Non-small Cell Lung Cancer Brain Metastases Research Articles

EP08.01-029 NIVIPI-BRAIN, A Phase II Study of Nivolumab plus Ipilimumab Combined with Chemotherapy for Patients with NSCLC and Synchronous Brain Metastases

Brain metastases (BM) are a common complication in cancer patients and have major impact on quality of life and prognosis. Chemotherapy plus immunotherapy has significant efficacy in patients with advanced non-small cell lung cancer (NSCLC) who have untreated brain metastases. In the CheckMate-9LA, nivolumab (NIVO) was combined with ipilimumab (IPI) and 2 cycles of chemotherapy and achieved high intracranial efficacy in patients with advanced NSCLC with previously treated BM. This combination was not previously assessed in patients with NSCLC and untreated BM.

Radiotherapy combined with PD-1/PD-L1 inhibitors in NSCLC brain metastases treatment: The mechanisms, advances, opportunities, and challenges.

At present, whole-brain radiation therapy/stereotactic radiosurgery is one of the main local treatments for brain metastasis of non-small-cell lung cancer (NSCLC). Currently, it has been proved that radiotherapy (RT) can regulate the immune response, and small-sample studies have shown that patients with NSCLC brain metastases (BMs) can benefit from RT combined with immunotherapy (IO). However, the efficacy and safety of the combination treatment have not been deeply elaborated. Notably, as a challenge that is still being explored, the timing of RT combined with IO is likely to be an important factor affecting efficacy and prognosis. This article reviews the current application and challenges of RT combined with IO from the perspectives of molecular mechanism, combination timing, safety, and efficacy. The purpose is to provide information on clinical evidence-based medicine of combination between RT with IO. For further investigation, we also discuss the major challenges and prospects of RT combined with IO in NSCLC BMs.

MiR-596-3p suppresses brain metastasis of non-small cell lung cancer by modulating YAP1 and IL-8

Brain metastasis (BM) frequently occurs in advanced non-small cell lung cancer (NSCLC) and is associated with poor clinical prognosis. Due to the location of metastatic lesions, the surgical resection is limited and the chemotherapy is ineffective because of the existence of the blood brain barrier (BBB). Therefore, it is essential to enhance our understanding about the underlying mechanisms associated with brain metastasis in NSCLC. In the present study, we explored the RNA-Seq data of brain metastasis cells from the GEO database, and extracted RNA collected from primary NSCLC tumors as well as paired brain metastatic lesions followed by microRNA PCR array. Meanwhile, we improved the in vivo model and constructed a cancer stem cell-derived transplantation model of brain metastasis in mice. Our data indicated that the level of miR-596-3p is high in primary NSCLC tumors, but significantly downregulated in the brain metastatic lesion. The prediction target of microRNA suggested that miR-596-3p was considered to modulate two genes essential in the brain invasion process, YAP1 and IL-8 that restrain the invasion of cancer cells and permeability of BBB, respectively. Moreover, in vivo experiments suggested that our model mimics the clinical aspect of NSCLC and improves the success ratio of brain metastasis model. The results demonstrated that miR-596-3p significantly inhibited the capacity of NSCLC cells to metastasize to the brain. Furthermore, these finding elucidated that miR-596-3p exerts a critical role in brain metastasis of NSCLC by modulating the YAP1-IL8 network, and this miRNA axis may provide a potential therapeutic strategy for brain metastasis.

Efficacy and Safety of EGFR Tyrosine Kinase Inhibitors Combined with Cranial Radiotherapy for Brain Metastases from Non-Small-Cell Lung Cancer: A Protocol for a Systematic Review and Meta-Analysis.

