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Contents lists available at ScienceDirect

Lung Cancer journal homepage: www.elsevier.com/locate/lungcan

Early report

Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers Deepa Rangachari a , Norihiro Yamaguchi a , Paul A. VanderLaan b , Erik Folch a,c , Anand Mahadevan d , Scott R. Floyd d , Erik J. Uhlmann e , Eric T. Wong e , Suzanne E. Dahlberg f , Mark S. Huberman a , Daniel B. Costa a,∗ a

Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States c Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States d Department of Radiation Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States e Department of Neurology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States f Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute and Harvard School of Public Health, Harvard Medical School, Boston, MA, United States b

a r t i c l e

i n f o

Article history: Received 16 December 2014 Received in revised form 16 January 2015 Accepted 24 January 2015 Keywords: Lung cancer NSCLC Brain metastases EGFR ALK Mutation Rearrangement Central nervous system CNS

a b s t r a c t Introduction: 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. Methods: The presence of BM, clinicopathologic data, and tumor genotype were retrospectively compiled and analyzed from a cohort of 381 patients. Results: 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. Conclusions: 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. © 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction Non-small-cell lung cancer (NSCLC) is the leading cause of brain metastases (BM) [1]. Amongst those with recurrent/advanced NSCLC, BM are a common culprit for cancer-related morbidity and mortality. The incidence of BM in NSCLC has been reported as >20% at diagnosis, with a significant proportion of patients

∗ Corresponding author at: Division of Hematology/Oncology, Beth Israel Deaconess Medical Center, 330 Brookline Ave., Boston, MA 02215, United States. Tel.: +1 617 667 9236; fax: +1 617 975 5665. E-mail address: [email protected] (D.B. Costa).

developing BM over the course of their disease [2,3]. Recent reports also demonstrate an increase in the documented incidence of BM in NSCLC, likely as a consequence of prolonged survival with newer therapies coupled with improvements in neuroimaging modalities [4]. Far less is known about the baseline incidence and subsequent evolution of BM in the subset of patients with oncogene-driven tumors, i.e. epidermal growth factor (EGFR)-mutated or anaplastic lymphoma kinase (ALK)-rearranged NSCLC [5,6]. Given the growing emphasis on molecular profiling and use of targeted therapeutics [7], this is a critical population. An improved understanding of the incidence and evolution of BM in these cases is therefore an area of ongoing need.

http://dx.doi.org/10.1016/j.lungcan.2015.01.020 0169-5002/© 2015 Elsevier Ireland Ltd. All rights reserved.

Please cite this article in press as: Rangachari D, et al. Brain metastases in patients with EGFR-mutated or ALK-rearranged non-small-cell lung cancers. Lung Cancer (2015), http://dx.doi.org/10.1016/j.lungcan.2015.01.020

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Table 1 Baseline characteristics of patients and tumors with EGFR-mutated and ALK-rearranged NSCLC. Tumor genotype

Age at time of biopsy Median (range) Women n (%) Race, n (%) White Asian Black Other Smoking status, n (%) Current smoker Former smoker Never smoker Stage, n (%) I–III IV/recurrent Histology, n (%) Adenocarcinoma Squamous cell carcinoma NSCLC (NOS) Use of precision TKI, n (%) When stage IV/recurrent Baseline brain metastases, n (%) When stage IV/recurrent

EGFR-mutated (n = 86)

ALK-rearranged (n = 23)

p-Value

65 (33–90) 64 (74.4)

56 (29–80) 11 (47.8)

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-driv...
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