Resection Of Brain Metastases Research Articles

Abstract P2-05-03: Whole genome transcriptome analysis of sequential breast to brain metastasis uncovers new signalling pathways and druggable targets

Abstract The occurrence of brain metastasis (BM) in breast cancer (BC) is currently on the rise across all molecular subtypes with 10-30% reported incidence. The need to uncover the mechanisms underlying this clinically devastating complication is apparent, and in the current study we sought to identify BC cell mediators of BM. In our cohort of metastatic patients (n=196) we found that BM developed in 13% of the cases. Despite the previous reports of negative ER status being a risk factor for BM, the ER+ve patients accounted for 42% of all diagnosed BM. To elucidate the gene alterations required for successful colonisation of the brain we undertook RNA sequencing (RNA-seq) of sequential breast to brain metastasis of known receptor status (n=7).This study presents the first whole transcriptome next-generation RNA-seq analysis of resected BM and their matching primary breast tumours. We identified 500 differentially expressed genes (DEGs) (< 0.05, fcThreshold >±1.5), accounting for those that were both upregulated and downregulated in BM compared to the primary. Analysis of protein-coding genes identified collective ER-specific metastatic pathways. Additionally, common functional pathways altered included ECM, cell adhesion and neuronal differentiation. Our analysis of the BM transcriptomic landscape and verification in cell line models that preferentially metastasise to the brain has unravelled a complex network of driver genes, cooperating with stromal derived factors, responsible for the organ-specific behaviour of the metastatic cells. Genes such as ANTRX1, THBS2, FAP, VCAN and TIMP2 were found to be part of the invasion and migration network that drives the extravasation of the BM cells. Furthermore, an EMT stemness signalling network driven by ANTRX1and WNT pathway driven RUNX was prominent in the cells acquiring the ability to migrate to the brain. Additional work is being carried out on uncovering the adaptations that re-activate the dormant brain metastatic cells and the contribution of the neuronal niche in the facilitating the colonisation by the MBC. This study highlights the requirement of unique gene sets for the invasion, migration and colonisation to the brain and that functional characterisation of the DEGs will enable the identification of novel molecular targets for prevention and treatment of breast cancer BM. Citation Format: Varešlija D, Fagan A, Buckley P, Farrell M, Hill A, Young L. Whole genome transcriptome analysis of sequential breast to brain metastasis uncovers new signalling pathways and druggable targets. [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 P2-05-03.

НЕДИФФЕРЕНЦИРОВАННАЯ ПЛЕОМОРФНАЯ САРКОМА СЕРДЦА: ВОЗМОЖНОСТИ СОВМЕЩЕННОЙ ПОЗИТРОННОЙ ЭМИССИОННОЙ И РЕНТГЕНОВСКОЙ КОМПЬЮТЕРНОЙ ТОМОГРАФИИ ДЛЯ ДИАГНОСТИКИ МЕСТНОГО РЕЦИДИВА ОПУХОЛИ И ОТДАЛЕННЫХ МЕТАСТАЗОВ (КЛИНИЧЕСКОЕ НАБЛЮДЕНИЕ)

The paper presents a case of a 52-year-old female patient with pleomorphic malignant fibrous histiocytoma/ undifferentiated pleomorphic sarcoma of the left atrium. One year after surgical resection of the primary tumor, microsurgical removal of the right parietal lobe metastatic tumor was performed. PET/CT with 11C-methionine and 18F-FDG performed 2 months after surgical resection of brain metastasis revealed local recurrence of sarcoma in the left atrium and left lateral ventricle metastases. This clinical case demonstrates high diagnostic accuracy of PET/CT with 18F-FDG and 11C-methionine in detecting local recurrence of cardiac undifferentiated sarcoma, however, PET/CT with 11C-methionine appears to be superior to PET/CT with18F-FDG in detecting brain metastasis.

全身転移を引き起こした甲状腺乳頭癌における脳転移摘出術の有効性

全身転移を引き起こした甲状腺乳頭癌における脳転移摘出術の有効性

Genetic variants associated with colorectal brain metastases susceptibility and survival.

