Metachronous Brain Metastases Research Articles

The development of brain metastases in patients with different therapeutic strategies for metastatic renal cell cancer.

A diagnosis of brain metastasis (BM) significantly affects quality of life in patients with metastatic renal cell cancer (mRCC). Although systemic treatments have shown efficacy in mRCC, active surveillance (AS) is still commonly used in clinical practice. In this single-center cohort study, we assessed the impact of different initial treatment strategies for metastatic RCC (mRCC) on the development of BM. All consecutive patients diagnosed with mRCC between 2011 and 2022 were included at the Erasmus MC Cancer Institute, the Netherlands, and a subgroup of patients with BM was selected. In total, 381 patients with mRCC (ECM, BM, or both) were identified. Forty-six patients had BM of whom 39 had metachronous BM (diagnosed ≥1 month after ECM). Twenty-five (64.1%) of these 39 patients with metachronous BM had received prior systemic treatment for ECM and 14 (35.9%) patients were treatment naive at BM diagnosis. The median BM-free survival since ECM diagnosis was significantly longer (p = .02) in previously treated patients (29.0 [IQR 12.6-57.0] months) compared to treatment naive patients (6.8 [IQR 1.0-7.0] months). In conclusion, patients with mRCC who received systemic treatment for ECM prior to BM diagnosis had a longer BM-free survival as compared to treatment naïve patients. These results emphasize the need for careful evaluation of treatment strategies, and especially AS, for patients with mRCC.

Potential of radiomics analysis and machine learning for predicting brain metastasis in newly diagnosed lung cancer patients

To explore the potential of utilising radiomics analysis and machine-learning models that incorporate intratumoural and peritumoural regions of interest (ROIs) for predicting brain metastasis (BM) in newly diagnosed lung cancer patients. The study comprised 183 lung cancer patients (training cohort: n=146; validation cohort: n=37) whose radiomics features were extracted from plain computed tomography (CT) images of the primary lesion. Four machine-learning algorithms (logistic regression [LR], support vector machine [SVM], k-nearest neighbour algorithm [KNN], and random forest [RF]) were employed to develop predictive models. Model diagnostic performance was assessed through receiver operating characteristic (ROC) analysis, and clinical utility was evaluated using decision curve analysis (DCA). Finally, the radiomics model's generalisation ability was further validated in the prediction of metachronous brain metastasis (MBM). After feature screening, 22 radiomics features were identified as highly predictive, of which nine were derived from the peritumour region. All four machine-learning models demonstrated predictive capability, with SVM showing superior efficiency and robustness. The area under the ROC curve (AUC) of SVM was 0.918 in the training cohort and 0.901 in the validation cohort. DCA indicated the highest net benefit. Furthermore, the time-dependent ROC curve exhibited predictive efficacy for MBM occurrence across 1-, 2-, and 3-year follow-up periods, with all AUC values exceeding 0.7. The optimal SVM model integrating intratumoural and peritumoural radiomics features was confirmed and defined as an imaging biomarker for predicting BM in newly diagnosed lung cancer patients, underscoring its potential to significantly impact clinical diagnosis and treatment.

Clinicopathological characteristics and prognosis of synchronous brain metastases from non-small cell lung cancer compared with metachronous brain metastases.

Brain metastasis (BM) from non-small cell lung cancer (NSCLC) is a serious complication severely affecting patients' prognoses. We aimed to compare the clinicopathological features and prognosis of synchronous and metachronous BM from NSCLC. Clinical data of 461 patients with brain metastases from NSCLC who visited the Cancer Hospital of China Medical University from 2005 to 2017 were retrospectively collected. We analyzed the pathophysiological characteristics of synchronous and metachronous BM from NSCLC and survival rates of the patients. Propensity score matching analysis was used to reduce bias between groups. In addition, we used the Kaplan-Meier method for survival analysis, log-rank test to compare survival rates, and Cox proportional hazards regression model for multivariate prognosis analysis. Among 461 patients with BM, the number of people who met the inclusion criteria was 400 cases, and after 1:2 propensity score matching,130 had synchronous BM and 260 had metachronous BM. The survival time was longer for metachronous BM in driver mutation-negative patients with squamous cell carcinoma than synchronous BM. Conversely, metachronous and synchronous BM with gene mutations and adenocarcinoma showed no differences in survival time. Multivariate analysis showed that metachronous BM was an independent prognostic factor for overall survival. Furthermore, the pathological type squamous cell carcinoma and Karnofsky Performance Status score <80 were independent risk factors affecting overall survival. BM status is an independent factor influencing patient outcome. Moreover, synchronous and metachronous BM from NSCLC differ in gene mutation profile, pathological type, and disease progression and hence require different treatments.

