Treatment Option For Brain Metastases Research Articles

Targeting Molecular Pathways in Intracranial Metastatic Disease.

The discovery and clinical application of agents targeting pivotal molecular pathways in malignancies such as lung, breast, renal cell carcinoma, and melanoma have led to impressive improvements in clinical outcomes. Mutations in epidermal growth factor receptor (EGFR), and rearrangements of anaplastic lymphoma kinase (ALK) are targetable in lung cancer, while BRAF mutations have been successfully targeted in metastatic melanoma. Targeting estrogen receptors, cyclin dependent kinases, and HER2 (Human Epidermal Receptor) have resulted in improvement in survival in breast cancer. Major strides have been made in the management of metastatic renal cell carcinoma by targeting the vascular endothelial growth factor (VEGF) pathway. However, intracranial metastases remain a major hurdle in the setting of targeted therapies. Traditional treatment options for brain metastases include surgery, whole brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). Surgery is effective in symptomatic patients with dominant lesions or solitary intracranial metastases, however, recovery time can be prolonged, often requiring an interruption in systemic treatment. WBRT and SRS provide symptomatic relief and local control but data on improving overall survival is limited. Most targeted therapies which provide extracranial control have limited penetration through the blood brain barrier. Given the limited therapeutic options and increasing prevalence of brain metastases, finding new strategies for the management of intracranial metastatic disease is critical. Genomic analysis of brain metastases has led to a better understanding of variations in the driver mutations compared to the primary malignancy. Furthermore, newer generations of targeted agents have shown promising intracranial activity. In this review, we will discuss the major molecular alterations in brain metastases from melanoma, lung, breast, and renal cell carcinoma. We will provide an in-depth review of the completed and ongoing clinical trials of drugs targeting the molecular pathways enriched in brain metastases.

Stereotactic Radiosurgery for Brain Metastases of Small Cell Lung Cancer at Diagnosis: Local Management Patterns

Retrospective reports have suggested up-front stereotactic radiosurgery (SRS) to be a potentially effective treatment option for brain metastases (BM) from small cell lung cancer (SCLC). However, due to the likelihood of multiple microscopic intracranial metastases and distant brain failure, SRS has not typically been deemed to be an appropriate stand-alone treatment for these patients, as it is in patients with BM due to non-small cell lung cancer. The purpose of the present study is to evaluate national practice patterns and clinical outcomes for SCLC patients with BM receiving up front SRS. The National Cancer Data Base was queried (2004-2013) for patients with metastatic SCLC receiving intracranial radiotherapy for management of BM. Patients were grouped into categories based on the radiation treatment selected for the brain: upfront SRS, whole-brain radiotherapy(WBRT) or WBRT with concomitant boost (SRS or fractionated radiotherapy). Univariable and multivariable logistic regression were performed to evaluate factors associated with SRS administration. Temporal trends were analyzed graphically. Survival was analyzed with the Kaplan-Meier method and Cox proportional hazards modeling was used to evaluate predictors of overall survival (OS). To account for indication bias, survival analysis was repeated following and propensity score matching. A total of 14,722 patients met the selection criteria, of whom 487 (3.3%), 13,657 (92.8%) and 578 (3.9%) received upfront SRS, WBRT and WBRT with boost, respectively. The utilization of upfront SRS showed a slight increase from 2004 to 2013 (2.7% to 4.3%). Diagnosis in more recent time periods (2011-2013) was predictive of SRS use (p=0.004). Other socioeconomic factors associated with upfront SRS use included receiving therapy at academic centers and residing in higher-educated regions. SRS was less likely to be used in patients with node positive disease (p<0.05). The upfront SRS cohort was found to have a higher overall survival (OS) than WBRT-based groups before and after propensity matching (p<0.001). Younger patients, female gender, Charlson Deyo Score of 0, treatment at an academic center, higher-income, private insurance, recent years at diagnosis, early T stage, node negative disease and receipt of chemotherapy independently predicted for higher OS. This NCDB analysis demonstrates that utilization of upfront SRS for SCLC BMs has been increasing over time. Socioeconomic disparities exist with regards to SRS utilization. Use of SRS was associated with improved OS, though this could partially be due to selection bias. Further research is required to further elucidate the role of SRS in BMs due to SCLC.

