Frequency Of Brain Metastases Research Articles

BSCI-06. FREQUENCY OF BRAIN METASTASIS FROM BREAST AND LUNG CANCER IN THE UNITED STATES -- A POPULATION-BASED ASSESSMENT

BACKGROUND: Brain metastases (BM) are the most common central nervous system tumor in the United States and occur with increasingly frequency due to improved screening and therapeutics leading to improved survival. Current estimates of frequency of BM vary significantly by cancer site and are typically not population-based. Population-based estimates of incidence have recently become possible due to collection of data on BM identified at diagnosis (“synchronous” BM, SBM). BM may occur at any point after cancer diagnosis. We report our recent population-based estimates of SBM and period incidence of BM (PBM) from breast (BC) and lung cancer (LC). METHODS: Data from Surveillance, Epidemiology, and End Results (SEER, 2010–2016 diagnoses) were used to estimate SBM and linked data from SEER-Medicare (2008–2012 diagnoses for individuals 65+, with 2007–2014 claims) were used to estimate PBM, for BC and LC overall and by BC and LC subtypes. RESULTS: Within the SEER data, 10.9% of LC cases presented with SBM (15.5% in small cell LC [SCLC], and 10.8% in non-small cell LC [NSCLC]); 0.4% of BC cases presented with SBM, 0.7% in triple negative (TNBC), 0.8% for HER2+, and 0.2% for ER+\\PR+\\HER2-. Within the SEER-Medicare data, 13.5% of LC overall had LBM with 23.1% for SCLC and 15.3% for NSCLC; 1.8% of BC overall had LBM with 4.2% in triple negative (TNBC), 3.1% for HER2+, and 1.1% for ER+\\PR+\\HER2. CONCLUSION: Frequency of synchronous and period BM varies by originating site as well as subtype. The new SBM variable in SEER allows for estimation of this important statistic, while the SEER-Medicare linked data allows for estimation of PBM, both on a population-level for the US population. These estimates are useful to clinical practice and critical for estimating morbidity and mortality due to BM.

Brain metastasis as exclusion criteria in extensive-stage small cell lung cancer trials: A trend over five decades.

e18048 Background: ASCO and Friends of Cancer Research have proposed that cancer clinical trials must ease eligibility criteria to make the trials more generalizable in “real-world” patient populations. The specific items in exclusion criteria included presence of brain metastasis (BM), which is commonly seen in small cell lung cancer patients. Frequency and trend of BM as exclusion criteria in extensive-stage (ES) SCLC trials is unknown. Methods: We conducted a comprehensive search to identify prospective clinical trials in patients with ES-SCLC. Pubmed search was conducted with key words “small cell lung cancer” and “extensive” in title. Websites of 20 oncology journals were also searched by their online archives. Recent review articles in ES-SCLC were also investigated for additional articles. Eligible studies must have enrolled primarily ES-SCLC and been published in English. Studies involving brain/chest radiation and brain metastasis specific trials were excluded. Studies were categorized into allowed/undefined, conditional, or complete exclusion of BM. Chi-squire test was used for categorial group comparison. Results: A total of 491 published studies were identified by Pubmed (240), journal websites (198), and review articles (53). Early publication year (1970-1999) and first-line/maintenance setting were associated with higher incidence of complete exclusion of cases with BM (p < 0.0001, 0.0233, respectively). Studies in the 1990s had the highest incidence (27%) of exclusion. In 2010, only 12% allowed or undefined BM. There is no correlation between complete exclusion of BMs and other clinical characteristics including journal impact factor, region, trial phase, randomization, sample size, patient performance status, and age limit. Conclusions: A significant number of ES-SCLC trials continue to exclude patients with BM. Future studies need to ease eligibility regarding BM according to ASCO/Friends recommendations.[Table: see text]

Association of neurologic manifestations and CEA levels with the diagnosis of brain metastases in lung cancer patients.