Clinical characteristics, treatment, and outcome of patients with large cell neuroendocrine carcinoma of the lung and brain metastases – data from a tertiary care center

Large cell neuroendocrine carcinoma (LCNEC) of the lung is an aggressive malignancy, with brain metastases (BM) occurring in approximately 20% of cases. There are currently no therapy guidelines for this population as only few data on the management of LCNEC and BM have been published. For this retrospective single center study, patients with LCNEC and BM were identified from the Vienna Brain Metastasis Registry. Data on clinicopathological features, BM-specific characteristics, treatment, and outcome were extracted. In total, 52/6083 (0.09%) patients in the dataset had a diagnosis of LCNEC and radiologically verified BM. Median age at diagnosis of LCNEC and BM was 59.1 and 60.1 years, respectively. Twenty-seven (51.9%) presented with single BM, while 12 (23%) exhibited > 3 BM initially. Neurologic symptoms due to BM were present in n = 40 (76.9%), encompassing neurologic deficits (n = 24), increased intracranial pressure (n = 18), and seizures (n = 6). Initial treatment of BM was resection (n = 13), whole brain radiation therapy (n = 19), and/or stereotactic radiosurgery (n = 25). Median overall survival (mOS) from LCNEC diagnosis was 16 months, and mOS after BM diagnosis was 7 months. Patients with synchronous BM had reduced mOS from LCNEC diagnosis versus patients with metachronous BM (11 versus 27 months, p = 0.003). Median OS after BM diagnosis did not differ between LCNEC patients and a control group of small cell lung cancer patients with BM (7 versus 6 months, p = 0.17). Patients with LCNEC and BM have a poor prognosis, particularly when synchronous BM are present. Prospective trials are required to define optimal therapeutic algorithms.

Epidemiology and survival outcomes of synchronous and metachronous brain metastases: a retrospective population-based study.

Brain metastases (BMs) are the most common CNS tumors, yet their prevalence is difficult to determine. Most studies only report synchronous metastases, which make up a fraction of all BMs. The authors report the incidence and prognosis of patients with synchronous and metachronous BMs over a decade. Study data were obtained from the TriNetX Research Network. Patients were included if they had a primary cancer diagnosis and a BM diagnosis, with primary cancer occurring between January 1, 2013, and January 1, 2023. Metachronous BM was defined as BM diagnosed more than 2 months after the primary cancer. Cohorts were balanced by propensity score matching for age, extracranial metastasis, and antineoplastic or radiation therapy. Kaplan-Meier plots were used to evaluate survival differences between synchronous and metachronous BMs and associations with clinical conditions. A log-rank test was used to evaluate BM-free survival for metachronous BM and overall survival (OS) for all BMs. Hazard ratios and 95% CIs were calculated. Of the 11,497,663 patients with 15 primary cancers identified, 300,863 (2.6%) developed BMs. BMs most commonly arose from lung and breast cancers and melanoma. Of all BMs, 113,827 (37.8%) presented synchronously and 187,036 (62.2%) presented metachronously. Lung and bronchial cancer had the highest metastasis rate (11.0%) and the highest synchronous presentation (51.0%). For metachronous presentations, the time from primary diagnosis to metastasis ranged from 1.3 to 2.5 years, averaging 1.8 years. Metachronous BM diagnosis was associated with longer survival over synchronous BM from primary diagnosis (11.54 vs 37.41 months, p < 0.0001), but shorter survival than extracranial metastases without BM (38.75 vs 69.18 months, p < 0.0001). Antineoplastic therapy prior to BM was associated with improved BM-free survival (4.46 vs 17.80 months, p < 0.0001) and OS (25.15 vs 42.26 months, p < 0.0001). Radiotherapy showed a similar effect that was statistically significant but modest for BM-free survival (5.25 vs 11.44 months, p < 0.0001) and OS (30.13 vs 32.82 months, p < 0.0001). The majority of BMs present metachronously and arise within 2 years of primary cancer diagnosis. The substantial rate of BMs presenting within 6 months of primary cancer, especially liver, lung, and pancreatic cancer, may guide future recommendations on intracranial staging. Antineoplastic therapy prior to the development of BM may prolong the time before metastasis and improve survival. Further characterization of this population can better inform screening, prevention, and treatment efforts.

A radiomic-based predictive model of lung adenocarcinoma brain metastases and molecular subtypes.

