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Molecular diagnostics for RET inhibition in NSCLC and thyroid cancers

Driver genes as predictive indicators of brain metastasis in advanced NSCLC

Read time: 10 mins
Last updated:17th Jan 2022
Published:17th Jan 2022

Driver genes as predictive indicators of brain metastasis in patients with advanced NSCLC: EGFR, ALK, and RET gene mutations

Wang H, Wang Z, Zhang G, et al. Driver genes as predictive indicators of brain metastasis in patients with advanced NSCLC: EGFR, ALK, and RET gene mutations. Cancer Med. 2020;9:487–495.

  • The incidence of brain metastasis can be as high as 30–40% in patients with non-small cell lung cancer1, with prognosis being generally poor2
  • The mechanisms of brain metastasis in patients with lung cancer are not well understood, and treatment strategies are suboptimal
  • This was a retrospective analysis of 552 patients with advanced non-small cell lung cancer, 153 (27.7%) of whom had brain metastases. The presence of eight driver genes was detected using next-generation sequencing, and statistical analysis revealed which genes contribute to brain metastasis associated with lung cancer
  • This study identified that positive RET gene fusion, positive EGFR mutation, and positive ALK gene fusion are independent risk factors for brain metastasis in patients with non-small cell lung cancer

In patients with lung cancer, brain metastasis is a common cause of disease progression and death

Non-small cell lung cancer (NSCLC) represents approximately 80% of all lung cancer cases3, and up to 30–40% of NSCLC patients have brain metastasis1. Lung cancer patients with brain metastasis who have not been treated typically survive just 1–2 months2, or 4–6 months if treated with whole-brain radiotherapy4. This poor prognosis highlights the need for better techniques to screen for patients at greater risk of progression to brain metastasis. 

Targeted therapy is a key focus of current research, with particular attention being paid to molecular biomarker expression. The mechanisms of various target genes (mutant genes) have been the subject of extensive research in lung cancer, with Wang and colleagues postulating that among these may be a factor which drives brain metastasis associated with lung cancer tumours.

What did the researchers do?

Wang and colleagues retrospectively analysed data from 552 patients with advanced NSCLC who had been treated at the Affiliated Cancer Hospital of Zhengzhou University between January 2015 and June 2017 and had brain metastases confirmed either by positron emission tomography-computed tomography or magnetic resonance imaging. Complete medical records were available for all patients, and at least two pathologists confirmed the pathological type. Patients were followed-up to 1 February 2018, the median follow-up time being 41 months (21–156 months).

Next-generation sequencing (NGS) was used to detect mutations in eight lung cancer driver genes recommended in the National Comprehensive Cancer Network (NCCN) guidelines, namely:

  • epidermal growth factor receptor (EGFR)
  • anaplastic lymphoma kinase (ALK)
  • Kirsten ratsarcoma viral oncogene homolog (KRAS)
  • receptor tyrosine kinase (ROS-1)
  • proto-oncogene B-Raf (BRAF)
  • erb-b2 receptor tyrosine kinase 2 gene (ERBB2, also known as HER2)
  • rearranged during transfection (RET)
  • c-mesenchymal-epithelial transition factor (c-MET)

The researchers utilised SPSS ver. 17.0 software to perform statistical analyses, and used a number of statistical methods to interrogate the data. The researchers considered a value of P<0.05 as statistically significant.

What were the findings?

The median age of the study population was 60 years (26–84 years), over half (n = 316, 57.2%) were male, and 62.0% had smoked for over 6 months (n = 342). Of the 552 enrolled patients, 153 (27.7%) had confirmed brain metastases, with 108 (19.6%) presenting with brain metastases at first diagnosis. Within this group, there were 55 cases of EGFR mutation, most being from exon 19 (18.5%), and 16.7% being from exon 21. During the follow-up period there were 45 cases of metastasis, with 22 EGFR gene mutations being responsible for 48.9% of these cases.

Results indicated that patients with positive RET gene fusion, positive EGFR mutations and positive ALK gene fusion were more likely to develop brain metastasis compared to patients without driver gene mutations. Table 1 outlines the results of the univariate analysis and logistic multivariate analysis. The univariate analysis identified the factors that impacted the incidence of brain metastasis, while the logistic multivariate analysis included all factors and revealed which factors were independent risk factors for brain metastasis in patients with lung cancer.

Table 1. Significant results from the univariate analysis and logistic multivariate analysis of the risk factors for brain metastases. 

Factor P value
Univariate analysis
Gene mutation status (EGFR) P=0.001
Lymph node metastasis P=0.003
Sex P=0.016
Smoking history P=0.010
Age at onset P=0.008
Logistic multivariate analysis
Age <60 years P<0.001
Lymph node metastasis P<0.001
Pathological type (adenocarcinoma) P=0.009
Positive RET gene fusion P=0.003
Positive EGFR mutation  P=0.012
Positive ALK gene fusion P=0.015

To help validate these results, receiver operating characteristic (ROC) curves were plotted using these independent risk factors, with an area under the curve (AUC) >0.5 deemed statistically significant. The AUC was 0.705 (95% CI, 0.671–0.739; P<0.001, SE=0.017). See figure 1 for detail.


Figure 1. Multifactor receiver operating characteristic curve plotting EGFR, RET, ALK status, lymph node metastasis, age, and pathological type. ALK, anaplastic lymphoma kinase, AUC, area under the curve; CI, confidence interval; EGFR, epidermal growth factor receptor; RET, rearranged during transfection; SE, standard error. Note: diagonal segments produced by ties.

According to Wang and colleagues, the presence of a RET fusion gene is significantly associated with the occurrence of brain metastasis in patients with lung cancer

What were the main conclusions?

In addition to investigating factors that potentially correlate with brain metastases in NSCLC at initial diagnosis or first progression, Wang and colleagues claim this as the first large-scale study to evaluate the effects of multi-driver genes in NSCLC on brain metastasis incidence.

Their findings indicate that ALK gene fusion, EGFR mutations, RET gene fusion, younger age (<60 years), lymph node metastasis, and pathological type of adenocarcinoma are independent risk factors for brain metastasis in patients with advanced NSCLC. While these findings indicate that assessment of these factors may provide predictive value for brain metastasis in NSCLC patients, they caution that further validation in randomised controlled trials is needed.


  1. Saad AG, Yeap BY, Thunnissen FBJM, Pinkus GS, Pinkus JL, Loda M, et al. Immunohistochemical markers associated with brain metastases in patients with nonsmall cell lung carcinoma. Cancer. 2008;113(8):2129–2138.
  2. Eichler AF, Kahle KT, Wang DL, Joshi VA, Willers H, Engelman JA, et al. EGFR mutation status and survival after diagnosis of brain metastasis in nonsmall cell lung cancer. Neuro-Oncology. 2010;12(11):1193–1199.
  3. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2012. CA: a Cancer Journal for Clinicians. 2012;62(1):10–29.
  4. 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. International Journal of Radiation Oncology*Biology*Physics. 2016;95(2):673–679.