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Background The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) from solid cancers based on clinical, magnetic resonance imaging (MRI), and cerebrospinal fluid (CSF) cytology presentation. MRI patterns are classified as linear, nodular, both, or neither. Type I LM is defined by positive CSF cytology (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the clinical utility of these LM subtypes. Patients and methods We retrospectively assembled data from 254 patients with newly diagnosed LM from solid tumors. Survival curves were derived using the Kaplan–Meier method and compared by Log-rank test. Results Median age at LM diagnosis was 56 years. Typical clinical LM features were noted in 225 patients (89%); 13 patients (5%) were clinically asymptomatic. Tumor cells in the CSF were observed in 186 patients (73%) whereas the CSF was equivocal in 24 patients (9.5%) and negative in 44 patients (17.5%). Patients with confirmed LM had inferior outcome compared with patients with probable or possible LM (P = 0.006). Type I patients had inferior outcome than type II patients (P = 0.002). Nodular disease on MRI was a negative prognostic factor in type II LM (P = 0.014), but not in type I LM. On multivariate analysis, administration of either intrathecal pharmacotherapy (P = 0.012) or systemic pharmacotherapy (P = 0.0003) was associated with improved outcome in type I LM, but not in type II LM. Conclusion The EANO ESMO LM subtypes are highly prognostic and should be considered for stratification and overall design of clinical trials.

The incidence and survival of patients with brain metastases is increasing which stresses the importance of treatment decisions regarding local control and toxicity. Unfortunately, the literature (that usually forms the backbone of treatment guidelines) encompasses mostly retrospective analysis of a wide variety of cancers and clinical presentations, and only limited data of the intracranial effects of novel systemic agents is available. The extrapolation of the literature to the individual patient should therefore be done with caution. For example, until more reliable prediction models are available, treatment guidelines should better avoid categorization of patients according to cut-off values (e.g. tumor size or number of metastases) to prevent suboptimal treatment decisions. For each patient the multidisciplinary team has to take all the individual factors that determine the prognosis into account and discuss the best options regarding symptomatology, local control and toxicity. This approach secures a tailored and optimised treatment strategy for every patient.

Tumor-associated macrophages (TAMs) and microglia (MG) are potent regulators of glioma development and progression. However, the dynamic alterations of distinct TAM populations during the course of therapeutic intervention, response, and recurrence have not yet been fully explored. Here, we investigated how radiotherapy changes the relative abundance and phenotypes of brain-resident MG and peripherally recruited monocyte-derived macrophages (MDMs) in glioblastoma. We identified radiation-specific, stage-dependent MG and MDM gene expression signatures in murine gliomas and confirmed altered expression of several genes and proteins in recurrent human glioblastoma. We found that targeting these TAM populations using a colony-stimulating factor-1 receptor (CSF-1R) inhibitor combined with radiotherapy substantially enhanced survival in preclinical models. Our findings reveal the dynamics and plasticity of distinct macrophage populations in the irradiated tumor microenvironment, which has translational relevance for enhancing the efficacy of standard-of-care treatment in gliomas.

Background It has been suggested that lack of ongoing registration of patient-centered outcomes has resulted in existing care trajectories that have not been optimized for sequelae experienced by meningioma patients. This study aimed to evaluate the structure of current meningioma care and identify issues and potential high-impact improvement initiatives. Methods Using the grounded theory approach, a thematic framework was constructed based on the Dutch Comprehensive Cancer Organisation survey about issues in meningioma care trajectories. This framework was used during 3 semistructured interviews and 2 focus groups with patient-partner dyads (n = 16 participants), and 2 focus groups with health care providers (n = 11 participants) to assess issues in current meningioma care trajectories and possible solutions, including barriers to and facilitators for implementation. Results Identified issues (n = 18 issues) were categorized into 3 themes: availability and provision of information, care and support, and screening for (neurocognitive) rehabilitation. A lack of information about the intervention and possible outcomes or complications, lack of support after treatment focusing on bodily and psychological functions, and reintegration into society were considered most important. Sixteen solutions were suggested, such as appointment of case managers (solution for 11/18 issues, 61%), assessment and treatment by physiatrists (22%), and routine use of patient-reported outcome measures for patient monitoring (17%). Barriers for these solutions were lack of budget, capacity, technology infrastructure, and qualified personnel with knowledge about issues experienced by meningioma patients. Conclusions This study identified issues in current multidisciplinary meningioma care that are considered unmet needs by patients, partners, and health care providers and could guide innovation of care.

