The impact of circulating tumor DNA in biliary tract cancer under chemotherapy

Abstract

Biliary tract cancer (BTC) is a highly aggressive cancer with a very poor prognosis. In general, the incidence of BTC is higher in Eastern countries than in Western countries. BTC was once considered a geographically region-specific disease. However, according to recent reports, the incidence of BTC has increased globally. Most patients with BTC were first diagnosed at the advanced stage because the disease is usually asymptomatic during the early stage. Tissue biopsy is the current gold standard for cancer diagnosis, but this invasive technique has challenges. Despite the increased incidence rate and poor prognosis of BTC, understanding this disease is still not satisfactory. To discover actionable target genes and monitor the drug response of patients, we enrolled unresectable BTC patients (n = 41), and circulating-tumor DNA (ctDNA) from plasma samples was collected at multiple timepoints while patients received chemotherapy (pre-1st chemotherapy, pre-2nd chemotherapy, pre-4th chemotherapy, and progression disease). All samples were deep sequenced with a large panel containing 531 pan-cancer genes. We identified highly observed variants, such as TP53, ARID2, KRAS, ARID1A, PDE4DIP, ARID1B, CHD4, FAT1, PIK3CA, SPEN, APC, ATM, ATR, ERBB4, FGFR2, and IDH1. In addition, copy number alterations (CNAs) of MYC, ERBB2, CDKN2A, GATA4, ARID2, MDM2, PIK3R3, CDK12, and EGFR were observed. Key pathways and genes were curated from the literature and detected single nucleotide variants (SNVs) were categorized by them. Epigenetic regulation, TP53 signaling, the PI3K/AKT/mTOR and RAS/RAF/ERK pathways, DNA damage, angiogenesis, and DNA repair were highly ranked. TP53, ARID2, and PTPRT frequently occurred under chemotherapy. In particular, the PTPRT mutation remarkably increased in a cohort with progression disease as compared with that of cohorts at other timepoints. The survival rate of BTC patients with a low tumor mutation burden (TMB) was higher than that of the high TMB patient group. Also, a new threshold by delta blood TMB (dTMB) showed potential as a marker for diagnosis. In the present study, we suggested the advantages of cell-free DNA (cfDNA)-targeted sequencing and discussed candidates of precision therapy and understanding molecular profiling of BTC patients under chemotherapy.