Occurrence Of Brain Metastases Research Articles

Maintenance treatment of trastuzumab for patients with advanced breast cancer to achieve long term survival: two case reports and literature review.

Molecular subtyping of breast cancer may provide additional prognostic information regarding patient outcome. The epidermal growth factor receptor (HER2) overexpressing breast cancers are designated as HER2-postive (HER2+) breast cancer and carry a particularly unfavorable prognosis. We present two cases of HER2-postive metastatic breast cancer (MBC) who are found to be a challenge to treat, especially due to the occurrence of brain metastasis. Trastuzumab-based therapy improves clinical outcomes, even if the patient has undergone multi-line treatment. These case reports also emphasize the importance of retesting HER2 status because it can be discordance in receptor status between primary and recurrent breast cancer.

Modeling and predicting the occurrence of brain metastasis from lung cancer by Bayesian network

The Bayesian network (BN) is a promising method for modeling cancer metastasis under uncertainty. BN is graphically represented using bioinformatics variables and can be used to support an informat...

Modeling and predicting the occurrence of brain metastasis from lung cancer by Bayesian network: A case study of Taiwan

The Bayesian network (BN) is a promising method for modeling cancer metastasis under uncertainty. BN is graphically represented using bioinformatics variables and can be used to support an informative medical decision/observation by using probabilistic reasoning. In this study, we propose such a BN to describe and predict the occurrence of brain metastasis from lung cancer. A nationwide database containing more than 50,000 cases of cancer patients from 1996 to 2010 in Taiwan was used in this study. The BN topology for studying brain metastasis from lung cancer was rigorously examined by domain experts/doctors. We used three statistical measures, namely, the accuracy, sensitivity, and specificity, to evaluate the performances of the proposed BN model and to compare it with three competitive approaches, namely, naive Bayes (NB), logistic regression (LR) and support vector machine (SVM). Experimental results show that no significant differences are observed in accuracy or specificity among the four models, while the proposed BN outperforms the others in terms of sampled average sensitivity. Moreover the proposed BN has advantages compared with the other approaches in interpreting how brain metastasis develops from lung cancer. It is shown to be easily understood by physicians, to be efficient in modeling non-linear situations, capable of solving stochastic medical problems, and handling situations wherein information are missing in the context of the occurrence of brain metastasis from lung cancer.

Risk factors and survival outcome in cerebral metastatic breast cancer

The development of brain metastases (BM) of primary breast cancer patients leads to limited survival. HER2-positive and triple-negative status are risk factors for the development of BM. Estrogen receptor (ER)/progesterone receptor (PR)/HER2 are important prognostic markers and are essential for effective treatment decisions. We retrospectively analyzed the impact of known risk factors and the outcome after the development of BM. Eighty consecutive patients, treated between January 1, 2001, and June 30, 2012, on the basis of primary non-metastatic operable breast cancer and who developed BM, were enrolled. Clinical parameters (TNM; ER, PR, HER2) and their impact on the occurrence of BM and additionally their prognostic influence after the occurrence of BM were investigated. A small tumor size, ductal histology, grade 3, hormone receptor-negative, triple-negative and HER2+ tumors were associated with BM. Median time from breast cancer diagnosis to BM was 35 months (range 26.2-43.8). Grade 3 versus 2 has significantly negative prognostic impact with earlier development of BM (median 23 vs. 41 months; p=0.033). HER2-positive patients had significantly longer survival after the occurrence of BM than HER2-negative patients (p=0.009). The risk of BM varies significantly by subtype. In high-risk patients, the occurrence of BM must be considered, and possibly, general screening in these patients is warranted. The survival advantage of HER2-positive breast cancer patients compared with HER2-negative patients after the occurrence of BM is possibly explainable by systemic control of disease. Standard of care for patients with BM is whole-brain radiotherapy, with/without surgery, or stereotactic radiosurgery. Perhaps novel therapies may additionally improve survival in these patients.

The molecular biology of lung cancer brain metastasis: an overview of current comprehensions and future perspectives.