Introduction. Brain metastases (BMs) are common in non-small-cell lung cancer (NSCLC), which leads to a poor prognosis. As the two most effective strategies available, the use of combination of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) and radiotherapy (RT) is still controversial. This protocol proposes a methodology for carrying out a systematic review and meta-analysis that is aimed at (1) focusing on the efficacy and safety role of EGFR-TKIs combined with RT for BMs from NSCLC and (2) displaying the difference in efficacy of EGFR-TKIs owing to the sites and number of BMs, different types of RT, EGFR mutation status, and the subtypes of EGFR mutations by subgroup analysis. Methods and Analysis. Electronic databases including PubMed, Embase, CENTRAL, Web of Science, CBM, CNKI, Wanfang database, and VIP database will be searched from their inception until May 2022. Only randomized controlled trials evaluating the clinical efficacy and safety of EGFR-TKIs combined with RT on BMs of NSCLC will be included. Two reviewers will select the articles, assess the risk of bias, and extract data independently and in duplicate. The RoB 2 tool will be used to assess the quality of included studies. The meta-analysis of data synthesis will be performed with Stata 16. Publication bias will be assessed with the funnel plot method and the Egger test. Quality of the evidence will be evaluated by the GRADE system. Discussion. The approval of an ethical committee is not required. All the included trials will comply with the current ethical standards and the Declaration of Helsinki. Given the ongoing controversies regarding the optimal sequencing of the available and expanding treatment options for EGFR-TKIs in NSCLC with BMs, a synthesis of available, high-quality clinical research evidence is essential to advance our understanding in the treatment of this complex and common disease. This systematic review will evaluate available evidence, will try to provide optimized advice in the applications of EGFR-TKIs, and will be published in a high-quality journal. This study is registered with PROSPERO registration number CRD42021291509.

Abstract 207: MET inhibition enhances the effect of radiation in MET mutated non-small cell lung cancer brain metastasis patient derived xenografts

Abstract Objective: The MET receptor is mutated in 3-4% and amplified in 1-6% of patients with non-small cell lung cancer. The most common MET mutation is in exon 14, which results in deletion of the intracellular juxtamembrane domain of the receptor, leading to enhanced signaling. Mutation at Asp-1000 in the juxtamembrane region has also been reported and can lead to inhibition of apoptosis and cell proliferation. MET is involved in multiple pathways associated with radiation response. Therefore, we investigated the effects of inhibiting MET in combination with radiation in two preclinical non-small cell lung cancer (NSCLC) brain metastasis patient derived xenograft (PDX) models. Methods: Surgically obtained tissue was implanted subcutaneously into immunodeficient mice. Histology and DNA loci were compared between original tumor and PDX. DNA sequencing was performed on tumors for mutation analysis. In vivo growth responses to the MET inhibitor capmatinib or savolitinib with and without radiation were assessed. Radiation was delivered in 10 daily fractions of 2 Gy. Drug was administered by oral gavage daily 1 hour prior to radiation at a dose of 2.5 mg/kg for savaolitnib or 20 mg/kg for capmatinib for 10 days. Immunohistochemistry (IHC) was performed to evaluate MET signaling and proliferation. Results: PDXs were successfully established from two patients with MET mutated NSCLC brain metastases: a lung adenocarcinoma with a MET exon 14 skipping mutation and a lung sarcomatoid carcinoma with adenocarcinoma component with an Asp-1000 frameshift mutation. Morphologically, strong retention of cytoarchitectural features was observed between original patient tumors and PDXs. Short tandem repeat analysis confirmed 100% matching of alleles between patient tumors and PDXs. DNA sequencing confirmed METex14 and MET Asp-1000 frameshift mutation. In the METex14 PDX, savolitinib alone significantly inhibited tumor growth with a growth inhibition value of 46% (p<0.01). Combination of savolitinib and radiation significantly delayed growth compared to vehicle control, savolitinib alone or radiation alone (p<0.001). The absolute growth delay was 42.4 days for savolitinib plus radiation treatment compared to 9.3 days for savolitinib alone and 28.2 days for irradiation. In the MET Asp-1000 PDX, capmatinib and radiation significantly delayed growth compared the other treatment arms (p<0.01). IHC demonstrated inhibition of phospho-MET and pS6 and a decrease in Ki67 with MET inhibition. Conclusion: Inhibition of MET enhanced the effect of radiation in our two preclinical in vivo MET mutated NSCLC brain metastasis models. Additional studies are currently underway evaluating the mechanisms of radiation sensitization and the efficacy of this combination in MET amplified PDX models. Citation Format: Kwangok P. Nickel, Shrey Ramesh, Saahil Javeri, Nitin Somasundaram, Nan Sethakorn, Randall J. Kimple, Andrew M. Baschnagel. MET inhibition enhances the effect of radiation in MET mutated non-small cell lung cancer brain metastasis patient derived xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 207.

