Brain Metastases – Clinical Challenges and Recent Advances

Imaging and clinical end points in brain metastases trials.

Brain metastasis, characterized by poor clinical outcomes, is a devastating disease. Despite significant mechanistic and therapeutic advances in recent years, pivotal improvements in clinical interventions have remained elusive. The heterogeneous nature of the primary tumor of origin, complications in drug delivery across the blood-brain barrier, and the distinct microenvironment collectively pose formidable clinical challenges in developing new treatments for patients with brain metastasis. Although current preclinical models have deepened our basic understanding of the disease, much of the existing research on brain metastasis has employed a reductionist approach. This approach, which often relies on either in vitro systems or in vivo injection models in young and treatment-naive mouse models, does not give sufficient consideration to the clinical context. Given the translational importance of brain metastasis research, we advocate for the design of preclinical experimental models that take into account these unique clinical challenges and align more closely with current clinical practices. We anticipate that aligning and simulating real-world patient conditions will facilitate the development of more translatable treatment regimens. This brief review outlines the most pressing clinical challenges, the current state of research in addressing them, and offers perspectives on innovative metastasis models and tools aimed at identifying novel strategies for more effective management of clinical brain metastasis.

BRAF is a key molecule activated by RAS in the MAPK pathway that mainly controls cell proliferation. BRAF mutation is detected in about 8% of all cancer population, and more than 50% is BRAFv600e, which causes constitutive MAPK activation. BRAFv600 mutation is found in various cancers such as melanoma, colorectal cancer, glioma, lung cancer, thyroid cancer, pancreatic cancer, ovary cancer etc. ABM-1310 is a novel small molecule BRAF inhibitor that specific inhibits BRAFv600 mutant form with high water solubility, cell permeability, and blood brain barrier (BBB) penetration. Although current target or immune-therapies are reported with some variable effects, melanoma with brain metastasis is still a significant challenge in clinic. With high BBB penetration and high exposure in brain, ABM-1310 has good potential to treat tumors bearing BRAFv600 mutation with brain metastasis. In-vitro data shown similar on-target enzyme activity of ABM-1310 to marketed BRAF inhibitors on BRAFv600e, as well as high anti-proliferation activity in multiple cancer cell lines with BRAF V600E mutation like A375, Colo-829, and HT-29 etc. In vivo pharmacology studies demonstrated that ABM-1310 had good potency of tumor growth inhibition with oral dose as low as 1mg/kg/day. ABM-1310 treatment also improved animal overall survival in several cell-line derived xenograft (CDX) models, including subcutaneous, intracranial and intracardiac melanoma models. Non-clinical pharmacokinetics studies also shown ABM-1310 had a favorable ADME profile both in vitro and in vivo in animals. ABM-1310 demonstrated excellent brain penetration in animals. Single-dose, seven-day repeat dose non-GLP studies and four-week GLP toxicity studies in SD rats and beagle dogs all revealed that ABM-1310 had a good safety profile with NOAEL of 100mg/kg/day in SD rats and 30mg/kg/day in beagle dogs. Based on these supportive preclinical study results, IND of ABM-1310 was submitted in 2019 Q4 to investigate its safety in humans as signal reagent, which will be followed by further clinic development of ABM-1310, or combination with other molecules to treat cancers with BRAFv600 mutation, especially with brain metastasis. Citation Format: Yong Hu, Chen Chen, Charles Huang, Min Xu, Youqin Chen, Xiyuan Chen, Li Zhao. Preclinical development of ABM-1310, a novel BRAF Inhibitor to treat cancer with brain metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4177.

