Single-Cell Mapping of Human Brain Cancer Reveals Tumor-Specific Instruction of Tissue-Invading Leukocytes.

Brain malignancies can either originate from within the CNS (gliomas) or invade from other locations in the body (metastases). A highly immunosuppressive tumor microenvironment (TME) influences brain tumor outgrowth. Whether the TME is predominantly shaped by the CNS micromilieu or by the malignancy itself is unknown, as is the diversity, origin, and function of CNS tumor-associated macrophages (TAMs). Here, we have mapped the leukocyte landscape of brain tumors using high-dimensional single-cell profiling (CyTOF). The heterogeneous composition of tissue-resident and invading immune cells within the TME alone permitted a clear distinction between gliomas and brain metastases (BrM). The glioma TME presented predominantly with tissue-resident, reactive microglia, whereas tissue-invading leukocytes accumulated in BrM. Tissue-invading TAMs showed a distinctive signature trajectory, revealing tumor-driven instruction along with contrasting lymphocyte activation and exhaustion. Defining the specific immunological signature of brain tumors can facilitate the rational design of targeted immunotherapy strategies.

Neural Signaling in Cancer.

Nervous system activity regulates development, homeostasis, and plasticity of the brain as well as other organs in the body. These mechanisms are subverted in cancer to propel malignant growth. In turn, cancers modulate neural structure and function to augment growth-promoting neural signaling in the tumor microenvironment. Approaching cancer biology from a neuroscience perspective will elucidate new therapeutic strategies for presently lethal forms of cancer. In this review, we highlight the neural signaling mechanisms recapitulated in primary brain tumors, brain metastases, and solid tumors throughout the body that regulate cancer progression.

An interdisciplinary consensus on the management of brain metastases in patients with renal cell carcinoma.

Brain metastases are a challenging manifestation of renal cell carcinoma. We have a limited understanding of brain metastasis tumor and immune biology, drivers of resistance to systemic treatment, and their overall poor prognosis. Current data support a multimodal treatment strategy with radiation treatment and/or surgery. Nonetheless, the optimal approach for the management of brain metastases from renal cell carcinoma remains unclear. To improve patient care, the authors sought to standardize practical management strategies. They performed an unstructured literature review and elaborated on the current management strategies through an international group of experts from different disciplines assembled via the network of the International Kidney Cancer Coalition. Experts from different disciplines were administered a survey to answer questions related to current challenges and unmet patient needs. On the basis of the integrated approach of literature review and survey study results, the authors built algorithms for the management of single and multiple brain metastases in patients with renal cell carcinoma. The literature review, consensus statements, and algorithms presented in this report can serve as a framework guiding treatment decisions for patients. CA Cancer J Clin. 2022;72:454-489.

Evolving standards of care and new challenges in the management of HER2-positive breast cancer.

The management of human epidermal growth factor receptor (HER2)-positive breast cancer (BC) has rapidly evolved over the last 20 years. Major advances have led to US Food and Drug Administration approval of 7 HER2-targeted therapies for the treatment of early-stage and/or advanced-stage disease. Although oncologic outcomes continue to improve, most patients with advanced HER2-positive BC ultimately die of their disease because of primary or acquired resistance to therapy, and patients with HER2-positive early BC who have residual invasive disease after preoperative systemic therapy are at a higher risk of distant recurrence and death. The concept of treatment de-escalation and escalation is increasingly important to optimally tailor therapy for patients with HER2-positive BC and is a major focus of the current review. Research efforts in this regard are discussed as well as updates regarding the evolving standard of care in the (neo)adjuvant and metastatic settings, including the use of novel combination therapies. The authors also briefly discuss ongoing challenges in the management of HER2-positive BC (eg, intrinsic vs acquired drug resistance, the identification of predictive biomarkers, the integration of imaging techniques to guide clinical practice), and the treatment of HER2-positive brain metastases. Research aimed at superseding these challenges will be imperative to ensure continued progress in the management of HER2-positive BC going forward.

An HLA-G/SPAG9/STAT3 axis promotes brain metastases.

