Non-small Cell Lung Cancer Brain Research Articles

Stereotactic radiosurgery in the management of non-small cell lung cancer brain metastases: a prospective study using the NeuroPoint Alliance Stereotactic Radiosurgery Registry.

The literature on non-small cell lung cancer (NSCLC) brain metastases (BMs) managed using stereotactic radiosurgery (SRS) relies mainly on single-institution studies or randomized controlled trials (RCTs). There is a literature gap on clinical and radiological outcomes of SRS for NSCLC metastases in real-world practice. The objective of this study was to benchmark mortality and progression outcomes in patients undergoing SRS for NSCLC BMs and identify risk factors for these outcomes using a national quality registry. The SRS Registry of the NeuroPoint Alliance was used for this study. This registry included patients from 16 enrolling sites who underwent SRS from 2017 to 2022. Data are prospectively collected without a prespecified research purpose. The main outcomes of this analysis were overall survival (OS), out-of-field recurrence, local progression, and intracranial progression. All time-to-event investigations included Kaplan-Meier analyses and multivariable Cox regressions. Two hundred sixty-four patients were identified, with a mean age of 66.7 years and a female proportion of 48.5%. Most patients (84.5%) had a Karnofsky Performance Status (KPS) score of 80-100, and the mean baseline EQ-5D score was 0.539 quality-adjusted life years. A single lesion was present in 53.4% of the patients, and 29.1% of patients had 3 or more lesions. The median OS was 28.1 months, and independent predictors of mortality included no control of primary tumor (hazard ratio [HR] 2.1), KPS of 80 (HR 2.4) or lower (HR 2.4), coronary artery disease (HR 2.8), and 5 or more lesions present at the time of SRS treatment (HR 2.3). The median out-of-field progression-free survival (PFS) was 24.8 months, and the median local PFS was unreached. Intralesional hemorrhage was an independent risk factor of local progression, with an HR of 6.0. The median intracranial PFS was 14.0 months and was predicted by the number of lesions at the time of SRS (3-4 lesions, HR 2.2; 5-14 lesions, HR 2.5). In this real-world prospective study, the authors used a national quality registry and found favorable OS in patients with NSCLC BMs undergoing SRS compared with results from previously published RCTs. The intracranial PFS was mainly driven by the emergence of new lesions rather than local progression. A greater number of lesions at baseline was associated with out-of-field progression, while intralesional hemorrhage at baseline was associated with local progression.

Short-term predictors of stereotactic radiosurgery outcome for untreated single non-small cell lung cancer brain metastases: a restrospective cohort study.

Stereotactic radiosurgery (SRS) is an option for brain metastases (BM) not eligible for surgical resection, however, predictors of SRS outcomes are poorly known. The aim of this study is to investigate predictors of SRS outcome in patients with BM secondary to non-small cell lung cancer (NSCLC). The secondary objective is to analyze the value of volumetric criteria in identifying BM progression. This retrospective cohort study included patients >18 years of age with a single untreated BM secondary to NSCLC. Demographic, clinical, and radiological data were assessed. The primary outcome was treatment failure, defined as a BM volumetric increase 12 months after SRS. The unidimensional measurement of the BM at follow-up was also assessed. One hundred thirty-five patients were included, with a median BM volume at baseline of 1.1 cm3 (IQR 0.4-2.3). Fifty-two (38.5%) patients had SRS failure at follow-up. Only right BM laterality was associated with SRS failure (p=0.039). Using the volumetric definition of SRS failure, the unidimensional criteria demonstrated a sensibility of 60.78% (46.11%-74.16%), specificity of 89.02% (80.18%-94.86%), positive LR of 5.54 (2.88-10.66) and negative LR of 0.44 (0.31-0.63). SRS demonstrated a 61.5% local control rate 12 months after treatment. Among the potential predictors of treatment outcome analyzed, only the right BM laterality had a significant association with SRS failure. The volumetric criteria were able to identify more subtle signs of BM increase than the unidimensional criteria, which may allow earlier diagnosis of disease progression and use of appropriate therapies.

CLO24-085: Precision Medicine Drivers in Non-Small Cell Lung Cancer Brain Metastases.

CLO24-085: Precision Medicine Drivers in Non-Small Cell Lung Cancer Brain Metastases.