2014 Background: Non-small cell lung cancer (NSCLC) comprises the largest portion of brain metastases (BM) from solid cancer with 40% of patients developing BM during the course of their disease. There are currently no reliable prediction tools for identifying patients at risk for BM, especially in the early-stage setting where MRI screening is not performed. Furthermore, in the later stage setting, brain MRI are only performed annually. Therefore, there is a critical need to identify high-risk patients for BM that could benefit from MRI surveillance. Methods: We identified 162 lung adenocarcinoma (LUAD) patients with (N = 66) or without (N = 96) BM that had treatment-naïve CT scans with a segmentable lesion. The tumor, surrounding ground glass opacity and necrosis were segmented via 3D slicer to create a volume of interest for radiomic texture analysis and 400 features were extracted. The Least Absolute Shrinkage and Selection Operator (LASSO) logistic regression feature selection method was used to select the most relevant features and models were built using the machine learning method XGBoost classifier. Training and testing sets with random splitting was used for cross validation. We report the accuracy, sensitivity, specificity, and area under the curve (AUC) for each model. Results: Among the extracted features that LASSO deemed as most discriminative for development of BM, we identified the most relevant features using XGBoost that predicted BM with 79% accuracy, 83% sensitivity, 72% specificity, and 79% AUC ( p= 0.01) in the overall population. The addition of ground glass opacity and necrosis to the model did not significantly improve performance. Furthermore, the model distinguished those with metachronous vs synchronous BM with 84% accuracy, 83% sensitivity, 86% specificity, and 83% AUC ( p = 0.04). Our model held up across molecular subtypes ( EGFR and KRAS mutant). Importantly, the model was predictive in early-stage patients with 92% accuracy, 96% sensitivity, 83% specificity, and 95% AUC ( p= 0.0005). Moreover, our model predicted for high vs. low overall survival, and was BM-specific as it was not predictive of other sites of metastases. We further developed a model from the CT features that correctly classified KRAS mutant vs. KRAS wild type LUAD with 77% accuracy, 73% sensitivity, 80% specificity, and 80% AUC ( p= 0.002). Conclusions: Utilizing a radiomics approach, we were able to predict BM from primary lung CT features including in stage I and II disease, predict synchronous vs metachronous BM, and distinguish distinct molecular LUAD subtypes. We are currently validating our BM prediction model in a large independent cohort and developing models to classify targetable LUAD-BM molecular alterations utilizing brain MRI scans. These studies will identify patients that require MRI surveillance in the early-stage setting and more intensive surveillance in the late-stage setting for BM.

Limiting mitochondrial plasticity by targeting DRP1 induces metabolic reprogramming and reduces breast cancer brain metastases.

Disseminated tumor cells with metabolic flexibility to utilize available nutrients in distal organs persist, but the precise mechanisms that facilitate metabolic adaptations remain unclear. Here we show fragmented mitochondrial puncta in latent brain metastatic (Lat) cells enable fatty acid oxidation (FAO) to sustain cellular bioenergetics and maintain redox homeostasis. Depleting the enriched dynamin-related protein 1 (DRP1) and limiting mitochondrial plasticity in Lat cells results in increased lipid droplet accumulation, impaired FAO and attenuated metastasis. Likewise, pharmacological inhibition of DRP1 using a small-molecule brain-permeable inhibitor attenuated metastatic burden in preclinical models. In agreement with these findings, increased phospho-DRP1 expression was observed in metachronous brain metastasis compared with patient-matched primary tumors. Overall, our findings reveal the pivotal role of mitochondrial plasticity in supporting the survival of Lat cells and highlight the therapeutic potential of targeting cellular plasticity programs in combination with tumor-specific alterations to prevent metastatic recurrences.

Validation of the initial brain metastasis velocity in non-small cell lung cancer at a single cancer center

The initial brain metastasis velocity (iBMV) was recently reported as a survival predictor after brain metastases (BM) in patients treated by stereotactic radiosurgery. In this study, we validated whether iBMV is a prognostic tool, regardless of treatment modality, in patients with non-small cell lung cancer (NSCLC) with metachronous BM. We retrospectively reviewed consecutive 3,792 new lung cancer cases in which no BM was found on magnetic resonance (MR) screening between February 2014 and December 2019, and enrolled 176 NSCLC patients with subsequent BM. Overall survival (OS) was calculated from the date of MR to identify the time from BM to death. The median iBMV score was 1.9. We used an iBMV score of 2.0 as the cutoff level, as previously reported. An iBMV score ≥ 2.0 was significantly associated with older age, high neutrophil-to-lymphocyte ratio, and Stage IV (P = 0.04, 0.02, and 0.02, respectively). The median OS was 0.92 years. The median OS for patients with iBMV score ≥ 2.0 and < 2.0 were 0.59 years and 1.33 years, respectively (P < 0.001). Multivariate analysis showed that an iBMV score ≥ 2.0, ECOG performance status score of 1-3, Stage IV, and non-adenocarcinoma histology were independent poor prognostic factors (hazard ratio (HR), 1.94; P = 0.0001; HR, 1.53; P = 0.04; HR, 1.45; P = 0.04; and HR, 1.14; P = 0.03, respectively). Patients with iBMV scores of < 2.0 were more likely to undergo craniotomy or stereotactic irradiation. An iBMV score ≥ 2.0 is an independent predictor of survival in NSCLC patients with metachronous BM, regardless of the treatment modality.