Brain metastases (BM) are the most common brain neoplasm in adults. Current BM therapies still offer limited efficacy and reduced survival outcomes, emphasizing the need for a better understanding of the disease. Herein, we analyzed the transcriptional profile of brain metastasis initiating cells (BMICs) at two distinct stages of the brain metastatic cascade-the "premetastatic" or early stage when they first colonize the brain and the established macrometastatic stage. RNA sequencing was used to obtain the transcriptional profiles of premetastatic and macrometastatic (non-premetastatic) lung, breast, and melanoma BMICs. We identified that lung, breast, and melanoma premetastatic BMICs share a common transcriptomic signature that is distinct from their non-premetastatic counterparts. Importantly, we show that premetastatic BMICs exhibit increased expression of HLA-G, which we further demonstrate functions in an HLA-G/SPAG9/STAT3 axis to promote the establishment of brain metastatic lesions. Our findings suggest that unraveling the molecular landscape of premetastatic BMICs allows for the identification of clinically relevant targets that can possibly inform the development of preventive and/or more efficacious BM therapies.

Immunity in malignant brain tumors: Tumor entities, role of immunotherapy, and specific contribution of myeloid cells to the brain tumor microenvironment.

Malignant brain tumors lack effective treatment, that can improve their poor overall survival achieved with standard of care. Advancement in different cancer treatments has shifted the focus in brain tumor research and clinical trials toward immunotherapy-based approaches. The investigation of the immune cell landscape revealed a dominance of myeloid cells in the tumor microenvironment. Their exact roles and functions are the subject of ongoing research. Current evidence suggests a complex interplay of tumor cells and myeloid cells with competing functions toward support vs. control of tumor growth. Here, we provide a brief overview of the three most abundant brain tumor entities: meningioma, glioma, and brain metastases. We also describe the field of ongoing immunotherapy trials and their results, including immune checkpoint inhibitors, vaccination studies, oncolytic viral therapy, and CAR-T cells. Finally, we summarize the phenotypes of microglia, monocyte-derived macrophages, border-associated macrophages, neutrophils, and potential novel therapy targets.

Spotlight on the treatment of non-small cell lung cancer with rare genetic alterations and brain metastasis: Current status and future perspectives.

In patients with non-small cell lung cancer (NSCLC), oncogenic variants present in <5% of cases are considered rare, the predominant of which include human epidermal growth factor receptor 2 (HER2) mutations, mesenchymal-epithelial transition (MET) alterations, c-ros oncogene 1 (ROS1) rearrangements, rearrangement during transfection (RET) fusions, v-raf mouse sarcoma virus oncogene homolog B1 (BRAF) mutations, and neurotrophic troponin receptor kinase (NTRK) fusions. Brain metastases (BMs) occur in approximately 10%-50% of patients with NSCLC harboring rare genetic variants. The recent advent of small-molecule tyrosine kinase inhibitors and macromolecular antibody-drug conjugates (ADCs) has conferred marked survival benefits to patients with NSCLC harboring rare driver alterations. Despite effective brain lesion control for most targeted agents and promising reports of intracranial remission associated with novel ADCs, BM continues to be a major therapeutic challenge. This review discusses the recent advances in the treatment of NSCLC with rare genetic variants and BM, with a particular focus on intracranial efficacy, and explores future perspectives on how best to treat these patients.

Can low-dose intravenous bevacizumab be as effective as high-dose bevacizumab for cerebral radiation necrosis?

