Therapy For Brain Metastases Research Articles

Blocking the MIF-CD74 axis augments radiotherapy efficacy for brain metastasis in NSCLC via synergistically promoting microglia M1 polarization.

Brain metastasis is one of the main causes of recurrence and death in non-small cell lung cancer (NSCLC). Although radiotherapy is the main local therapy for brain metastasis, it is inevitable that some cancer cells become resistant to radiation. Microglia, as macrophages colonized in the brain, play an important role in the tumor microenvironment. Radiotherapy could activate microglia to polarize into both the M1 and M2 phenotypes. Therefore, searching for crosstalk molecules within the microenvironment that can specifically regulate the polarization of microglia is a potential strategy for improving radiation resistance. We used databases to detect the expression of MIF in NSCLC and its relationship with prognosis. We analyzed the effects of targeted blockade of the MIF/CD74 axis on the polarization and function of microglia during radiotherapy using flow cytometry. The mouse model of brain metastasis was used to assess the effect of targeted blockade of MIF/CD74 axis on the growth of brain metastasis. Our findings reveals that the macrophage migration inhibitory factor (MIF) was highly expressed in NSCLC and is associated with the prognosis of NSCLC. Mechanistically, we demonstrated CD74 inhibition reversed radiation-induced AKT phosphorylation in microglia and promoted the M1 polarization in combination of radiation. Additionally, blocking the MIF-CD74 interaction between NSCLC and microglia promoted microglia M1 polarization. Furthermore, radiation improved tumor hypoxia to decrease HIF-1α dependent MIF secretion by NSCLC. MIF inhibition enhanced radiosensitivity for brain metastasis via synergistically promoting microglia M1 polarization in vivo. Our study revealed that targeting the MIF-CD74 axis promoted microglia M1 polarization and synergized with radiotherapy for brain metastasis in NSCLC.

Abstract 1449: Targeting squalene epoxidase for breast cancer brain metastasis: The evaluation of a new therapeutic target for brain extravasation and colonization using animal models

Abstract Breast cancer brain metastasis is one of the most common forms of breast cancer metastasis and a major cause of morbidity and mortality. Patients who develop brain metastases tend to be associated with progressive neurologic deficits and short overall survival, which represents an unmet medical need. Extensive research has been conducted to elucidate the mechanism of cancer metastasis with limited information gained as to how cancer cells extravasate and colonize to the brain. Recently, we identified a novel mechanism by which squalene epoxidase (SQLE), the second rate-limiting enzyme in cholesterol biosynthesis, plays a critical role in the process of breast cancer metastasis to the brain. Thus, toward a better understanding of the underlying molecular mechanisms and applications of molecular target(s) for brain metastasis therapy, murine models were employed for investigation of brain extravasation and colonization with intracardiac or direct intracranial injections of GFP/FLuc-labeled human MDA-MB-231 metastatic breast carcinoma cells. The MDA-MB-231 cells were found to metastasize to the brain and other organs following intracardiac implantation into nude mice and were further isolated from each tissue. Interestingly, the isolated brain-metastasized tumor cells (MDA-MB-231-BrM) exhibited a significant upregulation of SQLE expression when compared with those that metastasized to other distal sites. The essential role of SQLE in the specific steps of the breast cancer-to-brain metastatic process was evaluated by ex vivo immunofluorescence analysis and immunohistochemistry staining of brain slices from the study subjects. Our data demonstrate that high SQLE expression is essential for MDA-MB-231-BrM to extravasate into the parenchyma, as well as the formation of micro- and macro-metastases in the brain. Interestingly, we found that blood vessel co-option and the surrounding neuronal cells play key roles in supporting MDA-MB-231-BrM to develop brain macro-metastases. In vitro blood-brain barrier (BBB) models further demonstrated the critical role of SQLE in promoting tumor cell invasion and penetration through the BBB. To verify SQLE as an oncogenic factor that can be selected as a potential therapeutic target in suppressing breast cancer brain metastasis, we evaluated the inhibitory effects of terbinafine (a SQLE inhibitor) in both the MDA-MB-231-BrM orthotopic and intracardiac mouse models. Pharmacologic inhibition of SQLE by terbinafine suppressed MDA-MB-231-BrM tumor growth at the mammary fat pad and distal metastases to the brain, suggesting that targeting SQLE represents a therapeutic opportunity for breast cancer brain metastasis. Citation Format: Pony Yu-Ling Lee, Kun-Yuan Lin, Chao-Di Chang, Shan-Yun Cheng, Ya-Wen Hung, Chih-Chieh Yang, Yu-Hsien Chang, Chien-Chang Shen, Jia-Yun Yeh, Yung-Lung Yu, Shu-Ping Wang. Targeting squalene epoxidase for breast cancer brain metastasis: The evaluation of a new therapeutic target for brain extravasation and colonization using animal models [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 1449.