PC08.08 Debate #3: Brain Metastases with a Driver Mutation Should Be Treated with Systemic Therapy First (CON)

PC08.08 Debate #3: Brain Metastases with a Driver Mutation Should Be Treated with Systemic Therapy First (CON)

Management of Brain Metastases in the New Era of Checkpoint Inhibition.

Brain metastasis is a common complication of advanced malignancies, especially, lung cancer, breast cancer, renal cell carcinoma, and melanoma. Traditionally surgery, when indicated, and radiation therapy, either as whole-brain radiation therapy or stereotactic radiosurgery, constituted the major treatment options for brain metastases. Until recently, most of the systemic chemotherapy agents had limited activity for brain metastases. However, with the advent of small molecule tyrosine kinase inhibitors and immunotherapy agents, there has been renewed interest in using these agents in the management of brain metastases. Immune checkpoint inhibitors have revolutionized the treatment of metastatic melanoma, lung cancer, kidney cancer, and bladder cancer among others. They modulate the immune system to recognize tumor antigens as "non-self" antigens and mount an immune response against them. Initial studies of using immune checkpoint inhibitors in brain metastases have shown promising activity, and several clinical trials are currently underway. Studies are also assessing the combination of radiation therapy and immunotherapy in brain metastases. The results of these ongoing clinical trials have the potential to change the therapeutic paradigm in patients with brain metastases.

Abstract P1-17-10: Survival outcomes related to health care coverage in breast cancer patients with brain metastases in Brazil: A sub-analysis from the LACOG-0312 study

Abstract Background The incidence of brain metastases among women with metastatic breast cancer (MBC) ranges from 10 to 30% depending of breast cancer (BC) subtype. Inequities in the access to optimal treatment and shorter survival of BC by type of health care coverage were previously reported in an observational study in Brazil. The present analysis aims to analyze the impact of the type of health care coverage on survival outcomes of patients with MBC and brain involvement. Methods LACOG-0312 is a retrospective cohort study that enrolled patients with metastatic or locally advanced/recurrent unresectable BC diagnosed during 2012 in Brazil. Overall survival (OS) was defined as the time from the diagnosis of brain metastases and death from any cause. Comparisons were made using the Kaplan-Meier method based on the type of health care coverage (public vs. private) among patients who developed brain metastases. Cox regression analysis was performed for identification of independent prognostic factors associated with survival after brain metastases diagnosis. Results Among the 690 MBC patients included in the LACOG-0312 study, 145 (21%) were diagnosed with brain metastases. Of them, 94 (71,75%) were covered by the Brazilian public health care and 37 (28,25%) had private coverage. Baseline characteristics such as age at MBC diagnosis, stage IV at diagnosis and tumor subtypes were similar between both groups. Median time to develop brain metastases after diagnosis of MBC was 14 months in the whole population with no differences between public and private patients (13 vs. 17 months p=0.172). Median OS from the date of brain metastases diagnosis was similar for both groups: 10.0 months in private and 9.0 months in public health insured patients (HR 0.92 – 95%CI 0.55-1.51; p=0.729). In a multivariable analysis including type of health care coverage, only the triple negative BC subtype was associated with a worse survival post brain metastases diagnosis. Conclusion Our study indicates that health care coverage is not associated with survival outcomes in patients with MBC and brain metastases. Potential differences in the access to optimal care such as radiotherapy, surgery and systemic treatments may not play a significant role in the survival of theses patients possibly due to small clinical benefit of the current treatment options for brain metastases in breast cancer. Citation Format: Albuquerque C, Debiasi M, Werutsky G, Uema D, Cronenberger E, Cordeiro de Lima VC, de Sant'ana RO, Bines J, Santi PX, Goés RS, Liedke P, Batista MLM, Dybal V, Nerón YV, Beato CA, Borges G, Giacomazzi J, dos Santos LV, Ismael G, Rosa DD, Azambuja A, Andrade D, Martinez-Mesa J, Zaffaroni F, Barrios CH. Survival outcomes related to health care coverage in breast cancer patients with brain metastases in Brazil: A sub-analysis from the LACOG-0312 study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-17-10.

Therapy of breast cancer brain metastases: challenges, emerging treatments and perspectives.

Brain metastases are the most common central nervous system tumors in adults, and incidence of brain metastases is increasing due to both improved diagnostic techniques (e.g. magnetic resonance imaging) and increased cancer patient survival through advanced systemic treatments. Outcomes of patients remain disappointing and treatment options are limited, usually involving multimodality approaches. Brain metastases represent an unmet medical need in solid tumor care, especially in breast cancer, where brain metastases are frequent and result in impaired quality of life and death. Challenges in the management of brain metastases have been highlighted in this review. Innovative research and treatment strategies, including prevention approaches and emerging systemic treatment options for brain metastases of breast cancer, are further discussed.

