• Genomic profiling and prognostic factors of leptomeningeal metastasis in EGFR-mutant NSCLC after resistant to third-generation EGFR-tyrosine kinase inhibitors
• Clinicopathological factors vs. molecular model for predicting adjuvant EGFR-TKI benefit in stage I EGFR-mutant non-small cell lung cancer
• PD-1/PD-L1 inhibitors plus chemotherapy versus chemotherapy alone for TKIs-resistant, EGFR-Mutant, advanced non-small-cell lung cancer: a phase 3 RCTs based meta-analysis
• Identifying the genomic landscape of EGFR-mutant lung cancers with CNS metastases
• N6-methyladenosine-modified GPX2 impacts cancer cell stemness and TKI resistance through regulating of redox metabolism
• Targeting WEE1 to overcome ARID1A mutation-driven osimertinib resistance in EGFR-mutant lung cancer
• Optimizing management of stage IV EGFR mutant non-small cell lung cancer in Asia: An expert opinion
• A Neovascularization and EGFR Dual-Targeting Gold Nanotheranostic System for Non-Small Cell Lung Cancer Treatment

The discovery of epidermal growth factor receptor (EGFR) mutations is one of the most promising advances for the treatment of NSCLC ¹⁾.

Patients with EGFR-mutant tumors are more likely to experience brain metastases than patients with wild-type tumors ²⁾.

Chiang et al. prospectively enrolled patients with EGFR-mutant NSCLC who underwent CSF sampling for suspected Leptomeningeal metastases (LM). The supernatant of CSF after routine cytology examination was collected. The diagnosis of LM was established according to EANO-ESMO criteria. CSF and plasma cell-free DNA (cfDNA) were retrieved for Epidermal growth factor receptor mutation testing.

Fifty-one patients with a median age of 62.7 years were enrolled. The median duration from the initial diagnosis to CSF sampling was 23.0 months and most patients (94.1%) had received at least one Epidermal growth factor receptor tyrosine kinase inhibitor. Adenocarcinoma cells were found in 37 CSF samples (72.5%), and 48 (94.1%) patients had confirmed or probable LM. Thirty-five of these 48 patients (72.9%) had valid EGFR mutation-testing results using CSF cfDNA and tended to have higher white blood cell counts and positive cytology in their CSF compared to those with invalid mutation testing results. The overall detection rate of EGFR mutation in CSF cfDNA was 68.8%, and the T790M detection rate was 14.6%. In 37 patients with paired CSF and plasma samples, the concordance rate of the EGFR mutation results was 29.7%.

For patients with EGFR-mutant NSCLC with LM, CSF supernatant is a valuable source for EGFR mutation testing and may provide important information ³⁾.

Non-small cell lung cancer patients with EGFR mutation have a high rate of brain metastases, and Epidermal growth factor receptor tyrosine kinase inhibitors (TKIs) are the principal therapeutic approach.

However, acquired targeted therapy resistance is the main reason for EGFR-TKIs' treatment failure. At present, the mechanism of intracranial acquired targeted therapy resistance is limited, mainly due to the lack of a cell line that can be used for its study.

Kwon et al. investigated the risk factors for leptomeningeal carcinomatosis (LMC) and compared clinical efficacies of various treatment modalities including intrathecal chemotherapy in patients with lung adenocarcinoma harboring epidermal growth factor receptor mutations.

Using clinical research data from the Asan Medical Center, they retrospectively analyzed data of patients diagnosed with LMC, confirmed via cerebrospinal fluid (CSF) analysis from January 2008 to December 2017.

They identified 1189 patients with lung adenocarcinoma harboring EGFR mutations. Among these, 9.8% had a median duration of 13.5 (interquartile range [IQR] 6.8-23.6) months from the initial lung cancer diagnosis to LMC occurrence. Younger age (hazard ratio [HR] 1.043, P < 0.001), initial metastatic disease (HR 3.768, P < 0.001), and metastases to the brain (HR 8.682, P < 0.001) or lung (HR 2.317, P = 0.004) were risk factors associated with LMC. The median survival duration from LMC diagnosis was 3.8 (IQR 1.5-8.6) months. Eastern Cooperative Oncology Group performance status score ≤ 2 (HR 0.505, P = 0.007) and insertion of the Ommaya reservoir (HR 0.445, P = 0.005) were associated with longer survival. EGFR-tyrosine kinase inhibitor (TKI) conferred survival benefits compared to cytotoxic chemotherapy or best supportive care (HR 2.222, P = 0.018; HR 5.638, P < 0.001, respectively). Although IT chemotherapy showed no survival benefit, it was associated with improved neurologic symptoms and signs and CSF negative conversion.