Genomic analysis and clinical correlations of non-small cell lung cancer (NSCLC) brain metastasis (BM).

2008 Background: Approximately 30% of patients with NSCLC present with BM, and up to 50% of patients ultimately develop BM. While modern NSCLC-directed agents yield excellent systemic response, most patients require focal treatment. Prior reports of BM genomics have been limited by low numbers, missing clinical data, and lack of matched specimens. Here, we report the largest cohort to date of molecularly profiled NSCLC BM samples with clinical correlates. Methods: Clinical data and outcomes for 244 patients with NSCLC and resected BM were identified, and BM samples were assessed with one of four versions (341, 410, 468, 505) of MSK-IMPACT, a custom FDA-approved next generation sequencing-based tumor sequencing assay. 51 (20.9%) patients had matched primary site tissue, and 44 (18%) patients had matched tissue from another metastatic site or CSF. Genomic alterations were filtered for driver variants using OncoKB. Results: Median age was 66 years (range 31-91), and median follow-up was 2.3 years (IQR 1.3-4.3). Adenocarcinoma was the most common histology (183, 78%). Half presented with a single BM, and 121 (51%) patients were treatment naive. Most (197, 83%) received adjuvant stereotactic radiosurgery (SRS) to the resection site and 28% received SRS to additional BM. After resection, 130 (55.1%) had CNS progression, often regional (54, 42%). SRS to new BMs (32%) was the most common salvage treatment. Median overall survival from BM diagnosis was 2.5 years (95%CI 2.1-3.2). Median CNS-progression-free survival was 1.2 years (95%CI 0.9-1.4). The most frequently altered genes in BM samples were TP53 (72%), CDKN2A (34%), KRAS (31%), KEAP1 (26%), and EGFR (21%). CDKN2A was more frequently altered in BM samples when compared to NSCLC primary samples (34% vs 14%, p = 0.003, q = 0.034). With regard to overrepresented gene sets, cell cycle pathway alterations were enriched in BM (56% vs 31%, p = 0.002, q = 0.022). BM samples had a significantly higher fraction of genome altered relative to the primary samples (p < 0.0001, q < 0.0001). After grouping patients based on type of CNS progression, we found that EGFR alterations were enriched in patients with leptomeningeal failures when compared to both patients without progression (42% vs 18%, p = 0.03, q = 0.93) and to patients with either local or regional progression (42% vs 19%, p = 0.03, q = 0.9). Conclusions: In the largest-ever assembled cohort of genomically-profiled NSCLC BM, we found significant enrichment for CDKN2A and cell cycle pathway alterations in BM compared to extracranial disease, as well as a higher fraction of genome altered, in BMs compared to matched primary tumor controls. We also observed EGFR alteration enrichment in patients who develop LMD, suggesting specific biologic underpinnings driving patterns of CNS failure. Further investigation into the role of systemic therapy and time course will elucidate potential mechanisms for CNS failure in patients with NSCLC.

Longitudinal sequencing of T cell receptor revealed radiotherapeutic efficacy and prognosis in non-small cell lung cancer patients with brain metastasis.

e21056 Background: Liquid biopsy has played a unique role in long-term surveillance of brain metastasis in non-small cell lung cancer (NSCLC), due to the inaccessibility of solid metastatic biopsies. T cell-mediated immunity is critical in the oncogenesis and metastasis of NSCLC, and sequencing in T cell receptor (TCR) provides a robust method to quantify T cell diversity. Therefore, we aimed to explore the alteration of TCR through liquid biopsy before and after radiotherapy of NSCLC brain metastases. Methods: Thirty NSCLC patients with brain metastases receiving brain radiotherapy were enrolled in this study. Cerebrospinal fluid (CSF) and peripheral blood were collected at baseline, 24 hours (T0) and 28 days (T28) after treatment. TCR sequences were identified by high-throughput sequencing in both compartments. Results: At baseline, dimension reduction analysis identified distinct signatures of V and J gene recombination in blood and CSF TCR sequences. Throughout treatment, both compartments experienced a TCR diversity decrease, however, the degradation of low-abundance clones and the expansion of emerging clones might be two separate processes underwent in blood and CSF, respectively. Diversity changes in blood were possibly related to pulmonary responses, while the increase of maximal clone abundance in CSF might indicate a favorable intracranial response. Superior blood TCR diversity at T28 against baseline was associated with longer OS (HR = 5.700, p = 0.039). Patients with increase of maximal clone abundance ≥ 50 in CSF also had a better intracranial PFS (HR = 8.320, p = 0.011). The predictive effects of these markers were independent of other clinical factors in multivariate Cox analysis. Conclusions: CSF and peripheral blood were independent compartments showing disparate TCR signatures. Longitudinal surveillance of both compartments could be a promising method to predict clinical outcomes for NSCLC patients with brain metastases.