Patients with brain metastases (BM) from melanoma have an overall survival (OS) of 2-6 months after whole-brain radiotherapy. Targeted therapy (TT) is an effective treatment for BRAF-mutated metastatic melanoma. Moreover, recent studies indicate intracranial responses of TT in patients with BM. We analyzed 146 patients with BM from BRAF-mutated melanoma treated with vemurafenib, dabrafenib, or dabrafenib+trametinib between 2010 and 2016. We determined clinical and radiological response, progression-free survival (PFS), and OS. Median OS of patients treated with dabrafenib+trametinib was 11.2 months [n=30; 95% confidence interval (CI): 6.8-15.7], 8.8 months for dabrafenib alone (n=31; 95% CI: 3.9-13.7), and 5.7 months for vemurafenib (n=85; 95% CI: 4.6-6.8). A significantly longer OS was observed in the dabrafenib+trametinib group than in the vemurafenib group (hazard ratio for death, 0.52; 95% CI: 0.30-0.89; P=0.02). Median intracranial PFS of all patients was 4.1 months. Median intracranial PFS for patients treated with dabrafenib+trametinib was 5.8 months (95% CI: 3.2-8.5), 5.7 months (95% CI: 3.0-8.4) for dabrafenib, and 3.6 months (95% CI: 3.5-3.8) for vemurafenib (P=0.54). A total of 63 (43%) patients had symptomatic BM. Intracranial disease control rate at 8 weeks in these patients was 65 versus 70% extracranially. Neurological symptoms improved in 46% of patients with symptomatic BM, whereas in 21%, they remained stable. Median OS in patients with BM from BRAF-mutated melanoma treated with dabrafenib+trametinib was significantly longer than for vemurafenib. Improvement of neurological symptoms was seen in almost half of the patients with symptomatic BM treated with TT.

International audience; Background: A scorecard to evaluate magnetic resonance imaging (MRI) findings during the course of leptomeningeal metastases (LM) has been proposed by the Response Assessment in Neuro-Oncology (RANO) group.Methods: To explore the feasibility of the Leptomeningeal Assessment in Neuro-Oncology (LANO) scorecard, cerebrospinal MRIs of 22 patients with LM from solid tumors were scored by 10 neuro-oncologists and 9 neuroradiologists at baseline and at follow-up after treatment. Raters were blinded for clinical data including treatment. Agreement between raters of single items was evaluated using a Krippendorff alpha coefficient. Agreement between numerical parameters such as scores for changes between baseline and follow-up and total scores was evaluated by determining the intraclass coefficient of correlation.Results: Most raters experienced problems with the instructions of the scorecard. No acceptable alpha concordance coefficient was obtained for the rating of single items at baseline or follow-up. The most concordant ratings were obtained for spinal nodules. The concordances were worst for brain linear leptomeningeal enhancement and cranial nerve enhancement. Discordance was less prominent among neuroradiologists than among neuro-oncologists. High variability was also observed for evaluating changes between baseline and follow-up and for total scores.Conclusions: Assessing response of LM by MRI remains challenging. Central imaging review is therefore indispensable for clinical trials. Based on the present results, we propose a new, simplified scorecard that will require validation using a similar approach as pursued here. The main challenges are to define measurable versus nonmeasurable (target) lesions and measures of change that allow assessment of response.

BACKGROUND Delay in cancer care may adversely affect emotional distress, treatment outcome and survival. Optimal timings in multidisciplinary glioblastoma care are a matter of debate and clear national guidelines only exist for time to neurosurgery. We evaluated the between-hospital variation in timings to neurosurgery and adjuvant radiotherapy and chemotherapy in newly diagnosed glioblastoma patients in the Netherlands. MATERIAL AND METHODS Data were obtained from the nation-wide Dutch Brain Tumor Registry between 2014 and 2018. All adult patients with glioblastoma were included, covering all 18 neurosurgical hospitals, 28 radiotherapy hospitals, and 33 oncology hospitals. Long time-to-surgery (TTS) was defined as >3 weeks from the date of first brain tumor diagnosis to surgery, long time-to-radiotherapy (TTR) as either >4 or >6 weeks after surgery, and long time-to-chemotherapy (TTC) as either >4 or >6 weeks after completion of radiotherapy. Between-hospital variation in standardized rate of long timings was analyzed in funnel plots after case-mix correction. RESULTS A total of 4203 patients were included. Median TTS was 20 days and 52.4% of patients underwent surgery within 3 weeks. Median TTR was 20 days and 24.6% of patients started radiotherapy within 4 weeks and 84.2% within 6 weeks after surgery. Median TTC was 28 days and 62.6% of patients received chemotherapy within 4 weeks and 91.8% within 6 weeks after radiotherapy. After case-mix correction, three (16.7%) neurosurgical hospitals had significantly more patients with longer than expected TTS. Three (10.7%) and one (3.6%) radiotherapy hospitals had significantly more patients with longer than expected TTR for >4 and >6 weeks, respectively. In seven (21.2%) chemotherapy hospitals, significantly less patients with TTC >4 weeks were observed than expected. In four (12.1%) chemotherapy hospitals, significantly more patients with TTC >4 weeks were observed than expected. CONCLUSION Between-hospital variation in timings to multidisciplinary treatment was observed in glioblastoma care in the Netherlands. A substantial percentage of patients experienced timings longer than anticipated.

