Detection of minimal residual disease (MRD) in colorectal cancer (CRC) patients UICC stage II/III by ultra-deep sequencing of cfDNA from post-surgery plasma.

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26 Background: Detection of primary tumor mutations in cell-free DNA (cfDNA) of post-surgery plasma of patients with R0-resected not-metastasized solid tumors is a strong indicator of recurrence of disease. We explored whether ultra-deep sequencing of cfDNA could improve sensitivity and specificity with respect to time-to-progression. Methods: 84 CRC patients UICC stage II/III were recruited into the prospective, observational study “Molecular Signatures in Colorectal Cancer”. Matched tumor tissue samples, plasma depleted blood cells (PDBC), and cfDNA (drawn 1 to 34 days after R0-resection, median 7 days) were processed with the Roche AVENIO Tumor Tissue and ctDNA Surveillance Kits*. Samples of 79 patients passed all quality controls, in particular cfDNA was sequenced ultra-deep with a median of 180 Mio. instead of 50 Mio. reads/sample. Somatic variants were identified with AVENIO Oncology Analysis software 2.0*. PDBC informed germline variants were removed. If a tissue baseline variant was detected in cfDNA with a significant adjusted p-value, the patient was defined ctDNA+, and ctDNA- otherwise. Results: 8 ctDNA+ patients (28 variants, median AF = 0.15%) were identified of which 4 had a progression of disease at two years. Sensitivity was 44% (95% CI [0.137, 0.788]), specificity was 94% (95% CI [0.86, 0.984]), positive predictive value was 50% (95% CI [0.157, 0.843]), and negative predictive value was 93% (95% CI [0.843, 0.977]). Comparison of time-to-progression of ctDNA+ and ctDNA- patients using the log-rank test resulted in a p-value of 0.0058. Comparison of survival times of ctDNA+ and ctDNA- patients resulted in a p-value of 0.0333. Multivariate analyses of times-to-progression resulted in ctDNA-status (p = 0.0022, hazard ratio (HR) = 7.098) and neoadjuvant therapy (p = 0.0010, HR = 6.618) as significant parameters. Conclusions: Even in this small cohort of CRC UICC stage II/III patients, MRD detection in post-surgery plasma is the strongest predictor of shorter time to progression. Ultra-deep sequencing of cfDNA samples did not influence MRD detection on a patient-level. *for Research Use Only; not for use in diagnostic procedures.

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