Background: The incidence of brain metastases (BM) in breast cancer patients is rising and has become a major clinical challenge. So far, limited therapeutic options and insights into the biology of BM exist since only a few studies analyzed exclusively data of breast cancer patients. In order to improve this situation, our multicenter registry was initiated in 2014: Brain Metastases in Breast Cancer Network Germany (BMBC, GBG79). Materials and Methods: Patients with BM diagnosed since 2000, a history of breast cancer and no history of other malignant or neurologic disease can be included. Registration is allowed retrospectively as well as prospectively into a web–based database ("MedCodes"). Characteristics of the primary tumor, metastatic disease and BM as well as treatment details are documented. For this first analysis, 548 patients from 39 German centers were included. Results: Median age at first diagnosis of BM was 55 years (25 – 90 years). 43% of patients (233/548) were HER2 positive, 19% (n=105) were triple–negative and 25% (n= 138) had luminal primary tumors indicating a selection of patients with specific tumor biology who develop BM. 54 % of the patients (n=267) had up to three BM whereas 45% (n=223) had more than three BM. 19% of patients (n=106) had BM without evidence of extracranial disease. 27% of the patients (n=146) underwent surgery of the BM. Of these patients, 61% (n= 89) were treated with whole brain radiotherapy and 16% (n=23) with stereotactic radiotherapy. In patients without surgery (n=397), 73% (n=289) received whole brain radiotherapy and 7% (n=28) stereotactic radiotherapy. Median time from diagnosis of primary breast cancer to BM was 38.5 month for the entire cohort (CI95% 35.4 – 43.3). The time from first diagnosis to BM was shorter for triple–negative patients (20.9 month, CI95% 15.5 – 25.9) compared with patients with HER2–positive (37.0 month, CI95% 30.5 – 42.0) or luminal tumors (48.3 month, CI95% 38.2 – 54.0) (p<0.001). Median time from first diagnosis of BM to death in the entire cohort was 6.1 months (CI95%: 5.2 – 7.3). One year survival rate from diagnosis of BM was 32.2 % (CI95%: 2.2 – 67.8). Regarding tumor subtypes, HER2–positive patients had the longest median survival with 9.4 months (CI95%: 7.1 – 13.4) compared with 6 months (CI95%: 4.0 – 7.3) for luminal primary tumors and 3.2 months (CI95%: 2.1 – 4.6) for triple–negative patients (p<0.001). HER2 positive patients receiving HER2–directed therapy after the diagnosis of BM lived longer than those without (median 9.6 vs. 5.5 months, p=0.029). Regarding the number of BM, no difference in survival was observed between one, two or three BM (median survival of 7.8 months). However, survival was shorter in those patients with more than three BM (5.2 months; p=0.007). Conclusion: This is so far the largest analysis of breast cancer patients with BM treated in Germany. In this cohort, triple–negative subtype or more than three BM were associated with shorter survival from the diagnosis of BM. HER2 positive patients with no HER2 directed therapy after the diagnosis of BM showed a shorter survival. The recruitment of the registry is ongoing and we aim to include more than 1000 patients by the end of 2015. Citation Format: Witzel I, Loibl S, Laakmann E, Augustin D, Flock F, Dohmen H-H, Durmus G, Frank M, Hesse T, Ignatov A, Kühn T, Neunhöffer T, Park-Simon T-W, Schmidt M, Stefek A, Weide R, Würschmidt F, Fehm T, Moebus V, von Minckwitz G, Burchardi N, Mueller V. Brain metastases in breast cancer network Germany (BMBC, GBG 79): First analysis of 548 patients from the multicenter registry. [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 P6-17-08.

1305P - Factors Predicting Brain Metastases in Patients with Non-Small Cell Lung Cancer

Progress of immune checkpoint inhibitors therapy for non-small cell lung cancer with brain metastases

Immunotherapy targeting immune check-point(s) in brain metastases

Gamma knife treatment is a clinically effective, safe, and cost-effective adjunctive therapy for primary malignant brain tumors. For most brain metastases, radiosurgery is the treatment of choice and will result in effective tumor control in more than 90% of treated tumors.

18051 Background: Lung cancer remains the leading cause of cancer mortality in both women and men in the United States. Despite recent advances in treatments, many patients with stage II and III non-small cell lung cancer (NSCLC) die of recurrent disease. Methods: A retrospective review was conducted to determine the incidence of brain metastasis as first site of relapse as well as other patterns of failure in patients with stage II and III NSCLC. From 1995 to 2003, 239 patients were identified from Minneapolis Veterans Affairs Medical Center tumor registry. Data was collected on the following variables to identify prognostic factors for brain metastasis and others patterns of failure: patient’s age, tumor histology, tumor size, nodal status, use of adjuvant chemotherapy, and type of adjuvant chemotherapy. Results: Of the 239 patients, only 12 (5%) had brain metastasis as first site of relapse. Median survival for patients with brain metastasis was 0.9 year (95% CI, 0.75–1.50). Out of 12 patients, 8 (67%) developed brain metastasis between 6 and 12 months after the initial diagnosis, 3 (25%) developed brain metastasis between 12 and 18 months and 1 (8%) developed brain metastasis as first site of relapse more than 18 months after initial diagnosis. Other patterns of failure were as follows: Thorax 36%, primary site 22%, primary + thorax 14% and distant metastasis 32%. Among 88 patients who underwent surgery as a part of definitive therapy, thorax was again the most common site of relapse (23%). Multivariate analysis showed that use of non-platinum based chemotherapy is a significant risk factor for relapse (p=0.02). Conclusion: Brain metastasis as first site of relapse is uncommon in patients with stage II and III NSCLC. Due to very low incidence of brain metastasis in this cohort of patients, prophylactic cranial radiation (which is the focus of few ongoing clinical trials) may cause more harm than good. No significant financial relationships to disclose.