BACKGROUND Over the past years, increasing worldwide attention towards centralization of complex cancer care has been pursued as higher volume centers have shown improved outcomes. Changes in distribution of care and the impact on travel distance in glioblastoma patients have not been determined yet. In this study, we determine trends in distribution of glioblastoma care in the Netherlands over the last three decades and assess whether the observed trends affected travel distance for individual patients. MATERIAL AND METHODS Data were obtained from the Dutch Brain Tumor Registry from 1989 to 2018. All glioblastoma patients (≥18 years) were included for analysis. Patients, neurosurgical centers and radiotherapy centers were geocoded. Data were analyzed in six time intervals of 5 years. High volume hospitals were defined as >50 cases per year. Travel distance was examined in two categories, ≤60km and >60km respectively. Trend analyses for proportions were used to analyze hospital volume changes and travel distances. RESULTS A total of 16.477 glioblastoma patients were registered, with an annual increase from 203 patients in 1989 to 917 patients in 2018. Neurosurgical centers increased from 16 to 17 and for radiotherapy from 19 to 22 centers between 1989–1993 and 2014–2018. Mean neurosurgical- and radiotherapy center volumes increased from 12 to 39 (P=0.025) and 7 to 27 (P=0.025) patients per hospital per year from 1989–1993 to 2014–2018. High volume neurosurgical centers were observed since 2004, and an increased number of patients were treated in these centers, 27.8%, 52.6% and 64.1% in the time periods 2004–2008, 2009–2013, and 2014–2018 (P60km to the neurosurgical center reduced from 15.8% to 13.2% (P=0.033). Travel distance >60km to the radiotherapy center did not reduce significantly (10.4% to 8.8%, P=0.601). CONCLUSION An increasing number of glioblastoma patients were differentially treated in high volume neurosurgery and radiotherapy centers. The observation that this did not translate into increased travel distances, indicates accessible specialized Neuro-Oncology care for glioblastoma patients in The Netherlands.

BACKGROUND The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) based on clinical (typical/atypical), cytological (positive/negative/equivocal) and MRI (A linear, B nodular, C linear and nodular, D normal or hydrocephalus only) presentation. Type I LM is defined by the presence of tumor cells in the cerebrospinal fluid (CSF) (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the clinical utility of these EANO ESMO LM subtypes. PATIENTS AND METHODS We retrospectively assembled data from 254 patients with newly diagnosed LM from different solid tumors, including as main primary tumors breast cancer (n=98, 45%), lung cancer (n=65, 25.5%) and melanoma (n=51, 13.5%). Survival curves were estimated using the Kaplan-Meier method and compared by Log-rank test. RESULTS Median age at LM diagnosis was 56.5 years (range 20–82 years). Typical clinical LM symptoms or signs were noted in 225 patients (88.5%); only 13 patients (5%) were clinically asymptomatic. The most common MRI subtype was A seen in 117 patients (46%). Types B (n=33, 13%), C (n=54, 21%) and D (n=50, 19.5%) were less common. Tumor cells were observed in the CSF in 186 patients (73%) whereas the CSF was equivocal in 24 (9.5%) and negative in 44 (17.5%) patients. Patients with confirmed LM had inferior outcome than patients with probable or possible LM (p=0.0063). Type I patients had inferior outcome than type II patients (p=0.0019). Nodular disease was a negative prognostic factor in type II LM, but not in type I LM (p=0.0138). CONCLUSION The presence of tumor cells in the CSF appears to have a greater prognostic role than the neuroimaging presentation. EANO ESMO LM subtypes are highly prognostic and should be considered in the design of clinical trials.