Abstract 1797: Investigating the significance of OXPHOS activity in non-small cell lung cancer brain metastases

Abstract Background: Brain metastasis is a common and devastating occurrence for patients with non-small cell lung cancer (NSCLC). NSCLC patients with brain metastases have a poor median overall survival of 2-3 months, highlighting the urgency for novel treatment strategies. One approach to understanding and potentially targeting metastasis is via cancer metabolism. During the metastatic cascade, cancer cells must survive and adapt to the differential nutrient environments they encounter, including the brain. The blood brain barrier limits the availability of many metabolites, leading metastatic cells to alter their nutrient use to survive. RNA sequencing analyses of NSCLC brain metastases suggest that increased oxidative phosphorylation (OXPHOS) may be one such metabolic adaptation in the brain. The aim of this study was to determine the necessity of OXPHOS activity as a metabolic adaptation for NSCLC cells to proliferate in the unique metabolic environment of the brain. Materials and Methods: NSCLC cells were cultured in media mimicking the metabolic environments of the brain and blood. Expression of mitochondrial markers were evaluated by immunoblot in cells cultured across media conditions. The effects of the OXPHOS inhibitor IACS-010759 were assessed by cell growth as well as stable isotope tracing with [U-13C] glucose. Patient derived xenografts (PDXs) were derived from a cohort of patients with NSCLC who underwent stable isotope tracing with [U-13C] glucose. Mice bearing subcutaneously implanted PDXs were treated daily with 5mg/kg IACS-010759 and metastatic burden was measured by flow cytometry and histology. Results: Tracing studies in patients revealed that high enrichment in OXPHOS-related metabolites in the primary tumor correlated with worse patient outcomes. Compared with other media conditions, cells cultured in media replicating the metabolic environment of the brain have increased expression of mitochondrial proteins, increased 13C glucose labeling in the TCA cycle, and a larger reduction in proliferation with IACS-010759 treatment. Using our PDX models, inhibition of OXPHOS with IACS-010759 had little effect on subcutaneous tumor growth but reduced metastasis in the lung and the brain. Conclusions: OXPHOS activity may be enhanced in NSCLC brain metastases due to the unique metabolic environment of the brain. This elevated OXPHOS activity may be necessary for NSCLC brain metastasis growth, as OXPHOS inhibition reduced metastasis in the brain. NSCLC cells may undergo mitochondrial biogenesis to support survival in this unique metabolic environment, and this may represent an area of therapeutic vulnerability for brain metastases. Citation Format: Nia G. Hammond, Massar Alsamraae, Mayher Kaur, Rachel Zuckerman, Brianna Chang, Robert Cameron, Aaron Dyas, Brandon Faubert. Investigating the significance of OXPHOS activity in non-small cell lung cancer brain metastases [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1797.

Durable response to first-line treatment with AZD3759 (zorifertinib) in a patient with epithelial growth factor receptor mutated non-small cell lung cancer and untreated multiple brain metastasis

Central nervous system (CNS) metastases, including brain and leptomeningeal metastasis, are associated with poor prognosis in epidermal growth factor receptor (<i>EGFR</i>)-mutated non-small cell lung cancer (NSCLC) patients. CNS metastasis occurs in more than 50% of <i>EGFR</i>-mutated NSCLC cases during the treatment course. The treatment options for CNS metastases in these patients are limited, and there have been ongoing efforts to develop targeted agents with enhanced CNS penetration. AZD3759 (zorifertinib) is a novel <i>EGFR</i> tyrosine kinase inhibitor with a high capability of CNS penetration and proven efficacy with tolerable safety profiles. In this report, we describe a case of a patient with <i>EGFR</i>-mutant NSCLC that was initially diagnosed with multiple brain metastasis who demonstrated prolonged response of both intra- and extracranial lesions over 7 years with AZD3759 as first-line treatment.

Current approaches in the diagnosis and management of non-small cell lung cancer brain metastases

Brain metastases are a frequent consequence of “non-small cell lung cancer (NSCLC)”, one of the most prevalent cancers with a poor prognosis. For the best possible patient outcomes, detecting and treating NSCLC brain metastases involve substantial hurdles and calls for a multidisciplinary approach. This article intends to provide an overview of current methods for diagnosing and treating NSCLC brain metastases. It examines the various available treatment options, diagnostic techniques, and their effects on patient outcomes. A thorough literature review was done to find pertinent studies, clinical suggestions, and professional advice about the specialized management of NSCLC. The chosen articles were examined to learn about molecular screening techniques, individualized treatment plans, and diagnostic procedures. For individualized treatment, precise NSCLC identification and prognosis are essential. Techniques such as imaging and endoscopy are used to collect tissue samples. It is advised to do a molecular screening for oncogenic changes. Evaluation of PD-L1 expression informs therapy decisions. The molecular profile determines the first line of treatment, followed by chemotherapy and immunotherapy, and cancer tissue samples help to detect resistance mechanisms. For the best possible patient results, NSCLC therapy must be personalized and incorporate precise pathology evaluation, molecular assessment, and precision therapeutic approaches. To progress in precision medicine in lung cancer treatment, further research is required to find novel molecular markers, especially those that predict the effectiveness of immunotherapy.