Small pretreatment lesion size and high sphericity as favorable prognostic factors after laser interstitial thermal therapy in brain metastases.

The objective of this study was to identify baseline clinical and radiological characteristics of brain metastases (BMs) associated with a higher probability of lesion-specific progression-free survival (PFS-L) after laser interstitial thermal therapy (LITT). A total of 47 lesions in 42 patients with BMs treated with LITT were retrospectively examined, including newly diagnosed BM, suspected recurrent BM, and suspected radiation necrosis. The association of baseline clinical and radiological features with PFS-L was assessed using survival analyses. Radiological features included lesion size measurements, diffusion and perfusion metrics, and sphericity, which is a radiomic feature ranging from 1 (perfect sphere) to 0. The probability of PFS-L for the entire cohort was 88.0% at 3 months, 70.6% at 6 months, 67.4% at 1 and 2 years, and 62.2% at 3 years. For lesions progressing after LITT (n = 13), the median time to progression was 3.9 months, and most lesions (n = 11) progressed within 6 months after LITT. In lesions showing response to LITT (n = 17), the median time to response was 12.1 months. All 3 newly diagnosed BMs showed a long-term response. The mean (± SD) follow-up duration for all censored lesions (n = 34) was 20.7 ± 19.4 months (range 12 days to 6.1 years). The mean pretreatment enhancing volume was 2.68 cm3 and the mean sphericity was 0.70. Pretreatment small enhancing volume (p = 0.003) and high sphericity (p = 0.024) computed from lesion segmentation predicted a longer PFS-L after LITT. Lesions meeting optimal cutoffs of either enhancing volume < 2.5 cm3 (adjusted p = 0.004) or sphericity ≥ 0.705 (adjusted p = 0.019) had longer PFS-L, and their probability of PFS-L was 86.8% at 3 years. Lesions meeting both cutoffs showed a cumulative benefit (p < 0.0001), with a 100% probability of PFS-L at 3 years, which was unchanged at the end of follow-up (4.1 years). Manually computed estimates of lesion size (maximal axial diameter, p = 0.011) and sphericity (p = 0.043) were also predictors of PFS-L. Optimal cutoffs of diameter < 2 cm (adjusted p = 0.035) or manual sphericity ≥ 0.91 (adjusted p = 0.092) identified lesions with longer PFS-L, and lesions meeting both cutoffs showed a cumulative benefit (p = 0.0023). Baseline diffusion imaging did not predict PFS-L. A subset of lesions (n = 7) with highly perfused hotspots had worse PFS-L (adjusted p = 0.010), but perfusion signal contamination from vessels and cortex and underlying size differences were possible confounders. Small size and high sphericity are ideal baseline features for lesions considered for LITT treatment, with a cumulative PFS-L benefit when both features are present, that could aid patient selection.

New T-Cell Therapies for Brain Metastasis, CD133 in the Driver's Seat.

Chimeric antigen receptor (CAR)-T cell immunotherapy has revolutionized cancer therapy for some advanced cancers, but success is predicated on identifying the correct cell surface target. In a recent article, the authors leveraged the cancer stem cell surface antigen CD133 to develop a CAR-T therapy for brain metastasis. See related article by Kieliszek et al., p. 554.

Engineering CAR-NK cell derived exosome disguised nano-bombs for enhanced HER2 positive breast cancer brain metastasis therapy

HER2-positive breast cancer brain metastasis (HER2+ BCBM) is a refractory malignancy with a high recurrence rate and poor prognosis. The efficacies of conventional treatments, including radiation and the FDA-approved drug trastuzumab, are compromised due to their significant obstacles, such as limited penetration through the blood-brain barrier (BBB), off-target effects on HER2+ tumor cells, and systemic adverse reactions, ultimately resulting in suboptimal therapeutic outcomes. In order to address these challenges, a novel biomimetic nanoplatform was created, which consisted of a combination of chimeric antigen receptor-natural killer (CAR-NK) cell-derived exosomes (ExoCAR), and a nanobomb (referred to as Micelle). This nanoplatform, known as ExoCAR/T7@Micelle, was designed to enhance the effectiveness of antitumor treatment by disrupting ferroptosis defense mechanisms. Due to the transferrin receptor binding peptide (T7) modification and CAR expression on the exosome surface, the nanoplatform successfully traversed the blood-brain barrier and selectively targeted HER2+ breast cancer cells. Moreover, integration of the reactive oxygen species (ROS) -amplified and photodynamic therapy (PDT)-based nanobomb facilitated the spatiotemporal release of the cargos at specific sites. Upon systemic administration of ExoCAR/T7@Micelle, mice with orthotopic HER2+ BCBM demonstrated a robust antitumor response in vivo, leading to a significant extension in survival time. Furthermore, histological analyses and blood index studies revealed no discernible side effects. Collectively, this study is the first to indicate the possibility of HER2+ BCBM therapy with a CAR-NK cell-derived biomimetic drug delivery system.