Colorectal brain metastases (BM) are rare (1-2%) and a late-stage disease manifestation. Molecular mechanisms for BM development are not well understood. We tested whether variants within genes involved in overcoming the blood-brain barrier (BBB) are associated with BM susceptibility and survival in patients with BM. Germline single-nucleotide polymorphisms (SNPs, n=17) in seven genes (CXCR4, MMP9, ST6GALNAC5, ITGAV, ITGB1, ITGB3, KLF4) were analyzed from germline DNA in patients with resected BM (n=70) or no clinical evidence of BM after at least 24 months from diagnosis (control group, n=45). SNPs were evaluated for association with BM susceptibility and overall survival (OS) from BM diagnosis. ST6GALNAC5 rs17368584 and ITGB3 rs3809865 were significantly associated with BM susceptibility. In multivariable analysis adjusted for patient characteristics, KLF4 rs2236599, ITGAV rs10171481, ST6GALNAC5 rs1883778, CXCR4 rs2680880 and ITGB3 rs5918 were significant for OS. This study shows for the first time that variants within genes involved in breaching the BBB are associated with BM susceptibility and survival. These findings warrant further validation to develop better screening guidelines and to identify novel therapy targets for patients with BM.

Point/Counterpoint: Is stereotactic radiosurgery needed following resection of brain metastasis?

Point/Counterpoint: Is stereotactic radiosurgery needed following resection of brain metastasis?

Neurocognitive function and quality of life in patients with newly diagnosed brain metastasis after treatment with intra-operative cesium-131 brachytherapy: a prospective trial.

Intraoperative permanent Cesium-131 (Cs-131) brachytherapy can provide a viable alternative to WBRT with excellent response rates and minimal toxicity. This study reports the results of the prospective trial of the impact of intraoperative Cs-131 on neurocognitive function and quality of life (QoL) in patients with resected brain metastases. Between 2010 and 2012, 24 patients with newly diagnosed metastasis to the brain were accrued on a prospective protocol and treated with Cs-131 brachytherapy seeds after surgical resection. Physicians administered the mini-mental status examination (MMSE) and functional assessment of cancer therapy-brain (FACT-Br) questionnaire to all patients before treatment and again every 2months for the duration of 6months with additional follow-up again at 12months. Wilcoxon rank sum test was used to analyze statistically significant changes in MMSE over time and paired t test was used to analyze changes in FACT-BR. There was a statistical improvement in overall FACT-BR score at 4 and 6 months of follow-up when compared to baseline (162 vs. 143, P=0.004; 164 vs. 143, P=0.005 respectively) with a non-significant trend toward improvement at 2 and 12months (154 vs. 143, P=0.067; 159 vs. 149, P=0.4). MMSE score was statistically improved at 4 and up to 12months compared to pre-treatment MMSE (30 vs. 29, P=0.017; 30 vs. 29, P=0.001 respectively). Patients with brain metastasis who received intra-operative permanent Cs-131 brachytherapy implants saw an improvement of their neurocognitive status and self-assessment of QoL. In addition to the excellent local control of metastasis, this approach may contribute to the improvements in cognitive function and QOL.

Prognostic factors and multidisciplinary treatment modalities for brain metastases from colorectal cancer: analysis of 93 patients.

BackgroundThe purpose of this study was to review patient characteristics and evaluate the potential factors affecting prognosis in cases of brain metastasis (BM) from colorectal cancer (CRC).MethodsWe retrospectively reviewed 93 cases of BM from CRC in our hospital. Patient demographics, neurologic symptoms, and location and number of BMs were recorded. Factors analyzed included: age; sex; Karnofsky performance score; number of BMs; presence of extracranial metastases; dimensions; location of tumors; treatment modalities.ResultsThe overall 1- and 2-year survival rates were 27.7 and 9.9 %. On multivariate analysis, the number of BMs, extracranial metastases and the initial treatment modalities were found to be independent prognostic factors for overall survival. Patients treated with surgical resection followed by WBRT or SRS had an improved prognosis relative to those treated with surgery alone (P = 0.02 and P = 0.02, respectively). No significance difference in survival rate was found between patients treated with SRS alone or SRS plus WBRT (P = 0.11).ConclusionsSurgical resection of BMs from CRC in selected patients may help prolong survival. Additional radiotherapy following surgery is valuable in improving prognosis. Extracranial metastasis, multiple BM lesions and initial non operation can be considered as independent factors associated with poor prognosis.