Long-Term Intracranial Outcomes With Combination Dual Immune-Checkpoint Blockade and Stereotactic Radiosurgery in Patients With Melanoma and Non-Small Cell Lung Cancer Brain Metastases

The intracranial benefit of offering dual immune-checkpoint inhibition (D-ICPI) with ipilimumab and nivolumab to patients with melanoma or non-small cell lung cancer (NSCLC) receiving stereotactic radiosurgery (SRS) for brain metastases (BMs) is unknown. We hypothesized that D-ICPI improves local control compared with SRS alone. Patients with melanoma or NSCLC treated with SRS from 2014 to 2022 were evaluated. Patients were stratified by treatment with D-ICPI, single ICPI (S-ICPI), or SRS alone. Local recurrence, intracranial progression (IP), and overall survival were estimated using competing risk and Kaplan-Meier analyses. IP included both local and distant intracranial recurrence. Two hundred eighty-eight patients (44% melanoma, 56% NSCLC) with 1,704 BMs were included. Fifty-three percent of patients had symptomatic BMs. The median follow-up was 58.8 months. Twelve-month local control rates with D-ICPI, S-ICPI, and SRS alone were 94.73% (95% CI, 91.11%-96.90%), 91.74% (95% CI, 89.30%-93.64%), and 88.26% (95% CI, 84.07%-91.41%). On Kaplan-Meier analysis, only D-ICPI was significantly associated with reduced local recurrence (P = .0032). On multivariate Cox regression, D-ICPI (hazard ratio [HR], 0.4003; 95% CI, 0.1781-0.8728; P = .0239) and planning target volume (HR, 1.022; 95% CI, 1.004-1.035; P = .0059) correlated with local control. One hundred seventy-three (60%) patients developed IP. The 12-month cumulative incidence of IP was 41.27% (95% CI, 30.27%-51.92%), 51.86% (95% CI, 42.78%-60.19%), and 57.15% (95% CI, 44.98%-67.59%) after D-ICPI, S-ICPI, and SRS alone. On competing risk analysis, only D-ICPI was significantly associated with reduced IP (P = .0408). On multivariate Cox regression, D-ICPI (HR, 0.595; 95% CI, 0.373-0.951; P = .0300) and presentation with >10 BMs (HR, 2.492; 95% CI, 1.668-3.725; P < .0001) remained significantly correlated with IP. The median overall survival after D-ICPI, S-ICPI, and SRS alone was 26.1 (95% CI, 15.5-40.7), 21.5 (16.5-29.6), and 17.5 (11.3-23.8) months. S-ICPI, fractionation, and histology were not associated with clinical outcomes. There was no difference in hospitalizations or neurologic adverse events between cohorts. The addition of D-ICPI for patients with melanoma and NSCLC undergoing SRS is associated with improved local and intracranial control. This appears to be an effective strategy, including for patients with symptomatic or multiple BMs.

Using machine learning-based radiomics to differentiate between glioma and solitary brain metastasis from lung cancer and its subtypes

ObjectiveTo establish a machine learning-based radiomics model to differentiate between glioma and solitary brain metastasis from lung cancer and its subtypes, thereby achieving accurate preoperative classification.Materials and methodsA retrospective analysis was conducted on MRI T1WI-enhanced images of 105 patients with glioma and 172 patients with solitary brain metastasis from lung cancer, which were confirmed pathologically. The patients were divided into the training group and validation group in an 8:2 ratio for image segmentation, extraction, and filtering; multiple layer perceptron (MLP), support vector machine (SVM), random forest (RF), and logistic regression (LR) were used for modeling; fivefold cross-validation was used to train the model; the validation group was used to evaluate and assess the predictive performance of the model, ROC curve was used to calculate the accuracy, sensitivity, and specificity of the model, and the area under curve (AUC) was used to assess the predictive performance of the model.ResultsThe accuracy and AUC of the MLP differentiation model for high-grade glioma and solitary brain metastasis in the validation group was 0.992, 1.000, respectively, while the sensitivity and specificity were 1.000, 0.968, respectively. The accuracy and AUC for the MLP and SVM differentiation model for high-grade glioma and small cell lung cancer brain metastasis in the validation group was 0.966, 1.000, respectively, while the sensitivity and specificity were 1.000, 0.929, respectively. The accuracy and AUC for the MLP differentiation model for high-grade glioma and non-small cell lung cancer brain metastasis in the validation group was 0.982, 0.999, respectively, while the sensitivity and specificity were 0.958, 1.000, respectively.ConclusionThe application of machine learning-based radiomics has a certain clinical value in differentiating glioma from solitary brain metastasis from lung cancer and its subtypes. In the HGG/SBM and HGG/NSCLC SBM validation groups, the MLP model had the best diagnostic performance, while in the HGG/SCLC SBM validation group, the MLP and SVM models had the best diagnostic performance.