Deep Learning for Automated Contouring of Primary Gross Tumor Volumes by MRI for Radiation Therapy of Brain Metastasis

Radiotherapy is one of the most effective methods for the treatment of brain metastases (BMs). Traditional manual delineation of primary gross tumor volumes (GTV) of multiple BMs (especially small metastases) in radiotherapy practice is extremely labor intensive and highly dependent on oncologists' experience, achieving the precise and efficient automatic delineation of BMs is of great significance for efficient and homogeneous one-stop adaptive radiotherapy. We retrospectively collected 62 MRI (non-enhanced T1-weighted sequences) sequences of 50 patients with BMs from January 2020 to July 2021. An automatic model (BUC-Net) for automatic delineation BMs was proposed in this work, which was based on deep learning by combining 3D bottler layer module and the cascade architecture to improve the accuracy and efficient of BMs' automatic delineation, especially for small metastases with tiny size and relatively low contrast. The prosed method was compared with the existing 3D U-Net (U-Net) and 3D U-Net Cascade (U-Net Cascade). The performance of our proposed method was evaluated by Dice similarity coefficient (DSC), 95% Hausdorff distance (HD95) and average surface distance (ASD) with human experts. The automatic segmentation results of BUC-Net evaluated with 310 BMs in 13 test patients was summarized in Table 1. These BMs in each test patient were automatically delineated by two types of contours: as a whole tumor contour (Whole-delineation) and the multiple tumor contours (Multiple-delineation). BUC-Net performed the best mean DSC and HD95, which is significantly outperformed U-Net (Whole-delineation: 0.911 & 0.894 of DSC, Multiple-delineation: 0.794 & 0.754 of DSC, P < 0.05 for both) and U-Net cascade (Whole-delineation: 0.947 & 7.141 of HD95, Multiple-delineation: 0.902 & 1.171 of HD95, P < 0.05 for both); Additionally, BUC-Net achieved the best mean ASD for Whole-delineation and comparable ASD (0.290 & 0.277, P > 0) for Multiple-delineation with U-Net Cascade. Our results showed that the proposed approach is promising for the automatic delineation of BMs in MRI, which can be integrated into a radiotherapy workflow to significantly shorten segmentation time.

Development and validation of a radiomics-based prediction pipeline for the response to stereotactic radiosurgery therapy in brain metastases.

The first treatment strategy for brain metastases (BM) plays a pivotal role in the prognosis of patients. Among all strategies, stereotactic radiosurgery (SRS) is considered a promising therapy method. Therefore, we developed and validated a radiomics-based prediction pipeline to prospectively identify BM patients who are insensitive to SRS therapy, especially those who are at potential risk of progressive disease. A total of 337 BM patients (277, 30, and 30 in the training set, internal validation set, and external validation set, respectively) were enrolled in the study. 19,377 radiomics features (3 masks × 3 MRI sequences × 2153 features) extracted from 9 ROIs were filtered through LASSO and Max-Relevance and Min-Redundancy (mRMR) algorithms. The selected radiomics features were combined with 4 clinical features to construct a two-stage cascaded model for the prediction of BM patients' response to SRS therapy using SVM and an ensemble learning classifier. The performance of the model was evaluated by its accuracy, specificity, sensitivity, and AUC curve. Radiomics features were integrated with the clinical features of patients in our optimal model, which showed excellent discriminative performance in the training set (AUC: 0.95, 95% CI: 0.88-0.98). The model was also verified in the internal validation set and external validation set (AUC 0.93, 95% CI: 0.76-0.95 and AUC 0.90, 95% CI: 0.73-0.93, respectively). The proposed prediction pipeline could non-invasively predict the response to SRS therapy in patients with brain metastases thus assisting doctors to precisely designate individualized first treatment decisions. The proposed prediction pipeline combines the radiomics features of multi-modal MRI with clinical features to construct machine learning models that noninvasively predict the response of patients with brain metastases to stereotactic radiosurgery therapy, assisting neuro-oncologists to develop personalized first treatment plans. • The proposed prediction pipeline can non-invasively predict the response to SRS therapy. • The combination of multi-modality and multi-mask contributes significantly to the prediction. • The edema index also shows a certain predictive value.

