Can HCC Be Caught Early Using ctDNA?

Real-time evaluation of circulating tumor DNA (ctDNA) in patients with hepatocellular carcinoma (HCC) as a diagnostic tool appears feasible, according to preliminary results of a study published in the Journal of Gastrointestinal Oncology.

“Advancement of technologies enabling clinical assessment of circulating tumor DNA (ctDNA) are allowing for assessment of tumor specific genetic alterations in patients,” wrote authors, led by Kabir Mody, MD, Division of Hematology/Oncology, Mayo Clinic Cancer Center, Mayo Clinic Florida, Jacksonville. “This holds incredible promise for early detection of disease, serial monitoring of tumor heterogeneity, elucidation of therapeutic targets, and evaluation of treatment response and mechanisms of resistance.”

In the current study, researchers assessed patients with biliary tract cancer (BTC) who underwent ctDNA testing between January 2015 and February 2018 by means of a clinically available assay. Most of the samples were analyzed using a 73-gene panel which includes somatic genomic targets. Somatic genomic targets involve complete exon coverage in 30 genes and critical exon coverage in 40 genes. In some cases, somatic genomic targets included amplifications, fusions, and indels.

In total, 44 samples were obtained from 35 patients, with more than 70% exhibiting stage 3 or 4 disease. The median number of alterations per sample-excluding variants of undetermined significance (VUS)-was 3.5, with a median allele frequency of 0.65%. Furthermore, 122 unique genetic alterations-excluding VUS or synonymous alterations-were observed. Importantly, the top 10 genes altered in this cohort of patients-without VUS or synonymous alterations-included the following: TP53 (18%), TERT (14%), CTNNB1 (13%), ARID1A (9%), MYC (5%), BRAF (4%), CCND1 (4%), CDK6 (4%), and MET (4%), and EGFR (3%).

To date, limited work has been done on the feasibility of ctNDA testing in real-time in patients with HCC. HCC is commonly diagnosed late based on imaging findings alone; it also recurs commonly. The authors noted that patients with hepatobiliary cancers such as HCC are in a position to reap gains from ctDNA assay technologies because they are commonly diagnosed with advanced disease despite curable interventions including surgery. Furthermore, biopsies are not always feasible secondary to unavailability and insufficient quantities of tumor cells or tumor DNA for genomic profiling.

Notably, during the study period, the gene panel composition grew from 54 to 68 to 70 to 73 genes. The current 73-gene panel includes the addition of 5 genes to and subtraction of 2 genes from the previous list. The overwhelming majority (93%) of samples were tested using the 73-gene panel.

Promisingly, ctDNA-despite cancer type-is a noninvasive, comprehensive tool that enables precision medicine for patients. It could be used to identify therapeutic targets and to monitor disease response to treatment, as well as to identify emerging resistance. Nevertheless, to be used clinically, this technology must exhibit high concordance with tissue-based profiling, which is the current gold standard.

“This data emphasizes [emphasize] the emerging importance of genomic profiling for patients with HCC,” reflected the authors. “The standard for such profiling remains tissue-based testing. Unfortunately, tissue is very often not collected in patients with HCC given the ability to make the diagnosis based on imaging features alone. As such, ctDNA may represent a viable option for genomic profiling in this populating of patients.”

Finally, researchers pointed out that future studies including validation of ctDNA results with tissue-based profiling results, as well as important biomarkers such as serum alpha fetoprotein levels in HCC, is necessary to fully elucidate the universality of the current preliminary findings.