Survival after resection of brain metastasis: impact of synchronous versus metachronous metastatic disease

PurposePatients with brain metastasis (BM) from solid tumors are in an advanced stage of cancer. BM may occur during a known oncological disease (metachronous BM) or be the primary manifestation of previously unknown cancer (synchronous BM). The time of diagnosis might decisively impact patient prognosis and further treatment stratification. In the present study, we analyzed the prognostic impact of synchronous versus (vs.) metachronous BM occurrence following resection of BM.MethodsBetween 2013 and 2018, 353 patients had undergone surgical therapy for BM at the authors’ neuro-oncological center. Survival stratification calculated from the day of neurosurgical resection was performed for synchronous vs. metachronous BM diagnosis.ResultsNon-small-cell lung carcinoma (NSCLC) was the most common tumor entity of primary site (43%) followed by gastrointestinal cancer (14%) and breast cancer (13%). Synchronous BM occurrence was present in 116 of 353 patients (33%), metachronous BM occurrence was present in 237 of 353 patients (67%). NSCLC was significantly more often diagnosed via resection of the BM (56% synchronous vs. 44% metachronous situation, p = 0.0001). The median overall survival for patients with synchronous BM diagnosis was 12 months (95% confidence interval (CI) 7.5–16.5) compared to 13 months (95% CI 9.6–16.4) for patients with metachronous BM diagnosis (p = 0.97).ConclusionsThe present study indicates that time of BM diagnosis (synchronous vs. metachronous) does not significantly impact patient survival following surgical therapy of BM. These results suggest that the indication for neurosurgical BM resection should be made regardless of a synchronous or a metachronous time of BM occurrence.

Epidermal growth factor receptor mutations and brain metastases in non-small cell lung cancer.

Studies have revealed that non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations has a high incidence of brain metastases (BMs). However, the association between EGFR mutations and BMs remains unknown. This review summarizes detailed information about the incidence of BMs, clinical and imaging characteristics of BMs, brain surveillance strategies, influence of treatments on BMs, prognosis after BMs, and differences in EGFR mutations between paired primary tumors and BMs in EGFR-mutated NSCLC. The prognostic results demonstrate that patients with mutated EGFR have a higher incidence of BMs, EGFR tyrosine kinase inhibitors (EGFR-TKIs) (afatinib and osimertinib) delay the development of BMs, and patients with mutated EGFR with synchronous or early BMs have better overall survival after BMs than those with wild-type EGFR. The EGFR mutation status of BM sites is not always in accordance with the primary tumors, which indicates that there is heterogeneity in EGFR gene status between paired primary tumors and BMs. However, the EGFR gene status of the primary site can largely represent that of BM sites. Among patients developing synchronous BMs, patients with mutated EGFR are less likely to have central nervous system (CNS) symptoms than patients with wild-type EGFR. However, the possibility of neuro-symptoms is high in patients with metachronous BMs. Patients with mutated EGFR tend to have multiple BMs as compared to patients with wild-type EGFR. Regarding very early-stage NSCLC patients without neuro-symptoms, regular neuroimaging follow-up is not recommended. Among advanced NSCLC patients with EGFR mutation, liberal brain imaging follow-up in the first several years showed more advantages in terms of cost.

Breast Cancer Subtypes and Incidence of Brain Metastases in the SEER Database

<h3>Purpose/Objective(s)</h3> Despite the recognition that women with triple-negative (TNBC) and HER2+ breast cancer have a higher risk of developing brain metastases than other subtypes of breast cancer, the recently updated NCCN guidelines for breast cancer do not recommend MR imaging of the brain in women with either primary or metastatic breast cancer (of any type) unless there are neurologic signs/symptoms suspicious for brain metastases. We investigated the relative distribution of synchronous and metachronous brain metastases over the past decade. <h3>Materials/Methods</h3> We evaluated the Surveillance, Epidemiology, and End Results (SEER) SEER-18 database for breast cancer patients diagnosed from 2010-2017. Female patients with complete data regarding presence of brain metastases, stage, breast cancer subtype, and survival were selected. Relative frequencies of subtypes at diagnosis for all patients (localized and metastatic), synchronous brain metastases, and metachronous brain metastases were calculated. Metachronous brain metastases were defined as patients who had both a primary and localized breast cancer diagnosis and subsequent brain metastases diagnosis both recorded in SEER as separate entries from different years with the same patient identifying number. <h3>Results</h3> We found 394,153 patients who fit criteria. The percent incidence of brain metastases at diagnosis did not change significantly over the years examined (range 0.33-0.39%, chi-squared p=0.59) Overall frequency of brain metastases was 0.67%, 0.22%, 1.17%, and 0.71% for luminal B, luminal A, HER2+, TNBC, respectively (chi-squared p<0.001). Relative frequency of breast cancer subtypes among all cases, synchronous brain metastases, and metachronous brain metastases showed increasing proportion of patients with TNBC. Only 26 patients were found that had metachronous brain metastases in the database. Of those patients, 38.5% had TNBC. <h3>Conclusion</h3> This SEER-based analysis shows that although presentation with synchronous brain metastases is relatively balanced across all molecular subtypes, metachronous brain metastases are most commonly seen in TNBC patients, perhaps indicative of the prevalence of occult brain metastases at presentation in patients with TNBC. Unfortunately, metachronous brain metastases are not robustly recorded in SEER. Better data is needed on the prevalence of brain metastases at the time of initial diagnosis and when systemic progression occurs in TNBC patients.