Abstract LB_A04: Quantitative digital spatial protein profiling of non-small cell lung cancer brain metastasis

Abstract Metastatic brain tumor is the most common form of adult central nervous system (CNS) tumor, and the majority of the cerebral metastasis originate from lung cancer. Along with recent combination strategies applying immune checkpoint inhibitor, evaluating tumor microenvironment of the brain metastasis (BM) needs to be unveiled. In this study, we tried to disclose immune context information of BM of non-small cell lung cancer (NSCLC) by using highly multiplex NanoString digital spatial profiling (DSP) method. Seven cases of NSCLC and metastatic brain tumor were evaluated. To detect proteins at quantitative and high multiplex with spatial resolution, NanoString optical barcoding technology was used to digitally profile protein expression in FFPE samples. Immuno-oncology protein targets, including immune cell markers and checkpoint proteins are included. DSP identified differentially expressed proteins between primary NSCLC and BM. Proteins associated with immune regulation, evasion, and adaptive immunity, such as IDO-1, PD1, PDL1, STAT3, PTEN, and CD44 revealed decreased expression in patients with BM (P&amp;lt;0.01). The expression of pS6 was significantly increased in BM (P&amp;lt;0.01), which is associated with activation induced T-cell death. This study demonstrated differentially expressed proteins in BM associated with immune regulation and evasion via NanoString DSP platform. This study highlighted the localized expression of immune-related proteins of BM in patients with NSCLC. Moreover, our results presented the possibility of using digitally quantified and spatially allocated novel method in BM eliminating the subjectivity and variability associated with the immunohistochemistry techniques. Citation Format: Tae Jung Kim. Quantitative digital spatial protein profiling of non-small cell lung cancer brain metastasis [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A04.

Use of comprehensive genomic profiling for biomarker discovery for the management of non-small cell lung cancer brain metastases.

Clinical biomarkers for brain metastases remain elusive. Increased availability of genomic profiling has brought discovery of these biomarkers to the forefront of research interests. In this single institution retrospective series, 130 patients presenting with brain metastasis secondary to Non-Small Cell Lung Cancer (NSCLC) underwent comprehensive genomic profiling conducted using next generation circulating tumor deoxyribonucleic acid (DNA) (Guardant Health, Redwood City, CA). A total of 77 genetic mutation identified and correlated with nine clinical outcomes using appropriate statistical tests (general linear models, Mantel-Haenzel Chi Square test, and Cox proportional hazard regression models). For each outcome, a genetic signature composite score was created by summing the total genes wherein genes predictive of a clinically unfavorable outcome assigned a positive score, and genes with favorable clinical outcome assigned negative score. Seventy-two genes appeared in at least one gene signature including: 14 genes had only unfavorable associations, 36 genes had only favorable associations, and 22 genes had mixed effects. Statistically significant associated signatures were found for the clinical endpoints of brain metastasis velocity, time to distant brain failure, lowest radiosurgery dose, extent of extracranial metastatic disease, concurrent diagnosis of brain metastasis and NSCLC, number of brain metastases at diagnosis as well as distant brain failure. Some genes were solely associated with multiple favorable or unfavorable outcomes. Genetic signatures were derived that showed strong associations with different clinical outcomes in NSCLC brain metastases patients. While these data remain to be validated, they may have prognostic and/or therapeutic impact in the future. Using Liquid biopsy in NSCLC brain metastases patients, the genetic signatures identified in this series are associated with multiple clinical outcomes particularly these ones that lead to early or more numerous metastases. These findings can be reverse-translated in laboratory studies to determine if they are part of the genetic pathway leading to brain metastasis formation.

