Molecular residual disease assessment based on tumor-informed assay predict disease progression and postoperative recurrence of hepatobiliary cancer: A preliminary study.

Background: Hepatobiliary cancers present a heterogeneous group of diseases, and molecular residual disease (MRD) evaluation based on circulating tumor DNA (ctDNA) is anticipated to offer greater sensitivity in monitoring disease progression than glycoprotein-based tumor markers such as alpha-fetoprotein or carbohydrate antigen 19-9 (CA199).

Methods: The panels for MRD surveillance were customized for each patient based on their specific genetic mutation characteristics. The changes in ctDNA mean variant allele frequencies (mVAF) and single nucleotide variants (SNVs) were analyzed from baseline to post-operative and between post-operative measurements.

Results: A unique tumor-informed whole-exome sequencing (WES) assay revealed significant variations in gene mutations between individuals. Among 63 cases, a total of 1952 SNVs were detected in tumor tissue from 63 patients using WES; only 6 loci (0.3%) were shared by at least 2 patients, indicating that over 95% of the 20-40 loci screened were unique to individual patients . Only 17 gene alterations were common to at least 2 patients, suggesting that alterations vary widely between individuals. The mVAF and the number of SNVs in ctDNA at baseline was dramatically higher than in first post-operative MRD (MRD1). The mVAF clearance was observed in three patients, whose ctDNA was positive at MRD1 but subsequently became negative at the second post-operative MRD (MRD2). Patients exhibiting vascular invasion demonstrated a significant increase in mVAF levels and SNV numbers. Furthermore, we revealed that mVAF levels were significantly associated with clinicopathologic characteristics, including gender, age, tumor subtype, stage, metastasis, vascular invasion, hepatitis B, liver cirrhosis, and tumor differentiation. Importantly, we have shown that the detection of an MRD-guided medication regimen modification is crucial to achieve clinical complete remission.

Conclusions: This study provided data supporting the use of a more reliable assay for MRD analysis in hepatobiliary cancers based on a tumor-informed assay. Dynamic monitoring of post-operative MRD is important for assessing disease progression, risk of recurrence, and response to treatment.