Local and distant brain control in melanoma and NSCLC brain metastases with concurrent radiosurgery and immune checkpoint inhibition.

The treatment of brain metastases with stereotactic radiosurgery (SRS) in combination with immune checkpoint inhibitors (ICI) has become more common in recent years, but there is a lack of prospective data on cancer control outcomes when these therapies are administered concurrently. Data were retrospectively reviewed for patients with non-small cell lung cancer (NSCLC) and melanoma brain metastases treated with SRS at a single institution from May 2008 to January 2017. A parametric proportional hazard model is used to detect the effect of concurrent ICI within 30, 60, or 90days of ICI administration on local control and distant in-brain control. Other patient and lesion characteristics are treated as covariates and adjusted in the regression. A frailty term is added in the baseline hazard to capture the within-patient correlation. We identified 144 patients with 477 total lesions, including 95 NSCLC patients (66.0%), and 49 (34.0%) melanoma patients. On multivariate analysis, concurrent SRS and ICI (SRS within 30days of ICI administration) was not associated with local control but was associated with distant brain control. When controlling for prior treatment to lesion, number of lesions, and presence of extracranial metastases, patients receiving this combination had a statistically significant decrease in distant brain failure compared to patients that received non-concurrent ICI or no ICI (HR 0.15; 95% CI 0.05-0.47, p = 0.0011). Concurrent ICI can enhance the efficacy of SRS. Prospective studies would allow for stronger evidence to support the impact of concurrent SRS and ICI on disease outcomes.

Clinicopathologic and Genomic Landscape of Non-Small Cell Lung Cancer Brain Metastases.

BackgroundIn patients with non-small cell lung cancer (NSCLC), 10%-40% will eventually develop brain metastases. We present the clinicopathologic, genomic, and biomarker landscape of a large cohort of NSCLC brain metastases (NSCLC-BM) samples.Materials and MethodsWe retrospectively analyzed 3035 NSCLC-BM tested with comprehensive genomic profiling (CGP) during routine clinical care. In addition, we compared the NSCLC-BM to a separate cohort of 7277 primary NSCLC (pNSCLC) specimens. Finally, we present data on 67 paired patients with NSCLC-BM and pNSCLC.ResultsComprehensive genomic profiling analysis of the 3035 NSCLC-BMs found that the most frequent genomic alterations (GAs) were in the TP53, KRAS, CDKN2A, STK11, CDKN2B, EGFR, NKX2-1, RB1, MYC, and KEAP1 genes. In the NSCLC-BM cohort, there were significantly higher rates of several targetable GAs compared with pNSCLC, including ALK fusions, KRAS G12C mutations, and MET amplifications; and decreased frequency of MET exon14 skipping mutations (all P < .05). In the subset of NSCLC-BM (n = 1063) where concurrent PD-L1 immunohistochemistry (IHC) was performed, 54.7% of the patients with NSCLC-BM were eligible for pembrolizumab based on PD-L1 IHC (TPS ≥ 1), and 56.9% were eligible for pembrolizumab based on TMB-High status. In addition, in a series 67 paired pNSCLC and NSCLC-BM samples, 85.1% (57/67) had at least one additional GA discovered in the NSCLC-BM sample when compared with the pNSCLC sample.ConclusionsHerein, we defined the clinicopathologic, genomic, and biomarker landscape of a large cohort of patients with NSCLC-BM which can help inform study design of future clinical studies for patients with NSCLC with BM. In certain clinical situations, metastatic NSCLC brain tissue or cerebral spinal fluid specimens may be needed to fully optimize personalized treatment.

