Biology of brain metastases and novel targeted therapies: Time to translate the research

Brain metastases (BM) occur in 20% to 40% of patients with cancer and result in significant morbidity and poor survival. The main therapeutic options include surgery, whole brain radiotherapy, stereotactic radiosurgery and chemotherapy. Although significant progress has been made in diagnostic and therapeutic methods, the prognosis in these patients remains poor. Furthermore, the poor penetrability of chemotherapy agents through the blood brain barrier (BBB) continues to pose a challenge in the management of this disease. Preclinical evidence suggests that new targeted treatments can improve local tumor control but our clinical experience with these agents remains limited. In addition, several clinical studies with these novel agents have produced disappointing results. This review will examine the knowledge of targeted therapies in BM. The preclinical and clinical evidence of their use in BM induced by breast cancer, non-small cell lung cancer and melanoma will be presented. In addition, we will discuss the role of antiangiogenic and radiosensitising agents in the treatment of BM and the current strategies available to increase BBB permeability. A better understanding of the mechanism of action of these agents will help us to identify the best targets for testing in future clinical studies.     

The role of cancer stem cells and miRNAs in defining the complexities of brain metastasis

Researchers and clinicians have been challenged with the development of therapies for the treatment of cancer patients whose tumors metastasized to the brain. Among the most lethal weapons known today, current management of brain metastases involves multiple therapeutic modalities that provide little, if any, for improving the quality of life and overall survival. Recently the role of cancer stem cells (CSCs) in the development of cancer has been studied extensively, and thus its role in the prognosis, diagnosis, and treatment is now being investigated even in the realm of brain metastasis (BM). Recognizing the molecular make‐up of CSCs as well as understanding the role of these cells in resistance to treatment modalities is expected to benefit cancer patients. Additionally, past decade has witnessed an increase in awareness and understanding of the role of microRNAs (miRNAs) in various cancer types, and the deregulation miRNAs are critically important for the regulation of genes during the development and progression of human malignancies. The role miRNAs in BM is being investigated, and has also shown tremendous promise for future research. In this review, we discuss the problem and lethality of brain metastases and the current state of management, and further provide insight into novel avenues that are worth considering including the biological complexities of CSCs and miRNAs for designing novel therapies. J. Cell. Physiol. 228: 36–42, 2013. © 2012 Wiley Periodicals, Inc.     

Prostate‐specific membrane antigen expression in the vasculature of primary lung carcinomas associates with faster metastatic dissemination to the brain

Glioblastomas and brain metastases (BM) of solid tumours are the most common central nervous system neoplasms associated with very unfavourable prognosis. In this study, we report the association of prostate‐specific membrane antigen (PSMA) with various clinical parameters in a large cohort of primary and secondary brain tumours. A tissue microarray containing 371 cases of ascending grades of gliomas pertaining to astrocytic origin and samples of 52 cases of primary lung carcinomas with matching BM with follow‐up time accounting to 10.4 years was evaluated for PSMA expression using immunohistochemistry. In addition, PSMA expression was studied in BM arising from melanomas and breast carcinomas. Neovascular expression of PSMA was evident alongside with high expression in the proliferating microvasculature of glioblastomas when compared to the tumour cell expression. This result correlated with the results obtained from the in silico (cancer genome databases) analyses. In gliomas, only the vascular expression of PSMA associated with poor overall survival but not the tumour cell expression. In the matched primary lung cancers and their BM (n = 52), vascular PSMA expression in primary tumours associated with significantly accelerated metastatic dissemination to the brain with a tendency towards poor overall survival. Taken together, we report that the vascular expression of PSMA in the primary and secondary brain tumours globally associates with the malignant progression and poor outcome of the patients.     

Therapeutic potency of oncolytic virotherapy–induced cancer stem cells targeting in brain tumors,current status,and perspectives

Brain tumors are the most common form of solid tumors in children and is presently a serious therapeutic challenge worldwide. Traditional treatment with chemotherapy and radiotherapy was shown to be unsuccessful in targeting brain tumor cancer stem cells (CSCs), leading to recurrent, treatment-resistant secondary malignancies. Oncolytic virotherapy (OV) is an effective antitumor therapeutic strategy which offers a novel, targeted approach for eradicating pediatric brain tumor CSCs by utilizing mechanisms of cell killing that differ from conventional therapies. A number of studies and some clinical trials have therefore investigated the effects of combined therapy of radiations or chemotherapies with oncolytic viruses which provide new insights regarding the effectiveness and improvement of treatment responses for brain cancer patients. This review summarizes the current knowledge of the therapeutic potency of OVs-induced CSCs targeting in the treatment of brain tumors for a better understanding and hence a better management of this disease.     