IntroductionBrain metastases are the most common brain neoplasms observed clinically in adults, comprising more than half of all brain tumors. Brain metastases have been historically understudied, and they represent an emerging and urgent unmet medical need. The major impediment to effectively treating brain metastatic disease is the blood-brain barrier (BBB). This barrier excludes most chemotherapeutics from the brain and creates a sanctuary site for metastatic cancers. Recent studies have provided some evidence that astrocytes play a major role in brain metastasis by engaging different modes of interactions with incoming cancer cells. By contrast, little is known concerning the underlying mechanisms of brain metastasis formation, especially the role of pericytes. In this review, we discuss the recent advances in our understanding of the biology of pericytes, especially regarding its role in brain metastasis.MethodsLiterature review.ResultsThe primary function of pericytes is stabilizing the function of the BBB. By contrast, cancer cells can activate pericytes to participate in pathological angiogenesis and thus promote brain metastasis progression. It is important to understand both the stimulatory and inhibitory effects of pericytes on cells to reveal the mechanism of brain metastasis.ConclusionsBased on the findings of this review, pericytes could represent a key cellular target for the treatment and prevention of brain metastasis. These data provided new insights into the biology of pericytes and their potential roles in the pathogenesis of brain metastasis. These findings should spur additional studies to better clarify the mechanisms by which pericytes promote brain metastasis and stimulate the development of treatment strategies targeting these cells.

Background: Recent advances in chemotherapy have enabled to control the progression of metastases from breast cancer except for the brain, highlighting the symptoms associated with brain metastases. In addition, improvement in our understanding of breast cancer biology changed the treatment strategy, possibly leading to improved outcomes in patients with breast cancer and brain metastases. Object: The aim of this study was to investigate the correlation between biology of primary tumors and prognosis of patients with breast cancer metastasis to the brain. Patients and method: Among 3,171 patients with primary breast cancer undergoing surgery at out hospital from 2003 to 2010, 35 patients (1.1%) who developed brain metastases, excluding stage IV at the initial diagnosis. We reviewed 35 patients for a correlation between survival and clinicopathological variables, including stage, hormonal sensitivity, HER2 expression status, the number of brain metastases, and treatment for brain metastases. Results: The mean age of 35 patients was 52.1 years (range 22–68) and the median follow-up period was 41.0 months. The subtypes of primary tumors included triple-negative (TN) in 14 patients (40%), luminal in 11 patients (31.4%), luminal HER2-positive (luminal HER2) in 2 patients (5.7%), and HER2-positive (HER2) in 2 patients (5.7%). The duration from surgery to recurrence (disease-free survival, DFS, months) was 14.7 in TN, 26.5 in luminal, 29.8 in luminal HER2, and 31.0 in HER2. The duration from the first recurrence to the detection of brain metastases (months) was 7.2 in TN, 14.4 in luminal, 15.8 in luminal HER2, and 4.0 in HER2. The mean survival time after the diagnosis of brain metastases was 8.6 months (range, 0–40) with a survival time of ³ 1 year in 8/35 patients (23%) and that of < 1 year in 21/35 patients (60%). Both DFS and the duration from the first recurrence to the diagnosis of brain metastases were shorter in TN compared with other subtypes. In HER2 subtype, DFS was long but, once recurrence was detected, the duration to the development of brain metastases was short. In multivariate analysis of clinicopathological variables (age, DFS, ER, HG, HER2, the number of brain metastases (solitary versus multiple), the site of initial metastasis (brain versus other organs), and the presence or absence of chemotherapy after brain metastases, revealed solitary brain metastasis (p = 0.002) and the initial metastatic site of brain (p = 0.003) to be independent factors predicting survival. Conclusion: The clinical outcomes of brain metastases were different among tumor subtypes. Factors predicting survival in patients with breast cancer and brain metastases may be the site of initial metastasis, the number of brain metastasis, and local treatment for brain metastases. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-12-06.