Although intravenous bevacizumab (IVBEV) is the most promising treatment for cerebral radiation necrosis (CRN), there is no conclusion on the optimal dosage. Our retrospective study aimed to compare the efficacy and safety of high-dose with low-dose IVBEV in treating CRN associated with radiotherapy for brain metastases (BMs). This paper describes 75 patients who were diagnosed with CRN secondary to radiotherapy for BMs, treated with low-dose or high-dose IVBEV and followed up for a minimum of 6 months. The clinical data collected for this study include changes in brain MRI, clinical symptoms, and corticosteroid usage before, during, and after IVBEV treatment. At the 3-month mark following administration of IVBEV, a comparison of two groups revealed that the median percentage decreases in CRN volume on T2-weighted fluid-attenuated inversion recovery and T1-weighted gadolinium contrast-enhanced image (T1CE), as well as the signal ratio reduction on T1CE, were 65.8% versus 64.8% (p = 0.860), 41.2% versus 51.9% (p = 0.396), and 37.4% versus 35.1% (p = 0.271), respectively. Similarly, at 6 months post-IVBEV, the median percentage reductions of the aforementioned parameters were 59.5% versus 62.0% (p = 0.757), 39.1% versus 31.3% (p = 0.851), and 35.4% versus 28.2% (p = 0.083), respectively. Notably, the incidence of grade ≥3 adverse events was higher in the high-dose group (n = 4, 9.8%) than in the low-dose group (n = 0). Among patients with CRN secondary to radiotherapy for BMs, the administration of high-dose IVBEV did not demonstrate superiority over low-dose IVBEV. Moreover, the use of high-dose IVBEV was associated with a higher incidence of grade ≥3 adverse events compared with low-dose IVBEV.

Treatment and outcomes of clear cell sarcoma of the kidney: A report from the Children's Oncology Group studies AREN0321 and AREN03B2.

BACKGROUND: On the fifth National Wilms Tumor Study, treatment for clear cell sarcoma of the kidney (CCSK) included combined vincristine, doxorubicin, cyclophosphamide, and etoposide (regimen I) plus radiation therapy (RT), yielding 5-year event-free survival (EFS) rates of 100%, 88%, 73%, and 29% for patients who had with stage I, II, III, and IV disease, respectively. In the Children's Oncology Group study AREN0321 of risk-adapted therapy, RT was omitted for stage I disease if lymph nodes were sampled, and carboplatin was added for stage IV disease (regimen UH-1). Patients who had stage II/III disease received regimen I with RT. METHODS: Four-year EFS was analyzed for patients enrolled on AREN0321 and on those enrolled on AREN03B2 who received AREN0321 stage-appropriate chemotherapy. RESULTS: Eighty-two patients with CCSK enrolled on AREN0321, 50 enrolled on AREN03B2 only. The 4-year EFS rate was 82.7% (95% confidence interval [CI], 74.8%-91.4%) for AREN0321 and 89.6% (95% CI, 81.3%-98.7%) for AREN03B2 only (p = .28). When combining studies, the 4-year EFS rates for patients who had stage I (n = 10), II (n = 47), III (n = 65), and IV (n = 10) disease were 90% (95% CI, 73.2%-100.0%), 93.4% (95% CI, 86.4%-100.0%), 82.8% (95% CI, 74.1%-92.6%), and 58.3% (95% CI, 34%-100.0%), respectively. There were no local recurrences among seven patients with stage I disease who were treated without RT. One stage I recurrence occurred in the brain, which was the most common site of relapse overall. Among patients with local stage III tumors, neither initial procedure type, margin status, nor lymph node involvement were prognostic. CONCLUSIONS: Patients with stage I CCSK had excellent outcomes without local recurrences when treated without RT. Patients with stage IV disease appeared to benefit from a carboplatin-containing regimen, although their outcomes remained unsatisfactory. Further research is needed to improve outcomes for patients with advanced-stage disease (ClinicalTrials.gov identifiers NCT00335556 and NCT00898365).

Antiprogrammed death ligand 1 therapy failed to reduce the risk of developing brain metastases in patients with extensive-stage small cell lung cancer: A retrospective analysis.