Bone Metastasis: Current State of Play

Bone metastasis (BM) in cancer remains a critical issue because of its associated clinical and biological complications. Moreover, BM can alter the quality of life and survival rate of cancer patients. Growing evidence suggests that bones are a fertile ground for the development of metastasis through a “vicious circle” of bone resorption/formation and tumor growth. This review aims to outline the current major issues in the diagnosis and management of BM in the most common types of osteotropic cancers and describe the mechanisms and effects of BM. First, we discuss the incidence of BM through the following questions: Are we witnessing an increase in incidence, and are we now better equipped with modern imaging techniques? Is the advent of efficient bone resorption inhibitors affecting the bigger picture of BM management? Second, we discuss the potential effects of cancer progression and well-prescribed drugs, such as multitarget tyrosine kinase inhibitors, inhibitors of the mammalian target of rapamycin, and immune checkpoint inhibitors, on BM. Finally, we examine the duality of the effects of some therapies that may help in cancer treatment but may also contribute to further BM.     

Stereotactic radiosurgery for patients with breast cancer brain oligometastases — molecular subtypes and clinical outcomes

BackgroundWe sought to determine the clinical outcomes of patients with breast cancer (BC) who had undergone stereotactic radiosurgery (SRS) for a limited number of brain metastases (BM) and to identify factors influencing overall survival (OS) and local control.Materials and methodsThe records of 45 patients who underwent SRS for 72 brain lesions were retrospectively evaluated. Statistics included the chi-squared test, Kaplan-Meier method, and the multivariate Cox model.ResultsThe median number of treated BM was 2 (range 1–10). Median OS from BM diagnosis and post-SRS were 27.6 [95% confidence interval (CI): 14.8–40.5) and 18.5 months (95% CI: 11.1–25.8), respectively. One-year and two-year survival rates after BM diagnosis were 55% and 41%, respectively. In a univariate analysis, the Luminal-B-human-epidermal-growth-receptor-positive (HER2+) subtype had the longest median OS at 39.1 months (95% CI: 34.1–44.1, p = 0.004). In an adjusted analysis, grade 2 [hazard ratio (HR): 0.1; 95% CI: 0.1–0.6, p = 0.005), craniotomy (HR: 0.3; 95% CI: 0.1–0.7; p = 0.006), and ≥ 2 systemic therapies received (HR: 0.3; 95% CI: 0.1–0.9, p = 0.028) were associated with improved OS. One-year and two-year intracranial progression-free survival rates were 85% and 63%, respectively. Four factors for a higher risk of any intracranial recurrence remained significant in the adjusted analysis, as follows: age < 50 years (HR: 4.2; 95% CI: 1.3–36.3; p = 0.014), grade 3 (HR: 3.7; 95% CI: 1.1–13.2; p = 0.038), HER2+ (HR: 6.9; 95% CI: 1.3–36.3; p = 0.023), and whether the brain was the first metastatic site (HR: 4.7; 95% CI: 1.6–14.5; p = 0.006).ConclusionIntrinsic BC characteristics are important determinants for both survival and intracranial control for patients undergoing SRS for oligometastatic brain disease.     

Treatment of high-grade glioma with radiolabeled peptides

The management of high-grade glioma (HGG) patients in clinical routine represents a challenging task. HGG has a poor prognosis because of early recurrence or therapy-refractory disease following first-line standard therapy, which includes a multidisciplinary approach involving radical surgical resection followed by external beam radiation therapy in combination with chemotherapy.Glioma cells are known to express specific receptors or glycoproteins on their surface which can be used as biological targets for treatment. The application of radiopharmaceuticals consisting of a targeting and an effector domain has led to the introduction of new treatment approaches, aiming at a tumor-specific treatment sparing normal brain tissue.One of these new modalities is the peptide receptor radionuclide therapy (PRRT). Peptides labeled with radioactive nuclides can bind directly to the tumor cells and deliver high doses of radioactivity directly to the tumor tissue.This article reviews the literature for PRRT in HGG.     