Incidence and clinical profile of brain metastasis treated with whole brain radiotherapy in a tertiary hospital in eastern India: A retrospective audit.

Management of brain metastases (BM) is witnessing marked advancement worldwide and modern technologies with better outcomes are gradually being adopted in developing countries. However, data regarding current practice in this field is lacking from the Indian subcontinent prompting us to plan the current study. A retrospective, single institutional audit was performed on 112 patients with solid tumors metastasizing to the brain treated over the last 4 years at a tertiary care center in eastern India, of which 79 were ultimately evaluable. Demography, patterns of incidence, and overall survival (OS) were determined. The prevalence of BM was 5.65% among all patients with solid tumors. The median age was 55 years with a slight male preponderance. Lung followed by breast were the most common primary subsites. Multiple BM (54%), left-sided (61%), and frontal lobe lesions (54%) were the more common. Metachronous BM was found in 76% of patients. All patients received whole brain radiation therapy (WBRT). The median OS for the entire cohort was 7 months (95% confidence interval [CI]: 4 - 19 months). The median OS for lung and breast primaries were 6.5 and 8 months and for recursive partitioning analysis (RPA) classes I, II, and III the OS were 11.5, 7, and 3 months, respectively. Median OS did not differ by number of or other sites of metastases. The outcomes from our series about BM from solid tumors in patients from eastern Indian are in congruence to those available in the literature. Patients with BM are still largely treated with WBRT in resource-limited settings.

Abstract SY31-04: Uncovering targetable dependencies of latent brain metastatic cells

Abstract Uncovering Targetable Dependencies of Latent Brain Metastatic Cells Srinivas Malladi, Department of Pathology, Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, 75390, USA ABSTRACT HER2+ breast cancer patients presenting with brain metastases have poor survival outcomes. Metachronous brain metastases or relapse are observed in approximately fifty percent of HER2+ breast cancer patients considered disease free after a variable length of time post primary diagnosis and treatment. Disseminated latent residual cells that survive current therapies are responsible for these relapses or metachronous metastasis. How disseminated tumor cells survive as latent/dormant entities for extended period before initiating metachronous metastasis is poorly understood. Moreover, the basis for disparate metastatic fitness among disseminated tumor cells of similar oncotype within a distal organ is unknown and vital for better clinical management. Through a phenotypic screen in mice, we have isolated HER2+ latent (Lat) and brain metastatic (BM) cells.Transcriptomic and metabolic profiles of these brain-tropic breast cancer cells identified actionable dependencies and unique therapeutic opportunities. Brain-tropic Lat and metastatic cells have distinct metabolic profiles that determine their metastatic fitness. Both latent and metastatic cells survive in equilibrium with innate immune surveillance, oxidize glutamine and maintain cellular redox homeostasis through the anionic amino acid transporter xCT. Likewise, xCT expression was significantly higher in matched metachronous brain metastatic samples compared to primary tumors from HER2+ breast cancer patients. Genetic or pharmacological blockade of xCT eradicates residual disease and brain metastatic relapse in these preclinical models. Lactate secreted by aggressive metastatic cells limits innate immune surveillance and triggers overt metastasis. Furthermore, transcriptomic analysis identified augmented AXL expression. Depleting or inhibiting AXL in these HER2 targeted therapy resistant brain-tropic cells attenuates metastatic incidence. In sum, by investigating phenotypically distinct brain-tropic latent and metastatic cells, we uncovered the impact of metabolic diversity and adaptations on metastatic fitness and identified targetable vulnerabilities. Citation Format: Srinivas Malladi. Uncovering targetable dependencies of latent brain metastatic cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr SY31-04.