Lung cancer (LC) is the most common source of brain metastases (BM). Because of the difficulty in predicting LC patients who will develop BM, we aimed to identify the clinical and serologic markers that could predict the presence of BM in LC patients. We analyzed a cohort of LC patients sent for neurooncological consultation for any neurologic symptom at a cancer center from June 2013 to July 2017. histologically confirmed LC, age ≥ 18years and complete clinical records. BM diagnosis before our consultation and absence of MRI. Oncologic history, clinical symptoms and comorbidities were analyzed. From 199 patients, most (70%) had > 1 neurological symptom. The most common was headache (n = 46, 21%), followed by seizures (17%), altered mental status (16%) and focal motor weakness (13%). BM was found in 74% of the patients during follow-up. Multivariate logistic regression analysis showed factors associated with a higher frequency of BM: age < 65years [OR 3.15, 95% CI 1.3-7.5], headache (OR 3.8, 95% CI 1.2-11.8), seizures (OR 3.2, 95% CI 1.1-9.3) and CEA ≥ 15ng/mL (OR 5.5, 95% CI 2.2-13.8). Focal sensory deficit was associated with a lower frequency of BM (OR 0.2, 95% CI 0.06-0.92). The presence of certain clinical neurologic symptoms, together with CEA level, was associated with a higher risk of BM in LC patients. The clinical manifestations of patients with LC should not be overlooked because some may have a substantial correlation with BM.

Preoperative brain MRI for clinical stage IA lung cancer: is routine scanning rational?

PurposeEarly detection and control of lung cancer brain metastases (BMs) are important. However, several guideline recommendations are inconsistent with regard to routine preoperative brain MRI, especially in patients with clinical stage IA lung cancer. Our study evaluated the value of preoperative brain MRI in patients with clinical stage IA lung cancer.MethodsA retrospective analysis of patients with lung cancer was performed using a prospectively collected database. Clinical data and the results of brain MRI were collected and analyzed.ResultsPatients with pathologically proved primary lung cancer who underwent an MRI at initial diagnosis were identified (3392 patients). In total, 170 patients (5.0%) were diagnosed with BMs. The increased frequency of BMs was significantly associated with advanced clinical stage (P = 0.000) and pathological type (P = 0.011). BMs were detected in 11 out of 1595 patients with clinical stage IA lung cancer (0.7%). BMs were more common in patients with clinical stage cT1c lung cancer (1.9%) than those with clinical stage cT1a or cT1b (0.1%, odds ratio = 21.30, 95% confidence interval: 2.7–166.9, P = 0.000). All patients with stage IA lung cancer and BMs had solid lung lesions (P = 0.002).ConclusionsPreoperative brain MRI might help identify BMs in patients with lung cancer that has progressed beyond stage IA. In patients with clinical stage IA lung cancer, we do not recommend preoperative brain MRI, but it may potentially be beneficial in those with solid T1c cancers.

BRCA1 Mutations Associated With Increased Risk of Brain Metastases in Breast Cancer: A 1: 2 Matched-pair Analysis.

Brain metastases (BM) occur in ∼5% of breast cancer patients. BRCA1-associated cancers are often basal-like and basal-like cancers are known to have a predilection for central nervous system metastases. We performed a matched-pair analysis of breast cancer patients with and without BRCA mutations and compared the frequency of BM in both groups. From a database of 1935 patients treated for localized breast cancer at our institution from 2009 to 2014 we identified 20 patients with BRCA1 or BRCA2 mutations and manually matched 40 patients without BRCA mutations accounting for age, stage, estrogen receptor expression, and human epidermal growth factor receptor 2 (HER2) expression. Comparisons of freedom from brain metastasis, brain metastasis-free survival, and overall survival were made using the log rank test. Testing for a basal-type phenotype using the immunohistochemistry definition (ER/PR/HER2 and either CK 5/6 or EGFR) was performed for BRCA patients who developed BM and their matched controls. We analyzed 60 patients: 20 BRCA and 40 were matched controls. Median follow-up was 37 and 49 months, respectively. Three years freedom from brain metastasis was 84% for BRCA patients and 97% for BRCA controls (P=0.049). Three years brain metastasis-free survival was 84% and 97% for the BRCA+ and controls, respectively (P=0.176). Mean time to brain failure was 11 months from diagnosis for the BRCA patients. All 3 BRCA1 patients who developed BM were of a basal-type triple negative phenotype. Breast cancer patients with germline BRCA1 mutations appear to have a shorter interval to brain progression while accounting for confounding factors.

