Circulating Tumor DNA Profiling of Advanced Biliary Tract Cancers

Abstract

PURPOSE Recent advances in molecular diagnostic technologies have allowed for the evaluation of solid tumor malignancies via noninvasive blood sampling, including circulating tumor DNA (ctDNA) profiling. We sought to characterize the ctDNA genomic alteration landscape in patients with biliary tract cancers (BTCs). PATIENTS AND METHODS From January 2015 to February 2018, 124 patients with BTC at the Mayo Clinic Comprehensive Cancer Center underwent ctDNA testing using a clinically available assay. The majority of samples (n = 122) were tested using the 73-gene panel that includes somatic genomic targets, including complete or critical exon coverage in 30 and 40 genes, respectively, and in some, amplifications, fusions, and indels. RESULTS A total of 138 samples were included, with approximately 70% of patients having intrahepatic BTC. All patients had locally advanced or metastatic BTC. Samples with one or more alterations, when variants of unknown significance were excluded, numbered 105 (76%). Each sample contained, on average, three alterations with a median allelic fraction of 0.52%. The overall landscape of alterations is summarized in Figures 1 and 2. After excluding variants of unknown significance, therapeutically relevant alterations were observed in 76 patients (55%), including BRAF mutations, ERBB2 amplifications, FGFR2 fusions, FGFR2 mutations, and IDH1 mutations seen in 21% of patients. A different spectrum of alterations was observed in patients with early-onset BTC (younger than age 50 years) compared with older patients (older than age 50 years). CONCLUSION Data on ctDNA in BTC is currently limited. Our study, the largest cohort reported to date to our knowledge, demonstrates the feasibility of ctDNA testing in this disease. We provide a foundation upon which the field can continue to grow.

Favorable Outcomes in FGFR Fusion-Positive Cholangiocarcinomas and Evolution on Treatment Noted on Circulating Tumor DNA Liquid Biopsies

“…Tumor-based (whether tissue and/or liquid where tissue is not available) genetic testing using NGS platforms should become standard of care for all metastatic CCA patients [7]. This should be endorsed by guidelines and societies so that payers would reimburse as opposed to patients/physicians being responsible for fighting denials when ordered resulting in added financial costs/anxiety.…”

Comprehensive Genomic Landscape and Precision Therapeutic Approach in Biliary Tract Cancers

“…[7][8][9][10]24 To our knowledge, the detailed comprehensive genomic landscape of biliary tract cancers by using clinicalgrade ctDNA as well as its concordance analysis with tissue-DNA are limited. 25 We now demonstrate that each biliary tract cancer patient has distinct pattern of ctDNA and tissue-DNA genomic alterations which are frequently druggable and that targeted matched therapies based on the molecular profiling are associated with higher response rates and longer progression-free survival.…”

“…A previous study reported that 55% of patients with biliary tract cancers had therapeutically relevant characterized ctDNA alterations although genes considered as targetable were somewhat different with our study. 25 Altogether, nearly all biliary tract cancer patients had unique pattern of genomic alterations in ctDNA and tissue-DNA NGS, indicating that these two different sequencing techniques can be complementary. These findings also suggest the potential for precision clinical trials in biliary tract cancers, as well as that customized molecular targeting based on each individual genomic portfolio may be necessary to improve outcomes.…”

Targeted Therapies in Advanced Biliary Tract Cancer: An Evolving Paradigm

“…The largest study that evaluated the utility of ctDNA analysis in patients with advanced BTC enrolled 124 patients (70% patients with iCCA) who underwent ctDNA-based molecular profiling utilizing a clinically available NGS-based assay (Guardant 360) [39]. In this study, at least one therapeutically relevant alteration was observed in 55% of patients, and 21% of patients had one of the frequently occurring alterations, which included BRAF mutations, ERBB2 amplification, FGFR2 fusions, FGFR2 mutations, and IDH1 mutations.…”