The Strategies and Mechanisms of Immune Checkpoint Inhibitors for Brain Metastases in NSCLC.

Brain metastases are more and more common among patients with non-small cell lung cancer (NSCLC). TKI therapy could provide ideal outcomes for patients harboring epidermal growth factor receptor or ALK mutations. For wild-type patients, however, survival is poor because there are few effective treatments other than radiotherapy. Immune checkpoint inhibitors (ICIs) have changed the management of advanced NSCLC. However, the exclusion of patients with active brain metastasis (BM) from most ICI trials precludes the generalization of results. Accordingly, a variety of appropriate real-world studies and clinical trials are being developed to evaluate tumor response. Increasingly encouraging results have suggested that ICIs could be active in the central nervous system (CNS) in select patients with high PD-L1 expression and low CNS disease burden. With the extensive use of ICIs in NSCLC patients with BM, many important questions have emerged concerning issues such as the clinical response to a single ICI, use of ICIs combined with chemotherapy or radiation, the biological mechanism and appropriate sequencing of local and systemic therapy combinations, and safety and toxicity. The present review summarizes the advances in systemic ICIs for the treatment of NSCLC patients with BM, discusses factors associated with efficacy and toxicity, and explores future directions.

Effectiveness of Immune Checkpoint Inhibition vs Chemotherapy in Combination With Radiation Therapy Among Patients With Non–Small Cell Lung Cancer and Brain Metastasis Undergoing Neurosurgical Resection

Patients with brain metastases from non-small cell lung cancer (NSCLC) have regularly been excluded from prospective clinical trials that include therapy with immune checkpoint inhibitors (ICIs). Clinical data demonstrating benefit with ICIs, specifically following neurosurgical brain metastasis resection, are scarce. To evaluate and compare the association of radiation therapy with ICIs vs classic therapy involving radiation therapy and chemotherapy regarding overall survival in a cohort of patients who underwent NSCLC brain metastasis resection. This single-center 1:1 propensity-matched comparative effectiveness study at the largest neurosurgical clinic in Germany included individuals who had undergone craniotomy with brain metastasis resection from January 2010 to December 2021 with histologically confirmed NSCLC. Of 1690 patients with lung cancer and brain metastasis, 480 were included in the study. Key exclusion criteria were small-cell lung cancer, lack of tumor cells by means of histopathological analysis on brain metastasis resection, and patients who underwent biopsy without tumor resection. The association of overall survival with treatment with radiation therapy and chemotherapy vs radiation therapy and ICI was evaluated. Radiation therapy and chemotherapy vs radiation therapy and ICI following craniotomy and microsurgical brain metastasis resection. Median overall survival. From the whole cohort of patients with NSCLC (N = 384), 215 (56%) were male and 169 (44%) were female. The median (IQR) age was 64 (57-72) years. The 2 cohorts of interest included 108 patients (31%) with radiation therapy and chemotherapy and 63 patients (16%) with radiation therapy and ICI following neurosurgical metastasis removal (before matching). Median (IQR) follow-up time for the total cohort was 47.9 (28.2-70.1) months with 89 patients (23%) being censored and 295 (77%) dead at the end of follow-up in December 2021. After covariate equalization using propensity score matching (62 patients per group), patients receiving radiation therapy and chemotherapy after neurosurgery had significantly lower overall survival (11.8 months; 95% CI; 9.1-15.2) compared with patients with radiation therapy and ICIs (23.0 months; 95% CI; 20.3-53.8) (P < .001). Patients with NSCLC brain metastases undergoing neurosurgical resection had longer overall survival when treated with radiation therapy and ICIs following neurosurgery compared with those receiving platinum-based chemotherapy and radiation. Radiation and systemic immunotherapy should be regularly evaluated as a treatment option for these patients.

Activity of Adagrasib (MRTX849) in Brain Metastases: Preclinical Models and Clinical Data from Patients with KRASG12C-Mutant Non-Small Cell Lung Cancer.