Preclinical Modeling and Therapeutic Avenues for Cancer Metastasis to the Central Nervous System.

Metastasis is the dissemination of cells from the primary tumor to other locations within the body, and continues to be the predominant cause of death among cancer patients. Metastatic progression within the adult central nervous system is 10 times more frequent than primary brain tumors. Metastases affecting the brain parenchyma and leptomeninges are associated with grave prognosis, and even after successful control of the primary tumor the median survival is a dismal 2–3 months with treatment options typically limited to palliative care. Current treatment options for brain metastases (BM) and disseminated brain tumors are scarce, and the improvement of novel targeted therapies requires a broader understanding of the biological complexity that characterizes metastatic progression. In this review, we provide insight into patterns of BM progression and leptomeningeal spread, outlining the development of clinically relevant in vivo models and their contribution to the discovery of innovative cancer therapies. In vivo models paired with manipulation of in vitro methods have expanded the tools available for investigators to develop agents that can be used to prevent or treat metastatic disease. The knowledge gained from the use of such models can ultimately lead to the prevention of metastatic dissemination and can extend patient survival by transforming a uniformly fatal systemic disease into a locally controlled and eminently more treatable one.

Novel therapeutic agents in the management of brain metastases.

This review aims to highlight the novel therapeutic agents in the management of brain metastases which are in various stages of clinical development. We review the results from recent clinical trials, publications and presentations at recent national and international conferences. Several new systemic treatment options for brain metastases are in early or advanced clinical trials. These drugs have good intracranial and extracranial activities. As lung cancer, breast cancer, and melanoma are the three most common causes of brain metastases, most agents in clinical development are focused on these tumor types. Several of these therapies are small molecule tyrosine kinase inhibitors or monoclonal antibodies against the tyrosine kinase receptors. Another exciting development in brain metastases management is the use of immunotherapy agents. The anti-CTLA-4 and\or anti-PD-1 antibodies have shown promising intracranial activity in melanoma and nonsmall cell lung cancer patients with brain metastases. Contemporary clinical trials have shown encouraging intracranial activity of newer tyrosine kinase inhibitors, monoclonal antibodies against tyrosine kinase receptors and immunotherapy agents in select group of patients with brain metastases. Further studies are needed to develop therapeutic strategies, in order to improve survival in patients with brain metastases.

Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis.

Purpose Stereotactic radiosurgery (SRS), whole-brain radiotherapy (WBRT), and epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are treatment options for brain metastases in patients with EGFR-mutant non-small-cell lung cancer (NSCLC). This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI. Materials and Methods A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study. Exclusion criteria included prior EGFR-TKI use, EGFR-TKI resistance mutation, failure to receive EGFR-TKI after WBRT/SRS, or insufficient follow-up. Patients were treated with SRS followed by EGFR-TKI, WBRT followed by EGFR-TKI, or EGFR-TKI followed by SRS or WBRT at intracranial progression. Overall survival (OS) and intracranial progression-free survival were measured from the date of brain metastases. Results The median OS for the SRS (n = 100), WBRT (n = 120), and EGFR-TKI (n = 131) cohorts was 46, 30, and 25 months, respectively ( P < .001). On multivariable analysis, SRS versus EGFR-TKI, WBRT versus EGFR-TKI, age, performance status, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS. Although the SRS and EGFR-TKI cohorts shared similar prognostic features, the WBRT cohort was more likely to have a less favorable prognosis ( P = .001). Conclusion This multi-institutional analysis demonstrated that the use of upfront EGFR-TKI, and deferral of radiotherapy, is associated with inferior OS in patients with EGFR-mutant NSCLC who develop brain metastases. SRS followed by EGFR-TKI resulted in the longest OS and allowed patients to avoid the potential neurocognitive sequelae of WBRT. A prospective, multi-institutional randomized trial of SRS followed by EGFR-TKI versus EGFR-TKI followed by SRS at intracranial progression is urgently needed.

Preface on "Emerging treatment options for brain metastases from non-small cell lung cancer".