Impact of prophylactic cranial irradiation on pattern of brain metastases as a first recurrence site for limited-disease small-cell lung cancer.

This study sought to evaluate the impact of prophylactic cranial irradiation (PCI) on the pattern of brain recurrence after radical treatment in patients with limited-disease small-cell lung cancer (LD-SCLC). Patients treated with radiotherapy and chemotherapy between January 2006 and December 2014 at a single institution were retrospectively examined. Radiotherapy was performed using accelerated hyperfractionated radiotherapy (twice daily, 45 Gy in 30 fractions) or conventional fractionated radiotherapy (once daily, 50 Gy in 25 fractions). The chemotherapy regimen consisted of intravenous platinum–etoposide. A total of 162 patients were included and the median follow-up duration was 38 months. Ninety-three patients underwent PCI, and the 3-year overall survival (OS) rates were 14% among patients without PCI and 41% among those with PCI (P < 0.001). The frequency of brain metastases as a first recurrence site (BMFR) was significantly lower among patients who underwent PCI, compared with those who did not (P = 0.002). The median time to the l of BMFR was significantly shorter among patients without PCI than among those with PCI (P = 0.012). In addition, 68% of the BMFR patients who did not undergo PCI exhibited five or more lesions, while only 12% of BMFR patients who did undergo PCI exhibited five or more lesions (P < 0.001). PCI had a significant positive impact on patient prognosis after radical treatment for LD-SCLC, and the difference in the number of, and time to the appearance of, BMFR between patients treated with PCI and those treated without PCI might affect the clinical outcomes.

Frequency of Brain Metastases and Multikinase Inhibitor Outcomes in Patients With RET-Rearranged Lung Cancers.

In ret proto-oncogene (RET)-rearranged lung cancers, data on the frequency of brain metastases and, in particular, the outcomes of multikinase inhibitor therapy in patients with intracranial disease are not well characterized. A global, multi-institutional registry (cohort A, n= 114) and a bi-institutional data set (cohort B, n= 71) of RET-rearranged lung cancer patients were analyzed. Patients were eligible if they had stage IV lung cancers harboring a RET rearrangement by local testing. The incidence of brain metastases and outcomes with multikinase inhibitor therapy were determined. The frequency of brain metastases at the time of diagnosis of stage IV disease was 25% (95% confidence interval [CI]: 18%-32%) in all patients from both cohorts. The lifetime prevalence of brain metastasis in stage IV disease was 46% (95% CI: 34%-58%) in patients for whom longitudinal data was available. The cumulative incidence of brain metastases was significantly different (p= 0.0039) between RET-, ROS1-, and ALK receptor tyrosine kinase (ALK)-rearranged lung cancers, with RET intermediate between the other two groups. Although intracranial response data was not available in cohort A, the median progression-free survival of multikinase inhibitortherapy (cabozantinib, vandetanib, or sunitinib) in patients with brain metastases was 2.1 months (95% CI: 1.3-2.9 months, n= 10). In cohort B, an intracranial response was observed in 2 of 11 patients (18%) treated with cabozantinib, vandetanib (± everolimus), ponatinib, or alectinib; the median overall progression-free survival (intracranial and extracranial) was 3.9 months (95% CI: 2.0-4.9 months). Brain metastases occur frequently in RET-rearranged lung cancers, and outcomes with multikinase inhibitor therapy in general are suboptimal. Novel RET-directed targeted therapy strategies are needed.