Background. A scorecard to evaluate magnetic resonance imaging (MRI) findings during the course of leptomeningeal metastases (LM) has been proposed by the Response Assessment in Neuro-Oncology (RANO) group. Methods. To explore the feasibility of the Leptomeningeal Assessment in Neuro-Oncology (LANO) scorecard, cerebrospinal MRIs of 22 patients with LM from solid tumors were scored by 10 neuro-oncologists and 9 neuroradiologists at baseline and at follow-up after treatment. Raters were blinded for clinical data including treatment. Agreement between raters of single items was evaluated using a Krippendorff alpha coefficient. Agreement between numerical parameters such as scores for changes between baseline and follow-up and total scores was evaluated by determining the intraclass coefficient of correlation. Results. Most raters experienced problems with the instructions of the scorecard. No acceptable alpha concordance coefficient was obtained for the rating of single items at baseline or follow-up. The most concordant ratings were obtained for spinal nodules. The concordances were worst for brain linear leptomeningeal enhancement and cranial nerve enhancement. Discordance was less prominent among neuroradiologists than among neuro-oncologists. High variability was also observed for evaluating changes between baseline and follow-up and for total scores. Conclusions. Assessing response of LM by MRI remains challenging. Central imaging review is therefore indispensable for clinical trials. Based on the present results, we propose a new, simplified scorecard that will require validation using a similar approach as pursued here. The main challenges are to define measurable versus nonmeasurable (target) lesions and measures of change that allow assessment of response.

BACKGROUND Historically leptomeningeal metastases (LM) from melanoma have a poor prognosis, with a median survival of only 2 months despite treatment. Targeted therapy and immune checkpoint inhibitors are promising new treatment options in advanced melanoma. We sought to determine the impact of targeted therapy and immunotherapy on the outcome of melanoma patients with LM and to evaluate the influence of prognostic factors. PATIENTS AND METHODS We analyzed a series of 39 consecutive patients diagnosed with LM from melanoma between May 2010 and March 2015 treated at the Netherlands Cancer Institute. Thirty-four of these patients also had brain metastases (BM). Statistical analyses assessed the influence of clinical and biological characteristics on survival. RESULTS Median overall survival of the entire cohort was 6.9 weeks (95% confidence interval 0.9-12.8). Due to a poor performance status or rapidly progressive disease, 14 patients received no treatment. Median overall survival of untreated patients after the diagnosis of LM was 2.9 versus 16.9 weeks for treated patients (P < 0.001). The median survival of 21 patients treated with systemic targeted therapy and/or immunotherapy, with or without RT was 21.7 weeks (range 2-235 weeks). Five patients had LM without BM. Three of these patients died within 3 weeks before any treatment was given, whereas 2 patients are in ongoing remission for 26 weeks (following dabrafenib) and 235 weeks (following WBRT and ipilimumab). Elevated serum lactate dehydrogenase and S100B at diagnosis of LM were associated with shorter survival. CONCLUSION LM from melanoma still has an extremely poor prognosis. As observed in extracranial metastatic disease, new treatment modalities such as systemic targeted therapy and immune checkpoint inhibitors seem to increase overall survival in LM, and may result in long-term remission. These new treatment options should be considered in patients with LM.

BACKGROUND The EANO ESMO guidelines have proposed a classification of leptomeningeal metastases (LM) based on clinical (typical/atypical), cytological (positive/negative/equivocal) and MRI (A linear, B nodular, C linear and nodular, D normal or hydrocephalus only) presentation. Type I LM is defined by the presence of tumor cells in the cerebrospinal fluid (CSF) (confirmed LM) whereas type II LM is defined by typical clinical and MRI signs (probable or possible LM). Here we explored the clinical utility of these EANO ESMO LM subtypes for choice of treatment and outcome. PATIENTS AND METHODS We retrospectively assembled data from 254 patients with newly diagnosed LM from different solid tumors, including as main primary tumors breast cancer (n=98, 45%), lung cancer (n=65, 25.5%) and melanoma (n=51, 13.5%). Survival curves were estimated using the Kaplan-Meier method and compared by Log-rank test. RESULTS Median age at LM diagnosis was 56.5 years (range 20-82 years). Typical clinical LM symptoms or signs were noted in 225 patients (88.5%); only 13 patients (5%) were clinically asymptomatic. The most common MRI subtype was A seen in 117 patients (46%). Types B (n=33, 13%), C (n=54, 21%) and D (n=50, 19.5%) were less common. Tumor cells in the CSF were observed in 186 patients (73%) whereas the CSF was equivocal in 24 (9.5%) and negative in 44 (17.5%) patients. Patients with confirmed LM had inferior outcome than patients with probable or possible LM (p=0.0063). Type I patients had inferior outcome than type II patients (p=0.0019). Nodular disease was a negative prognostic factor in type II LM, but not in type I LM (p=0.0138). CONCLUSION The EANO ESMO LM subtypes are highly prognostic and should be considered for stratification and overall design of clinical trials.