Younger age, an initial diagnosis of metastatic disease, and metastases to the brain or different lobes were associated with LMC in patients with EGFR-mutant lung adenocarcinoma. Therapeutic interventions including EGFR-TKIs, cytotoxic chemotherapy, or Ommaya reservoir, and good performance status were related to favorable survival outcomes.

Age and disease status were associated with LMC in patients with EGFR-mutant adenocarcinoma, and EGFR-TKI, Ommaya reservoir, and good performance status were related to survival benefit ⁴⁾.

1: Chen L, Fu M, Zhou J, Yao Y, Zhou J. [Prognostic Analysis of EGFR-TKIs Combined with Gamma Knife in EGFR-mutant Lung Adenocarcinoma with Brain metastases]. Zhongguo Fei Ai Za Zhi. 2019 May 20;22(5):312-318. doi: 10.3779/j.issn.1009-3419.2019.05.08. Chinese. PubMed PMID: 31109441; PubMed Central PMCID: PMC6533187.

2: Huang Y, Chow KKH, Aredo JV, Padda SK, Han SS, Kakusa BW, Hayden Gephart M. Epidermal Growth Factor Receptor Mutation Status Confers Survival Benefit in Patients with Non-Small-Cell Lung Cancer Undergoing Surgical Resection of Brain Metastases: A Retrospective Cohort Study. World Neurosurg. 2019 May;125:e487-e496. doi: 10.1016/j.wneu.2019.01.112. Epub 2019 Jan 31. PubMed PMID: 30710723.

3: Hu F, Xu J, Zhang B, Li C, Nie W, Gu P, Hu P, Wang H, Zhang Y, Shen Y, Wang S, Zhang X. Efficacy of Local Consolidative Therapy for Oligometastatic Lung Adenocarcinoma Patients Harboring Epidermal Growth Factor Receptor Mutations. Clin Lung Cancer. 2019 Jan;20(1):e81-e90. doi: 10.1016/j.cllc.2018.09.010. Epub 2018 Sep 24. PubMed PMID: 30341018.

4: Grenda A, Jarosz B, Krawczyk P, Kucharczyk T, Wojas-Krawczyk K, Reszka K, Krukowska K, Nicoś M, Pankowski J, Bryl M, Ramlau R, Kuźnar-Kamińska B, Grodzki T, Szczęsna A, Siemiątkowska K, Szumiło J, Batura-Gabryel H, Palonka M, Milanowski J. Discrepancies between ALK protein disruption and occurrence of ALK gene rearrangement in Polish NSCLC patients. J Thorac Dis. 2018 Aug;10(8):4994-5009. doi: 10.21037/jtd.2018.07.28. PubMed PMID: 30233874; PubMed Central PMCID: PMC6129873.

5: Kobayashi H, Hamasaki M, Morishita T, Yoshimura M, Nonaka M, Abe H, Inoue T, Nabeshima K. Clinicopathological and genetic characteristics associated with brain metastases from lung adenocarcinoma and utility as prognostic factors. Oncol Lett. 2018 Oct;16(4):4243-4252. doi: 10.3892/ol.2018.9225. Epub 2018 Jul 27. PubMed PMID: 30214559; PubMed Central PMCID: PMC6126213.

6: Press RH, Zhang C, Cassidy RJ, Ferris MJ, Zhong J, Steuer CE, Pillai RN, Owonikoko TK, Kahn S, Ramalingam SS, Patel PR, Curran WJ, Shu HG, Sica GL, Higgins KA. Targeted sequencing and intracranial outcomes of patients with lung adenocarcinoma brain metastases treated with radiotherapy. Cancer. 2018 Sep 1;124(17):3586-3595. doi: 10.1002/cncr.31589. Epub 2018 Aug 18. PubMed PMID: 30120912.

7: Yomo S, Oda K. Impacts of EGFR-mutation status and EGFR-TKI on the efficacy of stereotactic radiosurgery for brain metastases from non-small cell lung adenocarcinoma: A retrospective analysis of 133 consecutive patients. Lung Cancer. 2018 May;119:120-126. doi: 10.1016/j.lungcan.2018.03.013. Epub 2018 Mar 14. PubMed PMID: 29656746.