1419P TACSTD2 (Trop-2) constitutes a promising antibody-drug conjugate target for patients with non-small cell lung cancer brain metastases

1419P TACSTD2 (Trop-2) constitutes a promising antibody-drug conjugate target for patients with non-small cell lung cancer brain metastases

Hippocampal Avoidance Whole Brain Radiotherapy with Reduced Whole Brain Dose in Patients with Non-Small Cell Lung Cancer Brain Metastases

Hippocampal avoidance whole brain radiation (HA-WBRT) results in improved neurocognitive function (NCF) compared to standard WBRT, but > 50% of patients still experience NCF failure. We examined whether gentler fractionation of HA-WBRT with lower biologically effective dose (BED), typically delivering 30 Gy over 15 versus 10 fractions, may allow for better hippocampal sparing without impacting intracranial disease control in patients with non-small cell lung cancer (NSCLC). We conducted a retrospective study of patients with NSCLC receiving HA-WBRT between 2014-2022. Endpoints were distant brain failure free survival (DBFFS), local brain failure free survival (LBFFS), left and right hippocampal mean BED2 and BED21%. Kaplan-Meier survival analysis and Welch's t-test were performed. NCF outcomes were graded with CTCAEv5. The IRB approved this study. Sixty-nine consecutive patients treated with HA-WBRT were included, with median follow up of 51.2 weeks. Median age was 63 years and 29% had a targetable mutation. Thirty-six patients received standard HA-WBRT with median dose of 30 Gy (range 30-35 Gy) in 10 fractions (range 10-14). Thirty-three patients received reduced BED HA-WBRT, with median dose of 30 Gy (range 23-30) in 15 fractions (range 9-15) to the radiographically uninvolved brain. All patients in the reduced BED (RD) group had a simultaneous integrated boost (SIB) to gross disease (median 37.5 Gy (range 36-37.5 Gy)), while 18/36 in the standard dose (SD) group had an SIB (median 35 Gy (range 34-39 Gy)). There were no significant differences between SD and RD cohorts in age, systemic therapy use before WBRT or targetable mutations. There was no significant difference in median DBFFS of the SD [23.1 weeks (IQR 11.3-49.3)] and RD groups [40 weeks, (IQR 20.9-109.1)] (p = 0.27). There was also no difference in LBFFS of the SD (median 26.4 weeks, IQR 11.3-76.2) and RD groups (median 40 weeks, IQR (21-71.4) (p = 0.84). For the left and right hippocampi, both mean BED2 and D1% were significantly lower in the RD group (Table 1). Median cognitive disturbance was Grade (G) 0 (range 0-3) in both groups, with 4 G>2 events in the SD cohort vs. 3 in the RD cohort. In this single-institution cohort, HA-WBRT using a gentler fractionation with SIB was associated with improved hippocampal sparing without compromising intracranial control in patients with NSCLC. We suggest that further optimization of HA-WBRT dose and schedule may improve both intracranial control and NCF outcomes. This study is limited by its retrospective nature and potential selection bias. A phase II prospective study to test these concepts is ongoing.

Immune Checkpoint Inhibition and Single Fraction Stereotactic Radiosurgery in Non-Small Cell Lung Cancer Brain Metastases: An International Multicenter Study of 395 Patients

Brain metastases most commonly arise from non-small cell lung cancer (NSCLC). In recent years, immune checkpoint inhibitors (ICI) have demonstrated improvements in overall survival (OS) in NSCLC. However, concerns remain about the risk of radiation necrosis (RN) when ICI are administered with stereotactic radiosurgery (SRS). Logistic regression was used to evaluate prognostic factors associated with the development of any grade RN and symptomatic RN. Cumulative incidence of RN was evaluated using competing risks analysis and the Fine and Gray model, where the null hypothesis was rejected for p < 0.05. There were 395 patients with 2,513 brain metastases treated across 11 international institutions included in the analysis. The median follow-up was 14.2 months. Median patient age was 67 years (Interquartile Range [IQR]: 61-73), 53.4% were male, the median Karnofsky Performance Status was 80 (IQR: 80-90), and 88.6% has active extracranial disease at the time of SRS. The median margin dose was 19 Gy (IQR: 18-20), 97.5% of patients were treated on the Gamma Knife ®, 3.8% underwent prior whole brain radiation therapy (WBRT). The median V12 Gy was 5.2 cm3 and 36.5% of patients had a V12 Gy ≥ 10 cm3, anti-PD-1 agents were administered in 91.6% of patients. A V12 Gy ³ 10 cm3 was associated with an increased risk of developing any grade RN; odds ratio (OR): 2.12, p = 0.04 and OR: 2.18; p = 0.03 on univariable and multivariable analysis, respectively. Similarly, a V12 Gy ≥ 10 cm3 was associated with an increased risk of developing symptomatic RN; OR: 3.80, p = 0.003 and OR: 3.95; p = 0.003 on univariable and multivariable analysis, respectively. Receipt of concurrent ICI and prior WBRT were not statistically significant. At 1-year, the cumulative incidence of any grade and symptomatic RN was 4.8% and 3.8%, respectively. The cumulative incidence of any grade RN was 3.8% vs. 5.3% for the concurrent and non-concurrent groups at 1-year, respectively (p = 0.35). The cumulative incidence of symptomatic RN was 3.8% vs. 3.6% for the concurrent and non-concurrent groups at 1-year, respectively (p = 0.95). The risk of any grade and symptomatic RN following SRS and ICI administration for NSCLC brain metastases increases as the V12 Gy exceeds 10 cm3. Concurrent ICI and SRS does not appear to increase this risk. Radiosurgical planning techniques should aim to minimize the V12 Gy.