Brain metastases occur in 20-40% of patients with advanced malignancies and lung cancer is one of the most common causes of brain metastases. The occurrence of brain metastases is associated with poor prognosis and high morbidity in patients with advanced lung cancer, even after intensive multimodal therapy. Progress in treating brain metastases has been hampered by a lack of model systems, a lack of human tissue samples, and the exclusion of brain metastatic patients from many clinical trials. While the biology of brain metastasis is still poorly understood, it is encouraging to see more efforts are beginning to be directed toward the study of brain metastasis. During the multi-step process of metastasis, functional significance of gene expressions, changes in brain vasculature, abnormal secretion of soluble factors and activation of autocrine/paracrine signaling are considered to contribute to the brain metastasis development. A better understanding of the mechanism of this disease will help us to identify the appropriate therapeutic strategies, which leads to circumvent brain metastases. Recent findings on the biology of lung cancer brain metastases and translational leads identified by molecular studies are discussed in this review.

Abstract P6-11-01: A randomized phase II clinical trial of whole-brain radiation therapy plus concomitant temozolomide in treatment of brain metastases from breast cancer: Six-month follow-up results

Abstract Background: Despite of therapeutics progress in advanced breast cancer, brain metastases occurrence remain a frequent and delicate situation. The efficacy of whole-brain radiation therapy (WBRT), still considered as the standard local treatment in case of multiple brain metastases, is limited. Recently, several phase II studies have shown some efficacy of the association of WBRT and temozolomide (TMZ), an oral alkylating agent already known as a radiosensitizer, with improved brain control rate (44 to 96%). Patients with breast cancer were underrepresented and none of these trials have studied this combined treatment issue in this specific population. The aim of this study was to assess the efficacy and safety of WBRT combined with temozolomide in the treatment of brain metastases from breast cancer. Materials and Methods: A prospective randomized multicenter phase II study was developed, using a modified two-stage Fleming design. Patients with newly diagnosed intraparenchymal brain metastases from breast cancer, not suitable for surgery nor radiosurgery, were included. All patients received conformational WBRT (3 Gy x 10 to 30 Gy). They were randomized to WBRT plus concomitant TMZ administered 75 mg/m2/day during radiation period versus WBRT alone. The primary endpoint was radiologic objective response at six weeks after the end of treatment, defined as a partial or complete response on systematic brain MRI (WHO modified criteria). We also evaluated neurologic symptoms, tolerance, safety, progression free survival (PFS) and overall survival (OS) as secondary endpoints. A longer clinical-brain MRI follow-up was planned, each three months during a two-year period. All of the patients gave their written informed consent to be part of the study, which was approved by the local committee. Results: One hundred patients were enrolled between February 2008 and December 2010 (50 in the WBRT + TMZ arm, 50 in the WBRT arm). The median age was 55 [29 -79]. Eighty (80) patients had brain metastases as single secondary localization. About one third of patients had a triple negative breast cancer subtype (38,3% in the association arm and 35,71% in the WBRT alone arm). There were 26,7% and 14,6% of HER2 positive subtype respectively. The median follow-up was 30 months [range 6-60]. At six months from brain metastases diagnosis (three months after the end of the treatment), objective response rate seems better in the WBRT + TMZ arm: 52% versus 40% in the arm WBRT alone but was not statistically significant (p = 0,54). No complete response was observed. In the WBRT + TMZ group, median PFS and OS at six-months were respectively 55,6% [range 46-7 – 66,0] and 67,7% [range 59,1 – 77,6]. No improvement in neurologic symptoms was noticed. In multivariate analysis, initial TNM status was significantly correlated with PFS and OS. The concurrent use of TMZ with WBRT was well-tolerated. The most frequent upper grade II acute toxicity was reversible leucopenia in the association arm. Conclusion: The addition of temozolomide to WBRT in patients with brain metastases from breast cancer did not improve local control or survival at six months follow-up. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P6-11-01.