ObjectiveThe primary objective was to determine the sensitivity and specificity of epithelial cell adhesion molecule (EpCAM) immunoflow cytometry circulating tumor cells (CTC) analysis in CSF in patients with suspected leptomeningeal metastases (LM). The secondary objective was to explore the distribution of driver mutations in the primary tumor, plasma, cell free CSF (cfCSF), and isolated CTC from CSF in non-small cell lung cancer (NSCLC).MethodsWe tested the performance of the CTC assay vs CSF cytology in a prospective study in 81 patients with a clinical suspicion of LM but a nonconfirmatory MRI. In an NSCLC subcohort, we analyzed circulating tumor (ct)DNA of the selected driver mutations by digital droplet PCR (ddPCR).ResultsThe sensitivity of the CTC assay was 94% (95% confidence interval [CI] 80–99) and the specificity was 100% (95% CI 91–100) at the optimal cutoff of 0.9 CTC/mL. The sensitivity of cytology was 76% (95% CI 58–89). Twelve of the 23 patients with NSCLC had mutated epidermal growth factor receptor (EGFR). All 5 tested patients with LM demonstrated the primary EGFR driver mutation in cfCSF. The driver mutation could also be detected in CTC isolated from CSF.ConclusionCTC in CSF are detected with a high sensitivity for the diagnosis of LM. ddPCR can determine EGFR mutations in both cfCSF and isolated CTC from CSF of patients with EGFR-mutated NSCLC and LM.Classification of evidenceThis study provides Class III evidence that EpCAM-based immunoflow cytometry analysis of CSF accurately identifies patients with LM.

International audience; Liquid biopsies collect and analyze tumor components in body fluids, and there is an increasing interest in the investigation of liquid biopsies as a surrogate for tumor tissue in the management of both primary and secondary brain tumors. Herein we critically review available literature on spinal fluid and plasma circulating tumor cells (CTCs) and cell-free tumor (ctDNA) for diagnosis and monitoring of leptomeningeal and parenchymal brain metastases. We discuss technical issues and propose several potential applications of liquid biopsies in different clinical settings (ie, for initial diagnosis, for assessment during treatment, and for guidance of treatment decisions). Last, ongoing clinical studies on CNS metastases that include liquid biopsies are summarized, and recommendations for future clinical studies are provided.

Primary CNS lymphoma (PCNSL) has been designated an acquired immune deficiency syndrome (AIDS)-defining disease since 1983 and accounts for up to 15% of non-Hodgkin lymphomas in human immunodeficiency virus (HIV) patients. The majority of HIV patients are Epstein-Barr virus (EBV)-related. The most likely etiology is ineffective immunoregulation of EBV, inducing oncogenic protein expression, and subsequent loss of apoptosis and increased proliferation of lymphocytes. PCNSL generally presents with supratentorial, single or multiple, contrast-enhancing lesions. Neurologic symptoms can be headache, cognitive function disorders, focal neurologic, deficit and epilepsy. Differential diagnosis includes other oncologic or infectious causes, with cerebral toxoplasmosis being the most important. Magnetic resonance imaging characteristics, activity on

The diagnosis of leptomeningeal metastases (LM) of solid tumors is complicated due to low sensitivities of both magnetic resonance imaging (MRI) and cytology. MRI has a sensitivity of 76% for the diagnosis of LM and cerebrospinal fluid (CSF) cytology has a sensitivity of 44-67% at first lumbar puncture which increases to 84-91% upon second CSF sampling. Epithelial cell adhesion molecule (EpCAM) is expressed by solid tumors of epithelial origin like non-small-cell lung cancer, breast cancer or ovarium cancer. Recently, a CELLSEARCH® assay and flow cytometry laboratory techniques have been developed to detect circulating tumor cells (CTCs) of epithelial origin in CSF. These laboratory techniques are based on capture antibodies labelled with different fluorescent tags against EpCAM. In this review, we provide an overview of the available laboratory techniques and diagnostic accuracy for tumor cell detection in CSF. The reported sensitivities of the EpCAM-based CTC assays for the diagnosis of LM across the different studies are highly promising and vary between 76 and 100%. An overview of the different EpCAM-based techniques for the enumeration of CTCs in the CSF is given and a comparison is made with CSF cytology for the diagnoses of LM from epithelial tumors.