Brain metastasis incidence in gastro-esophageal cancer: A meta-analysis

Abstract Objective Upper gastrointestinal cancers (UGC) are a leading cause of cancer related deaths. Brain metastases (BM) from gastric and esophageal cancer are rare and associated with a poor survival time. The precise incidence of BM for UGC is lacking. Methods We searched: “Gastric cancer OR Oesophageal Cancer AND Cerebral Metastasis” in Pubmed, EMBASE, Cochrane Library. Inclusion criteria were all studies with an incidence rate of BM from UGC cancer patients cohort. When the inclusion criteria were met, we extracted the following endpoints: year of publication, country of population, tumor localization, histology, number of brain lesion, synchronous or metachronous brain metastases, stage of the primary tumor, other localization of metastases, surgical treatment of the primary tumor, brain metastasis treatment (surgery, steatosic radiosurgery, whole brain radiation, gamma knife surgery), survival and follow-up. Results 52 studies were included. The total number of patients with oesophageal tumor were described in 30 studies with 41636 patients from which 1234 patients (2.9%) had BM. 526 patients (63%) had an adenocarcinoma, 287 (34%) had a SCC and 17 (3%) other histology. BM was unique in 288 patients (50%) and multiples in 282 patients (50%). A combined radiotherapy and surgery was performed in 129 patients (17.9%). Surgical metastasectomy was performed in 172 patients (24.25%). Stereotaxic radiotherapy was delivered in 60 patients. (8.5%) A whole brain radiotherapy was performed in 265 patients (35.9%). Gamma knife surgery was performed in 43 patients (5.9%). Chemotherapy in 10 patients (1.6%) and no treatment in 43 patients. (5.9%). The median survival was reported from 3 month to 24 months. We identified 12 articles which matched the research criteria for gastric cancer with a total of 73.781 primary gastric tumors where 645 presented brain metastasis (0.87%). 159 patients had single BM (42.3%) compared to 217 patients with multiple BM (57.7%). We identified 434 adenocarcinoma which represent 81.1% of the brain metastasis. Median survival for patients with brain metastasis from gastric cancer was described from 1.3 month to 27 months. Conclusion Brain metastases from UGI cancer are rare and associated with a low survival. Multimodal treatment is the most described treatment strategy. More studies are required to assess the role of brain imaging in the initial staging of UGI cancer.

88: BRAIN METASTASIS INCIDENCE IN GASTRO-ESOPHAGEAL CANCER: A META-ANALYSIS

Abstract Background and aim Upper gastrointestinal cancers (UGC) are a leading cause of cancer related deaths. Brain metastases (BM) from gastric and esophageal cancer are rare and associated with a poor survival time. In order to establish the most accurate incidence and characteristics of BM in UGC, we decide to review all studies and series published in the last years. Methods We searched the keywords ‘Gastric cancer OR Oesophageal Cancer + Cerebral Metastasis’ in Pubmed, EMBASE, Cochrane Library. Inclusion criteria were all studies treating with BM from UGC cancer. When inclusion criteria were met, we extracted the following endpoints for each study: author, year of publication, country of population, tumor localization, tumor histology, number of BM, synchronous or metachronous BM, other localization of metastases, surgical treatment of the primary tumor, different modality of BM treatment (surgery, steatosic radiosurgery, whole brain radiation, gamma knife surgery), survival and follow-up. Results In the final analysis, we included 52 studies. The number of patients with oesophageal tumor were described in 30 studies with 41636 patients from which 1234 patients (2.9%) had BM. 526 patients (63%) had an adenocarcinoma, 287 (34%) had a SCC and 17 (3%) other histology. BM was unique in 288 patients (50%) and multiples in 282 patients (50%). Combined radiotherapy and surgery was performed in 129 patients (17.9%). Surgical metastasectomy was performed in 172 patients (24.25%). Stereotaxic radiotherapy was delivered in 60 patients (8.5%). Whole brain radiotherapy was performed in 265 patients (35.9%), gamma knife surgery in 43 patients (5.9%), chemotherapy in 10 patients (1.6%) and no treatment in 43 patients (5.9%). Median survival was reported from 3 to 24 months. We identified 12 articles which matched criteria for gastric cancer with a total of 73.781 primary gastric tumors where 645 presented BM (0.87%). We could identify 159 patients with single BM (42.3%) compared to 217 patients with multiple BM (57.7%). We identified 434 adenocarcinoma which represent 81.1% of BM. Median survival was from 1.3 to 27 months with a median survival of 4.2 months. Conclusion BM from UGC are rare but with a low survival. Multimodal treatment is the most described treatment strategy.