Associations between Single-Nucleotide Polymorphisms in the PI3K–PTEN–AKT–mTOR Pathway and Increased Risk of Brain Metastasis in Patients with Non–Small Cell Lung Cancer

Non-small cell lung cancer (NSCLC) metastasizes fairly often to the brain, but identifying which patients will develop brain metastases is problematic. The phosphoinositide 3-kinase (PI3K)-AKT-mTOR signaling pathway is important in the control of cell growth, tumorigenesis, and cell invasion. We hypothesized that genotype variants in this pathway could predict brain metastasis in patients with NSCLC. We genotyped 16 single-nucleotide polymorphisms (SNP) in five core genes (PIK3CA, PTEN, AKT1, AKT2, and FRAP1) by using DNA from blood samples of 317 patients with NSCLC, and evaluated potential associations with the subsequent development of brain metastasis, the cumulative incidence of which was estimated with Kaplan-Meier analysis. Multivariate Cox regression analysis was used to analyze correlations between genotype variants and the occurrence of brain metastasis. In analysis of individual SNPs, the GT/GG genotype of AKT1: rs2498804, CT/TT genotype of AKT1: rs2494732, and AG/AA genotype of PIK3CA: rs2699887 were associated with higher risk of brain metastasis at 24-month follow-up [respective HRs, 1.860, 95% confidence interval (CI) 1.199-2.885, P = 0.006; HR 1.902, 95% CI 1.259-2.875, P = 0.002; and HR 1.933, 95% CI 1.168-3.200, P = 0.010]. We further found that these SNPs had a cumulative effect on brain metastasis risk, with that risk being highest for patients carrying both of these unfavorable genotypes (P = 0.003). Confirmation of our findings, the first to indicate that genetic variations in PI3K-AKT-mTOR can predict brain metastasis, in prospective studies would facilitate stratification of patients for brain metastasis prevention trials.

Dysarthria as the Initial Manifestation of Esophageal Adenocarcinoma

Purpose: The majority of patients with esophageal cancer typically present with dysphagia, weight loss, and/or odynophagia at the time of diagnosis. Half of all newly diagnosed cases are unresectable or have distant metastasis with involvement of the lungs, liver, and/or adrenal glands. Brain metastases from esophageal carcinoma are very rare. In the available literature, the incidence of brain metastasis has been shown to be at 0-2% in clinical studies and 0-5.1% in autopsy studies. We report a case of a 65-year-old Caucasian man presenting with a 7-day history of progressive dysarthria. He denied any other complaint and had no other physical exam findings. The patient did admit to using chewing tobacco on and off for the past 20 years. His medical history was positive for being treated for prostate cancer 4 years prior with radiation. The initial head computed tomography (CT) demonstrated a left frontal lobe mass measuring 25 mm with metastatic characteristics (Figure 1). A wide search for a primary source of the cancer was undertaken and a dilated distal esophagus just proximal to the gastroesophageal junction with wall thickening was noted on CT scan. Endoscopy demonstrated a circumferential distal esophageal ulcerated mass extending 5 cm to the proximal part of the stomach. Biopsy of the mass proved to be positive for moderately differentiated invasive adenocarcinoma which was Gastric HER-2 NEU positive. Due to the rare occurrence of brain metastasis from esophageal cancer and given the history of previously treated prostate cancer the patient underwent a brain biopsy which also confirmed metastatic adenocarcinoma. The lesion was unable to be completely resected due to worsening dysarthria during the procedure. Despite the low incidence of brain metastasis from esophageal cancer, when other more common sources are excluded, one must keep esophageal carcinoma as a possible primary lesion.Figure

Surgical Resection of Brain Metastases—Impact on Neurological Outcome

Brain metastases (BM) develop in about 30% of all cancer patients. Surgery plays an important role in confirming neuropathological diagnosis, relieving mass effects and improving the neurological status. To select patients with the highest benefit from surgical resection, prognostic indices (RPA, GPA) have been formulated which are solely focused on survival without considering neurological improvement. In this study we analyzed the impact of surgical resection on the neurological status in addition to overall survival in 206 BM patients. Surgical mortality and morbidity was 0.0% and 10.3% respectively. New neurologic deficits occurred in 6.3% of all patients. The median overall survival was 6.3 months. Poor RPA class and short time interval between diagnosis of cancer and the occurrence of BM were independent factors predictive for poor survival. Improvement of neurological performance was achieved in 56.8% of all patients, with the highest improvement rate seen in patients presenting with increased intracranial pressure and hemiparesis. Notably, the neurological benefits were independent from RPA class. In conclusion, surgical resection leads to significant neurological improvement despite poor RPA class and short overall survival. Considering the low mortality and morbidity rates, resection should be considered as a valid option to increase neurological function and quality of life for patients with BM.