Patients with KRAS-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small-molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic properties, including long half-life (∼24 hours), extensive tissue distribution, dose-dependent pharmacokinetics, and central nervous system penetration; however, BM-specific antitumor activity of KRASG12C inhibitors remains to be fully characterized. A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and pharmacokinetic properties of adagrasib. Mice bearing intracranial KRASG12C-mutant NSCLC xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated with clinically relevant adagrasib doses, and levels of adagrasib in plasma, cerebrospinal fluid (CSF), and brain were determined along with antitumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg twice daily in the phase Ib cohort of the KRYSTAL-1 trial; CSF was collected, adagrasib concentrations measured, and antitumor activity in BM evaluated. Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM (≥40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival in multiple preclinical BM models. In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain. These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM. See related commentary by Kommalapati and Mansfield, p. 3179.

The safety and efficacy of anlotinib in combination with stereotactic radiotherapy for the treatment of brain metastases from non-small cell lung cancer

Objective: To investigate the efficacy and safety of anti-vascular drug anlotinib in combination with stereotactic radiosurgery (SRS) for the treatment of brain metastases from non-small cell lung cancer (NSCLC). Methods: A total of 46 patients diagnosed with NSCLC brain metastases and treated with SRS in Peking University Third Hospital were included from October 2017 to June 2019. Of these, 21 patients (33 lesions) received anlotinib combined with SRS (combined treatment group), while 25 patients (35 lesions) only received SRS (SRS-alone group). The data of combined treatment group and SRS-alone group were compared, including remission rate of intracranial hypertension, response rate (RR) of local control of intracranial lesions, incidence of radiation-induced brain necrosis and intracranial progression-free survival (iPFS). The medication and adverse reactions of anlotinib in the combined treatment group were recorded. Results: The remission rate of intracranial hypertension in the combined treatment group was 71.4% (15/21), which was significantly higher than that in the SRS-alone group [12.0% (3/25), P<0.001). However, the RR of combined treatment group and SRS-alone group was 80.9% (17/21) and 60.0% (15/25), respectively, with no statistically significant difference (P=0.289). The incidence of radiation-induced brain necrosis in the combined treatment group was 3.0% (1/33), which was significantly lower than that in the SRS-alone group [20.0% (7/35), P=0.030]. The iPFS of the combination treatment group was (13.9±2.4) months, which was significantly longer than that in the SRS-alone group [(11.4±1.8) months, P<0.001]. The medication time of anlotinib in the combined treatment group was 6 (6, 18) weeks. One patient developed grade Ⅰ hypertension and one patient developed grade Ⅰ hand-foot syndrome. The incidence of drug-related adverse reactions was 9.5% (2/21). Conclusions: Anlotinib in combination with SRS may relieve brain edema, reduce the rate of radiation-induced brain necrosis, and the rate of drug-related adverse reactions were low.

Correlation of EGFR mutation subtypes and survival in surgically treated brain metastasis from non-small-cell lung cancer

ObjectiveEpidermal growth factor receptor (EGFR) mutation is a positive prognostic factor for survival in patients with non–small-cell lung cancer (NSCLC). In such patients, brain metastasis signifies negative outcomes. Patients with NSCLC brain metastasis that may benefit from neurosurgery is under investigation. We aim to investigate the impact of different mutation loci in surgically treated NSCLC brain metastasis patients. MethodsThis retrospective cohort study included patients with NSCLC brain metastasis who underwent brain lesionectomy, followed by radiotherapy and chemotherapy or targeted therapy. Demographics and tumor characteristics were compared between the EGFR mutant type and wild type groups. Postoperative survival and risk factors were analyzed using log rank and Cox regression methods. ResultsOverall, 101 patients were included, with 57 belonging to the EGFR mutant type group and 44 to the EGFR wild type group. The median postoperative survival was 17 months for the entire cohort, with the duration being 19 and 14 months for EGFR mutant type and wild type patients (p = 0.013), respectively. Multivariate analysis revealed that exon 19 del (p = 0.02) and a high Karnofsky Performance Scale score (p < 0.01) were independent positive prognostic factors to predict survival. The timing of development of the brain metastasis or the location of the intracranial metastasis was not associated with EGFR mutations. ConclusionEGFR mutations are associated with better survival outcomes in patients with NSCLC brain metastasis suitable for surgical treatment. This advantage was attributed to patients having a specific mutation of exon 19 deletion.

The Predictive Value of Peripheral Immune Cell Counts for the Presence of Brain Metastases in Stage IV Non-Small-Cell Lung Cancer (NSCLC).