Targeting squalene epoxidase in breast-to-brain metastasis: A new therapeutic target for brain extravasation and colonization using animal models.

1084 Background: Brain metastasis is the most common malignancy of the central nervous system which causes severe morbidity and mortality in multiple cancer types of patients and represents an unmet medical need. Several critical steps are required for a successful brain metastasis, including local invasion, intravasation, dissemination, extravasation, and colonization. Extensive research has been conducted to elucidate the mechanism of cancer metastasis with limited information toward how cancer cells extravasate and colonize. Methods: To understand the underlying molecular mechanisms and applications of molecular targets for brain metastasis therapy, murine models are employed for investigation of brain extravasation and colonization. To investigate the roles of SQLE in breast-to-brain metastasis in vivo, we silenced SQLE expression directly with lentiviral shRNA in the brain metastatic MDA-MB-231-BR cell line (231-BR/shSQLE) and used 231-BR cells expressing a scramble shRNA (231-BR/shScr) as the control. Brain metastases were induced by intracardiac, orthotopic, or direct intracranial injections of 231-BR/shSQLE or 231-BR/shScr cells into immune deficient mice. The essential roles of SQLE in the specific step(s) of breast-to-brain metastatic process were evaluated by ex vivo immunofluorescence analysis of brain slices from the animals. To verify SQLE as an oncogenic factor that can be selected as a potential therapeutic target in suppressing breast-to-brain metastasis, we evaluated the inhibitory effects of NB-598 (a SQLE inhibitor) in both the 231-BR orthotopic and intracardiac mouse models. Results: Recently, we identified a novel mechanism by which squalene epoxidase (SQLE), the second rate-limiting enzyme in the cholesterol biosynthesis, plays a critical role in the processes of breast cancer metastasized to the brain, especially in brain extravasation and colonization. Interestingly, the pharmacologic inhibition of SQLE has been widely used against fungal infections, and the next-generation SQLE inhibitors have been recently shown to exert an anticancer effect. Our data demonstrated that SQLE is essential for 231-BR cells to extravasate into the parenchyma as well as the formation of micro and macro-metastases in the brain. Interestingly, we found that astrocytes play a key role in supporting 231-BR-developed brain macro-metastasis. In vitro blood-brain barrier (BBB) models further demonstrated the critical roles of SQLE in promoting 231-BR cell invasion and penetration through BBB. Inhibition of SQLE by NB-598 demonstrated anti-tumor proliferation and anti-metastasis. Conclusions: Pharmacologic inhibition of SQLE by NB-598 suppressed 231-BR tumor growth at the mammary fat pad and distal metastases to organs, suggesting that targeting SQLE represents a therapeutic opportunity for breast cancer metastases.

Effectiveness of combined therapy for patients with brain metastasis

Introduction. Incidence of brain metastases rises in recent years. Local control after surgical resection of brain metastases is a priority for patients with limited intracranial disease and controlled primary tumor. Surgery should be combined with other methods because of the high risk of local recurrences.Aim. To analyze the overall survival (OS) and influencing factors for patients with brain metastasis after combined therapy. Materials and methods. The retrospective study included 196 patients with stable systemic cancer or available systemic therapy in cases of progressive disease. All patients had from 1 to 3 brain metastasis. Overall survival and influencing factors after surgical and combined therapy were analysed.Results. Median OS for the entire cohort was 16.9 months. The highest levels of OS were achieved for patients with renal cancer (median OS 32.5 months). For patients with non-small cell lung cancer, breast cancer, melanoma and other cancers OS were 18.8; 19.9; 11.0 and 15.3 months, appropriately. Age, continuation of local therapy in brain (surgical intervention, stereotactic radiosurgery), using of the cisplatin for patients with non-small lung cancer brain metastasis were independent factors that have influenced OS.Conclusion. Application of combined therapy for brain metastasis can provide reasonable OS for patients with controlled systemic disease. Using of the cisplatin as a part of combined therapy provide statistically meaningful rise in OS for patients with non-small lung cancer brain metastasis.