BACKGROUND: Immunotherapy (IO) has demonstrated promising results in treating extensive-stage small cell lung cancer (ES-SCLC), and the management of ES-SCLC brain metastases (BMs) is now receiving significant clinical attention. The objective of this study was to evaluate the role of IO in the clinical management of BMs. METHODS: Between January 2020 and December 2021, the study included the records of 250 patients who were diagnosed with ES-SCLC. Overall survival (OS), progression-free survival, intracranial progression-free survival, and the cumulative incidence of BMs were calculated using the Kaplan-Meier method and were compared using the log-rank test. In addition, the Cox regression model was used to analyze prognostic factors. RESULTS: In the entire group, 85 patients had baseline BMs (IO plus chemotherapy [IO + ChT], n = 38; ChT alone, n = 47), and 165 patients (IO + ChT, n = 86; ChT alone, n = 79) did not have BMs at the time of initial diagnosis. The median follow-up was 22.4 months. The OS benefit with first-line antiprogrammed death ligand 1 therapy was maintained regardless of whether patients had BMs (with BMs, 17.97 vs. 13.14 months [p = .03]; without BMs, 18.46 vs. 15.05 months [p = .047]). However, in patients without BMs, IO did not delay the median time to developing brain progression (10.84 vs. 10.74 months; p = .84), and it did not significantly reduce the risk of developing intracranial metastases (the 2-year actuarial risk of developing BMs was 57.0% vs. 50.6%, respectively). CONCLUSIONS: Antiprogrammed death ligand 1 therapy improved OS regardless of the presence of BMs. However, IO did not delay the median time to brain progression or reduce the risk of intracranial metastasis in patients without baseline BMs. The findings of this study have important clinical implications for the future management of BMs from ES-SCLC.

Clinical and molecular characteristics of patients with brain metastasis secondary to pancreatic ductal adenocarcinoma.

BACKGROUND: The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is poor. Secondary brain metastasis (Br-M) occurs in less than 1% of patients. Clinical characteristics and molecular alterations have not been characterized in this rare patients' subset. MATERIALS AND METHODS: The Foundry software platform was used to retrospectively query electronic health records for patients with Br-M secondary to PDAC from 2005 to 2023; clinical, molecular, and overall survival (OS) data were analyzed. RESULTS: Br-M was diagnosed in 44 patients with PDAC. Median follow-up was 78 months; median OS from initial PDAC diagnosis was 47 months. Median duration from PDAC diagnosis to Br-M detection was 24 months; median OS from Br-M diagnosis was 3 months. At Br-M diagnosis, 82% (n = 36) of patients had elevated CA19-9. Lung was the most common preexisting metastatic location (71%) with Br-M, followed by liver (66%). Br-M were most frequently observed in the frontal lobe (34%, n = 15), cerebellar region (23%, n = 10), and leptomeninges (18%, n = 8). KRAS mutations were detected in 94.1% (n = 16) of patients who had molecular data available (n = 17) with KRASG12V being the most frequent subtype 47% (n = 8); KRASG12D in 29% (n = 5); KRASG12R in 18% (n = 3). Patients who underwent Br-M surgical resection (n = 5) had median OS of 8.6 months, while median OS following stereotactic radiosurgery only (n = 11) or whole-brain radiation only (n = 20) was 3.3 and 2.8 months, respectively. CONCLUSION: Br-M is a late PDAC complication, resulting in an extremely poor prognosis especially in leptomeningeal disease. KRAS was mutated in 94.1% of the patients and the KRASG12V subtype was prevalent.

Neratinib and ado-trastuzumab emtansine for pretreated and untreated human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases: Translational Breast Cancer Research Consortium trial 022.