Background High neutrophil–lymphocyte ratio (NLR) is associated with poor survival in lung cancer. This study evaluates whether NLR is associated with baseline brain metastasis in stage IV non-small cell lung cancer (NSCLC). Methods Medical records of stage IV NSCLC patients treated at King Hussein Cancer Center (Amman-Jordan) between 2006 and 2016 were reviewed. Patients with baseline brain imaging and complete blood count (CBC) were included. Receiver operating characteristic (ROC) curve was used to identify the optimal cutoff value for the association between NLR and baseline brain metastasis. Association between age, gender, location of the primary tumor, histology, and NLR was assessed using univariate and multivariate logistic regression analyses. Results A total of 722 stage IV NSCLC patients who had baseline brain imaging were included. Median age was 59 years. Baseline brain metastasis was present in 280 patients (39.3%). Nine patients had inconclusive findings about brain metastasis. The ROC curve value of 4.3 was the best fitting cutoff value for NLR association with baseline brain metastasis. NLR ≥ 4.3 was present in 340 patients (48%). The multivariate analyses showed that high baseline NLR (≥ 4.3) was significantly associated with higher odds of baseline brain metastasis (odds ratio [OR]: 1.6, 95% confidence interval [CI]: 1.2–2.2; p = 0.0042). Adenocarcinoma histology was also associated with baseline brain metastasis (OR: 0.4, 95% CI: 0.25–0.6; p = 0.001). Conclusion High NLR is associated with baseline brain metastasis in advanced-stage NSCLC. In the era of immunotherapy and targeted therapies, whether high NLR predicts response of brain metastasis to treatment is unknown.

Research Progress on Risk Factors of Brain Metastasis in Non-small Cell Lung Cancer

非小细胞肺癌（non-small cell lung cancer, NSCLC）脑转移是常见的治疗失败模式，发生脑转移的NSCLC患者中位生存时间仅为1个月-2个月。预防性脑照射（prophylactic cranial irradiation, PCI）可延缓脑转移的发生，但对NSCLC患者的生存获益仍存在争议，因此，通过预测脑转移的风险筛选可能从PCI中获益的人群尤为重要。本文就NSCLC脑转移的高危因素进行综述。

Cathepsin F and Fibulin-1 as novel diagnostic biomarkers for brain metastasis of non-small cell lung cancer

BackgroundThe lack of non-invasive methods for detection of early micro-metastasis is a major cause of the poor prognosis of non-small cell lung cancer (NSCLC) brain metastasis (BM) patients. Herein, we aimed to identify circulating biomarkers based on proteomics for the early diagnosis and monitoring of patients with NSCLC BM.MethodsUpregulated proteins were detected by secretory proteomics in the animal-derived high brain metastatic lung cancer cell line. A well-designed study composed of three independent cohorts was then performed to verify these blood-based protein biomarkers: the serum discovery and verification cohorts (n = 80; n = 459), and the tissue verification cohort (n = 76). Logistic regression was used to develop a diagnostic biomarker panel. Model validation cohort (n = 160) was used to verify the stability of the constructed predictive model. Changes in serum Cathepsin F (CTSF) levels of patients were tracked to monitor the treatment response. Progression-free survival (PFS) and overall survival (OS) were analysed to assess their prognostic relevance.ResultsCTSF and Fibulin-1 (FBLN1) levels were specifically upregulated in sera and tissues of patients with NSCLC BM compared with NSCLC without BM and primary brain tumour. The combined diagnostic performance of CTSF and FBLN1 was superior to their individual ones. CTSF serum changes were found to reflect the therapeutic response of patients with NSCLC BM and the trends of progression were detected earlier than the magnetic resonance imaging changes. Elevated expression of CTSF in NSCLC BM tissues was associated with poor PFS, and was found to be an independent prognostic factor.ConclusionsWe report a novel blood-based biomarker panel for early diagnosis, monitoring of therapeutic response, and prognostic evaluation of patients with NSCLC BM.