PO84WHOLE BRAIN RADIOTHERAPY (WBRT) FOLLOWING RESECTION OF BRAIN METASTASES: WHO DECIDES? AN AUDIT OF OUTCOMES AND CLINICIAN CONFIDENCE

INTRODUCTION: Whole brain radiotherapy (WBRT) following brain metastases resection improves intra-cranial disease control without improving overall survival (OS). Expanding treatment options mean the role of WBRT should be individualised. We undertook a study to determine the rates and outcomes of post-op WBRT and the confidence of site-specific oncologists (e.g. breast, lung) in decision-making in this field. METHOD: Demographics and outcomes of patients who had brain metastases resected between 04/12 - 04/14 were retrospectively collected. Consultant opinion was collated via an on-line survey. RESULTS: 97 patients were identified (primary sites: lung 34%, breast 24%, colorectal 14%, renal 7%, melanoma 4%, others 17%). 68 (70%) underwent WBRT; it was omitted in 29 patients (21: too unwell/progressive disease, 5: previous cranial RT, 2: post-op chemo, 1: unknown). Median time to WBRT: 5.7 weeks, range 1-15.7 weeks. WBRT commenced >6 weeks post-op in 34%, with variation between disease groups. Median OS was 12.2 and 4.8 months in the WBRT and non-WBRT groups respectively. Intracranial progression was confirmed on imaging in 32% of patients in the WBRT group (73% local recurrence, 27% distant) and 45% in the non-WBRT group (69% local, 31% distant). For the whole group, 12 month OS was 40.8%, 24 month 21.5%. 78% (28/36) of survey respondents thought that decisions on WBRT use should be made by the neuro-oncology MDT. Only 14% felt completely confident in decision making and 11% very familiar with evidence in this field. CONCLUSION: WBRT is rarely electively withheld in our unit. There is scope to improve post-resection decision-making, pathways and education. Neuro-oncology MDTs play an important role in in this area.

Intracranial control after Cyberknife radiosurgery to the resection bed for large brain metastases

BackgroundStereotactic radiosurgery (SRS) is an alternative to post-operative whole brain radiation therapy (WBRT) following resection of brain metastases. At our institution, CyberKnife (CK) is considered for local treatment of large cavities ≥2 cm. In this study, we aimed to evaluate patterns of failure and characterize patients best suited to treatment with this approach.MethodsWe retrospectively reviewed 30 patients treated with CK to 33 resection cavities ≥2 cm between 2011 and 2014. Patterns of intracranial failure were analyzed in 26 patients with post-treatment imaging. Survival was estimated by the Kaplan-Meier method and prognostic factors examined with log-rank test and Cox proportional hazards model.ResultsThe most frequent histologies were lung (43 %) and breast (20 %). Median treatment volume was 25.1 cm3 (range 4.7–90.9 cm3) and median maximal postoperative cavity diameter was 3.8 cm (range 2.8–6.7). The most common treatment was 30 Gy in 5 fractions prescribed to the 75 % isodose line. Median follow up for the entire cohort was 9.5 months (range 1.0–34.3). Local failure developed in 7 treated cavities (24 %). Neither cavity volume nor CK treatment volume was associated with local failure. Distant brain failure occurred in 20 cases (62 %) at a median of 4.2 months. There were increased rates of distant failure in patients who initially presented with synchronous metastases (p = 0.02). Leptomeningeal carcinomatosis (LMC) developed in 9 cases, (34 %). Salvage WBRT was performed in 5 cases (17 %) at a median of 5.2 months from CK. Median overall survival was 10.1 months from treatment.ConclusionsThis study suggests that adjuvant CK is a reasonable strategy to achieve local control in large resection cavities. Patients with synchronous metastases at the time of CK may be at higher risk for distant brain failure. The majority of cases were spared or delayed WBRT with the use of local CK therapy.