Abstract PD4-07: Targeting latent residual HER2+ breast cancer brain metastatic cells

Abstract Approximately fifty percent of breast cancer patients with brain metastasis are positive for human epidermal growth factor receptor 2 (HER2+). Systemically effective cytotoxic drugs, and HER2 targeted therapies are ineffective on brain metastases. Current understanding of HER2 brain metastatic disease is limited as biopsying brain metastatic lesions and detecting micro-metastasis from asymptomatic patients with residual disease remains a challenge. Therefore, to isolate disseminated tumor cells that stay latent in the brain, while retaining their metastasis-initiating capabilities, we performed a phenotypic screen in mouse employing human breast cancer cell lines. Using this approach, we isolated isogenic latent residual cells (Lat) and metachronous brain metastatic outbreaks (M-BM). Phenotypically stable latent cells display stem cell-like characteristics, downregulate immune activating sensors and survive in equilibrium with innate immune surveillance, while M-BM escape and metastasize. Brain-tropic Lat and M-BM cells are resistant to HER2 targeted therapies - lapatinib, neratinib and tucatinib. Transcriptomic analysis identified AXL, a receptor tyrosine kinase from the TAM receptor family, to be highly enriched in brain-tropic Lat and M-BM. Moreover, AXL is over expressed in metachronous brain metastasis samples compared to matched primary tumors from HER2+ breast cancer patients. AXL activation and overexpression has been associated with chemoresitance mechanisms, dormancy maintenance, invasion, tumor angiogenesis, immune regulation, metastasis and poor prognosis in cancer patients. Therefore, we hypothesized AXL promotes residual/latent breast cancer survival and brain metastatic relapse in HER2+ breast cancer. shRNA depletion of AXL in Lat and M-BM resulted in reduced oncosphere formation, an assay used to measure tumor or metastasis initiating capacity. Brain metastatic incidence was significantly attenuated in mice bearing AXL depleted M-BM compared to their controls. Bemcentinib, an AXL inhibitor currently in clinical trials for non-small cell lung cancer, triple negative breast cancer, pancreatic cancer and melanoma, alone or in combination with lapatinib, neratinib or tucatinib, reduced oncosphere formation in HER2 therapy resistant Lat and M-BM cells. Ongoing experiments are designed to assess the impact of bemcentinib on brain metastasis in vivo and to mechanistically define how AXL promotes survival of latent residual and brain metastatic HER2+ breast cancer cells. Citation Format: Mauricio Marquez-Palencia, Srinivas Malladi. Targeting latent residual HER2+ breast cancer brain metastatic cells [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 PD4-07.

Thoracic CT radiomics analysis for predicting synchronous brain metastasis in patients with lung cancer.

We aimed to assess the feasibility of radiomics analysis based on non-contrast-enhanced thoracic CT images in predicting synchronous brain metastasis (SBM) in lung cancer patients at initial diagnosis. This retrospective study enrolled 371 lung cancer patients (with SBM n=147, without SBM n=224) confirmed by histopathology. Patients were allocated to the training set (n=258) and testing set (n=113). The optimal radiomics features were selected by using the least absolute shrinkage and selection operator (LASSO) algorithm. The radiomics, clinicoradiologic, and combined models were developed to predict SBM using multivariable logistic regression. Then the discrimination ability of the models was assessed. Furthermore, the prediction performance of the abovementioned three models for oligometastatic (1-3 lesions) or multiple (>3 lesions) brain metastases in SBM, metachronous brain metastasis (MBM), and total (SBM and MBM) groups were investigated. Six radiomics features and two clinicoradiologic characteristics were chosen for predicting SBM. Both the radiomics model (area under the receiver operating characteristic curve [AUC] = 0.870 and 0.824 in the training and testing sets, respectively) and the combined model (AUC = 0.912 and 0.859, respectively) presented better predictive ability for SBM than the clinicoradiologic model (AUC = 0.712 and 0.692, respectively). The decision curve analysis (DCA) demonstrated the clinical usefulness of the radiomics-based models. The radiomics model can also be used to predict oligometastatic or multiple brain metastases in SBM, MBM, and total groups (P = .045, P = .022, and P = .030, respectively). The radiomics model and the combined model we presented can be used as valuable imaging markers for predicting patients at high risk of SBM at the initial diagnosis of lung cancer. Furthermore, the radiomics model can also be utilized as an indicator for identifying oligometastatic or multiple brain metastases.

High-dose Chemotherapy in Germ Cell Cancer Patients With Brain Metastases: Experience of an Expert Center.