8: Jung WS, Park CH, Hong CK, Suh SH, Ahn SJ. Diffusion-Weighted Imaging of Brain metastases from Lung Cancer: Correlation of MRI Parameters with the Histologic Type and Gene Mutation Status. AJNR Am J Neuroradiol. 2018 Feb;39(2):273-279. doi: 10.3174/ajnr.A5516. Epub 2018 Jan 4. PubMed PMID: 29301782.

9: Cassidy RJ, Zhang X, Patel PR, Shelton JW, Escott CE, Sica GL, Rossi MR, Hill CE, Steuer CE, Pillai RN, Ramalingam SS, Owonikoko TK, Behera M, Force SD, Fernandez FG, Curran WJ, Higgins KA. Next-generation sequencing and clinical outcomes of patients with lung adenocarcinoma treated with stereotactic body radiotherapy. Cancer. 2017 Oct 1;123(19):3681-3690. doi: 10.1002/cncr.30794. Epub 2017 Jun 13. PubMed PMID: 28608966.

10: Fan Y, Xu Y, Gong L, Fang L, Lu H, Qin J, Han N, Xie F, Qiu G, Huang Z. Effects of icotinib with and without radiation therapy on patients with EGFR mutant non-small cell lung cancer and brain metastases. Sci Rep. 2017 Mar 23;7:45193. doi: 10.1038/srep45193. PubMed PMID: 28332624; PubMed Central PMCID: PMC5362911.

11: Basler L, Kroeze SG, Guckenberger M. SBRT for oligoprogressive oncogene addicted NSCLC. Lung Cancer. 2017 Apr;106:50-57. doi: 10.1016/j.lungcan.2017.02.007. Epub 2017 Feb 6. Review. PubMed PMID: 28285694.

12: Magnuson WJ, Yeung JT, Guillod PD, Gettinger SN, Yu JB, Chiang VL. Impact of Deferring Radiation Therapy in Patients With Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Who Develop Brain Metastases. Int J Radiat Oncol Biol Phys. 2016 Jun 1;95(2):673-9. doi: 10.1016/j.ijrobp.2016.01.037. Epub 2016 Feb 2. PubMed PMID: 27034176.

13: Nanjo S, Ebi H, Arai S, Takeuchi S, Yamada T, Mochizuki S, Okada Y, Nakada M, Murakami T, Yano S. High efficacy of third generation EGFR inhibitor AZD9291 in a leptomeningeal carcinomatosis model with EGFR-mutant lung cancer cells. Oncotarget. 2016 Jan 26;7(4):3847-56. doi: 10.18632/oncotarget.6758. PubMed PMID: 26716903; PubMed Central PMCID: PMC4826174.

14: Shin SM, Cooper BT, Chachoua A, Butler J, Donahue B, Silverman JS, Kondziolka D. Survival but not brain metastases response relates to lung cancer mutation status after radiosurgery. J Neurooncol. 2016 Feb;126(3):483-91. doi: 10.1007/s11060-015-1986-8. Epub 2015 Oct 31. PubMed PMID: 26520640.

15: Takano K, Kinoshita M, Takagaki M, Sakai M, Tateishi S, Achiha T, Hirayama R, Nishino K, Uchida J, Kumagai T, Okami J, Kawaguchi A, Hashimoto N, Nakanishi K, Imamura F, Higashiyama M, Yoshimine T. Different spatial distributions of brain metastases from lung cancer by histological subtype and mutation status of epidermal growth factor receptor. Neuro Oncol. 2016 May;18(5):716-24. doi: 10.1093/neuonc/nov266. Epub 2015 Oct 31. PubMed PMID: 26519739; PubMed Central PMCID: PMC4827044.

16: Shih J, Bashir B, Gustafson KS, Andrake M, Dunbrack RL, Goldstein LJ, Boumber Y. Cancer Signature Investigation: ERBB2 (HER2)-Activating Mutation and Amplification-Positive Breast Carcinoma Mimicking Lung Primary. J Natl Compr Canc Netw. 2015 Aug;13(8):947-52. PubMed PMID: 26285240; PubMed Central PMCID: PMC4763101.

17: Holzmann K, Kropfmüller R, Schinko H, Bogner S, Fellner F, Arzt W, Lamprecht B. Lung cancer in pregnancy. Wien Klin Wochenschr. 2015 Aug;127(15-16):639-44. doi: 10.1007/s00508-015-0726-6. Epub 2015 Mar 3. PubMed PMID: 25732916.