Do anti-angiogenic therapies prevent brain metastases in advanced renal cell carcinoma?

BackgroundWe analyzed renal cell carcinoma (RCC) brain metastasis (BM) risk factors and compared BM occurrence in metastatic RCC (mRCC) treated with or without anti-angiogenic agents (AA). MethodsData from all consecutive metastatic RCC patients (patients) treated in a french cancer center between 1995 and 2008 were reviewed. Patients had histologically confirmed advanced RCC without synchronous BM at the time of metastasis diagnosis. AA were sorafenib, sunitinib and bevacizumab. We also included patients treated with mTor inhibitors, temsirolimus and everolimus, as they also demonstrated anti-angiogenic activities. Characteristics of the two groups treated with or without AA were compared with a Fisher exact test. Impact of AA on overall survival (OS) and cumulative rate of brain metastasis (CRBM) was explored by Kaplan-Meier method. ResultsOne hundred and ninety-nine patients with advanced RCC were identified, 51 treated with AA and 148 without AA. The median follow-up duration was 40 months. BM occurred in 35 patients. Characteristics between AA treated and non-AA treated groups were unbalanced and favoring better prognostic factors in AA treated group. Median OS was 24 months. AA treatment was not associated with a lower CRBM (HR=0.58 [0.26-1.30], P=0.187). Median survival free of BM was 11.8 months, CI95% (4.95-18.65) in the group without AA treatment and 28.9 months in the AA group, CI95% (18.64-39.16). Alkaline phosphatase (AP) was an independent prognostic factor for BM (P=0.05). In multivariate Cox model, after adjustment to AP, AA did not improve the CRBM (aHR=0.53 [0.22-1.32]). ConclusionIn this retrospective study, AA did not decrease significantly the CRBM. Elevated AP was a predictive factor for BM in mRCC.

Clinical Relevance of Loss of 11p15 in Primary and Metastatic Breast Cancer: Association with Loss of PRKCDBP Expression in Brain Metastases

The occurrence of brain metastases among breast cancer patients is currently rising with approximately 20–25% incidence rates, underlining the importance of the identification of new therapeutic and prognostic markers. We have previously screened for new markers for brain metastasis by array CGH. We found that loss of 11p15 is common among these patients. In this study, we investigated the clinical significance of loss of 11p15 in primary breast cancer (BC) and breast cancer brain metastases (BCBM). 11p15 aberration patterns were assessed by allelic imbalance (AI) analysis in primary BC (n = 78), BCBM (n = 21) and metastases from other distant sites (n = 6) using six different markers. AI at 11p15 was significantly associated with BCBM (p = 0.002). Interestingly, a subgroup of primary BC with a later relapse to the brain had almost equally high AI rates as the BCBM cases. In primary BC, AI was statistically significantly associated with high grade, negative hormone receptor status, and triple-negative (TNBC) tumors. Gene expression profiling identified PRKCDBP in the 11p15 region to be significantly downregulated in both BCBM and primary BC with brain relapse compared to primary tumors without relapse or bone metastasis (fdr<0.05). qRT-PCR confirmed these results and methylation was shown to be a common way to silence this gene. In conclusion, we found loss at 11p15 to be a marker for TNBC primary tumors and BCBM and PRKCDBP to be a potential target gene in this locus.

The impact of bevacizumab on the occurrence and recurrence of intracranial brain metastases in non-small cell lung cancer (NSCLC) patients.