Germ cell tumor (GCT) patients with brain metastases (BM) have a poor prognosis and high risk of treatment failure. Optimal therapies for these patients remain controversial. The aim of this study was to report the outcomes of all GCT patients with BM treated with high-dose chemotherapy (HDCT) in our French expert center for GCT. We carried out a retrospective study of 35 GCT patients with BM who were treated from 2003 to 2019 with HDCT, followed by infusions of autologous peripheral blood hematopoietic stem cells. The overall survival at 2 years was 36.9% (95% confidence interval, 19.7-54). The median overall survival was 12 months and the median progression-free survival was 8 months. No variables were associated with better survival in the univariable analysis. Among the 35 patients included in our study, 31 completed HDCT and 4 stopped treatments after mobilization. Eleven patients (11) showed favorable responses (complete, partial, or stable disease) to HDCT and 20 patients died of disease progression (17) or toxicities (3). Among the 11 patients with favorable responses to HDCT, 8 (72.7%) had metachronous BM, mostly isolated. The majority of these patients did not receive local treatment at diagnosis or at relapse. Together, our study reveals that GCT patients can experience long-term survival even in the presence of BM. Metachronous BM can also be cured with HDCT even in the absence of local treatment. Biological and radiologic responses to mobilization could be a predictor of favorable responses to HDCT.

Emergency department visits and inpatient hospitalizations among older patients with brain metastases: a dual population- and institution-level analysis.

Older patients with brain metastases (BrM) commonly experience symptoms that prompt acute medical evaluation. We characterized emergency department (ED) visits and inpatient hospitalizations in this population. We identified 17 789 and 361 Medicare enrollees diagnosed with BrM using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2010-2016) and an institutional database (2007-2016), respectively. Predictors of ED visits and hospitalizations were assessed using Poisson regression. The institutional cohort averaged 3.3 ED visits/1.9 hospitalizations per person-year, with intracranial disease being the most common reason for presentation/admission. SEER-Medicare patients averaged 2.8 ED visits/2.0 hospitalizations per person-year. For patients with synchronous BrM (N = 7834), adjusted risk factors for ED utilization and hospitalization, respectively, included: male sex (rate ratio [RR] = 1.15 [95% CI = 1.09-1.22], P < .001; RR = 1.21 [95% CI = 1.13-1.29], P < .001); African American vs white race (RR = 1.30 [95% CI = 1.18-1.42], P < .001; RR = 1.25 [95% CI = 1.13-1.39], P < .001); unmarried status (RR = 1.07 [95% CI = 1.01-1.14], P = .02; RR = 1.09 [95% CI = 1.02-1.17], P = .01); Charlson comorbidity score >2 (RR = 1.27 [95% CI = 1.17-1.37], P < .001; RR = 1.36 [95% CI = 1.24-1.49], P < .001); and receipt of non-stereotactic vs stereotactic radiation (RR = 1.44 [95% CI = 1.34-1.55, P < .001; RR = 1.49 [95% CI = 1.37-1.62, P < .001). For patients with metachronous BrM (N = 9955), ED visits and hospitalizations were more common after vs before BrM diagnosis (2.6 vs 1.2 ED visits per person-year; 1.8 vs 0.9 hospitalizations per person-year, respectively; RR = 2.24 [95% CI = 2.15-2.33], P < .001; RR = 2.06 [95% CI = 1.98-2.15], P < .001, respectively). Older patients with BrM commonly receive hospital-level care secondary to intracranial disease, especially in select subpopulations. Enhanced care coordination, closer outpatient follow-up, and patient navigator programs seem warranted for this population.

Synchronous brain metastases as a poor prognosis factor in clear cell renal carcinoma: a strong argument for systematic brain screening.

Brain metastases (BM) usually represent a poor prognostic factor in solid tumors. About 10% of patients with renal cancer (RCC) will present BM. Local therapies such as stereotactic radiotherapy (SRT), whole brain radiotherapy (WBRT), and surgery are used to achieve brain control. We compared survival between patients with synchronous BM (SynBM group) and metachronous BM (MetaBM group). It is a retrospective study of patients with clear cell renal cell carcinoma (ccRCC) and BM treated with TKI between 2005 and 2019 at the Centre Léon Bérard in Lyon. We collected prognostic factors: The International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) risk score, the TNM stage, the histological subtypes and the Fuhrman grade. Overall survival (OS) was defined from diagnosis of metastatic ccRCC to death. Brain progression-free survival (B-PFS) was defined from focal brain therapy to brain progression or death. 99 patients were analyzed, 44 in the SynBM group and 55 in the MetaBM group. OS in the MetaBM group was 49.4months versus 19.6months in the SynBM group, p = 0.0002. The median time from diagnosis of metastasic disease to apparition ofBM in the MetaBM group was 22.9months (4.3; 125.7). SRT was used for 101 lesions (66.4%), WBRT for 25 patients (16.4%), surgery for 21 lesions (13.8%), surgery followed by radiation for 5 lesions (3.3%). B-PFS for all patients was 7months (IC95% [5.0-10.5]). Survival of patients with synchronous BM is inferior to that of patients with metachronous BM. Outcome is poor in both cases after diagnosis of BM. Brain screening should be encouraged at time of diagnosis of metastatis in ccRCC.