Role of whole brain radiotherapy in the management of infratentorial metastases from lung and breast cancer

BackgroundBrain metastases (BM) occur in almost one third of patients with systemic malignancies. Only a small number of studies focus on infratentorial location and whole brain radiotherapy (WBRT) as the main non-surgical management. The aim of the study was to compare the prognosis of patients treated with WBRT among patients with supra- or infratentorial lesions.Materials and methodsAt a single center, 263 patients with either breast (BC) or lung (LC) cancer, that had developed BM and received treatment with WBRT, were analyzed during an 8-year period.ResultsA total of 152 patients with BC and 111 with LC were analyzed, median age at the time of BM was 50.7 years, systemic activity other than BM was detected in 91%. Newly diagnosed BM were supratentorial in 40%, infratentorial in 10% and 51% in both locations. Median overall survival was 13 months (95% CI: 11.1–14.8 months), without significant difference between supra- or infratentorial location. WBRT alone was administered in 79% of patients, whereas WBRT with chemtoreapy was provided for 21%.ConclusionIn patients with BM from LC or BC that were not candidates for surgical resection, palliative WBRT appears to be equally effective in those with supra- or infratentorial locations.     

Impact of hospital volume on mortality for brain metastases treated with radiation

BackgroundThe impact of hospital volume on cancer patient survival has been demonstrated in the surgical literature, but sparsely for patients receiving radiation therapy (RT). This analysis addresses the impact of hospital volume on patients receiving RT for the most common central nervous system tumor: brain metastases.Materials and methodsAnalysis was conducted using the National Cancer Database (NCDB) from 2010–2015 for patients with metastatic brain disease from lung cancer, breast cancer, and colorectal cancer requiring RT. Hospital volume was stratified as high-volume (≥ 12 brain RT/year), moderate (5–11 RT/year), and low (< 5 RT/year). The effect of hospital volume on overall survival was assessed using a multivariable Cox regression model.ResultsA total of 18,841 patients [9479 (50.3%) men, 9362 (49.7%) women; median age 64 years] met the inclusion criteria. 16.7% were treated at high-volume hospitals, 36.5% at moderate-volume, and the remaining 46.8% at low-volume centers. Multivariable analysis revealed that mortality was significantly improved in high-volume centers (HR: 0.95, p = 0.039) compared with low-volume centers after accounting for multiple demographics including age, sex, race, insurance status, income, facility type, Charlson-Deyo score and receipt of palliative care.ConclusionHospitals performing 12 or more brain RT procedures per year have significantly improved survival in brain metastases patients receiving radiation as compared to lower volume hospitals. This finding, independent of additional demographics, indicates that the increased experience associated with increased volume may improve survival in this patient population.     

Heparanase mechanisms of melanoma metastasis to the brain: Development and use of a brain slice model

Heparanase (HPSE-1) is an endo-beta-D-glucuronidase that cleaves heparan sulfate (HS) chains of proteoglycans (HSPG), and its expression has been associated with increased cell growth, invasion, and angiogenesis of tumors as well as with embryogenesis and tissue development. Since metastatic cancer cells express HPSE-1, we have developed an orthotopic brain slice model to study HPSE-1 involvement in brain-metastatic melanoma. This model allows for the characterization of tumor cell invasion at both quantitative and qualitative levels. Brain-metastatic melanoma cells (B16B15b) showed augmenting levels of HPSE-1 protein expression in a time-dependent manner. Secondly, B16B15b cells pre-treated with HPSE-1 showed a significant increase in the number of cells that invaded into the brain tissue. Finally, HPSE-1 exposure-augmented invasion depth in brain sections by brain-metastatic melanoma cells. We concluded that applying this brain slice model can be beneficial to investigate HPSE-1- related in vivo modalities in brain-metastatic melanoma and brain invasion in general. These results also further emphasize the potential relevance of using this model to design therapies for controlling this type of cancer by blocking HPSE-1 functionality.     