Corrigendum to: Association of circulating markers with cognitive decline after radiation therapy for brain metastasis

Corrigendum to: Association of circulating markers with cognitive decline after radiation therapy for brain metastasis

The progress of microenvironment-targeted therapies in brain metastases.

The incidence of brain metastases (BrM) has become a growing concern recently. It is a common and often fatal manifestation in the brain during the end-stage of many extracranial primary tumors. Increasing BrM diagnoses can be attributed to improvements in primary tumor treatments, which have extended patients' lifetime, and allowed for earlier and more efficient detection of brain lesions. Currently, therapies for BrM encompass systemic chemotherapy, targeted therapy, and immunotherapy. Systemic chemotherapy regimens are controversial due to their associated side effects and limited efficacy. Targeted and immunotherapies have garnered significant attention in the medical field: they target specific molecular sites and modulate specific cellular components. However, multiple difficulties such as drug resistance and low permeability of the blood-brain barrier (BBB) remain significant challenges. Thus, there is an urgent need for novel therapies. Brain microenvironments consist of cellular components including immune cells, neurons, endothelial cells as well as molecular components like metal ions, nutrient molecules. Recent research indicates that malignant tumor cells can manipulate the brain microenvironment to change the anti-tumoral to a pro-tumoral microenvironment, both before, during, and after BrM. This review compares the characteristics of the brain microenvironment in BrM with those in other sites or primary tumors. Furthermore, it evaluates the preclinical and clinical studies of microenvironment-targeted therapies for BrM. These therapies, due to their diversity, are expected to overcome drug resistance or low permeability of the BBB with low side effects and high specificity. This will ultimately lead to improved outcomes for patients with secondary brain tumors.

Comparison of Three Transcytotic Pathways for Distribution to Brain Metastases of Breast Cancer.

Advances in drug treatments for brain metastases of breast cancer have improved progression free survival but new, more efficacious strategies are needed. Most chemotherapeutic drugs infiltrate brain metastases by moving between brain capillary endothelial cells, paracellular distribution, resulting in heterogeneous distribution, lower than that of systemic metastases. Herein, we tested three well-known transcytotic pathways through brain capillary endothelial cells as potential avenues for drug access: Transferrin receptor (TfR) peptide, Low density lipoprotein receptor 1 (LRP1) peptide, Albumin. Each was far-red labeled, injected into two hematogenous models of brain metastases, circulated for two different times, and their uptake quantified in metastases and uninvolved (nonmetastatic) brain. Surprisingly, all three pathways demonstrated distinct distribution patterns in vivo. Two were suboptimal: TfR distributed to uninvolved brain but poorly in metastases, while LRP1 was poorly distributed. Albumin distributed to virtually all metastases in both model systems, significantly greater than in uninvolved brain (P <0.0001). Further experiments revealed that albumin entered both macrometastases and micrometastases, the targets of treatment and prevention translational strategies. Albumin uptake into brain metastases was not correlated with the uptake of a paracellular probe (biocytin). We identified a novel mechanism of albumin endocytosis through the endothelia of brain metastases consistent with clathrin-independent endocytosis (CIE), involving the neonatal Fc receptor (FcRn), galectin-3 (Gal-3) and glycosphingolipids. Components of the CIE process were found on metastatic endothelial cells in human craniotomies. The data suggest a reconsideration of albumin as a translational mechanism for improved drug delivery to brain metastases and possibly other CNS cancers.

Immunotherapy Plus Stereotactic Body Radiation Therapy or Whole-Brain Radiation Therapy in Brain Metastases

Aim: To investigate the association of stereotactic radiation therapy (SRT) or whole-brain radiation therapy (WBRT) plus immunotherapy with the overall survival (OS) of cancer patients with brain metastases (BMs) regardless of the primary cancer. Patients & methods: Patients diagnosed with BMs were identified from the National Cancer Database. Results: A total of 34,286 patients were included. SRT plus immunotherapy was associated with improved OS compared with SRT without immunotherapy (hazard ratio: 0.774; 95% CI: 0.687-0.872; p<0.001), and WBRT plus immunotherapy was associated with improved OS compared with WBRT without immunotherapy (hazard ratio: 0.724; 95% CI;0.673-0.779; p<0.001). Conclusion: SRT plus immunotherapy was associated with improved OS compared with SRT. WBRT plus immunotherapy was associated with improved OS compared with WBRT in cancer patients who hadBMs at the time of primary cancer diagnosis.

Stereotactic radiosurgery for post operative brain metastasic surgical cavities: a single institution experience.