BACKGROUND: Treatment options for human epidermal growth factor receptor 2 (HER2)-positive breast cancer brain metastases (BCBMs) remain limited. We previously reported central nervous system (CNS) activity for neratinib and neratinib-capecitabine. Preclinical data suggest that neratinib may overcome resistance to ado-trastuzumab emtansine (T-DM1) when given in combination. In Translational Breast Cancer Research Consortium (TBCRC) 022's cohort 4, we examined the efficacy of neratinib plus T-DM1 in patients with HER2-positive BCBM. PATIENTS AND METHODS: In this multicenter, phase II study, patients with measurable HER2-positive BCBM received neratinib 160 mg daily plus T-DM1 3.6 mg/kg intravenously every 21 days in three parallel-enrolling cohorts [cohort 4A-previously untreated BCBM, cohorts 4B and 4C-BCBM progressing after local CNS-directed therapy without (4B) and with (4C) prior exposure to T-DM1]. Cycle 1 diarrheal prophylaxis was required. The primary endpoint was the Response Assessment in Neuro-Oncology-Brain Metastases (RANO-BM) by cohort. The overall survival (OS) and toxicity were also assessed. RESULTS: Between 2018 and 2021, 6, 17, and 21 patients enrolled in cohorts 4A, 4B, and 4C. Enrollment was stopped prematurely for slow accrual. The CNS objective response rate in cohorts 4A, 4B, and 4C was 33.3% [95% confidence interval (CI) 4.3% to 77.7%], 35.3% (95% CI 14.2% to 61.7%), and 28.6% (95% CI 11.3% to 52.2%), respectively; 38.1%-50% experienced stable disease for ≥6 months or response. Diarrhea was the most common grade 3 toxicity (22.7%). The median OS was 30.2 [cohort 4A; 95% CI 21.9-not reached (NR)], 23.3 (cohort 4B; 95% CI 17.6-NR), and 20.9 (cohort 4C; 95% CI 14.9-NR) months. CONCLUSIONS: We observed intracranial activity for neratinib plus T-DM1, including those with prior T-DM1 exposure, suggesting synergistic effects with neratinib. Our data provide additional evidence for neratinib-based combinations in patients with HER2-positive BCBM, even those who are heavily pretreated.

Survival analysis of patients with brain metastases at initial breast cancer diagnosis over the last decade.

PURPOSE: There have been significant advances in the treatment of metastatic breast cancer (BC) over the past years, and long-term outcomes after a diagnosis of brain metastases are lacking. We aimed to identify predictors of brain metastases at initial breast cancer diagnosis, describe overall survival (OS) in the past decade, and identify factors associated with OS after brain metastases diagnosis. METHODS: We evaluated patients with de novo stage IV BC using the Surveillance, Epidemiology and End Results database from 2010 to 2019. Multivariate logistic regression was conducted to assess predictors of brain metastases at initial breast cancer diagnosis. OS was estimated using the Kaplan-Meier method and log rank test was used to compare differences between groups. Cox regression was used to assess associations between several variables and OS. RESULTS: 1,939 patients with brain metastases at initial breast cancer diagnosis were included. Factors associated with this presentation were grade III/IV tumors, ductal histology, hormone receptor (HR)-negative/human epidermal growth factor receptor 2 (HER2)-positive subtype, and extracranial metastases. Patients with HR-positive/HER2-positive disease had the longest OS (median 18 months) and 12.2% were alive at 8 years. Factors associated with shorter OS included older age, lower income, triple-negative subtype, higher grade, and visceral metastases. CONCLUSION: Over the last decade, the median OS of patients with brain metastases at initial breast cancer diagnosis remained poor; however, a substantial minority survive 5 or more years, with rates higher in patients with HER2-positive tumors. In addition to tumor subtype, OS varied according to age, extracranial metastases, and sociodemographic factors.

Epigenetic remodeling to improve the efficacy of immunotherapy in human glioblastoma: pre-clinical evidence for development of new immunotherapy approaches.