Thymoma: a clinico pathological study of 21 cases and assessment of prognostic features

This is a retrospective and comprehensive study of 21 cases of thymoma treated during a period of 30 years (1954-1984). The tumors were staged into 3 categories: stage 1 for encapsulated completely resectable tumor, stage 2 for nonresectable intrathoracic tumor and stage 3 for tumor with extrathoracic spread. According to their lymphocytic content tumors were separated into 3 groups: 1) predominantly epithelioid (PE); 2) mixed cellular (MC) and predominantly lymphocytic (PL). Incidence of recurrence and survival were correlated with various treatment modalities. The tumor occurred in all age groups with highest incidence in the fourth decade. Six cases were asymptomatic. Myasthenia gravis was present only in one case. The most important prognostic factor was the stage of the tumor. Five-year survival was 69% for stage 2 and 0% for stage 3. All 12 patients who died with evidence of residual disease had PE tumors. Lymphocytic participation might be indicative of a residual functional competence and appears to confer a more favourable prognosis. This is a tumor of uncertain malignant potential which should be excised or debulked, and staged. Post-operative radiotherapy appears to prevent recurrence and improve the prognosis in stage 2. No therapeutic benefits were seen in the stage 3 cases. The value of chemotherapy is uncertain.     

Long-Term Outcomes and Prognostic Factors in Patients With Differentiated Thyroid Carcinoma and Bone Metastases

Objective: This institutional study sought to retrospectively evaluate disease progression and survival of patients with differentiated thyroid cancer (DTC) and bone metastases (BM) and to investigate variables predictive of better long-term outcomes.Methods: The Rabin Medical Center Thyroid Cancer Registry was searched for patients with bone-metastatic DTC. Variables including a patient's gender and age, pathology of the thyroid tumor, and characteristics of BM were retrieved and analyzed in association with disease progression and mortality.Results: The cohort included 64 patients (48.4% female). Mean age at diagnosis was 62.1 ± 14.3 years; mean primary tumor size was 41 ± 30 mm. Overall, 60.4% had stage T3/T4 disease; 46.3% had extrathyroidal extension; 40% had lymph-node metastases. Histopathology yielded papillary and follicular DTC in 40.6% and 32.8% of patients, respectively, and poorly/intermediately differentiated carcinoma in 26.6%. BM were synchronous in 50%. Mean follow-up was 11 ± 9.6 years from DTC detection. The common first sites of BM detection were spine (46.9% of patients), pelvis (37.5%) and ribs (21.9%). Nineteen patients (29.7%) presented with multiple-site BM, of whom 15 (78.9%) had spinal metastases. After initial treatment, 62/64 patients had structural persistence, and at last follow-up, 57.8% had progressive disease. Overall, 54.7% of patients died, 71.4% of DTC. Improved long-term outcomes were associated with younger age, lower tumor stage, no extrathyroidal extension, bone-only metastases, and non-spinal BM. Younger age and non-spinal BM were the only independent predictors for improved survival.Conclusions: Selected patients with bone-metastatic DTC may achieve fair long-term outcomes. Spinal metastases are associated with disseminated skeletal spread and increased mortality.Abbreviations: BM = bone metastases; COX = multivariate analyses; DM = distant metastases; DSM = disease-specific mortality; DSS = disease-specific survival; DTC = differentiated thyroid carcinoma; ETE = extrathyroidal extension; LNM = lymph node metastases; OM = overall mortality; OS = overall survival; PTCFV = papillary thyroid carcinoma; RAI = radioactive iodine; SM = spinal metastases; SRE = skeletal-related event; txWBS = whole-body scan after RAI therapy     

