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Incidence of brain metastases in a potentially high-risk group of patients with metastatic colorectal cancer: Results from a pilot study
Background
Brain metastases (BM) are an uncommon presentation of metastatic colorectal cancer (mCRC) and routine imaging of the brain is not recommended. The majority of patients with BM undergo a palliative treatment course with an expected survival of few months. However, appropriately selected patients could be candidates for metastasis-directed treatment with a potential for a curative outcome. In a registry-based CRC cohort study patients undergoing curatively intended treatment of BM had more frequently rectal cancers with lung metastases. Patients undergoing curative intended treatment of BM achieved a 5-year survival rate of 12.7%. The aim of our pilot study was to prospectively investigate the incidence of BM in a potentially high-risk group of patients with mCRC. Possible prognostic biological aspects were investigated by translational analysis of blood samples.
Methods
A prospective pilot study to investigate if the currently suggested risk factors, rectal cancer and lung metastases, could add to a relevant detection rate of asymptomatic BM from CRC. Inclusion criteria: rectal cancer; lung metastasis diagnosed by histo- or cytopathology, or by clinical and imaging criteria. Exclusion criteria: contraindications for magnetic resonance imaging (MRI); previously treated or known brain metastasis. Patients underwent a standard 3T MRI scan of the brain with intravenous contrast. MRI were described by a specialized radiologist. Positive findings were discussed at the multidisciplinary tumor board for potential treatment options according to best standard of care. The level of total cell free DNA (cfDNA) in plasma samples drawn at inclusion were measured by a direct fluorescence assay (as previously published). Blood samples were available from a cohort of healthy individuals.
Results
Twenty-nine patients were included. Four patients withdraw their consent, and the remaining 25 patients underwent screening MRI of the brain. The median age was 68 years (interquartile range [61-71]) and the majority males (68%). Twenty-one patients had active lung metastases, including six with lung-only disease, whereas four patients were included during follow-up after local ablative treatments. Mutational status in tumor tissue comprised 14 (67%) with KRAS mutations, seven wild-type, and four not done. Evidence of brain metastasis was detected in one patient (4.0%; 95%CI [0.1-20.4]). The cfDNA levels were significantly higher in the study cohort (median 0.73 ng/μl) compared to the healthy cohort (median 0.52 ng/μl, p < 0.001) and there was a tendency for higher cfDNA levels in patients with primary tumor in situ (p=0.14) and in patients with liver metastases (p=0.12). The cfDNA level was 0.81 ng/μl in the patient with BM and 0.72 ng/μl in the remaining. Numbers were, however, low for sub-analyses.
Conclusions
A single asymptomatic BM was detected but we did not find an incidence of BM, which justifies routine MRI of all patients in this selected population. Future studies should focus on identifying further characteristics and biomarkers associated with high risk of BM from CRC. This would enable early detection of BM, and thereby a possibility for early intervention, prolonged survival and improved quality of life. In accordance with the literature, we found a significantly higher cfDNA level in patients compared to healthy individuals.
Clinical trial identification
ClinicalTrials.gov Identifier: NCT05185557.
Legal entity responsible for the study
The author.
Funding
This project was funded by grants from The Danish Cancer Society (Kræftens Bekæmpelse; grant nos. R99-A6323-14 -S25 and R269-A15652), Health Research Foundation of Central Denmark Region (grant no. A1602), A. P. Moller foundation (grant no. 18-L-0355), and Aase and Ejner Danielsen Foundation (grant no. 10-002001).
Disclosures
All authors have declared no conflicts of interest.
