Brain Metastases in Resected Non-small Cell Lung Cancer: The Impact of Different Tyrosine Kinase Inhibitors

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2019 May 4

PMID 31048854

Citations 2

Authors

Po-Jen Yun

Guan-Chyuan Wang

Ying-Yi Chen

Ti-Hui Wu

Hsu-Kai Huang

Shih-Chun Lee

Hung Chang

Tsai-Wang Huang

Affiliations

Soon will be listed here.

Abstract

Objectives: The purpose of this study was to examine the impact of epidermal growth factor receptor (EGFR) mutation status and tyrosine kinase inhibitors (TKIs) on the survival of brain metastases (BM) in patients with surgically resected non-small cell lung cancer (NSCLC).

Methods: We selected the patients who had developed metastatic NSCLC; analyzed the differences between brain metastases and other sites of metastases, including patient characteristics, EGFR status, and survival; and selected the patients who had BM for further investigation. We also compared the treatment effects of first-generation TKIs with those of second-/third-generation TKIs.

Results: A total of 785 cases of stage I-IIIa NSCLC were reviewed. Thirty-six (4.6%) patients were identified as having BM. Among them, 14 patients had a mutated EGFR status. No association between EGFR mutation and the incidence of BM was observed (p = 0.199). Patients with mutated EGFRs had significantly longer overall survival and post-recurrence survival than patients with wild-type EGFR mutation (p = 0.001 for both). However, there was no survival difference between patients with exon 19 and exon 21 mutations (p = 0.426). Furthermore, patients who received the second- and/or third-generation EGFR-TKIs had better survival than patients who only received first-generation EGFR-TKIs (p = 0.031). A multivariate analysis indicated that the next-generation TKIs (HR, 0.007; 95% CI, 0.000 to 0.556; p = 0.026) and a longer interval before BM development (HR, 0.848; 95% CI, 0.733 to 0.980; p = 0.025) were significant factors in longer survival.

Conclusions: EGFR-TKIs were effective in treating NSCLC patients with BM after curative pulmonary surgery, especially in those patients harboring EGFR mutations. Furthermore, the second-/third-generation EGFR-TKIs showed more promising results than the first-generation EGFR-TKIs in treating those particular patients, though larger studies needed to further prove the results.

Citing Articles

Clinicopathologic and genomic features associated with brain metastasis after resection of lung adenocarcinoma.

Dunne E, Fick C, Mastrogiacomo B, Tan K, Toumbacaris N, Vanstraelen S JTCVS Open. 2025; 22():458-469.

PMID: 39780816 PMC: 11704575. DOI: 10.1016/j.xjon.2024.09.030.

First- versus Third-Generation EGFR Tyrosine Kinase Inhibitors in EGFR-Mutated Non-Small Cell Lung Cancer Patients with Brain Metastases.

Tatineni V, OShea P, Ozair A, Khosla A, Saxena S, Rauf Y Cancers (Basel). 2023; 15(8).

PMID: 37190312 PMC: 10137202. DOI: 10.3390/cancers15082382.

Simultaneous analysis of , , and gene fusions by NanoString in Brazilian lung adenocarcinoma patients.

Novaes L, Sussuchi da Silva L, De Marchi P, de Oliveira Cavagna R, de Paula F, Zanon M Transl Lung Cancer Res. 2021; 10(1):292-303.

PMID: 33569313 PMC: 7867767. DOI: 10.21037/tlcr-20-740.

References

Lee C, Wu Y, Ding P, Lord S, Inoue A, Zhou C . Impact of Specific Epidermal Growth Factor Receptor (EGFR) Mutations and Clinical Characteristics on Outcomes After Treatment With EGFR Tyrosine Kinase Inhibitors Versus Chemotherapy in EGFR-Mutant Lung Cancer: A Meta-Analysis. J Clin Oncol. 2015; 33(17):1958-65. DOI: 10.1200/JCO.2014.58.1736. View

Hsiao S, Chou Y, Lin S, Hsu R, Chung C, Kao Y . Brain metastases in patients with non-small cell lung cancer: the role of mutated- with an exon 19 deletion or L858R point mutation in cancer cell dissemination. Oncotarget. 2017; 8(32):53405-53418. PMC: 5581119. DOI: 10.18632/oncotarget.18509. View

Hoffknecht P, Tufman A, Wehler T, Pelzer T, Wiewrodt R, Schutz M . Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2014; 10(1):156-63. PMC: 4276567. DOI: 10.1097/JTO.0000000000000380. View

Maemondo M, Inoue A, Kobayashi K, Sugawara S, Oizumi S, Isobe H . Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med. 2010; 362(25):2380-8. DOI: 10.1056/NEJMoa0909530. View

