.

BACKGROUND: EGFR exon 20 insertion (EGFR ex20ins) mutations account for about 10-12% of all EGFR-mutated tumors, which are usually associated with primary drug resistance to conventional EGFR-TKI therapy and worse survival outcomes, and are currently a major problem for clinicians in clinical management. In recent years, with the rapid improvement of sequencing technology and careful review of clinical data, investigators have gained a deeper understanding and clearer cognition of the clinicopathological features and molecular mechanisms of these EGFR ex20ins mutations. PURPOSE: The aim of this study was to systemically review the molecular structure and clinical characteristics of EGFR ex20ins mutations, and focus on summarizing the latest data of emerging therapies (including novel small-molecule EGFR-TKI drugs, specific monoclonal antibodies, novel drugs targeting other mechanisms, and immunotherapy) for those patients. CONCLUSION: Advances in overcoming these systemic challenges have greatly accelerated the development of new drugs targeting EGFR ex20ins, and are committed to designing more rational combination therapies to overcome or delay the emergence of drug resistance, ultimately improve the prognosis of such uncommon mutant populations.

Diverse and precision therapies open new horizons for patients with advanced pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is a common cause of cancer-related death, and most patients are with advanced disease when diagnosed. At present, despite a variety of treatments have been developed for PDAC, few effective treatment options are available; on the other hand, PDAC shows significant resistance to chemoradiotherapy, targeted therapy, and immunotherapy due to its heterogeneous genetic profile, molecular signaling pathways, and complex tumor immune microenvironment. Nevertheless, over the past decades, there have been many new advances in the key theory and understanding of the intrinsic mechanisms and complexity of molecular biology and molecular immunology in pancreatic cancer, based on which more and more diverse new means and reasonable combination strategies for PDAC treatment have been developed and preliminary breakthroughs have been made. With the continuous exploration, from surgical local treatment to comprehensive medical management, the research-diagnosis-management system of pancreatic cancer is improving. This review focused on the variety of treatments for advanced PDAC, including traditional chemotherapy, targeted therapy, immunotherapy, microenvironment matrix regulation as well as the treatment targeting epigenetics, metabolism and cancer stem cells. We pointed out the current research bottlenecks and future exploration directions.

Correlation of circulating tumor DNA EGFR mutation levels with clinical outcomes in patients with advanced lung adenocarcinoma.

BACKGROUND: Circulating tumor DNA (ctDNA) is a promising biomarker for non-invasive epidermal growth factor receptor mutations (EGFRm) detection in lung cancer patients, but existing methods have limitations in sensitivity and availability. In this study, we used the ΔCt value (mutant cycle threshold [Ct] value-internal control Ct value) generated during the polymerase chain reaction (PCR) assay to convert super-amplification-refractory mutation system (superARMS) from a qualitative method to a semi-quantitative method named reformed-superARMS (R-superARMS), and evaluated its performance in detecting EGFRm in plasma ctDNA in patients with advanced lung adenocarcinoma. METHODS: A total of 41 pairs of tissues and plasma samples were obtained from lung adenocarcinoma patients who had known EGFRm in tumor tissue and were previously untreated. EGFRm in ctDNA was identified by using superARMS. Through making use of ΔCt value generated during the detection process of superARMS, we indirectly transform this qualitative detection method into a semi-quantitative PCR detection method, named R-superARMS. Both qualitative and quantitative analyses of the data were performed. Kaplan-Meier analysis was performed to estimate the progression-free survival (PFS) and overall survival (OS). Fisher exact test was used for categorical variables. RESULTS: The concordance rate of EGFRm in tumor tissues and matched plasma samples was 68.3% (28/41). At baseline, EGFRm-positive patients were divided into two groups according to the cut-off ΔCt value of EGFRm set at 8.11. A significant difference in the median OS (mOS) between the two groups was observed (EGFRm ΔCt ≤8.11 vs. >8.11: not reached vs. 11.0 months; log-rank P = 0.024). Patients were divided into mutation clearance (MC) group and mutation incomplete clearance (MIC) group according to whether the ΔCt value of EGFRm test turned negative after 1 month of treatment. We found that there was also a significant difference in mOS (not reached vs. 10.4 months; log-rank P = 0.021) between MC group and MIC group. Although there was no significant difference in PFS between the two groups, the two curves were separated and the PFS of MC group tended to be higher than the MIC group (not reached vs. 27.5 months; log-rank P = 0.088). Furthermore, EGFRm-positive patients were divided into two groups according to the cut-off of the changes in ΔCt value of EGFRm after 1 month of treatment, which was set at 4.89. A significant difference in the mOS between the two groups was observed (change value of ΔCt >4.89 vs. ≤4.89: not reached vs. 11.0 months; log-rank P = 0.014). CONCLUSIONS: Detecting EGFRm in ctDNA using R-superARMS can identify patients who are more likely sensitive to targeted therapy, reflect the molecular load of patients, and predict the therapeutic efficacy and clinical outcomes of patients.

