Cell-free tumor DNA in CSF decodes breast cancer brain metas
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: Development of a less invasive, genetic brain tumor marker will allow treating physicians to track how the genetic spectrum of breast cancer tumors in the central nervous system (CNS; i.e. brain and spinal cord) change over time and with therapy. Tumors originating from breast cancer have a marked propensity to seed the brain, eventually present in 30% of breast cancer patients with stage IV disease. While treatments have improved for primary tumors, the development of CNS metastases severely limits life expectancy and few therapeutic options exist. 
 
 
 
 
 
 Tumors carry unique mutations in their DNA that enable them to grow and invade inappropriately, with disastrous consequences for the patient. Usually only the cancer harbors these mutations, so the mutations can be used to uniquely identify the tumors, like a fingerprint. This tumor fingerprint can suggest which therapeutic drugs would best stop the tumor, potentially personalizing the treatment plan for a particular patient. Currently, determining how the mutation fingerprint may have changed as the tumor grows and its DNA mutates would require an invasive opening of the skull or spine to remove tumor tissue. The high risk and cost of such a procedure, let alone repetitive ones, is prohibitive. In addition, the underlying mechanism by which breast cancer metastasizes to the CNS, engrafts and flourishes in this unique niche is still poorly understood. While we have made gains in characterizing primary breast cancers based on gene expression (e.g. ER, PR, HER2, etc.), we still do not understand how mutations within the metastatic brain tumor may be different from the primary tumor. Translating this genetic insight to applying currently available medications not known to be relevant in breast cancer, or developing new treatment for breast cancer patients requires more specific laboratory models for human breast cancer which has metastasized to the brain. 
 
 
 
 
 
 The question(s) or central hypotheses of the research: We have developed a less invasive method to obtain a tumor’s DNA from blood and fluid samples, which we hypothesize has the potential to guide clinical decision making regarding the most appropriate medications to treat breast cancer which has metastasized to the CNS. As tumor cells die, they shed their DNA, which can be detected in the patient’s blood (cell-free DNA; cfDNA). Unfortunately, the plasma cfDNA may not represent the tumor mutation profile within the protected environment of the CNS. Cutting-edge DNA sequencing techniques allow us to identify and study tumor cfDNA at very low levels, such as those present in cerebral spinal fluid (CSF). As we begin to study breast cancer cells within the CNS, we will need to test our hypotheses in cell lines reflective of the unique brain metastasis environment. We believe our new cell lines, derived directly from breast cancer cells which have been growing within the brain, will allow us to identify novel treatments. 
 
 
 
 
 
 The general methodology: Our preliminary data show we can identify brain metastasis tumor cfDNA in CSF, and use it as an important diagnostic and scientific tool. The breast cancer brain tumor cfDNA fingerprint will be followed prospectively to elucidate novel mutations during disease progression and response to treatment. The changed tumor cells may be susceptible to treatments that would not have affected the original tumor, so our method allows matching tumors with specific chemotherapeutics. Patients who undergo surgery to have a breast cancer removed from the brain will have those same brain metastases cells grown in the laboratory, allowing us to test theories of tumor biology and potential therapeutics.
 
 
 
 
 
 Innovative elements of the project: We propose the first application of cfDNA sequencing to better characterize breast cancer tumors metastatic to the CNS. Circulating cfDNA in CSF could provide a powerful, specific, real-time surrogate for cytology or tissue-based biomarkers, with the added benefit of a holistic sampling of a tumor’s mutation profile. Identifying and following the tumor cfDNA fingerprint in patient CSF and plasma ultimately enables more sophisticated, personalized, and targeted therapies. This insight will provide new information regarding tumor biology and how some tumors escape treatment. Our creation of breast cancer brain metastases-specific cell culture tools will allow us to test hypotheses derived from the cfDNA sequencing data, as well as determine the mechanism and therapeutic potential of genes previously implicated in breast cancer metastases and brain tumors. These tangible, translational tools have immediate potential applications for remodeling the approach to diagnostic intervention, scientific discovery, and drug targeting of breast cancer metastases to the brain.