The Impact of Time Interval on Prognosis in Patients with Non-Small Cell Lung Cancer Brain Metastases After Metastases Surgery

Non-small cell lung cancer (NSCLC) is a prominent malignancy often linked to the development of brain metastases (BM), which commonly appear at diverse time intervals (TI) following the lung cancer diagnosis. This study endeavors to determine the prognostic significance of the time interval in patients with NSCLC who undergo BM surgery. Through this investigation, we aim to improve our understanding of the factors impacting the prognosis of BM cases originating from NSCLC. We analyzed data from 74 patients (2011-2021) who underwent BM surgery at our institution. The relationship between various clinical, radiological, and histopathological factors, as well as TI and overall survival (OS), was examined. The median TI from initial NSCLC diagnosis to BM surgery was 19months (range: 9-36months). Notably, a shorter TI of less than 23months was found to be independently associated with postoperative survival (adjusted odds ratio [aOR] 2.87, 95% confidence interval [CI] 1.03-8.02, P= 0.045). Additionally, a shorter TI was independently correlated with the absence of adjuvant chemotherapy for NSCLC (aOR 0.25, 95% CI 0.07-0.83, P= 0.023) and lack of targeted therapy (aOR 0.02, 95% CI 0.00-0.16, P<0.001). Late-onset BM (TI≥36months) was observed in 15 cases (20.3%), in this subgroup, patients aged 60years or older at the time of lung cancer diagnosis exhibited a significant independent correlation with late-onset BM (aOR 7.24, 95% CI 1.59-32.95, P= 0.011). NSCLC patients who underwent adjuvant chemotherapy displayed a notable correlation with late-onset BM (aOR 6.46, 95% CI 1.52-27.43, P= 0.011), while those who received targeted therapy also exhibited an independent association (aOR 2.27, 95% CI 1.70-3.03, P < 0.001). Multiple factors contribute to the variability in the onset interval of BM subsequent to NSCLC diagnosis. The occurrence of BM within TI<23months following the initial diagnosis of NSCLC was demonstrated as an independent factor associated with an unfavorable prognosis following BM surgery. Furthermore, patients with NSCLC who did not receive adjuvant chemotherapy and lacked targeted therapy were shown to have an elevated likelihood of developing BM after a long progression-free survival.

Multisequence MRI-based radiomics nomogram for early prediction of osimertinib resistance in patients with non-small cell lung cancer brain metastases

BackgroundOsimertinib resistance is a major problem in the course of targeted therapy for non-small cell lung cancer (NSCLC) patients. To develop and validate a multisequence MRI-based radiomics nomogram for early prediction of osimertinib resistance in NSCLC with brain metastases (BM). MethodsPretreatment brain MRI of 251 NSCLC patients proven with BM were retrospectively enrolled from two centers (training cohort: 196 patients; testing cohort: 55 patients). According to the gene test result of osimertinib resistance, patients were labeled as resistance and non-resistance groups (training cohort: 65 versus 131 patients; testing cohort: 25 versus 30 patients). Radiomics features were extracted from T2WI, T2 fluid-attenuated inversion recovery (T2-FLAIR), diffusion weighted imaging (DWI) and contrast-enhanced T1-weighted imaging (T1-CE) sequences separately and radiomics score (rad-score) were built from the four sequences. Then a multisequence MRI-based nomogram was developed and the predictive ability was evaluated by ROC curves and calibration curves. ResultsThe rad-scores of the four sequences has significant differences between resistance and non-resistance groups in both training and testing cohorts. The nomogram achieved the highest predictive ability with area under the curve (AUC) of 0.989 (95 % confidence interval, 0.976–1.000) and 0.923 (95 % confidence interval, 0.851–0.995) in the training and testing cohort respectively. The calibration curves showed excellent concordance between the predicted and actual probability of osimertinib resistance using the radiomics nomogram. ConclusionsThe multisequence MRI-based radiomics nomogram can be used as a noninvasive auxiliary tool to identify candidates who were resistant to osimertinib, which could guide clinical therapy for NSCLC patients with BM.