Frequency of brain metastases and outcomes in patients with HER2-, KRAS-, and EGFR-mutant lung cancers.

9081 Background: HER2 mutations are oncogenic drivers in 3% of lung cancers. Here we describe the frequency and course of patients with HER2 mutant lung cancers with spread to brain and compare results to individuals with KRAS- and EGFR-driven cancers. Methods: We compared cohorts of consecutive patients with HER2-(n = 98), KRAS- (n = 200) and EGFR- (n = 200) mutant lung cancers. Multivariate logistical regressions adjusted for follow-up length were performed to evaluate baseline and subsequent development of brain metastases and survival from the date of diagnosis of stage IV disease. Results: In total, brain metastases occurred in 41% of 498 patients (95% CI 37 to 45%). At diagnosis of stage IV disease, 19% (19/98) in the HER2 cohort, 24% (48/200) in KRAS, and 31% (62/200) in EGFR had brain metastases (p= 0.8). Among those without brain metastases at baseline, 34% (27/79) of patients with HER2 vs 11% (16/152) with KRAS (p < 0.001), vs 23% (32/138) with EGFR (p= 0.048) developed brain metastases during treatment. The overall incidence of brain metastases was 47% (46/98) in patients with HER2, 32% (64/200) with KRAS), and 47% (94/200) with EGFR (p = 0.73). The occurrence of any brain metastases imparted a shorter median survival in patients with HER2- (25 vs 30 months, p< 0.001) and EGFR- (29 vs 92 months, p < 0.001) driven cancers but not with KRAS (14 vs 21 months, p= 0.44). The median overall survival was 1.6 years (range 1.3 – 2.2 years) for HER2, 1.1years (range 0.8 – 1.3 years) for KRAS, and 3.0 years (range 2.5 – 4.0 years) for EGFR (p< 0.0001). Conclusions: In our patients with lung cancers driven by HER2, KRAS, and EGFR, brain metastases occurred in 41% overall. The risk is numerically higher with HER2 and EGFR than KRAS. While the incidence of brain metastases in patients with HER2 mutant lung cancers is numerically lower than EGFR at diagnosis, it rises over the disease course to 47%, equal that of EGFR. Among those without brain metastases at baseline, a greater number of patients with HER2-mutant tumors subsequenty developed brain metastases during treatment compared to the EGFR and KRAS cohorts. With one third of patients with HER2 mutant lung cancers developing brain metastases during treatment, close surveillance is critical.

Chapter 2 - Brain metastases: epidemiology

Brain metastases (BM) are the most commonly diagnosed type of central nervous system tumor in the United States. Estimates of the frequency of BM vary significantly, as there is no nationwide reporting system for metastases. BM may be the first sign of a previously undiagnosed cancer, or occur years or decades after the primary cancer was diagnosed. Incidence of BM varies significantly by primary cancer site. Lung, breast, and melanoma continue to be the leading cause of BM. These tumors are increasingly more common as new therapeutics, advanced imaging, and improved screening have led to lengthened survival after primary diagnosis for cancer patients. BM are difficult to treat, and for most individuals the diagnosis of BM generally portends a poor prognosis.

P3.01-010 High Probability and Frequency of EGFR Mutations in Non-Small Cell Lung Cancer with Brain Metastases

Lung cancer is the leading cause of cancer death in men and women worldwide. Brain metastasis (BMs) of NSCLC is the most important cause of death. This study aimed to explore the association of epidermal growth factor receptor (EGFR) mutations and brain metastases (BMs) in non-small cell lung cancer (NSCLC). We analyzed 50 NSCLC patients with BMs and 50 match-paired NSCLC patients with no brain metastases (NBMs). The EGFR mutation status of primary lesions was detected using the amplification refractory mutation system (ARMS) polymerase chain reaction. The BMs patients had a higher frequency of EGFR mutations than the NBMs patients (52.0% vs. 22.0% respectively, P<0.001), in both adenocarcinoma (60.5% vs 30.6%, P=0.003) and squamous carcinoma (37.5% vs. 0%, P=0.04). The incidence of BMs in patients with EGFR mutations was higher than in patients with wild-type EGFR (70.3% vs. 38.1%, P=002). NSCLC patients with BMs had a higher incidence of EGFR mutations and those with mutant EGFR had a higher frequency of BMs. EGFR mutations may promote brain metastasis growth of NSCLC.