Advances in novel molecular typing and precise treatment strategies for small cell lung cancer.

Small cell lung cancer (SCLC) is a high-grade neuroendocrine (NE) cancer characterized by high circulating tumor-cell burden and early extensive metastasis. Considering the complexity of SCLC genes and the immune microenvironment, their unique molecular heterogeneity profiles have been continuously explored. The understanding of SCLC subtypes has recently changed from traditional "classical" and "variant" types to "NE" and "non-NE" phenotypes and to the subtypes defined by major transcriptional regulators, which indicates the gradual revelation of high intratumoral heterogeneity and plasticity characteristics of SCLCs. Advances in genomics as well as the development of single-cell sequencing analysis and new preclinical models have helped investigators gain many new insights into SCLCs and the development of targeted therapy and immunotherapy strategies. This article provides an overview of changes in molecular typing, tumor heterogeneity, and plasticity and that of advances in the precise treatment of different subtypes of SCLC.

The Chinese Thoracic Oncology Group (CTONG) therapeutic option scoring system: a multiple-parameter framework to assess the value of lung cancer treatment options.

BACKGROUND: Currently, there is no standard context that conforms to the Chinese national framework for evaluating medical decisions regarding the treatment of lung cancer. METHODS: This draft was formulated after a systematic review and a focus group discussion among 20 experts, who were senior physicians with extensive clinical experience from the Chinese Thoracic Oncology Group (CTONG) task force. Subsequently, a draft and a five-point Likert scale were sent to 300 CTONG working group members. These were modified according to feedback from a four-round modified Delphi approach. Hence, the first version of the 'Therapeutic option of lung cancer: CTONG scoring system' was formulated. Afterward, a corresponding questionnaire was designed to collect opinions on the weight allocation of various indicators. This was issued through the WeChat platform, "Oncology News" application and e-mails from October 23, 2020, to November 25, 2020. Participants from numerous occupations in cancer-related fields from various regions of China were included in the study. Overall and subgroup analyses regarding weight allocations were performed. The differences between participant-allocated and reference weights were considered to adjust the framework. RESULTS: The framework contained four aspects and six indicators, including efficacy [progression-free survival (PFS)/overall survival (OS) and subsequent treatment], safety [treatment-related severe adverse event (SAE), dose adjustment], quality of life (Qol), and compensation. The reference weights were 50%, 5%, 10%, 5%, 10%, and 20% for each indicator. By November 25, 2020, 1,043 valid questionnaires had been obtained. The majority of the questionnaires were completed by physicians (86.5%). Subgroup analysis among the various groups showed an overall consistent trend. Besides, significant differences between the participant-allocated and reference weights were found among PFS/OS (difference: -11.5%), compensation (difference: -10.1%), and subsequent treatment (difference: 9.7%) indicators. After discussion, the final weight allocations were set at 45%, 10%, 15%, 5%, 10%, and 15% for PFS/OS, subsequent treatment, treatment-related SAE, dose adjustment, Qol, and compensation, respectively. CONCLUSIONS: The CTONG scoring system, as an objective evaluation model that involves multiple parameters, is a breakthrough method for evaluating the therapeutic value of lung cancer treatment options in China, which is worthy of further verification in future clinical practice.