2081 Background: Patients (pts) with brain metastases (BM) have a poor prognosis and limited treatment options. Approximately 40-50% of pts with NSCLC will develop BM during the course of their disease. A better understanding of the pathobiology of BM and the development of targeted agents hold promise for improved prophylaxis and therapy of BM which could have significant impact on disease progression and pt's survival. Vascular Endothelial Growth Factor has been implicated in setting up a metastatic niche allowing cells to seed and grow in the brain parenchyma. Inhibition of this signaling has been studied and shown to be effective in reducing BM in animal models. Methods: The objective of this retrospective study was to determine whether bevacizumab decreases the incidence and or the recurrence of BM in pts with NSCLC. We retrospectively identified NSCLC pts with and without BM treated with bevacizumab. The primary endpoint was the proportion of patients who developed BM on or after bevacizumab therapy. Secondary endpoints were rate of local or regional recurrence after stereotactic radiosurgery (SRS). Occurrence of BM was evaluated by retrospectively reviewing MRI and or CT scans. Results: A total of 30 pts with stage IV non-squamous NSCLC who had no BM at diagnosis treated with bevacizumab (Non-BM group, NBMG) and 85 pts with non-squamous NSCLC who had BM and underwent SRS (BM group, BMG) were studied (46%M; median age 60 years (range 32-84). In the NBMG, 28% of pts developed BM. Median time to development of BM was 10.5 months. In the BMG, 4 pts were treated with bevacizumab following SRS. Of these 4 pts, 3 pts (75%) had no recurrence while 1 pt (25%) developed local then regional recurrence at 7 and 9 months, respectively. Of the remaining 81 pts who underwent SRS but never received bevacizumab, 27% of pts had local recurrence and 41% had regional recurrence at median time of 4 and 4.5 months, respectively. Conclusions: Bevacizumab may have a role in the treatment of NSCLC in regards to development and recurrence of brain metastases. These results support the need for further prospective investigation in a larger patient population with matched controls.

Chemoradiotherapy duration correlates with overall survival in limited disease SCLC patients with poor initial performance status who successfully completed multimodality treatment

Limited data concerning treatment-related prognostic factors in limited disease (LD) small-cell lung cancer (SCLC) patients with poor initial performance status (PS) who successfully completed chemoradiotherapy (CRT) are available. A total of 125 patients with initial PS WHO 2-3 who successfully completed CRT were retrospectively reviewed. Thoracic radiation therapy (TRT) was applied in the concurrent (group1) or sequential (group2) mode. Influence of treatment type, time from diagnosis to start of TRT, number of chemotherapy cycles, prophylactic cranial irradiation (PCI), occurrence of brain metastases (BMs), and duration of CRT on overall survival (OS) were analyzed. Median duration of CRT was 156days in group1 and 195days in group2 (p < 0.001). Median progression-free survival and OS were 11.6 (95% confidence interval (CI) 10-13.2) and 14.9 (95% CI 11.7-17.6) months with no difference between the groups. The 2- and 3-year survival rates were 37.9 ± 6.9% and 22.7 ± 6.3% in group1 and 22.4 ± 4.9% and 15.2 ± 4.3% in group2, respectively. Duration of CRT was only treatment-related factor predicting OS in the uni- (p < 0.014) and multivariate (p < 0.025) analyses. Short dose-dense CRT was associated with improved OS. Duration of CRT affects OS in LD SCLC patients with poor initial performance status who successfully completed multimodality treatment.

Abstract C41: Analysis of Her-2/neu status in brain metastases of breast cancer.