High probability and frequency of EGFR mutations in non-small cell lung cancer with brain metastases.

Lung cancer is the leading cause of cancer death in men and women worldwide. Brain metastasis (BMs) of non-small cell lung cancer (NSCLC) is the most important cause of death. This study aimed to explore the association of epidermal growth factor receptor (EGFR) mutations and BMs in NSCLC. We analyzed 50 NSCLC patients with BMs and 50 match-paired NSCLC patients with no brain metastases (NBMs). The EGFR mutation status of primary lesions was detected using the amplification refractory mutation system polymerase chain reaction. The BMs patients had a higher frequency of EGFR mutations than the NBMs patients (52.0 vs. 22.0% respectively, P < 0.001), in both adenocarcinoma (60.5 vs. 30.6%, P = 0.003) and squamous carcinoma (37.5 vs. 0%, P = 0.04). The incidence of BMs in patients with EGFR mutations was higher than in patients with wild-type EGFR (70.3 vs. 38.1%, P = 002). NSCLC patients with BMs had a higher incidence of EGFR mutations and those with mutant EGFR had a higher frequency of BMs. EGFR mutations may promote brain metastasis growth of NSCLC.

BRAF-V600 mutational status affects recurrence patterns of melanoma brain metastasis.

Brain metastasis is common and carries a poor prognosis in melanoma. A single institution, retrospective cohort of 225 melanoma patients was analyzed to determine if BRAF-V600 mutational status was associated with brain metastasis. Eighty-three of the 225 patients (37%) had BRAF-V600 mutations. At initial diagnosis, BRAF-V600 mutations were associated with younger age (p ≤ 0.001), higher proportion of females (p = 0.0037), higher AJCC stage (p = 0.030), regional lymph node involvement (p = 0.047), and family history of cancer (p = 0.044). Compared to BRAF-WT, BRAF-V600 patients had an increased risk of brain metastasis in multivariate analysis (OR = 2.24; 95% CL = 1.10-4.58; p = 0.027). However, BRAF-V600 patients treated with a selective BRAF inhibitor (BRAFi) had a similar risk of brain metastasis compared to BRAF-WT patients (OR = 1.00; 95% CL = 0.37-2.65; p = 0.98). Moreover, treatment with BRAFi significantly prolonged the time from initial diagnosis to brain metastasis diagnosis (HR = 0.30; 95% CL = 0.11-0.79; p = 0.015). Compared to other tissues, the brain was the most frequent site of metastasis in BRAF-V600 patients without BRAFi (42% ± 7%). The frequency of brain metastasis was lower in BRAF-WT and BRAF-V600 patients with BRAFi (25% ± 4% and 25% ± 8%, respectively). The proportion of patients with brain metastasis as the only site was 40%, 60%, and 0% in the BRAF-WT, BRAF-V600 without BRAFi, and BRAF-V600 with BRAFi groups, respectively. This study provides evidence on the clinical importance of BRAF-V600 mutations and BRAF inhibition in the progression to melanoma brain metastasis.

MTE26.02 EGFR Targeted Therapies: Lessons Learned

MTE26.02 EGFR Targeted Therapies: Lessons Learned

Brain metastasis features and association with tumor epidermal growth factor receptor mutation in patients with adenocarcinoma of the lung.

