Circulating Exosomal Integrin β3 Is Associated with Intracranial Failure and Survival in Lung Cancer Patients Receiving Cranial Irradiation for Brain Metastases: A Prospective Observational Study

SIMPLE SUMMARY: Brain metastases (BM) are the most common brain tumors in adults, and it remains a major complication in cancer patients. Exosomes or extracellular vesicles (EV) and integrins contribute to the development of BM, and exosomal integrins have been shown to determine organotropic metastasis. To our knowledge, this is the first clinical evidence demonstrating that high plasma EV integrin β3 level is associated with worse overall survival and intracranial control in BM patients undergoing whole brain radiotherapy, and supports the determination of organotropic metastases by exosomal integrins in the clinical setting. As utilization of whole brain radiotherapy for BM gradually declines in favor of local therapy such as neurosurgery and stereotactic radiosurgery (SRS), intracranial and distant brain control remain relevant because of the improved survival. Circulating EV integrin β3 may serve as a novel biomarker in predicting the progression of BM and survival. ABSTRACT: Brain metastasis (BM) is a major problem in patients with cancer. Exosomes or extracellular vesicles (EV) and integrins contribute to the development of BM, and exosomal integrins have been shown to determine organotropic metastasis. We hypothesized that circulating EV integrins are able to influence the failure patterns and outcomes in patients treated for BM. We prospectively enrolled 75 lung cancer patients with BM who received whole brain radiotherapy (WBRT). We isolated and quantified their circulating EV integrins, and analyzed the association of EV integrins with clinical factors, survival, and intracranial/extracranial failure. Circulating EV integrin levels were independent of age, sex, histology, number of BM, or graded prognostic assessment score. Age, histology, and graded prognostic assessment score correlated with survival. Patients with higher levels of circulating EV integrin β3 had worse overall survival (hazard ratio: 1.15 per 1 ng/mL increase; p = 0.04) following WBRT. Multivariate regression analysis also showed a higher cumulative incidence of intracranial failure (subdistribution hazard ratio: 1.216 per 1 ng/mL increase; p = 0.037). In conclusion, circulating EV integrin β3 levels correlated with survival and intracranial control of patients with lung cancer after WBRT for BM. This supports that EV integrin β3 mediates a brain-tropic metastasis pattern, and may serve as a novel prognostic biomarker for BM.