Targeting polarized phenotype of microglia via IL6/JAK2/STAT3 signaling to reduce NSCLC brain metastasis

Tumor-associated macrophages have emerged as crucial factors for metastases. Microglia are indispensable components of the brain microenvironment and play vital roles in brain metastasis (BM). However, the underlying mechanism of how activated microglia promote brain metastasis of non-small cell lung cancer (NSCLC) remains elusive. Here, we purified cell lines with brain-metastatic tropism and employed a co-culture system to reveal their communication with microglia. By single-cell RNA-sequencing and transcriptome difference analysis, we identified IL6 as the key regulator in brain-metastatic cells (A549-F3) to induce anti-inflammatory microglia via JAK2/STAT3 signaling, which in turn promoted the colonization process in metastatic A549-F3 cells. In our clinical samples, patients with higher levels of IL6 in serum showed higher propensity for brain metastasis. Additionally, the TCGA (The Cancer Genome Atlas) data revealed that NSCLC patients with a lower level of IL6 had a longer overall survival time compared to those with a higher level of IL6. Overall, our data indicate that the targeting of IL6/JAK2/STAT3 signaling in activated microglia may be a promising new approach for inhibiting brain metastasis in NSCLC patients.

Tumor Immune Microenvironment and Immunotherapy in Brain Metastasis From Non-Small Cell Lung Cancer.

Brain metastasis (BM), a devastating complication of advanced malignancy, has a high incidence in non-small cell lung cancer (NSCLC). As novel systemic treatment drugs and improved, more sensitive imaging investigations are performed, more patients will be diagnosed with BM. However, the main treatment methods face a high risk of complications at present. Therefore, based on immunotherapy of tumor immune microenvironment has been proposed. The development of NSCLC and its BM is closely related to the tumor microenvironment, the surrounding microenvironment where tumor cells live. In the event of BM, the metastatic tumor microenvironment in BM is composed of extracellular matrix, tissue-resident cells that change with tumor colonization and blood-derived immune cells. Immune-related cells and chemicals in the NSCLC brain metastasis microenvironment are targeted by BM immunotherapy, with immune checkpoint inhibition therapy being the most important. Blocking cancer immunosuppression by targeting immune checkpoints provides a suitable strategy for immunotherapy in patients with advanced cancers. In the past few years, several therapeutic advances in immunotherapy have changed the outlook for the treatment of BM from NSCLC. According to emerging evidence, immunotherapy plays an essential role in treating BM, with a more significant safety profile than others. This article discusses recent advances in the biology of BM from NSCLC, reviews novel mechanisms in diverse tumor metastatic stages, and emphasizes the role of the tumor immune microenvironment in metastasis. In addition, clinical advances in immunotherapy for this disease are mentioned.

Relationship Between Neutrophil-To-Lymphocyte Ratio and Brain Metastasis in Non-Small Cell Lung Cancer Patients.

ObjectiveTo investigate the relationship between the neutrophil-to-lymphocyte ratio (NLR) of patients with non-small cell lung cancer (NSCLC) and their risk of developing brain metastases after adjusting for confounding factors.MethodsA retrospective observational study of the general data of patients with NSCLC diagnosed from January 2016 to December 2020. Multivariate logistic regression was used to calculate the dominance ratio (OR) with 95% confidence interval (CI) for NLR and NSCLC brain metastases with subgroup analysis. Generalized summation models and smoothed curve fitting were used to identify whether there was a nonlinear relationship between them.ResultsIn all 3 models, NLR levels were positively correlated with NSCLC brain metastasis (model 1: OR: 1.12, 95% CI: 1.01-1.23, P = .025; model 2: OR: 1.16, 95% CI: 1.04-1.29, P = .007; model 3: OR: 1.20, 95% CI: 1.05-1.37, P = .006). Stratified analysis showed that this positive correlation was present in patients with adenocarcinoma (LUAD) and female patients (LUAD: OR: 1.30, 95% CI: 1.10-1.54, P = .002; female: OR: 1.52, 95% CI: 1.05-2.20, P = .026), while there was no significant correlation in patients with squamous carcinoma (LUSC) and male patients (LUSC: OR:0.76,95% CI:0.38- 1.53, P = .443; male: OR:1.13, 95% CI:0.95-1.33, P = .159).ConclusionThis study showed that elevated levels of NLR were independently associated with an increased risk of developing brain metastases in patients with NSCLC, and that this correlation varied by TYPE and SEX, with a significant correlation in female patients and patients with LUAD.