Hendriks L, Smit E, Vosse B, Mellema W, Heideman D, Bootsma G . EGFR mutated non-small cell lung cancer patients: more prone to development of bone and brain metastases?. Lung Cancer. 2014; 84(1):86-91. DOI: 10.1016/j.lungcan.2014.01.006. View

Rosell R, Moran T, Queralt C, Porta R, Cardenal F, Camps C . Screening for epidermal growth factor receptor mutations in lung cancer. N Engl J Med. 2009; 361(10):958-67. DOI: 10.1056/NEJMoa0904554. View

Li B, Sun S, Yang M, Shi J, Xu W, Wang X . The correlation between EGFR mutation status and the risk of brain metastasis in patients with lung adenocarcinoma. J Neurooncol. 2015; 124(1):79-85. DOI: 10.1007/s11060-015-1776-3. View

Yang J, Zhou C, Huang Y, Feng J, Lu S, Song Y . Icotinib versus whole-brain irradiation in patients with EGFR-mutant non-small-cell lung cancer and multiple brain metastases (BRAIN): a multicentre, phase 3, open-label, parallel, randomised controlled trial. Lancet Respir Med. 2017; 5(9):707-716. DOI: 10.1016/S2213-2600(17)30262-X. View

Tsakonas G, De Petris L, Ekman S . Management of brain metastasized non-small cell lung cancer (NSCLC) - From local treatment to new systemic therapies. Cancer Treat Rev. 2017; 54:122-131. DOI: 10.1016/j.ctrv.2017.02.004. View

10.

Lynch T, Bell D, Sordella R, Gurubhagavatula S, Okimoto R, Brannigan B . Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. N Engl J Med. 2004; 350(21):2129-39. DOI: 10.1056/NEJMoa040938. View

11.

Yang Z, Guo Q, Wang Y, Chen K, Zhang L, Cheng Z . AZD3759, a BBB-penetrating EGFR inhibitor for the treatment of EGFR mutant NSCLC with CNS metastases. Sci Transl Med. 2016; 8(368):368ra172. DOI: 10.1126/scitranslmed.aag0976. View

12.

Sperduto P, Yang T, Beal K, Pan H, Brown P, Bangdiwala A . Estimating Survival in Patients With Lung Cancer and Brain Metastases: An Update of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA). JAMA Oncol. 2016; 3(6):827-831. PMC: 5824323. DOI: 10.1001/jamaoncol.2016.3834. View

13.

Dearden S, Stevens J, Wu Y, Blowers D . Mutation incidence and coincidence in non small-cell lung cancer: meta-analyses by ethnicity and histology (mutMap). Ann Oncol. 2013; 24(9):2371-6. PMC: 3755331. DOI: 10.1093/annonc/mdt205. View

14.

Shin D, Na I, Kim C, Park S, Baek H, Yang S . EGFR mutation and brain metastasis in pulmonary adenocarcinomas. J Thorac Oncol. 2014; 9(2):195-9. DOI: 10.1097/JTO.0000000000000069. View

15.

Zeng Y, Liao H, Qin T, Zhang L, Wei W, Liang J . Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy. Oncotarget. 2015; 6(10):8366-76. PMC: 4480758. DOI: 10.18632/oncotarget.3187. View

16.

Ballard P, Yates J, Yang Z, Kim D, Yang J, Cantarini M . Preclinical Comparison of Osimertinib with Other EGFR-TKIs in EGFR-Mutant NSCLC Brain Metastases Models, and Early Evidence of Clinical Brain Metastases Activity. Clin Cancer Res. 2016; 22(20):5130-5140. DOI: 10.1158/1078-0432.CCR-16-0399. View

17.

Zhang F, Zheng W, Ying L, Wu J, Wu S, Ma S . A Nomogram to Predict Brain Metastases of Resected Non-Small Cell Lung Cancer Patients. Ann Surg Oncol. 2016; 23(9):3033-9. DOI: 10.1245/s10434-016-5206-3. View

18.

Langer C, Mehta M . Current management of brain metastases, with a focus on systemic options. J Clin Oncol. 2005; 23(25):6207-19. DOI: 10.1200/JCO.2005.03.145. View

19.

Sequist L, Yang J, Yamamoto N, OByrne K, Hirsh V, Mok T . Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013; 31(27):3327-34. DOI: 10.1200/JCO.2012.44.2806. View

20.

Zhou C, Wu Y, Chen G, Feng J, Liu X, Wang C . Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2011; 12(8):735-42. DOI: 10.1016/S1470-2045(11)70184-X. View