Genomic analysis and clinical correlations of non-small cell lung cancer brain metastasis

Up to 50% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), yet the study of BM genomics has been limited by tissue access, incomplete clinical data, and a lack of comparison with paired extracranial specimens. Here we report a cohort of 233 patients with resected and sequenced (MSK-IMPACT) NSCLC BM and comprehensive clinical data. With matched samples (47 primary tumor, 42 extracranial metastatic), we show CDKN2A/B deletions and cell cycle pathway alterations to be enriched in the BM samples. Meaningful clinico-genomic correlations are noted, namely EGFR alterations in leptomeningeal disease (LMD) and MYC amplifications in multifocal regional brain progression. Patients who developed early LMD frequently have had uncommon, multiple, and persistently detectable EGFR driver mutations. The distinct mutational patterns identified in BM specimens compared to other tissue sites suggest specific biologic underpinnings of intracranial progression.

BSBM-18 SINGLE-CELL PROFILING TUMOR-INFILTRATING IMMUNE CELLS REVEALS CXCL13+ FOLLICULAR HELPER-LIKE CD4+ T CELLS IN HUMAN BRAIN TUMORS

Abstract While therapies enhancing antitumor T cell function have clinical efficacy for patients with brain metastases, patients with high-grade gliomas fail to benefit. How the brain tumor microenvironment differentially shapes T cell function remains unknown. We performed droplet-based single-cell RNA and T cell receptor sequencing on immune cells from tumor and blood of patients with newly diagnosed non-small cell lung cancer brain metastases (n=10) and high-grade glioma (n=12). In total, we examined 220,049 high-quality immune cells, including 159,043 T cells. Tumor-infiltrating T cells in metastases were more abundant (p=0.005), more clonally expanded (p=0.039), and had a less diverse clonal repertoire (p=0.033). While no differences were observed among CD8+ T cells, a population of CXCL13+CD4+ T cells was more abundant in metastases (6.03% vs. 1.82%, p=0.004). This population expressed genes encoding transcriptional factors (BCL6, MAF), co-inhibitory receptors (PDCD1, LAG3, TIGIT), and effector cytokines (IL21, IL4, IFNG) characteristic of follicular helper T cells though notably lacked expression for the canonical chemokine receptor CXCR5. CXCL13+CD4+ T cells were highly expanded, had minimal clonal overlap with other populations, largely confined to the tumor, associated with germinal center B cell and plasma cell signatures, and resembled T cell populations predictive of anti-PD-1 therapy response in extracranial disease. Based on the expression of potential ligand-receptors and downstream signaling targets, CXCL13+CD4+ T cells were predicted to interact with B cells and antigen-presenting cells, as seen in tertiary lymphoid structures. To investigate the relevance of CXCL13+CD4+ T cells in glioblastoma, we analyzed bulk RNA sequencing data from The Cancer Genome Atlas (n=160) and observed a trend towards longer overall survival in patients with high follicular helper-like expression. In summary, we identified a follicular helper-like CD4+ T cell population that is preferentially found in brain metastases and may be a feature of productive antitumor immune responses in human brain tumors.

Effects of Ataxia-Telangiectasia Mutated Variants on Radionecrosis and Local Control After Stereotactic Radiation Surgery for Non-Small Cell Lung Cancer Brain Metastases