Significant progress in the treatment of advanced non-small cell lung cancer (NSCLC) became first evident with the recognition that certain molecular subtypes (e.g., EGFR-mutant or ALK-rearranged tumors) could tremendously benefit from sequential treatment with small molecules tyrosine-kinase inhibitors (TKIs). In fact, an unprecedented median survival of more than 24 months has been reported in patients with oncogene-addicted disease when appropriate targeted therapies are used (1,2). More recently, the introduction of immunotherapy for use after failure of platinum-based chemotherapy has significantly improved the survival of some patients with no identifiable driver mutations (3), and future treatment landscape is rapidly evolving in order to incorporate immunotherapy in the front-line setting (4,5). Having made this preliminary remark, the downside of the improved survival experienced by patients has led to a significant increase in the spread of the disease to the brain, a phenomenon which already affects nearly one third of advanced NSCLCs at diagnosis. On the other hand, frequent use of serial CT scan or MRI of the brain for tumor (re-) staging has significantly contributed to the increased detection of brain metastases (BMs), especially when asymptomatic. Once developed, BMs predictably represent an important cause of morbidity and mortality in NSCLC patients, and counteracting strategies against BMs are crucial in this context.

ANG1005, a novel brain-penetrant taxane derivative, for the treatment of recurrent brain metastases and leptomeningeal carcinomatosis from breast cancer.

2004Background: Treatment options for brain metastases (BM) and leptomeningeal carcinomatosis (LC) are limited due to the inability of most anti-cancer agents to cross the blood-brain barrier (BBB)...

Pre-treatment factors associated with detecting additional brain metastases at stereotactic radiosurgery.

The number of brain metastases identified on diagnostic magnetic resonance imaging (MRI) is a key factor in consideration of stereotactic radiosurgery (SRS). However, additional lesions are often detected on high-resolution SRS-planning MRI. We investigated pre-treatment clinical characteristics that are associated with finding additional metastases at SRS. Patients treated with SRS for brain metastases between the years of 2009-2014 comprised the study cohort. All patients underwent frame-fixed, 1mm thick MRI on the day of SRS. Patient, tumor, and treatment characteristics were analyzed for an association with increase in number of metastases identified on SRS-planning MRI. 289 consecutive SRS cases were analyzed. 725 metastases were identified on pre-treatment MRI and 1062 metastases were identified on SRS-planning MRI. An increase in the number of metastases occurred in 34% of the cases. On univariate analysis, more than four metastases and the diameter of the largest lesion were significantly associated with an increase in number of metastases on SRS-planning MRI. When stratified by the diameter of the largest lesion into <2, 2-3, or ≥3cm, additional metastases were identified in 37, 29, and 18%, respectively. While this increase in the number of metastases is largely due to the difference in imaging technique, the number and size of the metastases were also associated with finding additional lesions. These clinical factors may be considered when determining treatment options for brain metastases.

Abstract P6-17-04: A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant taxane derivative, in breast cancer patients with recurrent CNS metastases