Epidermal growth factor receptor (EGFR) mutations are frequent in pulmonary adenocarcinoma patients. The association between tumor EGFR mutation and characteristics of brain metastasis (BM) is still unclear. We retrospectively reviewed pulmonary adenocarcinoma patients with and without BMs, and characteristics of BM to analyze the association between tumor EGFR mutation and characteristics of BM. Of 374 cases, 239 had EGFR mutations; 69 had BM at initial diagnosis, and 82 with BMs after treatment. All eligible patients received EGFR-tyrosine kinase inhibitors treatment. Older patients (≥70 years old) were less likely to have BMs than younger patients (25.8% vs 48%, P < 0.001). Patients with higher N stage had higher proportion of BMs (P = 0.006). Patients with exon 19 deletion were more likely to have BMs than those without EGFR mutation (48.1% vs 34.1%, P = 0.021). Patients with exon 19 deletion didn't have significantly higher chance of BMs at initial diagnosis but had higher chance to develop BM after treatment than those without EGFR mutation (35.6% vs 21.2%, P = 0.019). Patients with exon 19 deletion survived longer than those without EGFR mutation (1-year survival rate 95.8% vs 78.7%, P = 0.003). Thus, longer survival may lead to higher proportion of BM occurrence in patients with exon 19 deletion than those without EGFR mutation. In pulmonary adenocarcinoma, there is no significant difference in frequency of BMs at initial diagnosis between patients with EGFR mutation and wild type. However, after treatment, patients with EGFR mutations are significantly more likely to develop BM.

Prevalence, clinical risk factors and outcomes of patients with lung cancer presenting with brain metastases.

2075Background: There is limited data on the prevalence of brain metastases at presentation in patients with non-small cell lung cancer (NSCLC). We queried the National Cancer Database (NCDB) to determine the frequency of brain metastases in patients diagnosed with NSCLC and clinical risk factors associated with their presence. Methods: We identified patients with NSCLC diagnosed between 2010 and 2013 using the NCDB database, as during this time period, brain metastasis information was captured. Odds ratios (ORs) for presence of brain metastasis were calculated for individual pre-specified covariates of interest using logistic regression analysis. All statistical tests were 2-sided and p < 0.05 was considered significant. Results: Brain metastases were observed in 47,546 (9.4%) of the 504,151 patients with NSCLC during our study time period. On multivariate analysis the following variables were significantly associated with presence of brain metastasis: age (OR, 0.72 per 10 year increase in age; 95% confi...

RTRB-05DEFINING THE ROLE OF PROPHYLACTIC CRANIAL IRRADIATION IN NSCLC: A SYSTEMATIC REVIEW AND META-ANALYSIS OF THE WORLD'S LITERATURE

INTRODUCTION: Brain metastases remain common in patients with cell lung cancer despite markedly improved systemic therapy. Prophylactic cranial (PCI) in NSCLC remains controversial even though nearly all studies show a clinically and statistically significant decrease in the rate of brain metastases. We present the results of a comprehensive meta-analysis to define the role of PCI in NSCLC. METHODS: An evidence-based literature search querying Medline and the Cochrane Database was completed with the assistance of an expert librarian using the search terms: prophylactic cranial irradiation AND non-small cell lung carcinoma. Primary outcomes were 1-year survival and the rate of brain metastases. Included studies were graded for level of evidence using AAN criteria. One-year survival was determined using pixel coordinates when not explicitly stated. Meta-analyses using a random effects model were performed using Cochrane software. RESULTS: The systematic review produced 112 unique citations. Seventeen studies were identified as potentially eligible for analysis. Of these, twelve studies provided information on the rate of brain metastases, and five provided data on 1-year survival. No study provided greater than Class III evidence. The meta-analysis showed a relative risk of brain metastases (PCI versus non-PCI) of 0.34 [95% CI 0.25-0.45], p < 0.001, NNT = 10. The relative risk for 1-year survival (PCI vs. non-PCI) did not achieve statistical significance (RR = 1.04 [95% CI 0.95-1.13]). Confidence in these results using GRADE criteria was low to very low. CONCLUSIONS: A systematic review of the literature demonstrates a dramatic reduction in the frequency of brain metastases in patients with NSCLC receiving PCI without an increase in one-year survival. Despite multiple randomized controlled trials, the quality of the evidence is low, however the flaws in study methodology are easily remediable. A multi-national effort to resolve this critical question should be a worldwide priority.

