Brain Metastases Higher in Advanced NSCLC With Targetable Genomic Alterations

Non-small cell lung cancer (NSCLC) is the most common variety of lung cancer, accounting for 85% of all cases. Advanced (stage III) and metastatic (stage IV) NSCLC are linked to poor prognosis, with 5-year survival rates of 15% and 5%, respectively. Recent trials have shown improved overall survival (OS) with targeted therapies for tumors carrying specific genomic alterations. Development of brain metastases specifically in NSCLC is associated with reduced overall OS, progression-free survival, and quality of life. There is a knowledge gap about the prevalence of brain metastases, the rate at which they develop, and factors that drive the process. The discovery of genomic alterations in NSCLC has furthered the development of targeted therapies; however, the effect of these alterations on brain metastases remains unclear.

According to Conor S. Gillespie, MBChB, and colleagues, a systematic review and meta-analysis of the incidence and prevalence of brain metastases in NSCLC, both overall and stratified by genomic alteration, is important. Identifying genomic alterations associated with brain metastases could impact screening and determine targeted treatments. The researchers conducted a systematic review and meta-analysis of the incidence and prevalence of brain metastases in NSCLC, stratified by genomic alterations. They addressed two questions in the review: (1) in patients with advanced or metastatic NSCLC, what is the frequency of brain metastases at diagnosis and the incidence of new brain metastases per year, and (2) do the results differ by the presence of the most common genomic alterations?

The analysis included articles published in MEDLINE, EMBASE, and the Cochrane Database of Systematic Reviews between January 1, 2000, and May 30, 2000. Studies of adults (aged ≥16 years) with stage III or IV NSCLC with either the prevalence of brain metastases at diagnosis, incidence, or both were included. Studies were excluded if they were conference abstracts and published prior to 2000, had selective populations (including studies of only brain metastases), and when stage-specific data were unavailable. For studies that were randomized, controlled trials (RCTs), the researchers excluded treatment arms with prophylactic cranial irradiation (PCI) as an intervention, as PCI is not currently the standard of care and could impact brain metastases incidence. Prevalence at diagnosis and incidence of new brain metastases per year were obtained, including patients with EGFR, ALK, KRAS, and other alterations. Pooled incidence rates were calculated using random effects models. Results were reported in the Journal of Thoracic Oncology [2023;12:1703-1713; doi:10.1016/
j.jtho.2023.06.017].

Data pulled from each study included the total population of NSCLC; number of patients with brain metastases at diagnosis; prevalence at diagnosis; median follow-up time, total patient population without brain metastases who had a follow-up; total number of patients developing brain metastases; overall incidence of brain metastases; and incidence per year of patient follow-up. The researchers identified 64 unique articles for inclusion (24,784 patients with NSCLC with prevalence data from 45 studies and 9058 patients with NSCLC with incidence data from 40 studies). Of the 64 studies, six were RCTs, four were post hoc analyses of RCTs, and 54 were observational studies. Eleven studies reported screening patients for brain metastases as part of follow-up protocols. Among the 40 studies with incidence data, the median follow-up was 24 months.

The pooled brain metastases prevalence at diagnosis for the 24,784 patients with NSCLC was 28.4% (95% CI, 26.0-30.9). The pooled prevalence among stage IV studies was 26.8% (95% CI, 24.0-29.6), and the prevalence for mixed studies containing both stage III and IV was 33.1% (95% CI, 27.3-39.2). The analysis showed that brain metastases prevalence in patients with specific genomic alterations was highest in the ALK-positive group (34.9%) and those who had RET translocations (32.2%).

The per-year incidence of new brain metastases was 0.11. The pooled incidence of brain metastases per year among stage III and IV was 0.11 and 0.12, respectively. The pooled incidence of new brain metastases stratified by genomic alterations showed 0.16 incidence in the EKGF group, 0.17 in the ALK group, 0.10 in the KRAS group, 0.13 in the ROS1 group, and 0.12 in the RET group.

“At a median of 2 years from diagnosis, 55% of patients with advanced and metastatic NSCLC will have [brain metastases (BM)], either because they had it at presentation or they developed it in the intervening period. ALK-positive (17.0%/y) and EGFR-positive (15.8%/y) NSCLC have higher rates of BM development than the wild type (12.5%/y),” wrote the researchers.

The authors cited study limitations, including that many of the studies were retrospective and some were excluded because they did not have median follow-up time or stage-specific data. The study did not include incidence for stage I and II lung cancer. The researchers used median follow-up time rather than mean follow-up time to calculate cumulative incidence. Although the study included more than 15 EGFR-positive studies, the rarer the alteration, the fewer studies were available for meta-analysis.

The findings could help clinicians better understand the full burden of the disease, evaluate the potential benefit of brain metastases screening programs, and individualize treatment and monitoring in any subgroups at greater risk, the authors noted.

“This is the first systematic review and meta-analysis to evaluate the prevalence and incidence of BM in advanced and metastatic NSCLC, stratified by molecular and genomic alterations,” the authors concluded. “The high prevalence at diagnosis (around 30%) and incidence during follow-up (11%/y) indicate that careful attention to the current brain screening and follow-up arrangements both locally and nationally are needed, and personalizing such pathways in higher-risk patients (ALK– and EGFR-positive) should be considered.”