BACKGROUND: Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor, that is refractory to standard treatment and to immunotherapy with immune-checkpoint inhibitors (ICI). Noteworthy, melanoma brain metastases (MM-BM), that share the same niche as GBM, frequently respond to current ICI therapies. Epigenetic modifications regulate GBM cellular proliferation, invasion, and prognosis and may negatively regulate the cross-talk between malignant cells and immune cells in the tumor milieu, likely contributing to limit the efficacy of ICI therapy of GBM. Thus, manipulating the tumor epigenome can be considered a therapeutic opportunity in GBM. METHODS: Microarray transcriptional and methylation profiles, followed by gene set enrichment and IPA analyses, were performed to study the differences in the constitutive expression profiles of GBM vs MM-BM cells, compared to the extracranial MM cells and to investigate the modulatory effects of the DNA hypomethylating agent (DHA) guadecitabine among the different tumor cells. The prognostic relevance of DHA-modulated genes was tested by Cox analysis in a TCGA GBM patients' cohort. RESULTS: The most striking differences between GBM and MM-BM cells were found to be the enrichment of biological processes associated with tumor growth, invasion, and extravasation with the inhibition of MHC class II antigen processing/presentation in GBM cells. Treatment with guadecitabine reduced these biological differences, shaping GBM cells towards a more immunogenic phenotype. Indeed, in GBM cells, promoter hypomethylation by guadecitabine led to the up-regulation of genes mainly associated with activation, proliferation, and migration of T and B cells and with MHC class II antigen processing/presentation. Among DHA-modulated genes in GBM, 7.6% showed a significant prognostic relevance. Moreover, a large set of immune-related upstream-regulators (URs) were commonly modulated by DHA in GBM, MM-BM, and MM cells: DHA-activated URs enriched for biological processes mainly involved in the regulation of cytokines and chemokines production, inflammatory response, and in Type I/II/III IFN-mediated signaling; conversely, DHA-inhibited URs were involved in metabolic and proliferative pathways. CONCLUSIONS: Epigenetic remodeling by guadecitabine represents a promising strategy to increase the efficacy of cancer immunotherapy of GBM, supporting the rationale to develop new epigenetic-based immunotherapeutic approaches for the treatment of this still highly deadly disease.

Whole brain radiation therapy for patients with brain metastases: survival outcomes and prognostic factors in a contemporary institutional series.

PURPOSE: To study survival outcomes and prognostic factors in patients undergoing whole brain radiation therapy (WBRT) for brain metastases in the contemporary setting. METHODS: Patients undergoing WBRT from 2013-2021 were retrospectively included in an ethics-approved institutional database. Patient and treatment characteristics were assessed, including patient age, primary tumor histology, Karnofsky Performance Status (KPS), extracranial disease, as well as WBRT dose. Overall survival (OS) was calculated from onset of WBRT using the Kaplan-Meier method. RESULTS: A total of 328 patients (median age 63 years) were included. Most patients (52%) had ≥ 10 brain metastases, and 17% had leptomeningeal disease. WBRT was delivered with 10â€¯× 3 Gy (64%), 5â€¯× 4 Gy (25%), or other regimens (11%). Median follow-up was 4.4 months (range, 0.1-154.3), and median OS was 4.7 months (95%CI, 3.8-6.0). OS differed between histologies (p = 0.01), with the longest survival seen in breast cancer (median 7.7 months). Patients with KPS of 90-100 survived for a median of 8.3 months, compared to 4.1 months with KPS 70-80, and 1.7 months with KPS < 70 (p < 0.01). Multivariate analyses revealed that KPS had the largest impact on survival. Patients who received a WBRT dose of ≥ 30 Gy also had a reduced risk of death (HR 0.45; p < 0.001). Survival differed between subgroups reclassified according to the Rades scoring system (p < 0.01). CONCLUSION: Survival outcomes of patients undergoing WBRT in the contemporary era appear comparable to historical cohorts, although individual patient factors need to be considered. Patients with otherwise favorable prognostic factors may benefit from longer-course WBRT.

Quality requirements for MRI simulation in cranial stereotactic radiotherapy: a guideline from the German Taskforce "Imaging in Stereotactic Radiotherapy".

Accurate Magnetic Resonance Imaging (MRI) simulation is fundamental for high-precision stereotactic radiosurgery and fractionated stereotactic radiotherapy, collectively referred to as stereotactic radiotherapy (SRT), to deliver doses of high biological effectiveness to well-defined cranial targets. Multiple MRI hardware related factors as well as scanner configuration and sequence protocol parameters can affect the imaging accuracy and need to be optimized for the special purpose of radiotherapy treatment planning. MRI simulation for SRT is possible for different organizational environments including patient referral for imaging as well as dedicated MRI simulation in the radiotherapy department but require radiotherapy-optimized MRI protocols and defined quality standards to ensure geometrically accurate images that form an impeccable foundation for treatment planning. For this guideline, an interdisciplinary panel including experts from the working group for radiosurgery and stereotactic radiotherapy of the German Society for Radiation Oncology (DEGRO), the working group for physics and technology in stereotactic radiotherapy of the German Society for Medical Physics (DGMP), the German Society of Neurosurgery (DGNC), the German Society of Neuroradiology (DGNR) and the German Chapter of the International Society for Magnetic Resonance in Medicine (DS-ISMRM) have defined minimum MRI quality requirements as well as advanced MRI simulation options for cranial SRT.