Abstract Background: Treatment options for brain metastases are limited to local therapies due to the inability of most anti-cancer agents to cross the blood brain barrier (BBB). ANG1005 is a novel taxane derivative, being developed for targeted treatment of brain metastases. It consists of 3 paclitaxel molecules covalently linked to Angiopep-2 designed to cross the BBB and to penetrate malignant cells, regardless of location, via the low density lipoprotein (LDL) receptor related protein-1 (LRP-1) transport system. Methods: Adult patients with measurable recurrent brain metastases from breast cancer with, or without, leptomeningeal disease are currently being enrolled in this multi-center, open-label study (planned n=56). ANG1005 is administered IV at 600 mg/m2 every three weeks (one cycle) until disease progression, unacceptable toxicity or consent withdrawal. HER2+ patients are allowed to continue HER2 targeted therapies. The primary endpoint is intracranial objective response rate, as assessed by MRI using CNS RECIST 1.1. Secondary endpoints include duration of intracranial response, median progression-free survival, 3/6/12-month progression-free survival rate, overall survival at 6 months, extracranial objective response rate, safety and tolerability. Extracranial response is also assessed by CT using RECIST 1.1. An imaging sub-study, evaluating the use of 18F-FLT-PET in comparison to MRI, is also ongoing in 10 patients with measurable brain metastases from breast cancer, receiving ANG1005 IV at 550 mg/m2. Results: Accrual is ongoing and to date, 48 patients have been treated with a range of 1-18 cycles of ANG1005. Median age is 47 years (range: 26-65). Safety profile is similar to that of paclitaxel with myelosuppression as the predominating toxicity. Based on data from patients evaluated to date for intracranial response, 6/30 (20%) patients had a partial response (PR) and 17/30 (57%) had a stable disease (SD), as best response. A sub-analysis, based on breast cancer sub-type is presented below: Intracranial Response by Breast Cancer SubsetOutcome by CNS RECISTHER2- (n=13)HER2+ (n=17)TNBC (n=6)LMD (n=11)PR, n (%)1 (8%)5 (29%)1 (17%)4 (36%)SD, n (%)6 (46%)10 (59%)2 (33%)5 (45%)PD, n (%)6 (46%)2 (12%)3 (50%)2 (18%)TNBC, triple-negative breast cancer, a sub-group of HER2-; LMD, leptomeningeal disease, including 3 HER2- and 8 HER2+ patients The longest duration on treatment is for 18 cycles, seen in a patient with an intracranial PR that sustained for 10 cycles; the treatment is still ongoing. Extracranial tumor evaluations were completed in 14 patients, all showing disease control including in those previously treated with paclitaxel. One (7%) patient had a PR and 13 (93%) patients had an SD. Conclusions: CNS activity was observed in all subsets of breast cancer, suggesting that ANG1005 is a promising therapy for treatment of brain and leptomeningeal metastases from breast cancer. ANG1005 treatment also resulted in disease control in extracranial lesions, including patients previously treated with paclitaxel. The dose and treatment regimen were well tolerated with a safety profile similar to paclitaxel. Updated efficacy and safety data will be presented at the meeting. Citation Format: Tang S-C, Bates S, Kesari S, Brenner AJ, Anders CK, Garcia A, Ibrahim NK, Tkaczuk KHR, Kumthekar P. A phase II, open-label, multi-center study of ANG1005, a novel brain-penetrant taxane derivative, in breast cancer patients with recurrent CNS metastases. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-17-04.

Optimal Treatment Decision for Brain Metastases of Unknown Primary Origin: The Role and Timing of Radiosurgery

BackgroundUp to 15% of all patients with brain metastases have no clearly detected primary site despite intensive evaluation, and this incidence has decreased with the use of improved imaging technology. Radiosurgery has been evaluated as one of the treatment modality for patients with limited brain metastases. In this study, we evaluated the effectiveness of radiosurgery for brain metastases from unknown primary tumors.MethodsWe retrospectively evaluated 540 patients who underwent gamma knife radiosurgery (GKRS) for brain metastases radiologically diagnosed between August 1992 and September 2007 in our institution. First, the brain metastases were grouped into metachronous, synchronous, and precocious presentations according to the timing of diagnosis of the brain metastases. Then, synchronous and precocious brain metastases were further grouped into 1) unknown primary; 2) delayed known primary; and 3) synchronous metastases according to the timing of diagnosis of the primary origin. We analyzed the survival time and time to new brain metastasis in each group.ResultsOf the 540 patients, 29 (5.4%) presented precocious or synchronous metastases (34 GKRS procedures for 174 lesions). The primary tumor was not found even after intensive and repeated systemic evaluation in 10 patients (unknown primary, 34.5%); found after 8 months in 3 patients (delayed known primary, 1.2%); and diagnosed at the same time as the brain metastases in 16 patients (synchronous metastasis, 55.2%). No statistically significant differences in survival time and time to new brain metastasis were found among the three groups.ConclusionIdentification of a primary tumor before GKRS did not affect the patient outcomes. If other possible differential diagnoses were completely excluded, early GKRS can be an effective treatment option for brain metastases from unknown primary tumor.

Integrating bevacizumab and radiation treatment of brain metastasis: is there sense and sensibility in this approach?

The incidence of brain metastasis has increased over the past decade. Standard treatment options for brain metastases include whole brain radiation therapy (WBRT), stereotactic radiosurgery (SRS) and surgery for patients with operable lesions and either mass effect or need for histologic confirmation of the diagnosis. Patients are living longer due to improvements in systemic therapeutic approaches, included targeted therapies such as inhibition of vascular endothelial growth factor (VEGF) using the monoclonal antibody bevacizumab (Bev). A recent phase I trial (REBECA) investigated adding Bev to whole-brain radiation for patients with brain metastasis from solid tumors. In this Perspectives article, we discuss the results of the REBECA trial in context of advancements in radiation and medical oncology in the era of targeted therapies, and discuss pertinent questions of interest in this field.