Comparison of radiographic characteristics of renal cell carcinoma (RCC) brain metastases treated with vascular endothelial growth factor (VEGF)-directed therapies or radiotherapy.

479 Background: With improvements in systemic therapy for metastatic RCC (mRCC), an increased frequency of brain metastases (BM) has been observed, perhaps owing to the central nervous system (CNS) serving as a sanctuary site. The response of BM to VEGF-directed therapies has been poorly characterized. Methods: Patients (pts) with mRCC BM were identified from an institutional database. Selection of pts was further refined to pts who had received either VEGF-directed therapy during their diagnosis with BM or radiotherapy directed to their BM. Only those pts with brain MRI straddling systemic therapy and radiotherapy were selected for analysis. Imaging studies were anonymized and transmitted to an independent radiologist for review. Descriptive statistics were applied to characterize the change in sum of long axis dimensions (SLD) in two separate groups: (1) pts treated with VEGF-directed therapy and (2) pts treated with radiotherapy. Results: Of 276 pts with mRCC in our institutional database, 34 pts with BM were identified. Of these pts, 6 pts had serial MRI assessments at timepoints straddling receipt of VEGF-directed therapy. Pts had received sunitinib (n=2), sorafenib (n=2) or bevacizumab (n=2). A further 13 pts received radiotherapy with MRI imaging straddling delivery of either stereotactic radiation therapy (SRT) and whole brain radiotherapy (WBRT). Of these 19 patients, all patients had clear cell histology, and 13 patients were male. In pts receiving VEGF-directed agents, the average change in SLD of BM was -13.8%. In pts receiving radiotherapy, the average change in SLD was -6.5% (-13.0% in pts receiving SRT and +2.0% in pts receiving WBRT). Qualitatively, greater tumor necrosis and lesser rim enhancement was observed in post-treatment scans amongst pts receiving VEGF-directed agents. Conclusions: This pilot study suggested differences in CNS response with VEGF-directed therapy and radiotherapy. Multicenter collaborations are underway to validate these results in larger series.

Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers.

Brain metastases (BM) are common in non-small-cell lung cancer (NSCLC). However, the baseline incidence and evolution of BM over time in oncogene-driven NSCLCs are seldom reported. In this study, we evaluated the frequency of BM in patients with epidermal growth factor receptor (EGFR)-mutated or anaplastic lymphoma kinase (ALK)-rearranged NSCLC. The presence of BM, clinicopathologic data, and tumor genotype were retrospectively compiled and analyzed from a cohort of 381 patients. We identified 86 EGFR-mutated (90.7% with metastatic disease; 85.9% received an EGFR inhibitor) and 23 ALK-rearranged (91.3% with metastatic disease; 85.7% received an ALK inhibitor) NSCLCs. BM were present in 24.4% of EGFR-mutated and 23.8% of ALK-rearranged NSCLCs at the time of diagnosis of advanced disease. This study did not demonstrate a difference in the cumulative incidence of BM over time between the two cohorts (EGFR/ALK cohort competing risk regression [CRR] coefficient of 0.78 [95% CI 0.44-1.39], p=0.41). In still living patients with advanced EGFR-mutated NSCLC, 34.2% had BM at 1 year, 38.4% at 2 years, 46.7% at 3 years, 48.7% at 4 years, and 52.9% at 5 years. In still living patients with advanced ALK-rearranged NSCLC, 23.8% had BM at 1 year, 45.5% at 2 years, and 58.4% at 3 years. BM are frequent in advanced EGFR-mutated or ALK-rearranged NSCLCs, with an estimated >45% of patients with CNS involvement by three years of survival with the use of targeted therapies. These data point toward the CNS as an important unmet clinical need in the evolving schema for personalized care in NSCLC.