Symptomatic brain metastases in melanoma.

Although clinical outcomes in metastatic melanoma have improved in recent years, the morbidity and mortality of symptomatic brain metastases remain challenging. Response rates and survival outcomes of patients with symptomatic melanoma brain metastases (MBM) are significantly inferior to patients with asymptomatic disease. This review focusses upon the specific challenges associated with the management of symptomatic MBM, discussing current treatment paradigms, obstacles to improving clinical outcomes and directions for future research.

Clinical characteristics and MRI based radiomics nomograms can predict iPFS and short-term efficacy of third-generation EGFR-TKI in EGFR-mutated lung adenocarcinoma with brain metastases.

BACKGROUND: Predicting short-term efficacy and intracranial progression-free survival (iPFS) in epidermal growth factor receptor gene mutated (EGFR-mutated) lung adenocarcinoma patients with brain metastases who receive third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) therapy was of great significance for individualized treatment. We aimed to construct and validate nomograms based on clinical characteristics and magnetic resonance imaging (MRI) radiomics for predicting short-term efficacy and intracranial progression free survival (iPFS) of third-generation EGFR-TKI in EGFR-mutated lung adenocarcinoma patients with brain metastases. METHODS: One hundred ninety-four EGFR-mutated lung adenocarcinoma patients with brain metastases who received third-generation EGFR-TKI treatment were included in this study from January 1, 2017 to March 1, 2023. Patients were randomly divided into training cohort and validation cohort in a ratio of 5:3. Radiomics features extracted from brain MRI were screened by least absolute shrinkage and selection operator (LASSO) regression. Logistic regression analysis and Cox proportional hazards regression analysis were used to screen clinical risk factors. Single clinical (C), single radiomics (R), and combined (C + R) nomograms were constructed in short-term efficacy predicting model and iPFS predicting model, respectively. Prediction effectiveness of nomograms were evaluated by calibration curves, Harrell's concordance index (C-index), receiver operating characteristic (ROC) curves and decision curve analysis (DCA). Kaplan-Meier analysis was used to compare the iPFS of high and low iPFS rad-score patients in the predictive iPFS R model and to compare the iPFS of high-risk and low-risk patients in the predictive iPFS C + R model. RESULTS: Overall response rate (ORR) was 71.1%, disease control rate (DCR) was 91.8% and median iPFS was 12.67 months (7.88-20.26, interquartile range [IQR]). There were significant differences in iPFS between patients with high and low iPFS rad-scores, as well as between high-risk and low-risk patients. In short-term efficacy model, the C-indexes of C + R nomograms in training cohort and validation cohort were 0.867 (0.835-0.900, 95%CI) and 0.803 (0.753-0.854, 95%CI), while in iPFS model, the C-indexes were 0.901 (0.874-0.929, 95%CI) and 0.753 (0.713-0.793, 95%CI). CONCLUSIONS: The third-generation EGFR-TKI showed significant efficacy in EGFR-mutated lung adenocarcinoma patients with brain metastases, and the combined line plot of C + R can be utilized to predict short-term efficacy and iPFS.

Analysis of the efficacy of upfront brain radiotherapy versus deferred radiotherapy for EGFR/ALK-positive non-small cell lung cancer with brain metastases: a retrospective study.