BackgroundThe standard therapy for brain metastasis was surgery combined with whole brain radiotherapy (WBRT). The latter is however, associated with important neurocognitive toxicity. To reduce this toxicity, postoperative stereotactic radiosurgery (SRS) is a promising technique. We assessed the efficacy and the tolerance to postoperative Gamma Knife radiosurgery (GK) on the tumor bed after resection of brain metastases.MethodsBetween February 2011 and December 2016, following macroscopic complete surgical resection, 64 patients and 65 surgical cavities were treated by GK in our institution. The indication for adjuvant radiosurgery was a multidisciplinary decision. The main assessment criteria considered in this study were local control, intracranial metastasis-free survival (ICMFS), overall survival and toxicity.ResultsMedian follow-up: 11.1 months. Median time between surgery and radiosurgery: 35 days. Median dose was 20 Gy prescribed to the 50% isodose line, for a median treated volume of 5.6 cc. Four patients (7%) suffered from local recurrence. Local recurrence-free, intracranial recurrence-free and overall survival at 1 year were 97.5%, 57.6% and 62.4% respectively. In total, 23 patients (41%) suffered from intracranial recurrence outside the tumor bed. In univariate analysis: concomitant GK treatment of multiple lesions and the tumor bed was associated with a decrease in ICMFS (HR = 1.16 [1.005–1.34] p = 0.04). In multivariate analysis: a non-lung primary tumor was significantly associated with a decrease in ICMFS (HR = 8.04 [1.82–35.4] p = 0.006). An increase in performance status (PS) and in the initial number of cerebral metastases significantly reduced overall survival (HR = 5.4 [1.11–26.3] p = 0.037, HR = 2.7 [1.004–7.36] p = 0.049, respectively) and One radiation necrosis histologically proven.ConclusionOur study confirmed that postoperative GK after resection of cerebral metastases is an efficient and well-tolerated technique, to treat volumes of all sizes (0.8 to 40 cc). Iterative SRS or salvage WBRT can be performed in cases of intracranial relapse, postponing WBRT with its potential side effects.

Factors correlating with survival following adjuvant or definitive radiosurgery for large brain metastases.

We sought to identify variates correlating with overall survival (OS) in patients treated with surgery (S) plus adjuvant stereotactic radiosurgery (SRS) versus definitive SRS for large (&gt;4 cc) brain metastases (BrM). We used univariate (UVA) and multivariate analyses (MVA) to identify survival correlates among eligible patients identified from a prospective registry and compared definitive SRS to S+ adjuvant SRS cohorts using propensity score-matched analysis (PSMA). Secondary outcomes were measured using the cumulative incidence (CI) method. We identified 364 patients; 127 and 237 were treated with S+SRS and definitive SRS, respectively. On UVA, SRS alone [HR1.73 (1.35,2.22) P &lt; .001), BrM quantity [HR 1.13 (1.06-1.22) (P &lt; .001)]; performance status (PS) [HR 2.78 (1.73-4.46) (P &lt; .001)]; extracranial disease (ECD) [HR 1.82 (1.37,2.40) (P &lt; .001)]; and receipt of systemic treatment after BrM therapy, [HR 0.58 (0.46-073) (P &lt; .001)] correlated with OS. On MVA, SRS alone [HR 1.81 (1.19,2.74) (P &lt; .0054)], SRS target volume [HR 1.03 (1.01,1.06) (P &lt; .0042)], and receipt of systemic treatment [HR 0.68 (0.50,0.93) (P &lt; .015)] correlated with OS. When PSMA was used to balance ECD, BrM quantity, PS, and SRS target volume, SRS alone remained correlated with worsened OS [HR 1.62 (1.20-2.19) (P = 0.0015)]. CI of local failure requiring resection at 12 months was 3% versus 7% for S+SRS and SRS cohorts, respectively [(HR 2.04 (0.89-4.69) (P = .091)]. CI of pachymeningeal failure at 12 months was 16% versus 0% for S+SRS and SRS. SRS target volume, receipt of systemic therapies, and treatment with S+SRS instead of definitive SRS correlated with improved survival in patients with large BrM.

