Julie Wu, MD, PhD @julie_t_wu @Stanford #IASLC22 #BrainMetastasis Molecular Driver Mutations In Brain Metastasis

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Julie Wu, MD, Ph.D., Medical Oncology Fellow at Stanford University. In this video, she speaks about the IASLC 2022 Abstract - The Impact of Molecular Driver Mutations on Brain Metastasis Risk Depends on Timing of Brain Metastasis Relative to Diagnosis.




Patients with ALK- or EGFR-mutated lung cancer have a higher prevalence of brain metastases (BrM). However, it is unclear if this is attributable to patients' extended survival, a lack of earlier targeted therapeutic brain penetration, or intrinsic driving biology. Patients who present with BrM at the time of distant metastasis, i.e., synchronous BrM, may be less influenced by targeted therapy selection or have higher survival (against driver biology) than those who acquire brain metastasis later, i.e., metachronous BrM. The goal of this study was to evaluate clinical and genetic characteristics of individuals with synchronous vs metachronous BrM, as well as to look at factors that are related to each kind of BrM risk.




We looked for individuals who had been diagnosed with metastatic lung cancer at Stanford between January 2017 and June 2019 and had access to next-generation sequencing. Synchronous BrM was defined as BrM discovered within 60 days of the diagnosis of metastatic illness, and metachronous BrM after 60 days. We concentrated our genomic study on known BrM-associated genes such as EGFR, ALK, and RB1. We performed two sets of association analyses to compare the connections between genetic features and each category of BrM risk. The outcome for synchronous BrM risk was defined as synchronous BrM versus no BrM at the time of distant metastasis, and it was analyzed using logistic regression. The outcome of the metachronous BrM risk analysis was defined as the time from distant metastasis without BrM to the occurrence of metachronous BrM, death, or last follow-up, as determined by cause-specific Cox regression in the presence of competing risk of death.




In the study population of 566 patients (mean age 66 years, male 46 percent, smoking 57 percent), 199 (35.1 percent) had synchronous BrM and 99 (17.4 percent) had metachronous BrM. Patients with synchronous BrM had more advanced stage disease at diagnosis than those with metachronous BrM (81 percent vs. 65 percent diagnosed at stage IV for synchronous vs. metachronous). Both EGFR and ALK mutations were more common in metachronous BrM than in synchronous BrM. (35 percent vs. 20 percent for EGFR, 7 percent vs. 4 percent for ALK). In comparison, RB1 was equally represented (8 percent for both). RB1 was linked to a 2.5-fold increase in the risk of synchronous BrM (p=0.02) and a 3.7-fold rise in the risk of metachronous BrM (p0.001). ALK was found to be substantially linked with an elevated risk of metachronous BrM (HR 3.2, p=0.003), but not with synchronous BrM risk (OR 1.4, P>0.1). In either context, EGFR was not linked with BrM (synchronous: OR 1.1, p=0.68; metachronous: HR 1.0, p=1.0).




According to our findings, patients with metachronous BrM exhibit less aggressive disease characteristics than patients with synchronous BrM.

ALK-positive patients showed a higher risk of BrM in the metachronous context, which is consistent with survival playing a role in BrM risk. RB1, on the other hand, is connected with BrM in both contexts despite not being associated with enhanced survival. Because of the use of contemporary CNS-penetrant treatment, EGFR was not linked with BrM risk. Driver gene connections with BrM can differ depending on the timing of BrM relative to diagnosis, which may need to be considered when setting MRI screening frequency.