18: Park JH, Hyun SJ, Kim KJ, Jahng TA. Total en bloc thoracic and lumbar spondylectomy for non-small cell lung cancer with favorable prognostic indicators: is it merely indicated for solitary spinal metastases? J Korean Neurosurg Soc. 2014 Nov;56(5):431-5. doi: 10.3340/jkns.2014.56.5.431. Epub 2014 Nov 30. PubMed PMID: 25535523; PubMed Central PMCID: PMC4273004.

19: Lee DW, Shin DY, Kim JW, Keam B, Kim TM, Kim HJ, Kim DW, Wu HG, Paek SH, Kim YW, Heo DS, Kim DG, Lee SH. Additional prognostic role of EGFR activating mutations in lung adenocarcinoma patients with brain metastases: integrating with lung specific GPA score. Lung Cancer. 2014 Dec;86(3):363-8. doi: 10.1016/j.lungcan.2014.10.001. Epub 2014 Oct 13. PubMed PMID: 25453849.

20: Cai L, Zhu JF, Zhang XW, Lin SX, Su XD, Lin P, Chen K, Zhang LJ. A comparative analysis of EGFR mutation status in association with the efficacy of TKI in combination with WBRT/SRS/surgery plus chemotherapy in brain metastases from non-small cell lung cancer. J Neurooncol. 2014 Nov;120(2):423-30. doi: 10.1007/s11060-014-1570-7. Epub 2014 Aug 7. PubMed PMID: 25098700; PubMed Central PMCID: PMC4206296.

21: Gerber NK, Yamada Y, Rimner A, Shi W, Riely GJ, Beal K, Yu HA, Chan TA, Zhang Z, Wu AJ. Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014 Jun 1;89(2):322-9. doi: 10.1016/j.ijrobp.2014.02.022. Epub 2014 Mar 25. PubMed PMID: 24679729; PubMed Central PMCID: PMC5691362.

22: Mitsuya K, Nakasu Y, Mizokami Y, Takahashi T, Nakamura Y, Ono A, Toda Y, Yamamoto N, Harada H, Nishimura T. [Multidisciplinary treatment of leptomeningeal metastases in patients with lung adenocarcinoma: the triple modality combination of EGFR-TKI, VP shunt and irradiation]. No Shinkei Geka. 2012 Jun;40(6):503-9. Japanese. PubMed PMID: 22647509.

23: Nagano T, Kotani Y, Kobayashi K, Hatakeyama Y, Hori S, Kasai D, Funada Y, Nishimura H, Kondoh T, Nishimura Y. Long-term outcome after multidisciplinary approach for leptomeningeal carcinomatosis in a non-small cell lung cancer patient with poor performance status. Intern Med. 2011;50(24):3019-22. Epub 2011 Dec 15. Review. PubMed PMID: 22185996.

24: Takahashi M, Soejima Y, Yamamoto J, Saito T, Nishizawa S. Focal leptomeningeal metastases following curative surgery for lung cancer: case report. Neurol Med Chir (Tokyo). 2011;51(3):247-50. PubMed PMID: 21441747.

25: Kubo T, Takigawa N, Kiura K, Nishida A, Ochi N, Kashihara H, Umemura S, Hisamoto A, Tanimoto M. Efficacy of a lumbo-peritoneal shunt for meningeal carcinomatosis refractory to gefitinib treatment. Anticancer Res. 2009 Jul;29(7):2759-60. PubMed PMID: 19596957.

26: Bean J, Brennan C, Shih JY, Riely G, Viale A, Wang L, Chitale D, Motoi N, Szoke J, Broderick S, Balak M, Chang WC, Yu CJ, Gazdar A, Pass H, Rusch V, Gerald W, Huang SF, Yang PC, Miller V, Ladanyi M, Yang CH, Pao W. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proc Natl Acad Sci U S A. 2007 Dec 26;104(52):20932-7. Epub 2007 Dec 18. PubMed PMID: 18093943; PubMed Central PMCID: PMC2409244.

27: Chou WC, Huang SF, Yeh KY, Wang HM, Liu MY, Hsieh JJ, Cheung YC, Chang JW. Different responses to gefitinib in lung adenocarcinoma coexpressing mutant- and wild-type epidermal growth factor receptor genes. Jpn J Clin Oncol. 2006 Aug;36(8):523-6. Epub 2006 Jun 27. PubMed PMID: 16803841.