Investigation of a methylated BCAT1 and IKZF1 circulating tumour DNA blood test for monitoring treatment response in patients with colorectal cancer.

PURPOSE: Colorectal cancer (CRC) treatment failure results in high mortality. The current CRC treatment response monitoring blood biomarker carcinoembryonic antigen (CEA) lacks specificity. Methylated BCAT1/IKZF1 circulating tumour DNA (ctDNA) indicates CRC, but its utility during therapy is uncertain. This study examined whether during-treatment measurement of BCAT1/IKZF1 ctDNA reflects CRC treatment efficacy.

METHODS

Plasma was collected from CRC patients before and during chemotherapy, targeted therapy and/or radiotherapy. Cell-free DNA was extracted, bisulphite-converted and assayed via multiplex qPCR for BCAT1/IKZF1 methylation (%pg/ACTB). Patients with detectable ctDNA pre-treatment were included. CEA was measured via chemiluminescent immunoassay. Radiological treatment response assessments were performed ± 3 months of blood collection or < 8 months post-treatment. Biomarker levels were compared using Mann-Whitney U and Kruskal-Wallis tests.

RESULTS

56 samples from 29 patients (64.3% male, median age 55 years) were analysed. Patients with residual cancer had higher ctDNA levels (median 0.036%, IQR 0-1.17%) than cancer-free patients (0%, IQR 0-0.005%; p < 0.05). There were no significant differences for CEA. When normalised to pre-treatment measurements, treatment-responders demonstrated a median 100% ctDNA reduction from baseline (IQR - 100% to - 7.53%), which was greater than non-responders (0.13% reduction, IQR - 38.1% to + 0.03%; p < 0.001). Responders also demonstrated greater CEA reduction (median - 1.50 ng/mL, IQR - 6.28 to 0.18 ng/mL) compared to non-responders (median 2.3 ng/mL, IQR - 0.50 to 17.7 ng/mL; p = 0.001).

CONCLUSIONS

Methylated BCAT1/IKZF1 ctDNA reflects treatment response, offering a tool for personalised treatment.