Correlation of Peripheral Blood Parameters and Immune-Related Adverse Events with the Efficacy of Immune Checkpoint Inhibitors.

OBJECTIVE: We aimed to retrospectively analyze the predictors of immune checkpoint inhibitors (ICIs)-efficacy in patients with advanced pancancer who were treated with various ICIs in the real world and focused on the correlation between ICIs-efficacy and immune-related adverse events (irAEs). METHODS: We retrospectively analyzed data from 103 patients with advanced pancancer treated receiving various ICIs in the First Hospital of Jilin University from January 1, 2016 to August 1, 2020. Survival probabilities of progression-free survival (PFS) and overall survival (OS) were estimated using Kaplan-Meier curves and log-rank tests and the multivariate Cox proportional hazards model. Receiver-operating characteristic curve was used to determine a cutoff value for parameters and area under the curve. Correlations between the two variables were analyzed by logistic regression. RESULTS: All patients were analyzed for survival predictors of OS, while 87 of 103 patients experienced evaluable disease progression of immunotherapy and were included in the analysis of predictors of PFS. First, we found that lower platelet (cutoff = 201.5 × 109/L) and lactate dehydrogenase (LDH) (cutoff = 227 U/L) were independently associated with significantly improved PFS, while lower platelet-lymphocyte ratio (cutoff = 206.5), absolute monocyte count (cutoff = 0.62 × 109/L), and LDH (cutoff = 194.5 U/L) were significantly and independently associated with better OS. In the analysis of the immune cell subgroup, a lower absolute countof CD8+CD28-suppressor T cells was an independent factor associated with better PFS (6.60 vs.4.13 months (mo), hazard ratios (HR) = 3.17, p = 0.0038), and OS (29.4 vs. 9.57 mo, HR = 3.05, p = 0.03). Second, the results of the analysis for irAEs showed that patients with any grade irAEs had higher objective response rate (30% vs. 10%, HR = 4.34, p = 0.009), disease control rate (69.7% vs. 50%, HR = 2.3, p = 0.028), PFS (8.37 vs. 3.77 mo, HR = 2.02, p = 0.0038), and OS (24.77 vs.13.83 mo, HR = 1.84, p = 0.024). Moreover, the groups with irAEs of grade ≥2 and with "multi-site" irAEs had significantly better PFS and OS (p < 0.05) compared with the other groups. We also proved that endocrine irAEs (usually thyroid dysfunction) were significantly associated with better mPFS (p = 0.01), and hepatic irAEs were significantly associated with better mOS (p = 0.023). CONCLUSIONS: This retrospective study explored the availability and effectiveness of some cost-effective and readily available blood biochemical parameters in routine clinical practice to predict the ICIs-efficacy and demonstrated the predictive role of different categories of irAEs on efficacy.

Analysis of characteristics and predictive factors of immune checkpoint inhibitor-related adverse events.

