The Underlying Biology and Therapeutic Vulnerabilities of Leptomeningeal Metastases in Adult Solid Cancers

Simple Summary Leptomeningeal metastases occur when cancer cells reach the fluid-filled space that surrounds the brain and spinal cord. This type of brain lesion is most prevalent in patients with lung cancer, breast cancer and melanoma. While the clinical characteristics of leptomeningeal metastases have been well described, fundamental research revealing insights into how these lesions develop and grow has only just begun. This review describes the clinical and basic science literature surrounding leptomeningeal metastases from adult solid tumors, proposing novel ways the clinical and research communities can work together to make important advances for patients suffering from this devastating complication of advanced cancer. Metastasis to the central nervous system occurs in approximately 20% of patients with advanced solid cancers such as lung cancer, breast cancer, and melanoma. While central nervous system metastases most commonly form in the brain parenchyma, metastatic cancer cells may also reside in the subarachnoid space surrounding the brain and spinal cord to form tumors called leptomeningeal metastases. Leptomeningeal metastasis involves cancer cells that reach the subarachnoid space and proliferate in the cerebrospinal fluid compartment within the leptomeninges, a sequela associated with a myriad of symptoms and poor prognosis. Cancer cells exposed to cerebrospinal fluid in the leptomeninges must contend with a unique microenvironment from those that establish within the brain or other organs. Leptomeningeal lesions provide a formidable clinical challenge due to their often-diffuse infiltration within the subarachnoid space. The molecular mechanisms that promote the establishment of leptomeningeal metastases have begun to be elucidated, demonstrating that it is a biological entity distinct from parenchymal brain metastases and is associated with specific molecular drivers. In this review, we outline the current state of knowledge pertaining to the diagnosis, treatment, and molecular underpinnings of leptomeningeal metastasis.