Intraoperative real-time MRI-guided stereotactic biopsy followed by laser thermal ablation for progressive brain metastases after radiosurgery

Stereotactic radiosurgery is one of the treatment options for brain metastases. However, there are patients who will progress after radiosurgery. One of the potential treatments for this subset of patients is laser ablation. Image-guided stereotactic biopsy is important to determine the histopathological nature of the lesion. However, this is usually based on preoperative, static images, which may affect the target accuracy during the actual procedure as a result of brain shift. We therefore performed real-time intraoperative MRI-guided stereotactic aspiration and biopsies on two patients with symptomatic, progressive lesions after radiosurgery followed immediately by laser ablation. The patients tolerated the procedure well with no new neurologic deficits. Intraoperative MRI-guided stereotactic biopsy followed by laser ablation is safe and accurate, providing real-time updates and feedback during the procedure.

BMET-23ANG1005, A NOVEL BRAIN-PENETRANT PEPTIDE-TAXANE CONJUGATE, FOR THE TREATMENT OF CNS METASTASES FROM BREAST CANCER

BACKGROUND: Treatment options for brain metastases are limited due to the inability of most anti-cancer agents to cross the blood brain barrier (BBB). ANG1005 is a novel peptide-taxane conjugate, being developed for targeted treatment of brain metastases. It consists of 3 paclitaxel molecules covalently linked to Angiopep-2 designed to cross the BBB and to penetrate malignant cells via the LDL receptor related protein-1 (LRP-1) transport system. METHODS: Adult patients with measurable recurrent brain metastases from breast cancer with, or without, leptomeningeal disease are being enrolled in this multi-center, open-label study, for up to 56 patients. ANG1005 is administered IV at 600 mg/m2 q21d (one cycle). HER2+ patients are allowed to continue HER2 targeted therapies. The primary endpoint is intracranial objective response rate, as per CNS RECIST v.1.1. An imaging sub-study, comparing 18F-FLT-PET to MRI, is also ongoing in 10 patients with brain metastases from breast cancer. RESULTS: Accrual is ongoing and to date, 48 patients have been treated with a range of 1-18 cycles of ANG1005. Median age is 47 years (range: 26-65). Safety profile has been similar to paclitaxel with myelosuppression as the predominating toxicity. Based on data from patients evaluated to date for intracranial response, 6/30 (20%) patients had a partial response (PR) and 17/30 (57%) had a stable disease (SD). Among patients with leptomeningeal disease, 4/11 (36%) had a PR. The longest duration on treatment is for 18 cycles, seen in a patient with a PR that sustained for 10 cycles. Furthermore, ANG1005 treatment resulted in disease control in extracranial lesions in all 14 evaluated patients (1 PR and 13 SD), even after prior taxane therapy. CONCLUSIONS: The efficacy and safety data to date suggest that ANG1005 is a promising therapy for treatment of brain and leptomeningeal metastases from breast cancer.

The future of targeted therapies for brain metastases.

Brain metastases (BM) are an increasing challenge in the management of patients with advanced cancer. Treatment options for BM are limited and mainly focus on the application of local therapies. Systemic therapies including targeted therapies are only poorly investigated, as patients with BM were frequently excluded from clinical trials. Several targeted therapies have shown promising activity in patients with BM. In the present review we discuss existing and emerging targeted therapies for the most frequent BM primary tumor types. We focus on challenges in the conduction of clinical trials on targeted therapies in BM patients such as patient selection, combination with radiotherapy, the obstacles of the blood-brain barrier and the definition of study end points.

Abstract LB-096: Blood-brain barrier-penetrating terpolymer nanoparticles deliver docetaxel and trastuzumab to brain metastases of breast cancer