OBJECTIVE: We aimed to retrospectively analyze the toxicity profiles and predictors of immune-related adverse events (irAEs) as well as the correlation between irAEs and the clinical efficacy of multi-type immune checkpoint inhibitors (ICIs) in patients with advanced pan-cancer in a real-world setting. METHODS: We retrospectively analyzed data from 105 patients with advanced pan-cancer treated with multi-type ICIs at the First Hospital of Jilin University between January 1, 2016 and August 1, 2020. We used logistic regression analyses to investigate the associations of irAEs with clinical baseline characteristics, blood count parameters, and biochemical indicators during treatment. Receiver operating characteristic curves were used to determine cutoff values for parameters and area under the curve values. KaplanMeier and Cox multivariate regression analyses were performed to estimate the relationships of baseline characteristics and irAEs with progression-free survival (PFS) and overall survival (OS). RESULTS: A lower relative lymphocyte count (cutoff = 28.5%), higher albumin level (cutoff = 39.05 g/L), and higher absolute eosinophil count (AEC) (cutoff = 0.175 × 109/L) were significantly associated with the occurrence of irAEs, among which a higher AEC (cutoff = 0.205 × 109/L) was strongly associated with skin-related irAEs [odds ratios (ORs) = 0.163, P = 0.004]. Moreover, a higher lactate dehydrogenase level (cutoff = 237.5 U/L) was an independent predictor of irAEs of grade ≥ 3 (OR = 0.083, P = 0.023). In immune cell subgroup analysis, a lower absolute count of CD8+CD28- suppressor T cells (OR = 0.806; 95% confidence interval: 0.643-1.011; P = 0.062), which are regulatory T lymphocytes, was associated with the occurrence of irAEs, although the difference was not statistically significant. Furthermore, a higher percentage of CD19+ B cells was associated with the occurrence of irAEs of grade ≥ 3 (P = 0.02) and grade ≥ 2 (P = 0.051). In addition, patients with any grade of irAE had a significantly high PFS (8.37 vs. 3.77 months, hazard ratios (HR) = 2.02, P = 0.0038) and OS (24.77 vs. 13.83 months, HR = 1.84; P = 0.024). CONCLUSIONS: This retrospective study reports clinical profile data for irAEs in unselected patients in a real-world setting and explored some parameters that may be potential predictive markers of the occurrence, type, or grade of irAEs in clinical practice. Evidence of a correlation between safety and efficacy may facilitate a complete assessment of the risk-benefit ratio for patients treated with ICIs.

Single Nucleotide Polymorphisms in HOTAIR Are Related to Breast Cancer Risk and Prognosis in the Northeastern Chinese Population.

BACKGROUND: The long noncoding RNA HOX transcript antisense RNA (HOTAIR) is highly expressed in breast cancer (BC) tissues and is associated with the recurrence and metastasis of BC. Until now, the results of studies on associations between several functional single nucleotide polymorphisms(SNPs) (rs920778, rs1899663, and rs4759314) in HOTAIR with BC susceptibility carried out in different regions of China are still inconsistent. There is no study on correlation between HOTAIR SNPs and prognosis of Chinese population. Therefore, we investigated the relationship between HOTAIR SNPs and susceptibility to and prognosis of BC. METHOD: We conducted a population-based case-control study involving 828 BC cases and 905 healthy controls. Peripheral blood DNA was used for genotyping. The association between HOTAIR genotypes and BC risk were estimated by odds ratios (ORs) computed using the binary logistic regression model. The relationships between HOTAIR SNPs and clinicopathological features were tested by Pearson's chi-square test or Fisher's exact test. Survival was analyzed using the Kaplan-Meier method. RESULTS: The functional rs920778 genetic variant increased BC risk in the codominant model. Individuals with the rs920778 GG genotype had an OR of 2.426 (95% confidence interval [CI] = 1.491-3.947, P < 0.001) for developing BC compared to individuals with the AA genotype. Individuals with the AG genotype had an OR of 1.296 (95% CI = 1.040-1.614, P = 0.021) for developing BC compared to individuals with the AA genotype. Individuals with the rs4759314 GA genotype had a lower BC risk than individuals with the rs4759314 AA/GG genotype (OR = 0.566, 95% CI = 0.398-0.803, P = 0.001). The rs1899663 genotype had no correlation with BC susceptibility. Haplotypes composed of rs920778-rs1899663 and rs920778-rs1899663-rs4759314 could increase BC risk (all P < 0.001). There were no statistically significant associations between HOTAIR SNPs and clinicopathological characteristics. The rs920778 GG/AG genotypes were associated with worse disease-free survival (DFS) (p = 0.012), and the rs4759314 GA genotype was associated with worse DFS and overall survival (OS) (p = 0.011). CONCLUSION: HOTAIR SNPs(rs920778 and rs4759314) are significantly related to BC susceptibility and prognosis in the northeastern Chinese population, indicating the significance in the occurrence and development of BC.

A brand new era of cancer immunotherapy: breakthroughs and challenges.