Local Control Following Postoperative Stereotactic Radiation Therapy for Brain Metastases

Stereotactic radiosurgery (SRS) and fractionated stereotactic radiation therapy (FSRT) have emerged as viable alternatives to whole brain radiation therapy (WBRT) in patients with resected brain metastases. We performed a systematic review and quantitative analysis of the published experiences with adjuvant SRS and FSRT to determine local control (LC) rates and any relationship with dose-response, fractionation, and treatment delivery parameters. We identified published articles that reported local control rates following post-operative SRS or FSRT to the resection cavity in patients with brain metastases. For series in which uniform dosing schedules were used, biologically effective doses (BED) were calculated using the linear quadratic model and assuming an α/β ratio of 10 Gy. Local control data for the individual resection cavities treated in each study were extracted from actuarial survival curves and aggregated to form a single dataset. Kaplan-Meier curves for local control in the entire dataset and after grouping by treatment platform, fractionation, use of margin expansion, and BED were generated, and statistical comparisons were made using the log-rank test. Seventeen studies (1104 patients with 1155 resection cavities) met all inclusion criteria. Median dose for single fraction regimens was 14-20 Gy, while FSRT was used in 8 studies with regimens ranging from 9 Gy x 3 to 4 Gy x 10 (BED range of 41 Gy10 to 56 Gy10). One and two-year actuarial LC rates for the entire cohort were 83% and 75%, respectively. FSRT was associated with slightly higher one-year (87% v. 81%) and two-year (78% v. 73%) actuarial LC rates than SRS (p=0.049). For patients treated with SRS, use of Gamma Knife was associated with inferior LC compared to treatment with linear accelerator-based platforms (p=0.002). There was no association between use of a planning margin and LC. Most SRS series utilized a wide range of doses, so dose-response analysis could not be performed. In FSRT series, there was no significant association between BED and LC. The overall toxicity rate, which predominantly included radiation necrosis, was approximately 7% and not significantly different between treatment platforms or fractionation schemes. Adjuvant SRS and FSRT provide high rates of local control following resection of brain metastases. FSRT should be considered in cases where therapeutic doses cannot be safely delivered in a single fraction. Prospective trials are warranted to further characterize the optimal regimen and treatment parameters.

Adjuvant Stereotactic Radiosurgery to the Tumor Bed Improves Local Control and Progression Free Survival Following Gross Total Resection of Brain Metastases

Adjuvant Stereotactic Radiosurgery to the Tumor Bed Improves Local Control and Progression Free Survival Following Gross Total Resection of Brain Metastases

Hypofractionated Stereotactic Radiation Therapy Following Surgical Resection for Brain Metastases: A Retrospective Analysis of 95 Patients

Hypofractionated Stereotactic Radiation Therapy Following Surgical Resection for Brain Metastases: A Retrospective Analysis of 95 Patients

Resection Followed by Involved-Field Fractionated Radiotherapy in the Management of Single Brain Metastasis.

We expanded upon our previous experience using involved-field fractionated radiotherapy (IFRT) as an alternative to whole brain radiotherapy or stereotactic radiosurgery for patients with surgically resected brain metastases (BM). All patients with single BM who underwent surgical resection followed by IFRT at our institution from 2006 to 2013 were evaluated. Local recurrence (LR)-free survival, distant failure (DF)-free survival, and overall survival (OS) were determined. Analyses were performed associating clinical variables with LR and DF. Salvage approaches and toxicity of treatment for each patient were also assessed. Median follow-up was 19.1 months. Fifty-six patients were treated with a median dose of 40.05 Gy/15 fractions with IFRT to the resection cavity. LR-free survival was 91.4%, DF-free survival was 68.4%, and OS was 77.7% at 12 months. No variables were associated with increased LR; however, melanoma histopathology and infratentorial location were associated with DF on multivariate analysis. LRs were salvaged in 5/8 patients, and DFs were salvaged in 24/29 patients. Two patients developed radionecrosis. Adjuvant IFRT is feasible and safe for well-selected patients with surgically resected single BM. Acceptable rates of local control and salvage of distal intracranial recurrences continue to be achieved with continued follow-up.