Genetic variants affecting the radiation response protein ataxia-telangiectasia mutated (ATM) have been associated with increased adverse effects of radiation but also with improved local control after conventional radiation therapy. However, it is unknown whether ATM variants affect rates of radionecrosis (RN) and local intracranial progression (LIP) after stereotactic radiosurgery (SRS) for brain metastases. Patients undergoing an initial course of SRS for non-small cell lung cancer (NSCLC) brain metastases at a single institution were retrospectively identified. Kaplan-Meier estimates were calculated and Cox proportional hazards testing was performed based on ATM variant status. A total of 541 patients completed SRS for brain metastasis secondary to NSCLC, of whom 260 completed molecular profiling. Variants of ATM were identified in 36 cases (13.8%). Among patients who completed molecular profiling, RN incidence was 4.9% (95% CI, 1.6%-8.2%) at 6 months and 9.9% (95% CI, 4.8%-15.0%) at 12 months. Incidence of RN was not significantly increased among patients with ATM variants, with an RN incidence of 5.3% (95% CI, 0.0%-15.3%) at both 6 and 12 months (P=.46). For all patients who completed genomic profiling, LIP was 5.4% (95% CI, 2.4%-8.4%) at 6 months and 9.8% (5.5%-14.1%) at 12 months. A significant improvement in LIP was not detected among patients with ATM variants, with an LIP incidence of 3.1% (0.0%-9.1%) at both 6 and 12 months (P=.26). Although differences according to ATM variant type (pathologic variant or variant of unknown significance) did not reach significance, no patients with ATM pathologic variants experienced LIP. We did not detect significant associations between ATM variant status and RN or LIP after SRS for NSCLC brain metastases. The current data set allows estimation of patient cohort sizes needed to power future investigations to identify genetic variants that associate with significant differences in outcomes after SRS.

Immune checkpoint inhibitors for the treatment of non-small cell lung cancer brain metastases.

Lung cancer has the highest risk of brain metastasis (BM) among all solid carcinomas. The emergence of BM has a significant impact on the selection of oncologic treatment for patients. Immune checkpoint inhibitors (ICIs) are the most promising treatment option for patients without druggable mutations and have been shown to improve survival in patients with non-small cell lung cancer (NSCLC) BM in clinical trials with good safety. Moreover, ICI has shown certain effects in NSCLC BM, and the overall intracranial efficacy is comparable to extracranial efficacy. However, a proportion of patients showed discordant responses in primary and metastatic lesions, suggesting that multiple mechanisms may exist underlying ICI activity in BM. According to studies pertaining to tumor immune microenvironments, ICIs may be capable of provoking immunity in situ. Meanwhile, systematic immune cells activated by ICIs can migrate into the central nervous system and exert antitumor effects. This review summarizes the present evidence for ICI treatment efficacy in NSCLC BM and proposes the possible mechanisms of ICI treatment for NSCLC BMs based on existing evidence.

Efficacy and safety of combined immunotherapy and stereotactic radiosurgery in NSCLCBM patients and a novel prognostic nomogram: A real-world study.

To explore the effectiveness of combined immunotherapy (IT) and stereotactic radiosurgery (SRS) and address the gap between evidence-based clinical practice and academic knowledge of optimal timing of IT relative to SRS. In addition, to meet the unmet need for an up-to-date prognostic assessment model in the era of IT. The data of 86 non-small cell lung cancer brain metastasis (NSCLCBM) patients treated with SRS to 268 brain metastases (BMs) were retrospectively extracted from our hospital database. The Kaplan-Meier analysis was employed for overall survival (OS) and a log-rank test for comparison between groups. Cox proportional hazards regression models were used to identify the significant prognostic factors. The prognostic nomogram was established utilizing the rms package of R software. IT was found to be associated with improved OS (from BM diagnosis: HR 0.363, 95% CI 0.199 - 0.661, P < 0.001; from SRS: HR 0.472, 95% CI 0.260 - 0.857, P = 0.014). Individuals who received IT in combination with SRS had better OS than those who didn't (from the day of BM diagnosis: 16.8 vs. 8.4 months, P = 0.006; from the day of SRS: 12 vs. 7 months, P = 0.037). Peri-SRS timing of IT administration was a significant prognostic factor for OS (from BM diagnosis: HR 0.132, 95% CI 0.034 - 0.517, P = 0.004; from SRS: HR 0.14, 95% CI 0.044 - 0.450, P = 0.001). Initiating IT after SRS led to superior OS than concurrent or before (from BM diagnosis: 26.5 vs. 14.1 vs. 7.1 months; from SRS: 21.4 vs. 9.9 vs. 4.1 months, respectively). Additionally, we build a nomogram incorporating IT, cumulative intracranial tumor volume (CITV), and recursive partitioning analysis (RPA), demonstrating a remarkable prognosis prediction performance for SRS-treated NSCLCBM patients. Peri-SRS IT is a promising approach in treating NSCLCBM, as improved OS was observed without significantly increasing adverse events. Receipt of IT post-SRS was associated with superior OS than those who received IT concurrently or before. Incorporating IT and CITV into the RPA index could augment its prognosis assessment value for SRS-treated NSCLCBM patients, predominantly in the wild-type.