Abstract Introduction: Breast carcinoma is the second common type of cancer metastasizing into the brain. Although the frequency of Her-2 positive primary breast tumors is no more than 30%, a higher occurrence of brain metastases has been reported for patients with positive Her-2/neu primary tumors. We investigated here expression of Her-2 protein and amplification of Her-2 gene in brain metastasis tissues of breast carcinoma patients. Patients and Methods: FFPE tumor tissues were obtained from consented patients treated with surgery at the NN Burdenko Neurosurgery Institute in 2004–2007. Total of 42 cases of brain metastases (BM) with breast tissue origin were evaluated. Solitary BM occurred in 59% (16/27) patients, while multiple metastatic lesions were observed in 41% (11/27) patients. The median age was 53 (range 29 − 73 years). Her-2/neu gene amplification was analyzed by fluorescent in situ hybridization (FISH). Levels of protein expression were detected by immunohistochemistry (IHC) according to the DAKO HercepTest grading system. Membranous staining intensiveness was estimated by a semi-quantitative method (from 0 to 3+). Cases with Her-2 IHC expression score of 2+ were reconfirmed by FISH analysis. Statistical analysis was done using STATISTICA 6.0 software. Results: Over-expression of Her-2 protein was observed in 50% (21/42) cases, while only in 7% (3/42) cases level of HER-2 protein was graded as negative (scores 0 and 1+). In 43% (18/42) cases IHC score was scored as 2+, and for those cases HER-2/neu gene amplification was performed using FISH analysis. Amplification of Her-2/neu was detected in 72% (13/18) cases in that group. Over-expression of Her-2/neu was similar in tissues from patients with a single metastatic lesion (63% (10/16) cases) compared to that of patients with multiple brain metastases (60% (25/42) of cases). Conclusions: Despite relatively lower incidence in primary tumors, Her-2/neu positive breast cancer tumors prevail in breast cancer brain metastases (about 60%), perhaps attributing to the higher malignant potential of such tumors. We found no difference in Her-2/neu protein expression levels in patients with single and multiple brain metastases. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr C41.

Nomogram for predicting development of brain metastasis in patients with inflammatory breast cancer.

243 Background: Inflammatory breast cancer (IBC) is associated with poor prognosis and high rates of distant metastasis. Brain metastasis is particularly important due to its morbidity and mortality. The purpose of this study was to construct a nomogram from clinicopathological factors that could predict the risk of occurrence of brain metastasis in patients with IBC. Methods: We performed a retrospective analysis of 406 patients with IBC, who were seen at the University of Texas M. D. Anderson Cancer Center between 1991 and 2009. Data was collected from IBC registry. Patients were divided in a randomized manner into a training cohort (n = 206) and a validation (n = 200) cohort. A multivariate cox proportional hazards regression analysis of selected prognostic features was performed on the training cohort. The model estimated in the training cohort was cross-validated with the validation cohort. Based on this model a nomogram was constructed to assess 5- and 10-year risk of developing brain metastasis. Results: A total of 115 (28%) patients developed brain metastasis. Univariate analysis identified menopausal status, progesterone receptor expression, number of distant metastasis, adjuvant taxane-based therapy and age at diagnosis as significant factors associated with brain metastasis (p &lt; 0.05). Subsequent multivariate analysis showed menopausal status and number of metastasis were independently associated with development of brain metastasis (p &lt; 0.05). Nomogram constructed using above model was evaluated for its ability to discriminate among likelihood of occurrence of brain metastasis in patients, using the validation set. The validation set showed good discrimination with the area under the receiver operating characteristic curve of 0.68. Conclusions: We have formulated a distinct predictive tool to evaluate 5 and 10-year risk for developing brain metastasis in patients with IBC. This nomogram can be potentially helpful for designing risk adapted therapeutic trials. Identifying patients at high risk for brain metastasis in IBC can help personalize therapy, surveillance, and prognostication. [Table: see text]

Brain Metastases as the Primary Site of Relapse in Two Randomized Phase III Pemetrexed Trials in Advanced Non–Small-Cell Lung Cancer

