Genes associated with increased brain metastasis risk in non–small cell lung cancer: Comprehensive genomic profiling of 61 resected brain metastases versus primary non–small cell lung cancer (Guangdong Association Study of Thoracic Oncology 1036)

Abstract

BACKGROUND: Patients with brain metastases (BMs) have a poor prognosis and limited therapeutic options. Lung cancer is the most common primary malignancy giving rise to BMs; thus, understanding the molecular mechanisms behind increased BM risk is essential for identifying therapeutic targets and developing effective interventions. METHODS: Sixty-one patients who underwent surgical resection of primary non-small cell lung cancer (NSCLC) and BMs were retrospectively studied. Comprehensive genomic profiling of primary NSCLC and matched BMs was performed with next-generation sequencing targeting 416 cancer-relevant genes. RESULTS: Mutations of major drivers, including EGFR, KRAS, TP53, and ALK, were highly concordant between primary NSCLC and matched BMs (>80%), whereas discordance suggested the unique genomic evolution and oncogenic mechanisms of NSCLC BMs. BMs also demonstrated higher levels of copy number variations in comparison with primary NSCLC. Furthermore, the alterations of genes encoding CDK4/CCND1, CDKN2A/2B, and PI3K signaling pathways were enriched in BMs, and this suggested their correlation with increased metastatic risk. Indeed, patients with activated PI3K signaling in their primary NSCLC had significantly shorter BM-free survival (hazard ratio, 8.49; P = .0005). In addition, mutated TP53 or an activated WNT pathway via CTNNB1, APC, and AXIN2 mutations trended toward shorter BM-free intervals but not significantly so. CONCLUSIONS: These findings yield detailed insights into the genomic complexity and heterogeneity of primary NSCLC and matched BMs. This study highlights the significant correlation of PI3K signaling with increased metastatic risk in patients with NSCLC and identifies genomic alterations enriched in NSCLC BMs that could serve as prognostic markers and potential therapeutic targets for treating patients with NSCLC BMs. Cancer 2019;125:3535-3544.

Association of Cerebrospinal Fluid Tumor DNA Genotyping With Survival Among Patients With Lung Adenocarcinoma and Central Nervous System Metastases

“…Cell cycle pathway alterations were frequently detected and may be one of the mechanisms in BM or LM. 7 Our study further verified that cell cycle–regulated genes were also identifiers of CNS metastases in patients with poorer survival. Likewise, MET copy number gain has been associated with resistance to gefitinib in LM, 8 but we did not see a statistically significant association between MET alterations and inferior survival in our study.…”

Timing of Development of Symptomatic Brain Metastases from Non-Small Cell Lung Cancer: Impact on Symptoms, Treatment, and Survival in the Era of Molecular Treatments

“…This reflects the change in paradigms which has taken place within the last few decades: the appearance of BM is no longer a substantial reason for a treatment decision towards local measures such as whole brain radiation therapy (WBRT) with a palliative intention, but is rather one step in a comprehensive oncological treatment concept including novel molecular substances crossing the blood-brain barrier. Since the largest number of treatable driver mutations have been discovered for lung cancers, subsequent effective therapy after BM treatment is available to a larger extent than for most other tumors [17][18][19][20], and the discordance rate between primary tumor and BM has been reported as low [21]. This is reflected by the high percentage of systemic treatments after BM therapy and the increase in such treatments over time in this present cohort, which was observed to be independent from the timing of BM development.…”

Advances in Lung Cancer Driver Genes Associated With Brain Metastasis

“…Patil confirmed that brain metastasis is common in patients with ROS1 -positive advanced NSCLC ( 31 ). New brain metastasis driver genes, such as MYC , AXIN2 , and NRG1 , have also been discovered ( 32 – 35 ). At present, researchers have mainly studied the incidence of common driver genes and the rate of brain metastasis in NSCLC patients.…”