Control of the blood–brain barrier function in cancer cell metastasis

Cerebral metastases are the most common brain neoplasms seen clinically in the adults and comprise more than half of all brain tumours. Actual treatment options for brain metastases that include surgical resection, radiotherapy and chemotherapy are rarely curative, although palliative treatment improves survival and life quality of patients carrying brain‐metastatic tumours. Chemotherapy in particular has also shown limited or no activity in brain metastasis of most tumour types. Many chemotherapeutic agents used systemically do not cross the blood–brain barrier (BBB), whereas others may transiently weaken the BBB and allow extravasation of tumour cells from the circulation into the brain parenchyma. Increasing evidence points out that the interaction between the BBB and tumour cells plays a key role for implantation and growth of brain metastases in the central nervous system. The BBB, as the tightest endothelial barrier, prevents both early detection and treatment by creating a privileged microenvironment. Therefore, as observed in several in vivo studies, precise targetting the BBB by a specific transient opening of the structure making it permeable for therapeutic compounds, might potentially help to overcome this difficult clinical problem. Moreover, a better understanding of the molecular features of the BBB, its interrelation with metastatic tumour cells and the elucidation of cellular mechanisms responsible for establishing cerebral metastasis must be clearly outlined in order to promote treatment modalities that particularly involve chemotherapy. This in turn would substantially expand the survival and quality of life of patients with brain metastasis, and potentially increase the remission rate. Therefore, the focus of this review is to summarise the current knowledge on the role and function of the BBB in cancer metastasis.     

Detection of isolated tumor cells in peripheral blood and in BM: evaluation of a new enrichment method

Cell enrichment methods that deal with larger volumes of peripheral blood and BM are needed for increased sensitivity of detection, characterization and quantification of isolated tumor cells (ITC). This study was designed to evaluate a new procedure, the RosetteSep-Applied Imaging Rare Event (RARE) detection method, which depletes the majority of the erythrocytes and leucocytes in a peripheral blood (PB) sample, thereby negatively enriching tumor cells if present. This enrichment procedure allows for increased sensitivity, by analyzing a 5-10 fold larger volume of blood, compared with a direct immunocytochemical (ICC) technique, with minimal impact on laboratory workload. Model experiments showed comparable tumor cell recoveries between the two tested methods, both in PB and BM. Clinical samples were evaluated using paired PB and BM samples from 95 carcinoma patients. Analysis of PB results showed that 25.3% had > or = 1 tumor cell detected by the RARE procedure, compared with 5.2% after direct ICC analysis, analyzing a 10-fold larger volume by the RARE procedure. The direct ICC analysis of BM from the same patients revealed 16.8% positive. The ITC detection differed both quantitatively and qualitatively between BM and PB, as samples with high numbers of ITC in BM were still negative in PB. The clinical significance of ITC in blood still needs to be established. However, the easy access of peripheral blood, and the increased sensitivity obtained by increasing the sample volume with the RARE procedure, suggests that the value of peripheral blood analysis should be tested in parallel in studies where ITC detection in BM is performed.     

Communication between bone marrow mesenchymal stem cells and multiple myeloma cells: Impact on disease progression

Multiple myeloma (MM) is a hematological malignancy characterized by the accumulation of immunoglobulin-secreting clonal plasma cells at the bone marrow (BM). The interaction between MM cells and the BM microenvironment, and specifically BM mesenchymal stem cells (BM-MSCs), has a key role in the pathophysiology of this disease. Multiple data support the idea that BM-MSCs not only enhance the proliferation and survival of MM cells but are also involved in the resistance of MM cells to certain drugs, aiding the progression of this hematological tumor. The relation of MM cells with the resident BM-MSCs is a two-way interaction. MM modulate the behavior of BM-MSCs altering their expression profile, proliferation rate, osteogenic potential, and expression of senescence markers. In turn, modified BM-MSCs can produce a set of cytokines that would modulate the BM microenvironment to favor disease progression. The interaction between MM cells and BM-MSCs can be mediated by the secretion of a variety of soluble factors and extracellular vesicles carrying microRNAs, long non-coding RNAs or other molecules. However, the communication between these two types of cells could also involve a direct physical interaction through adhesion molecules or tunneling nanotubes. Thus, understanding the way this communication works and developing strategies to interfere in the process, would preclude the expansion of the MM cells and might offer alternative treatments for this incurable disease.     