HSR22-134: Outcomes of Patients who Received Radiation Therapy for Brain Metastases From Gynecologic Malignancies

HSR22-134: Outcomes of Patients who Received Radiation Therapy for Brain Metastases From Gynecologic Malignancies

Impact of sequential therapy with osimertinib on the overall survival in patients with EGFR-mutant non-small cell lung cancer

PurposeWe conducted a retrospective analysis of the data of patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) to investigate the associations between clinical factors and the overall survival.MethodsWe retrieved the patient data from the medical charts. Patients who were diagnosed as having EGFR-mutant NSCLC and treated with EGFR-tyrosine kinase inhibitors (EGFR-TKIs) between 2007 and 2020 at our institution were included in the analysis.ResultsA total of 130 patients were included in the analysis. A log-rank test identified EGFR exon 19 deletion in the tumor, an Eastern Cooperative Oncology Group performance status of 0–1, serum lactate dehydrogenase level, local therapy for brain metastasis, and sequential osimertinib therapy for patients with the T790M mutation acquired after primary EGFR-TKI therapy as being significantly associated with a better overall survival. Analysis using a Cox proportional hazards model identified EGFR exon 19 deletion in the tumor, an Eastern Cooperative Oncology Group performance status of 0–1, serum lactate dehydrogenase level, local therapy for brain metastasis, and sequential therapy with osimertinib as being independently associated with a prolonged overall survival.ConclusionOur analysis suggested that EGFR mutation status, an Eastern Cooperative Oncology Group performance status, serum lactate dehydrogenase level, local therapy for brain metastasis, and sequential therapy with osimertinib were associated with overall survival in patients with EGFR-mutant NSCLC in clinical practice settings.

Local recurrence and cerebral progression-free survival after multiple sessions of stereotactic radiotherapy of brain metastases: aretrospective study of 184patients : Statistical analysis.

Forty to sixty percent of patients treated with focal therapy for brain metastasis (BM) will have distant brain recurrence (C-LR), while 10-25% of patients will have local recurrence (LR) within 1year after stereotactic radiotherapy (SRT). The purpose of this study was to analyze cerebral progression-free survival (C-PFS) and LR of BM among patients treated with repeated courses of radiotherapy in stereotactic conditions. We retrospectively reviewed data from 184 patients treated for 915 BMs with at least two courses of SRT without previous WBRT. Initial patient characteristics, patient characteristics at each SRT, brain metastasis velocity (BMV), delay between SRT, MRI response, LR and C‑LR were analyzed. In all, 123(66.9%), 39 (21.2%), and 22 (12%) patients received 2, 3, or4 or more SRT sessions, respectively. Ninety percent of BMs were irradiated without prior surgery, and 10% were irradiated after neurosurgery. The MRI response at 3, 6, 12 and 24months after SRT was stable regardless of the SRT session. At 6, 12 and 24months, the rates of local control were 96.3, 90.1, and 85.8%, respectively. In multivariate analysis, P‑LR was statistically associated with kidney (HR = 0.08) and lung cancer (HR = 0.3), ECOG1 (HR = 0.5), and high BMV grade (HR = 5.6). The median C‑PFS after SRT1, SRT2, SRT3 and SRT4 and more were 6.6, 5.1, 6.7, and 7.7months, respectively. C‑PFS after SRT2 was significantly longer among patients in good general condition (HR = 0.39), patients with high KPS (HR = 0.91), patients with no extracerebral progression (HR = 1.8), and patients with alow BMV grade (low vs. high: HR = 3.8). Objective MRI response rate after repeated SRT is stable from session to session. Patients who survive longer, such as patients with breast cancer or with low BMV grade, are at risk of local reirradiation. C‑PFS after SRT2 is better in patients in good general condition, without extracerebral progression and with low BMV grade.

Intracranial Response Rate in Patients with Breast Cancer Brain Metastases after Systemic Therapy.

Simple SummaryFor many years, patients with breast cancer and brain metastases were excluded from participation in clinical trials. It was believed that anticancer drugs could not cross the blood–brain barrier. However, recent evidence strongly suggests that some drugs can act against brain metastases, with the greatest intracranial response rate reported in the case of capecitabine, neratinib plus capecitabine, trastuzumab deruxtecan and tucatinib plus trastuzumab and capecitabine. In this article, we discuss the achievements in systemic therapy of breast cancer patients with brain metastases. We stress on the newest clinical trial results which indicate tremendous progress in HER2-positive breast cancer. On the other hand, in patients with triple-negative breast cancer or hormone-receptor-positive brain metastases, much fewer compounds were discovered. Based on the presented results, patients with active brain metastases should be routinely included in clinical trials with novel agents.Brain metastases are detected in 5% of patients with breast cancer at diagnosis. The rate of brain metastases is higher in HER2-positive and triple-negative breast cancer patients (TNBC). In patients with metastatic breast cancer, the risk of brain metastases is much higher, with up to 50% of the patients having two aggressive biological breast cancer subtypes. The prognosis for such patients is poor. Until recently, little was known about the response to systemic therapy in brain metastases. The number of trials dedicated to breast cancer with brain metastases was scarce. Our review summarizes the current knowledge on this topic including very significant results of clinical trials which have been presented very recently. We focus on the intracranial response rate of modern drugs, including new antibody–drug conjugates, HER2- targeted tyrosine kinase inhibitors and other targeted therapies. We highlight the most effective and promising drugs. On the other hand, we also suggest that further efforts are needed to improve the prognosis, especially patients with TNBC and brain metastases. The information contained in this article can help oncologists make treatment-related decisions.