2591 Surgical resection of brain metastasis from renal cancer: Is it worth it? The experience of a French Cancer Center

2591 Surgical resection of brain metastasis from renal cancer: Is it worth it? The experience of a French Cancer Center

1838 Survival of breast cancer patients after radically resected brain metastasis

1838 Survival of breast cancer patients after radically resected brain metastasis

Integrated genomic and transcriptomic analysis of human brain metastases identifies alterations of potential clinical significance.

Treatment options for patients with brain metastases (BMs) have limited efficacy and the mortality rate is virtually 100%. Targeted therapy is critically under-utilized, and our understanding of mechanisms underpinning metastatic outgrowth in the brain is limited. To address these deficiencies, we investigated the genomic and transcriptomic landscapes of 36 BMs from breast, lung, melanoma and oesophageal cancers, using DNA copy-number analysis and exome- and RNA-sequencing. The key findings were as follows. (a) Identification of novel candidates with possible roles in BM development, including the significantly mutated genes DSC2, ST7, PIK3R1 and SMC5, and the DNA repair, ERBB-HER signalling, axon guidance and protein kinase-A signalling pathways. (b) Mutational signature analysis was applied to successfully identify the primary cancer type for two BMs with unknown origins. (c) Actionable genomic alterations were identified in 31/36 BMs (86%); in one case we retrospectively identified ERBB2 amplification representing apparent HER2 status conversion, then confirmed progressive enrichment for HER2-positivity across four consecutive metastatic deposits by IHC and SISH, resulting in the deployment of HER2-targeted therapy for the patient. (d) In the ERBB/HER pathway, ERBB2 expression correlated with ERBB3 (r(2) = 0.496; p < 0.0001) and HER3 and HER4 were frequently activated in an independent cohort of 167 archival BM from seven primary cancer types: 57.6% and 52.6% of cases were phospho-HER3(Y1222) or phospho-HER4(Y1162) membrane-positive, respectively. The HER3 ligands NRG1/2 were barely detectable by RNAseq, with NRG1 (8p12) genomic loss in 63.6% breast cancer-BMs, suggesting a microenvironmental source of ligand. In summary, this is the first study to characterize the genomic landscapes of BM. The data revealed novel candidates, potential clinical applications for genomic profiling of resectable BMs, and highlighted the possibility of therapeutically targeting HER3, which is broadly over-expressed and activated in BMs, independent of primary site and systemic therapy.

Dose painting with Gamma Knife: Two techniques for delivering different doses to areas of recurrent or residual tumor after resection of brain metastases

PurposeWe investigated the feasibility of using Gamma Knife (GK) radiosurgery for “dose painting” to deliver higher doses to residual or recurrent nodules and surgical cavity after resection of brain metastases. Methods and materialsTwo integrated boost techniques were developed with GK. The single-target technique delineated both the surgical cavity (cavity) and gross disease (nodule) as a single target. Dose was prescribed to the target with the goal of covering the nodule with a higher dose. The 2-target technique delineated the cavity and nodule as separate target volumes, each prescribed to its own dose and planned separately. Two cases were used to illustrate each technique. The single-target technique was used to deliver 16 Gy to a smaller cavity (7 cm3) and a 20-Gy integrated boost to 2 nodules (case 1). The 2-target technique was used to deliver 12 Gy to a larger cavity (21.5 cm3) and 20 Gy to a single nodule (case 2). ResultsFor both cases, the cavity coverage with the prescribed dose was 100% with the standard plan and integrated boost techniques. For case 1, compared with a standard plan, the single-target technique improved the 20-Gy nodule coverage from 89.7% (nodule 1) and 97.9% (nodule 2) to 100% (both) and increased the minimum dose from 16.6 Gy to 20.8 Gy (nodule 1) and from 19.4 Gy to 20.8 Gy (nodule 2). For case 2, compared with a standard plan, the 2-target technique improved the 20-Gy nodule coverage from 4% to 100% and the minimum dose from 13.8 Gy to 21 Gy. ConclusionsBoth GK integrated boost approaches allowed for effective delivery of higher doses to residual or recurrent nodules in a surgical cavity. In our experience, the single-target technique works well for small cavities, whereas the 2-target technique is well suited for larger cavities.