Abstract Background: Brain metastases occur in up to one third of all metastatic breast cancer patients, with high prevalence and earlier development in triple-negative and HER2-positive breast cancers. Treatment options for brain metastases are severely limited due to the inability of many therapeutic agents, including docetaxel (DTX), a small molecule hydrophobic drug, and trastuzumab (TRA), a macromolecular antibody, to cross the blood-brain barrier (BBB) at adequate levels. Here we developed multifunctional BBB-penetrating terpolymer-lipid nanoparticles (TPN) for delivering DTX and TRA to brain metastases of breast cancer, and evaluated their tumor accumulation and efficacy in multiple lesion brain metastases mouse models. Methods: Fluorescence-labeled TPN were prepared by microemulsion using poly(methacrylic acid) and polysorbate 80-grafted starch loaded with either DTX (DTX-TPN) or TRA (TRA-TPN). In vitro cytotoxicity of the formulations was evaluated by the MTT assay. Brain metastases of triple negative MDA-MB-231-luc-D3H2LN or HER2 positive BT474 human breast cancer were established in SCID mice by stereotactic intracranial inoculation of the cells into the cortex. The biodistribution and tumor accumulation of the NPs were examined by whole body fluorescence imaging at various times after tail vein injection. The NP distribution within the brain tumor microenvironment was detected ex vivo using laser scanning confocal microscopy. The efficacy of DTX-TPN against brain metastases was assessed by measuring bioluminescence intensity weekly following administration of 2×20 mg/kg DTX-TPN or Taxotere. Results: In vitro DTX-TPN exhibited greater cytotoxicity against MDA-MB-231 cells compared to free DTX (IC50 = 40 vs. 63 nM), while TRA-TPN decreased the IC50 by 4.5-fold (IC50 = 0.6 vs. 2.7 μg/mL) in the inhibition of BT474 cells compared to free TRA. In vivo TPN was able to transport DTX and TRA across the BBB to brain metastasis lesions. The TPNs were observed to extravasate the brain microvessels and accumulate within the perivascular tissue throughout the tumor core and periphery. DTX-TPN increased the median mouse survival time by 2-fold (Saline group: 20 ± 3 days; free Taxotore: 18 ± 4 days; DTX-TPN: 36 ± 3 days) and delayed tumor growth by 9.8-fold (58% vs. 5.9%) as compared to clinically used Taxotere in mice with brain metastasis of triple negative breast cancer. No change in tissue morphology was observed in the liver, lungs, heart and kidneys of mice treated with DTX-TPN compared to the saline control group. Conclusions: These results demonstrate that TPNs are a promising BBB-penetrating carrier for the delivery of small molecule therapeutic agents or antibodies to the brain and for the treatment of brain metastases of breast cancer. Citation Format: Chanson(Chunsheng) He, Ping Cai, Jason Li, Jeffrey T. Henderson, Andrew M. Rauth, Xiao Yu Wu. Blood-brain barrier-penetrating terpolymer nanoparticles deliver docetaxel and trastuzumab to brain metastases of breast cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-096. doi:10.1158/1538-7445.AM2015-LB-096

Linear accelerator-based stereotactic radiosurgery in 140 brain metastases from malignant melanoma.

BackgroundTo retrospectively access outcome and prognostic parameters of linear accelerator-based stereotactic radiosurgery in brain metastases from malignant melanoma.MethodsBetween 1990 and 2011 140 brain metastases in 84 patients with malignant melanoma (median age 56 years) were treated with stereotactic radiosurgery. At initial stereotactic radiosurgery 48 % of patients showed extracerebral control. The median count of brain metastases in a single patient was 1, the median diameter was 12 mm. The median dose applied was 20 Gy/80 % isodose enclosing.ResultsThe median follow-up was 7 months and the median overall survival 9 months. The 6-, 12- and 24 month overall survival rates were 71 %, 39 % and 25 % respectively. Cerebral follow-up imaging showed complete remission in 20 brain metastases, partial remission in 39 brain metastases, stable disease in 54 brain metastases, progressive disease in 24 brain metastases and pseudo-progression in 3 brain metastases. Median intracerebral control was 5.3 months and the 6- and 12-month intracerebral progression-free survival rates 48 % and 38 %, respectively. Upon univariate analysis, extracerebral control (log-rank, p < 0.001), the response to stereotactic radiosurgery (log-rank, p < 0.001), the number of brain metastases (log-rank, p = 0.007), the recursive partitioning analysis class (log-rank, p = 0.027) and the diagnosis-specific graded prognostic assessment score (log-rank, p = 0.011) were prognostic for overall survival. The most common clinical side effect was headache common toxicity criteria grade I. The most common radiological finding during follow-up was localized edema within the stereotactic radiosurgery high dose region.ConclusionStereotactic radiosurgery is a well-tolerated and effective treatment option for brain metastases in malignant melanoma and was able to achieve local remissions in several cases. Furthermore, especially patients with controlled extracerebral disease and a low count of brain metastases seem to benefit from this treatment modality. Prospective trials analysing the effects of combined stereotactic radiosurgery and new systemic agents are warranted.