Brain metastases (BM), which most commonly originate from lung, breast, or skin cancers, remain a major clinical challenge, with standard treatments such as stereotactic radiosurgery (SRS), surgical resection, and whole-brain radiation therapy (WBRT). The prognosis for patients with BM remains poor, with a median overall survival (OS) of just 10–16 months. Although recent advances in systemic therapies, including small molecule inhibitors, monoclonal antibodies, chemotherapeutics, and gene therapies, have demonstrated success in other malignancies, their effectiveness in central nervous system (CNS) cancers is significantly limited by poor blood–brain barrier (BBB) permeability and subtherapeutic drug concentrations in the brain. Nanoparticle-based drug delivery systems have emerged as a promising strategy to overcome these limitations by enhancing CNS drug penetration and selectively targeting metastatic brain tumor cells while minimizing off-target effects. This review summarizes recent preclinical and clinical developments in nanoparticle-based therapies for BM. It is evident from these studies that NPs can carry with them a range of therapeutics, including chemotherapy, immunotherapy, small molecule inhibitors, gene therapies, radiosensitizers, and modulators of tumor microenvironment to the BM. Moreover, preclinical studies have shown encouraging efficacy in murine models, highlighting the potential of these platforms to improve therapeutic outcomes. However, clinical translation remains limited, with few ongoing trials. To close this translational gap, future work must address clinical challenges such as trial design, regulatory hurdles, and variability in BBB permeability while developing personalized nanoparticle-based therapies tailored to individual tumor characteristics.

Approximately 40% of unselected non-small cell lung cancer (NSCLC) patients develop brain metastases (BMs) during their disease, with considerable morbidity and mortality. The management of BMs in patients with NSCLC is a clinical challenge and requires a multidisciplinary approach to gain effective intracranial disease control. Over the last decade, immune checkpoint inhibitors (ICIs) have emerged as a game-changer in the treatment landscape of advanced NSCLC, with significant improvements in survival outcomes, although patients with BMs are mostly underrepresented in randomized clinical trials. Moreover, the safety and activity of ICIs and radiotherapy combinations compared with single-agent or sequential modalities is still under evaluation to establish the optimal management of these patients. The aim of this review is to summarize the state-of-the-art of clinical evidence of ICIs intracranial activity and the main challenges of incorporating these agents in the treatment armamentarium of NSCLC patients with BMs.

Brain metastases represent a significant clinical challenge in the treatment of non-small-cell lung cancer (NSCLC), often leading to a severe decline in patient prognosis and survival. Recent advances in imaging and systemic treatments have increased the detection rates of brain metastases, yet clinical outcomes remain dismal due to the complexity of the metastatic tumor microenvironment (TME) and the lack of specific biomarkers for early detection and targeted therapy. The intricate interplay between NSCLC tumor cells and the surrounding TME in brain metastases is pivotal, influencing tumor progression, immune evasion, and response to therapy. This underscores the necessity for a deeper understanding of the molecular underpinnings of brain metastases, tumor microenvironment, and the identification of actionable biomarkers that can inform multimodal treatment approaches. The goal of this review is to synthesize current insights into the TME and elucidate molecular mechanisms in NSCLC brain metastases. Furthermore, we will explore the promising horizon of emerging biomarkers, both tissue- and liquid-based, that hold the potential to radically transform the treatment strategies and the enhancement of patient outcomes.

Brain metastases continue to be a major and growing challenge in oncology, but recent advances in surgery, radiosurgery, and chemotherapy have broadened the number of treatment options. Current approaches to the management of brain metastases focus on individualizing patient care based on factors including the Karnofsky Performance Status, the tumor histology, the number of metastases, and the status of the systemic disease. A number of treatment approaches have been shown to be effective for brain metastases, including surgery; radiosurgery; whole-brain radiotherapy; and, more recently, chemotherapy. The use of adjuvant whole-brain radiotherapy with local therapies, such as surgery or radiosurgery, along with newer chemotherapy options, such as targeted biological agents, temozolomide, and implantable 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) Gliadel wafers, are at the forefront of recent advances in the treatment of patients with brain metastases that may provide longer survival and improved quality of life. Although there is no current standard treatment, some general guidelines are recommended for single metastases, oligometastases (two to three brain metastases), and multiple (four or more) brain metastases, and for new or recurrent disease. With advances in systemic therapy for cancer, the treatment of brain metastases is becoming an increasingly important determinant of the length of survival and quality of life for cancer patients.