BM-19 * SYMPTOMATIC AND ECONOMIC BURDEN OF BRAIN METASTASES IN PATIENTS WITH ALK+ NSCLC

BACKGROUND: Brain is one of the most common sites of metastasis in anaplastic lymphoma kinase positive (ALK+) locally advanced or metastatic non-small cell lung cancer (NSCLC). This study investigated symptoms and costs of ALK+ NSCLC patients before and after brain metastases (BM) as well as their treatment changes. METHODS: Retrospective data from 3 large US administrative databases (06/2011 to 06/2013) were evaluated. ALK+ NSCLC patients with BM were identified based on the use of crizotinib and diagnoses for secondary malignant brain tumors. Symptoms and costs were analyzed pre and post BM diagnosis (30 days before the first BM diagnosis). RESULTS: Among 213 ALK+ NSCLC patients with BM 70.4% had BM before initiating crizotinib, 19.2% were diagnosed with BM during crizotinib, and 10.3% after crizotinib. The frequency of BM-related symptoms post BM increased compared to pre BM, including fatigue (from 15% to 39%), headache (from 5% to 24%), depression (from 5% to 15%), altered mental status (from 1% to 13%), seizure (from 1% to 12%), stroke (from 0% to 10%), vision disorder (from 2% to 8%), drowsiness (from 0% to 6%), cognitive impairment (from 1% to 5%), and speech problems (from 0% to 4%). Average medical costs per patient per month were 5 times higher post BM compared to pre BM ($13,095 vs $2,517; p < .001), while pharmacy costs were more than 3 times higher post BM compared to pre BM ($7,213 vs $1,958; p < .001). The difference of medical costs was due to increases in inpatient costs ($6,677 vs $851) and outpatient costs ($5,863 vs $1,600), which were mainly related to radiotherapy or radiosurgery ($2,371 vs $410). CONCLUSIONS: BM presents a substantial symptomatic and economic burden in patients with ALK+ NSCLC. Given the large percentage of ALK+ NSCLC patients who will eventually develop BM, this highlights an important unmet need.

Frequency of brain metastases in non-small-cell lung cancer, and their association with epidermal growth factor receptor mutations

The brain is a frequent site of metastases from non-small-cell lung cancer (NSCLC). We analyzed the frequency of brain metastases (BMs) from NSCLC in the era of magnetic resonance images, and evaluated the correlation between epidermal growth factor receptor (EGFR) mutations and BMs among East Asian patients. Frequency, number, and size of BMs, and survival of 1,127 NSCLC patients were retrospectively reviewed. Mutation status of EGFR was evaluated in all cases, and its association with BMs was statistically evaluated. EGFR mutations were found for 331 cases (29.4 %). BM was the cause of primary symptoms for 52 patients (4.6 %), and found before initiation of treatment for 102 other patients (9.1 %); In addition to these 154 patients, 107 patients (9.5 %) developed BMs, giving a total of 261 patients (23.2 %) who developed BMs from 1,127 with NSCLC. BM frequency was higher among EGFR-mutated cases (31.4 %) than EGFR-wild cases (19.7 %; odds ratio: 1.86; 95 % confidence interval (CI) 1.39-2.49; P < 0.001). BMs from EGFR-mutated NSCLC were small, but often became disseminated. EGFR mutations accounted for 39.9 % of BMs, but patient survival after BMs was significantly longer for EGFR-mutated cases than for EGFR-wild cases (hazard ratio: 2.23; 95 % CI 1.62-3.10; P < 0.001). Patients with EGFR-mutated NSCLC were more likely to develop BMs, but apparently also survived longer after BMs.