ABSTRACT: Immunotherapy has opened a new era in cancer treatment. Drugs represented by immune checkpoint inhibitors have led to important breakthroughs in the treatment of various solid tumors, greatly improving the survival rate of cancer patients. Many types of immunotherapeutic drugs have become widely available; however, their efficacy is variable, and relatively few patients with advanced cancer experience life-altering durable survival, reflecting the complex and highly regulated nature of the immune system. The research field of cancer immunotherapy (CIT) still faces many challenges in pursuing the broader social goal of "curing cancer." Increasing attention has been paid to strengthening the understanding of the molecular or cellular drivers of resistance to immunotherapy, actively exploring more effective therapeutic targets, and developing combination therapy strategies. Here, we review the key challenges that have emerged in the era of CIT and the possible solutions or development directions to overcome these difficulties, providing relevant references for basic research and the development of modified clinical treatment regimens.

Cost-effectiveness of icotinib versus whole-brain irradiation with or without chemotherapy in EGFR-mutant NSCLC patients with brain metastases.

PURPOSE: Nonsmall cell lung cancer (NSCLC) patients with brain metastases (BM) have a poor prognosis. Despite the traditional methods including radiotherapy and chemotherapy, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) might benefit patients on survival and quality of life. We investigated the cost-effectiveness of icotinib compared with whole-brain irradiation (WBI) with or without chemotherapy for NSCLC patients with BM. MATERIALS AND METHODS: A Markov model was conducted based on the data of BRAIN trial. We compared the economic benefit between icotinib and the combination of WBI and WBI plus chemotherapy group. We considered disease progression as intracranial progression and overall progression separately. Sensitivity analyses were performed to observe the stability of the model. The willingness-to-pay (WTP) was set as 3× per capita gross domestic product ($25929/quality-adjusted life year [QALY]) from the Chinese healthcare perspective. RESULTS: When considering progression as intracranial progression and overall progression, respectively, the incremental cost-effectiveness ratio was $14 882.64/QALY and $13 484.21/QALY between icotinib and WBI/WBI-chemotherapy. Besides, both of the average cost-effective ratio (ACER) and net benefit showed advantage of icotinib (ACER: $34 521.42/QALY for intracranial progression and $36 562.63/QALY for overall progression; net benefit: -$8407.36 for intracranial progression and -$9836.41 for overall progression). One-way sensitivity analyses demonstrated that no thresholds were encountered. The probabilistic sensitivity analyses showed even at a WTP under $18 000/QALY, icotinib could be cost-effective. CONCLUSION: Icotinib was cost-effective compared with WBI with or without chemotherapy.

Immune checkpoint inhibitor-related adverse events: New exploration, new challenges / 中国肿瘤生物治疗杂志

@#近年来，通过增强机体免疫系统对肿瘤细胞的杀伤作用，免疫检查点抑制剂（immune checkpoint inhibitor，ICI）在抗 肿瘤治疗中的应用获得了显著的临床疗效。然而，多项证据表明，免疫治疗激活免疫系统的同时可导致独特的免疫相关不良反 应（immune-related adverse events，irAEs），影响免疫治疗的疗效或需要中止治疗。近几年，随着 ICI 治疗临床试验的广泛开展， irAEs 的发生情况、毒性谱及其有效管理手段的开发越来越得到临床医生的关注。常见的 irAEs 包括皮炎和甲状腺炎等，而不 同种类免疫检查点抑制剂、不同治疗剂量或组合疗法，均可导致不同的 irAEs 毒性谱，同一免疫检查点抑制剂作用于不同肿瘤 所致的毒副反应谱亦有不同。目前认为，irAEs 的发生与机体自身免疫系统功能的改变相关，包括机体免疫系统过度激活、自身 免疫耐受性的打破等，但其具体机制仍不十分清楚。本文结合近年来在 ICI 治疗中 irAEs 相关分子机制和预测标志物的关键理 论和认识方面取得的诸多新进展，对 irAEs 的发生特点和分子机制进行总结，并就其预测性标志物开发、irAEs 管理原则改进和 治疗新探索进行述评。