Background Symptomatic brain metastases (BM) frequently occurs after initial treatment of non–small-cell lung cancer (NSCLC). Therefore, 2 large randomized trials that involved pemetrexed were retrospectively analyzed to determine the pattern of symptomatic relapse in the brain and to gauge if pemetrexed could influence the incidence. Methods Two large phase III studies of pemetrexed in advanced NSCLC were included. One study compared pemetrexed with docetaxel in previously treated patients (n = 571); the other study tested cisplatin plus pemetrexed vs. cisplatin plus gemcitabine in chemotherapy-naive patients with advanced NSCLC (n = 1725). Patients with known BM at study entry were excluded from this analysis. Each study was analyzed separately, then jointly to determine the rate of BM reported as the only site of progressive disease by treatment group and histology. Logistic regression was used to obtain an odds ratio for the treatment effect on the overall occurrence of BM while controlling for potential confounding factors. Results Overall, 71.5% of patients in pemetrexed-containing arms (819 of 1145), and 68.2% of patients in non–pemetrexed-containing arms (785 of 1151) experienced progressive disease. BM recurrence rates were 3.2% (95% confidence interval [CI], 2.1%-4.6%) in the pemetrexed-containing arms vs. 6.6% (95% CI, 5.0%-8.6%) in the non–pemetrexed-containing arms ( P = .002). The odds ratio for BM recurrence associated with exposure to pemetrexed was 0.49 (95% CI, 0.32-0.76; P = .001). The beneficial effect of pemetrexed on BM was confined to patients with nonsquamous NSCLC. Conclusions Patients with advanced nonsquamous NSCLC treated with pemetrexed either in first-line or second-line therapy may reduce the risk of developing BM as the first site of progressive disease. This retrospective analysis is limited due to the lack of baseline and periodic brain scans, and it reflects symptomatic BM only. Regardless, these findings suggest a potential beneficial effect of pemetrexed-based treatments on the control of BM.

Brain, the last fortress of sarcoma: Similar dismal outcome but discrepancy of timing of brain metastasis in bone and soft tissue sarcoma

Brain metastasis is a rare but dismal event in sarcomas. However, the pattern of occurrence and the prognostic factors associated with post-brain metastasis survival (PBMS) are not yet well-characterized. Sarcoma patients treated at one institute within 10-year period were retrospectively reviewed and those with brain metastasis were identified. The incidence of brain metastasis was demonstrated by case per person-years and cumulative incidence curves. Univariate factors associated with PBMS were analyzed. Among 611 sarcoma patients, 20 (3.3%) developed brain metastasis. Alveolar soft part sarcoma (ASPS) and osteosarcoma were the most common subtypes. Overall, the cumulative incidence was 3.9% at 5 years and 8.4% at 10 years. However, the incidence in STS patients continued to rise up to 10 years after primary diagnosis, whereas it reached a plateau in bone sarcoma patients at 3 years. Median PBMS was 1.67 months. Univariate factors associated with better PBMS included ASPS histology, initial surgical treatment, and brain irradiation for non-surgically treated patients. Our study revealed a discrepancy in the timing of occurrence of brain metastasis between STS and bone sarcoma. However, patients with brain metastasis had a poor prognosis, implicating the brain as the last fortress of sarcoma.

Extracranial metastatic patterns on occurrence of brain metastases

Extracranial metastases and their frequency by sites have been described as prognostic factors for survival of patients with brain metastasis. However, these factors must be identified and described in more detail for a large series of patients. Using routine data from the largest German health insurance fund, 5,074 patients with brain metastasis who were diagnosed and treated in 2008 were analyzed to identify the frequency and distribution of extracranial metastatic sites concurrent with brain metastasis in relation to age, gender, and tumor type. Brain metastases were observed in males more frequently than in females (56.4 and 43.6% respectively P<0.001), and were most often from lung (51.2%), breast (12.3%), and unknown (7.5%) primaries. Extracranial metastatic sites were observed in 58.8% of patients; the number of sites was from 1 to 7, with a mean of 1.11. For the 16 most common primary sites the range was from 0.13 to 1.91 . In 11 of these 16 sites, lungs were the most common concurrent metastatic site. Lung cancer, breast cancer, non-Hodgkin's lymphoma, and testicular cancer most commonly metastasized to bone, and bladder cancer to kidneys. Different primary tumors have different frequencies and patterns of extracranial metastatic sites concurrently with brain metastasis. The lung is the most common metastatic site of most primary tumors, bone for a few tumors, and kidneys for bladder cancer. For the unknown primary tumor type, screening for these most common metastatic sites must be intensified, in particular when molecular assessment is not available.

