Monitoring minimal residual disease (MRD) by KRAS mutation burden in urinary or plasma circulating tumor (ct) DNA in colorectal cancer (CRC) patients with resectable liver metastases.

Background: Over half of patients with CRC will develop liver metastases. Surgical resection greatly improves outcomes in these patients. Non-invasive markers are needed to better monitor treatment responses and guide complex treatment decisions. This study evaluated the utility of quantifying KRAS mutation burden in urine and plasma ctDNA for monitoring MRD in surgical CRC patients with liver metastases. Methods: A blinded retrospective ctDNA analysis was conducted in 20 Stage I-IV CRC patients with KRAS positive primary tumor, 16 of whom had undergone curative or palliative intent surgical resection of primary tumor or liver metastases in combination with various systemic therapies. Urine and plasma specimens were collected prior, during, immediately after surgery, and at additional time points post-surgery. 193 matched urine and plasma specimens (archived 3-5 years) were tested using a novel, NGS-based method for quantitative detection of KRASmutations in ctDNA. Results: In a blinded analysis, a KRAS mutation that correlated with KRAS mutation in tissue was identified in 95% of evaluable baseline plasmas (19 of 20) and 92% of evaluable baseline urines (11 of 12). 12 of 12 (100%) matched urine and plasma pairs at baseline were concordant (11 KRAS positive and 1 KRAS negative). Analysis of 193 archival longitudinal urine and plasma samples demonstrated a clear correlation and highly comparable fold change between plasma and urinary ctDNA KRAS levels on treatment. Significantly, in 5 of 5 patients with curative intent surgery, urine or plasma ctDNA KRAS levels were undetectable at 7 days post-surgery. In contrast, ctDNA KRAS remained detectable or increased after surgery in 10 of 11 patients with incomplete, palliative surgery. Conclusions: We demonstrate for the first time a clear correlation between the dynamics of urine and plasma KRAS ctDNA changes, and clinical applicability of ctDNA for assessing post-surgery MRD in CRC patients. A prognostic significance of post-surgical KRAS levels and the overall survival in Stage IV CRC patients with liver metastases is being evaluated in a larger cohort. Supported by IGA MZ Grant 13660.

Citation:
J Clin Oncol 33, 2015 (suppl; abstr 3594)

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