BACKGROUND: For brain metastases (BMs) from EGFR/ALK-positive non-small cell lung cancer (NSCLC), the best time to administer tyrosine kinase inhibitors (TKIs) and brain radiotherapy (RT) has not been identified. This analysis was an attempt to solve this problem in part. METHODS: A total of 163 patients with EGFR/ALK-positive NSCLC and brain metastasis (BM) who were diagnosed between January 2017 and July 2022 were included in this study. Ninety-one patients underwent upfront RT, and 72 patients received deferred RT. Comparing the clinical efficacy and safety in these two patient cohorts was the main goal of the study. RESULTS: The average follow-up period was 20.5 months (range 2.0 to 91.9 months). The median overall survival (OS) was 26.5 months, and the median intracranial progression-free survival (iPFS) was 23.6 months. Upfront RT considerably increased the iPFS (26.9 vs. 20.2 months, hazard ratio [HR] = 5.408, P = 0.020) and OS (31.2 vs. 22.3 months, HR = 4.667, P = 0.031) compared to deferred RT. According to multivariate analysis, upfront RT was an independent risk factor for predicting iPFS (HR = 1.670, P = 0.021). Upfront RT (HR = 1.531, P = 0.044), TKI therapy (HR = 0.423, P < 0.001), and oligometastases (HR = 2.052, P = 0.021) were found to be independent risk factors for OS. CONCLUSION: This study showed that upfront RT combined with TKI treatment can significantly improve intracranial disease management and prolong survival in patients with EGFR/ALK mutations in BMs from NSCLC.

Spatial and temporal heterogeneity of tumor immune microenvironment between primary tumor and brain metastases in NSCLC.

BACKGROUND: Brain metastasis is a common outcome in non-small cell lung cancer, and despite aggressive treatment, its clinical outcome is still frustrating. In recent years, immunotherapy has been developing rapidly, however, its therapeutic outcomes for primary lung cancer and brain metastases are not the same, suggesting that there may be differences in the immune microenvironment of primary lung cancer and brain metastases, however, we currently know little about these differences. METHODS: Seventeen paired samples of NSCLC and their brain metastases and 45 other unpaired brain metastases samples were collected for the current study. Immunohistochemical staining was performed on all samples for the following markers: immune checkpoints CTLA-4, PD-1, PD-L1, B7-H3, B7-H4, IDO1, and EphA2; tumor-infiltrating lymphocytes (TILs) CD3, CD4, CD8, and CD20; tumor-associated microglia/macrophages (TAMs) CD68 and CD163; and tumor proliferation index Ki-67. The differences in expression of these markers were compared in 17 paired samples, and the effect of the expression level of these markers on the prognosis of patients was analyzed in lung adenocarcinoma brain metastases samples. Subsequently, multiplex immunofluorescence staining was performed in a typical lung-brain paired sample based on the aforementioned results. The multiplex immunofluorescence staining results revealed the difference in tumor immune microenvironment between primary NSCLC and brain metastases. RESULTS: In 17 paired lesions, the infiltration of CTLA-4+ (P = 0.461), PD-1+ (P = 0.106), CD3+ (P = 0.045), CD4+ (P = 0.037), CD8+ (P = 0.008), and CD20+ (P = 0.029) TILs in brain metastases were significantly decreased compared with primary tumors. No statistically significant difference was observed in the CD68 (P = 0.954) and CD163 (P = 0.654) TAM infiltration between primary NSCLC and paired brain metastases. In all the brain metastases lesions, the expression of PD-L1 is related to the time interval of brain metastases in NSCLC. In addition, the Cox proportional hazards regression models showed high expression of B7-H4 (hazard ratio [HR] = 3.276, 95% confidence interval [CI] 1.335-8.041, P = 0.010) and CD68 TAM infiltration (HR = 3.775, 95% CI 1.419-10.044, P = 0.008) were independent prognosis factors for lung adenocarcinoma brain metastases patients. CONCLUSIONS: Both temporal and spatial heterogeneity is present between the primary tumor and brain metastases of NCSLC. Brain metastases lesions exhibit a more immunosuppressive tumor immune microenvironment. B7-H4 and CD68+ TAMs may have potential therapeutic value for lung adenocarcinoma brain metastases patients.