Long-term survival results after treatment for oligometastatic brain disease

AimThe aim of this study was to characterize the survival results of patients with up to four brain metastases after intense local therapy (primary surgery or stereotactic radiotherapy) if extracranial metastases were absent or limited to one site, e.g. the lungs.BackgroundOligometastatic disease has repeatedly been reported to convey a favorable prognosis.Material and methodsThis retrospective study included 198 German and Norwegian patients treated with individualized approaches, always including brain radiotherapy. Information about age, extracranial spread, number of brain metastases, performance status and other variables was collected. Uni- and multivariate tests were performed.ResultsMedian survival was 16.5 months (single brain metastasis) and 9.8 months (2–4, comparable survival for 2, 3 and 4), respectively (p = 0.001). After 5 years, 15 and 2% of the patients were still alive. In patients alive after 2 years, added median survival was 23 months and the probability of being alive 5 years after treatment was 26%. In multivariate analysis, extracranial metastases were not significantly associated with survival, while primary tumor control was.ConclusionLong-term survival beyond 5 years is possible in a minority of patients with oligometastatic brain disease, in particular those with a single brain metastasis. The presence of extracranial metastases to one site should not be regarded a barrier towards maximum brain-directed therapy.     

Outcomes following stereotactic radiosurgery or whole brain radiation therapy by molecular subtype of metastatic breast cancer

BackgroundThis study quantified clinical outcomes by molecular subtype of metastatic breast cancer (BC) following whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS). Doing so is important for patient counseling and to assess the potential benefit of combining targeted therapy and brain radiotherapy for certain molecular subtypes in ongoing trials.Materials and methodsThe National Cancer Database was queried for BC (invasive ductal carcinoma) cases receiving brain radiotherapy (divided into WBRT and SRS ). Statistics included multivariable logistic regression to determine factors associated with SRS delivery, Kaplan-Meier analysis to evaluate overall survival (OS), and Cox proportional hazards modeling.ResultsOf 1,112 patients, 186 (16.7%) received SRS and 926 (83.3%) underwent WBRT. Altogether, 410 (36.9%), 195 (17.5%), 162 (14.6%), and 345 (31.0%) were ER+/HER2−, ER+/HER2+, ER−/HER2+, and ER−/HER2−, respectively. In the respective molecular subtypes, the proportion of subjects who underwent SRS was 13.4%, 19.4%, 24.1%, and 15.7%. Respective OS for WBRT patients were 12.9, 22.8, 10.6, and 5.8 months; corresponding figures for the SRS cohort were 28.3, 40.7, 15.0, and 12.9 months (p < 0.05 for both). When comparing OS between treatment different histologic subtypes, patients with ER−/HER2+ and ER−/HER2− disease had worse OS than patients with ER+/HER2− disease, for both patients treated with SRS and for patients treated with WBRT.ConclusionsMolecular subtype may be a useful prognostic marker to quantify survival following SRS/WBRT for metastatic BC. Patients with HER 2-enriched and triple-negative disease had the poorest survival following brain irradiation, lending credence to ongoing studies testing the addition of targeted therapies for these subtypes.     

The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer

Non-small cell lung cancer (NSCLC) often metastasizes to the brain, but identifying which patients will develop brain metastases (BM) is difficult. Macroautophagy/autophagy is critical for cancer initiation and progression. We hypothesized that genetic variants of autophagy-related genes may affect brain metastases (BM) in NSCLC patients. We genotyped 16 single nucleotide polymorphisms (SNPs) in 7 autophagy-related (ATG) genes (ATG3, ATG5, ATG7, ATG10, ATG12, ATG16L1, and MAP1LC3/LC3) by using DNA from blood samples of 323 NSCLC patients. Further, we evaluated the potential associations of these genes with subsequent BM development. Lung cancer cell lines stably transfected with ATG16L1: rs2241880 (T300A) were established. Mouse models of brain metastasis were developed using cells transfected with ATG16L1–300T or ATG16L1–300A. ATG10: rs10036653 and ATG16L1: rs2241880 were significantly associated with a decreased risk of BM (respective hazard ratios [HRs]=0.596, 95% confidence interval [CI] 0.398–0.894, P = 0.012; and HR = 0. 655, 95% CI 0.438–0.978, P = 0.039, respectively). ATG12: rs26532 was significantly associated with an increased risk of BM (HR=1.644, 95% CI 1.049–2.576, P = 0.030). Invasion and migration assays indicated that transfection with ATG16L1–300T (vs. 300A) stimulated the migration of A549 cells. An in vivo metastasis assay revealed that transfection with ATG16L1–300T (vs. 300A) significantly increased brain metastasis. Our results indicate that genetic variations in autophagy-related genes can predict BM and that genome analysis would facilitate stratification of patients for BM prevention trials.