Over 108,000 Americans will be diagnosed with a primary brain tumor this year.[1] Additionally up to 1 in 5 cancer patients will develop secondary brain tumors during their disease course.[2]

And when that happens, understanding what is driving the disease becomes significantly harder.

Consider a patient with EGFR-mutated lung cancer had initially responded well to targeted therapy [3].

Then new problems emerged.

She developed worsening neurological symptoms while tumor marker levels continued rising. Brain imaging showed concerning changes, but no clear evidence of visible tumor spread. Examination of her cerebrospinal fluid (CSF) under the microscope also failed to detect malignant cells.

The usual diagnostic tools were not giving clear answers.

The Tools Doctors Rely On, and Where They Fall Short

Modern cancer care depends on combining multiple diagnostic tools.

Conventional CSF cytology remains an important diagnostic standard for detecting cancer cells in the central nervous system [4]. But it depends on identifying intact cancer cells under the microscope, which can limit sensitivity, particularly from the first spinal tap [4].

Imaging remains highly sensitive for detecting structural changes in the brain. But scans alone cannot fully characterize tumor biology or reveal which mutations may be driving the disease.

Tissue biopsy is still foundational for profiling the original tumor and guiding targeted therapy selection. But cancer cells that invade the central nervous system can become diffuse, making tissue biopsy difficult and risky [5].

Each tool contributes something important.

Sometimes the most important signals remain hidden.

A Familiar Idea, Applied to a Different Fluid

Over the last decade, liquid biopsy has transformed cancer care.

Instead of relying only on tissue samples, clinicians can not analyze fragments of tumor DNA circulating in the bloodstream. These blood-based tests can help profile advanced cancers, identifying actionable mutations, and capture signals from multiple metastatic sites throughout the body. They are especially useful when tissue is limited or when rapid results are needed.

But brain metastases present a unique problem.

The brain is protected by the blood-brain barrier, a tightly regulated system that shields the central nervous system from pathogens, toxins, and harmful substances circulating in the bloodstream.

It is essential for normal brain function.

It also limits what escapes into the bloodstream.

Tumor DNA from cancers growing in the brain may cross the blood-brain barrier inconsistently and in limited amounts, making blood-based liquid biopsy less sensitive in central nervous system disease [6].

CSF testing applies the same principles of liquid biopsy, but uses different fluid.

Instead of analyzing tumor DNA from blood, clinicians can sequence tumor-derived DNA directly from cerebrospinal fluid collected during a spinal tap.

Tumors in the central nervous system are often more likely to shed detectable molecular signal into CSF than into the bloodstream. One study reported 18-fold higher median tumor DNA signal in CSF compared with plasma [7]. This applies to primary CNS tumors as well. A meta-analysis found that ctDNA was detected in 82% of CSF samples from adult glioma patients, compared to just 16% in plasma [8].

That additional visibility may reveal clinically important information that blood testing misses.

Cancer cells in the brain may also evolve differently from disease elsewhere in the body. A recent study showed that 1 in 6 patients had newly identified actionable resistance-associated alteration detected in CSF that had not been identified on prior testing [9].

CSF testing is not limited to metastases. Especially in cases where primary tumors are located in deep, delicate areas of the brain, detecting a key H3 K27M mutation through a quick spinal tap offers a safer alternative to risky surgery [10].

CSF genomic analysis may also detect disease even when conventional cytology remains negative. That same study found tumor-derived signal could be identified 4 times more often than with CSF cytology alone [10].

That was the case for the patient described earlier. Despite no malignant cells being identified on CSF cytology, genomic analysis of the cerebrospinal fluid detected tumor DNA and helped guide escalation of EGFR-targeted therapy using an approach designed for improved penetration into the central nervous system [4].

Her symptoms improved. Tumor marker levels declined. Follow-up imaging showed response.

The Right Tool for the Right Question

This is not about replacing existing diagnostics.

Imaging, tissue biopsy, blood-based liquid biopsy, and CSF cytology all continue to play important clinical roles.

But when cancer develops behind the blood-brain barrier and blood tests fall silent, cerebrospinal fluid may offer the clearest molecular window.

References

1. National Brain Tumor Society. Brain tumor facts. Accessed May 21, 2026.

2. Achrol A, et al. Nat Rev Dis Primers. 2019; 5.

3. Chan D, et al. Ann Oncol. 2022; 33(9): S1534. DOI: 10.1016/j.annonc.2022.10.288

4. Mollica L, et al. Drugs Context. 2021; 10:2021-6-6.

5. Gao T, et al. Cancer Med. 2022; 12(3): 2248-2261.

6. Diaz M, et al. Transl Oncol. 2024; 41:101881.

7. Azad T, et al. npj Precis Oncol. 2024; 8:121.

8. Pérez-Alfayate R, et al. Front Oncol 2025;15:1714287.

9. Leung J, et al. Paper presented at: ESMO Asia 2025; FPN 770P.

10. Patel J, et al. Neuro Oncol. 2024; 26(Supp_2): S101-S109