Abstract P1-21-06: Phase I study of T-DM1 and metronomic temozolomide in secondary prevention of HER2+ breast cancer brain metastases following local radiation therapy

Abstract Background: The incidence of breast cancer brain metastases is rising, and, these lesions in the central nervous system (CNS) and their treatments cause physical and neurocognitive impairment. Only modest incremental advances in progression free survival have been achieved with drugs to treat CNS lesions, while nearly half of the patients who receive SRS will develop new brain metastases within 1 year. In murine models of breast cancer, we demonstrated that low doses of temozolomide (TMZ) administered in a prophylactic, metronomic fashion significantly prevented development of brain metastases. No effect, however, was seen in established brain metastases or systemic breast cancer metastases. We hypothesize that low dose, metronomic TMZ will prevent the outgrowth of brain lesions in HER2+ patients, when added to an active anti-HER2 treatment. We present here the results of the phase I trial combining T-DM1 to TMZ for the prevention of additional brain metastases after their first occurrence and local treatment. Methods: Eligible patients had HER2+ breast cancer with brain metastases and were within 12 weeks of local brain metastases therapy (WBRT, SRS and or surgery), with PS 0-2 and adequate end organ function. Standard doses of T-DM1 were administered IV every 21 days (3.6 mg/kg) and TMZ was given PO daily in a 3+3 design at 30, 40 or 50 mg/m2, continuously. The DLT period was one 21d cycle. Safety was assessed by CTCAEv4.0 and response by RECISTv1.1 and RANO-BM. Brain MRI and systemic CT scans were performed every 6 weeks. Blood samples for correlatives evaluation were collected at baseline and every cycle while on trial. CSF was collected at baseline and C3D1 for all patients. Questionnaires (MDASI-BT and PROMIS®) for evaluation of symptoms and quality of life were completed every 6 weeks. Results: Twelve women with median age 55.5yr (44-67) were enrolled. Only 3 (25%) patients had HR+/HER2+ tumors at initial diagnosis. Nine (75%) patients presented stages II and III disease at initial diagnosis, and developed brain metastases at the diagnosis of first recurrence. Nine (75%) patients received SRS therapy and 3 (25%) received WBRT prior to trial enrollment. Grade 3 or 4 AEs included thrombocytopenia (1/12), neutropenia (1/12), lymphopenia (6/12) and decreased CD4 (6/12), requiring pentamidine for PCP prophylaxis. No DLT was observed. Four patients underwent dose reductions (thrombocytopenia, fatigue and peripheral neuropathy), all of them enrolled on the highest TMZ dose. Median follow-up on study is now 9.6m (1.2-32) and no patient developed new parenchymal brain metastases. Five patients remain on study, while 7 are off study due to progression at previously irradiated CNS lesion (2), progression of systemic disease (2), focal leptomeningeal involvement (1), new cancer (1) and persistent thrombocytopenia (1). Completion rates for the questionnaires were 99% by Cycle 15 (81 completed out of expected 82) and 90% by Cycle 41 (123/137), and will be reported at presentation. Conclusion: Metronomic TMZ in combination with standard dose T-DM1 is tolerable and shows promising activity in secondary prevention of HER2+ brain metastases. Systematic longitudinal symptom assessments in breast cancer patients with brain metastasis are feasible. A randomized phase II expansion of this trial with T-DM1 or T-Dxd +/- TMZ is planned. Citation Format: Alexandra S Zimmer, Seth Steinberg, Mark Gilbert, Terri Armstrong, Eric Burton, Nicole Houston, Dee Dee Smart, Nadia Biassou, John Butman, Priscilla K Brastianos, Carey K Anders, Stanley Lipkowitz, Patricia S Steeg. Phase I study of T-DM1 and metronomic temozolomide in secondary prevention of HER2+ breast cancer brain metastases following local radiation therapy [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-06.