ERCC1 influence on the incidence of brain metastases in patients with non-squamous NSCLC treated with adjuvant cisplatin-based chemotherapy

BackgroundWe recently demonstrated that excision repair cross-complementing group 1 protein (ERCC1) is predictive of adjuvant cisplatin-based chemotherapy benefit in resected non-small-cell lung cancer (NSCLC). Non-squamous cell carcinomas (non-SCCs) carry an increased risk of brain metastases (BMs). We hypothesised that there might be an increased incidence of BMs in ERCC1-negative non-SCCs when treated with adjuvant cisplatin-based chemotherapy. Patients and methodsIncidence of BMs and histoclinical parameters were analysed in a population of 761 patients enrolled in the International Adjuvant Lung Cancer Trial. A subgroup analysis was carried out in patients with ERCC1-negative non-SCCs. ResultsOf 761 patients, 98 developed BMs alone or in association with other metastatic sites, with a 5-year incidence rate of 18.0% (14.7%-21.8%). In the multivariate analysis, the clinical parameters associated with the occurrence of BMs were the nodal status (P = 0.02) and histological type [give hazard ratio (HR) for non-squamous to quantify introduction assertion, P = 0.002]. Chemotherapy had no effect on BMs [HR = 1.4 (0.90-2.1), P = 0.14]. In patients with non-SCC histology (n = 335), adjuvant chemotherapy was associated with an increased risk of BMs [HR = 2.1 (1.01-4.3), P = 0.04] for ERCC1-negative tumours, whereas there was no evidence of an effect on BMs for ERCC1-positive tumours [HR = 1.1 (0.38-3.0), P = 0.90]. Nevertheless, these two effects are not different (P = 0.30 for interaction) possibly due to a lack of power in this subgroup. ConclusionsThis study suggests that adjuvant cisplatin-based chemotherapy is associated with an increased risk of BMs in patients with resected chemosensitive non-SCCs. If confirmed, these data could provide a rationale for new follow-up and/or prophylactic strategies.

Brain metastasis in metastatic renal cell carcinoma: Predictive factors of occurrence and survival with or without antiangiogenic therapy.

394 Background: We analyzed renal cell carcinoma (RCC) brain metastasis (BM) risk factors and compared BM occurrence in advanced RCC treated with or without antiangiogenic agents (AAA). Methods: Data from all consecutive metastatic RCC patients (pts) treated in the Northern France Cancer Center (Centre Oscar Lambret, Lille) between 1995 and 2008 were reviewed. Eligible pts had histologically confirmed advanced RCC without synchronous BM at the time of metastasis diagnosis. Bellini duct and neuroendocrine carcinoma and sarcoma were excluded. AAA were sorafenib, sunitinib, bevacizumab, temsirolimus, and everolimus. Characteristics of the two groups, treated with or without AAA, were compared with a Fisher exact test. Impact of AAA on overall survival (OS) and BM-free survival (BMFS) was explored by Kaplan-Meier method and adjusted to confounders parameters in a Cox model. Results: A total of 199 pts with advanced RCC were identified, 51 treated with AAA and 148 treated without AAA. The median follow-up duration was 40 months. BM occurred in 35 pts. As expected in this retrospective analysis, characteristics between AAA treated and non AAA treated groups were unbalanced for 11 parameters including age, Motzer prognostic factors, performance status and favoring better prognostic factors in the AAA treated group. The median overall survival was 24 months. Overall survival was higher in patients with AAA versus patients without AAA (31 versus 18 months, hazard ratio (HR) 0.67 [0.45–0.97], p=0.038). The AAA were not associated with better BMFS (HR=0.58 [0.26–1.30], p=0.187). The alkaline phosphatase was an independent prognostic factor for BM (p=0.05). In multivariate cox model, AAA treatment improved the OS (adjusted HR 0.60 [0.38–0.94] but not the BMFS (adjusted HR 0.53 [0.22–1.32]. Conclusions: In this retrospective single center study, elevated alkaline phosphatase is a predictive factor for brain metastasis in metastatic RCC. AAA significantly improved overall survival in advanced RCC without any significant impact on brain-metastasis-free survival. No significant financial relationships to disclose.