Background: The incidence of brain metastases (BM) in breast cancer (BC) patients (pts) has increased over the past decade. The brain is regarded as a sanctuary site for metastatic cells which are partially protected from drugs by the blood-brain barrier (BBB). 2B3-101 is a doxorubicin (DOX) liposomal formulation that uses glutathione transporters on the BBB to penetrate the brain. Non-clinical studies have shown a 5-fold enhanced delivery of DOX to the brain after IV administration of 2B3-101 compared to liposomal DOX, without signs of cardio- or neurotoxicity. Methods: This phase 1/2a open label study assessed the safety, tolerability, MTD, PK, and anti-tumor activity of single agent 2B3-101 in pts with BM of solid tumors, or high-grade gliomas. For this analyses BCBM pts (n=25) were included. These pts received 2B3-101 at a starting dose of either 40 (n=3) or 50 (n=22) mg/m2 IV every 3 weeks, until disease progression or unacceptable toxicity. Anti-tumor activity was assessed by RECIST 1.1. Patients with HER2-positive BCBM were treated with concurrent trastuzumab. Results: As of May 30, 2014, 88 cycles (median 2, range 1-10) of 2B3-101 alone or with trastuzumab were administered to 25 heavily pretreated BC pts, 3 pts are still on treatment. Median age was 47 (33–61) years and 18 (72%) pts had HER2+ disease. Pts had received a median of 7 (4–15) prior regimens; 18 (72%) had received prior radiation therapy to the brain. In phase 1, 2B3-101 alone or with trastuzumab was well tolerated up to a dose intensity of 15 mg/m2/wk. Cycle 1 MTD was not reached. Phase 2a dose of 50 mg/m2 was selected based upon tolerability after repeated dosing. The most frequent reported treatment emergent AEs are qualitatively consistent with conventional PEGylated liposomal DOX and were (≥ grade 2): neutropenia (59%), palmar plantar erythrodysesthesia (PPE) (50%), fatigue (45%), stomatitis (22%), and infusion reaction (18%). Notable Grade 3–4 AEs were neutropenia (35%) and PPE (13%). All AEs were transient and manageable with dose delays, reductions and standard medication. 57% of pts had 2B3-101 dose delays and 39% of pts required dose reductions. 2B3-101 showed no neuro- or cardiotoxicity. PK data showed non-linear exposure of 2B3-101 without signs of accumulation upon repeat dosing, a mean half-life of 69h (range 43-120h) and independent of trastuzumab co-treatment. Best overall and intracranial tumor responses of 2B3-101 in 23 evaluable BCBM pts (92% of total) are summarized in Table 1. Table 1: Anti-tumor activity results of 2B3-101 in BCBM patientsPopulationNumber of evaluable ptsOverall partial responseOverall stable diseaseIntracranial tumor response of ≥ 20%.12-weeks overall PFS rateOverall232 (9%)11 (48%)4 (17%)48%"Luminal"40 (0%)2 (50%)1 (25%)50%HER2 positive162 (13%)9 (56%)3 (19%)56%TNBC30 (0%)0 (0%)0 (0%)0% Conclusions: 2B3-101 alone or with trastuzumab is safe and well tolerated and shows intra- and extracranial anti-tumor activity in heavily pretreated BC pts. A 12-week PFS rate of 56% in HER2+ BCBM was observed, which warrants further clinical studies. An international, multicenter, randomized, controlled phase IIb study in HER2+ BCBM is being planned. NCT01386580, sponsored by to-BBB technologies BV. Citation Format: Philippe G Aftimos, Bojana Milojkovic-Kerklaan, Véronique Diéras, Sevilay Altintas, Carey Anders, Monica Arnedos, Hans Gelderblom, Patricia Soetekouw, Werner Gladdines, Pieter Gaillard, Carlos de Sousa, Agnes Jager, Myra van Linde, Ahmad Awada, Jan Schellens, Dieta Brandsma. Phase 1/2a study of glutathione PEGylated liposomal doxorubicin (2B3-101) in breast cancer patients with brain metastases [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P6-16-04.