Effectiveness of Postoperative Gamma Knife Radiosurgery to the Tumor Bed After Resection of Brain Metastases

The role of Gamma knife radiosurgery (GKS) after the resection of brain metastases remains undefined. We evaluated the outcomes of postoperative GKS to the tumor bed after the resection of brain metastasis compared with GKS alone without resection in the same patients. We performed a retrospective review of 24 patients who underwent GKS to the tumor bed after the resection of brain metastases. In this cohort, 25 metastatic lesions were treated with postoperative GKS, and 37 brain metastatic lesions were simultaneously managed with GKS alone without resection. The median target volume and marginal dose of GKS to the surgical bed were 10.5 cm(3) and 15.0 Gy, respectively. The median target volume and marginal dose of GKS alone for the metastatic lesions were 0.5 cm(3) and 21.0 Gy, respectively. The actuarial 1-year and 2-year overall survival of the patients were 43.1% and 28.7%, respectively. The median overall survival of all patients was 11 months. The actuarial 6-month and 12-month local progression-free survival of GKS alone for metastatic lesions without resection were 92.6% and 84.9%; however, the actuarial 6-month and 12-month local progression-free survival of GKS to the surgical bed were 82% and 71%, respectively. For patients with brain metastases treated with surgical resection, postoperative GKS to the resection area is an effective and safe treatment option. Particularly, concurrent postoperative GKS to the surgical cavity with GKS alone for multiple small metastatic lesions is a feasible treatment strategy for multiple brain metastases.

Simultaneous integrated boost using stereotactic radiosurgery for resected brain metastases: rationale, dosimetric parameters, and preliminary clinical outcomes.

Radiosurgery has been shown to reduce the rates of local recurrence in the postoperative bed after the resection of brain metastases, but the ideal radiation dose has not been well defined. To present dosimetric parameters and preliminary clinical outcomes for patients undergoing postoperative stereotactic radiosurgery (SRS) with simultaneous integrated boost (SIB) for brain metastases. 3 patients underwent surgery for a dominant metastatic focus and had residual or recurrent disease in the resection cavity. Our technique delivered a low dose to the resection cavity with an SIB dose to the gross tumor. Clinical target volume (CTV) was the magnetic resonance (MR)-defined resection cavity. Gross tumor volume (GTV) was the MR-defined residual disease. No additional margin was added to either the resection cavity or the residual disease area. Doses ranged from 14-15 Gy for CTV and 17-18 Gy for GTV prescribed to the 71%-78% isodose line. A traditional postoperative radiosurgery plan was constructed for each patient, and dosimetric values were compared using the paired t-test. 3 patients were treated at our institution using SRS with SIB. No patient experienced local recurrence. 2 patients developed distant brain failure (mean, 3.5 months). No grade 3 or greater toxicities were observed. The volume of brain receiving 12 Gy was significantly reduced using SIB compared with traditional postoperative SRS (𝑃 = .04). There were no differences in the maximum dose delivered to the tumor (𝑃 = .15) and cavity (𝑃 = .13). The average mean cavity dose was 16.20 Gy using the SIB plan, compared with 19.71 Gy using the traditional plan (𝑃 = .05). In patients with either recurrent or residual disease following surgical resection, SRS using SIB is technically feasible and safe.

Adjuvant radiosurgery for a resected brain metastasis: A case report and literature review

Adjuvant radiosurgery for a resected brain metastasis: A case report and literature review