Comparison of genomic profiling of circulating tumor DNA in pancreaticobiliary malignancies in plasma and bile

Abstract

Background: Obtaining sufficient pancreaticobiliary tumor tissue for genomic profiling has limitations. Liquid biopsies using plasma do not provide sufficient sensitivity. Thus, this study aimed to determine the effectiveness of liquid biopsy between bile and plasma for identifying oncogenic and drug-matched mutations.Methods: This study created a panel of 60 significantly mutated genes specific to pancreaticobiliary cancer (PBCA) and used it for genomic analysis of 212 deoxyribonucleic acid (DNA) samples (87 bile supernatant, 87 bile precipitate, and 38 plasma) from 87 patients with PBCA. The quantity of extracted DNA from bile and plasma was compared, as were genomic profiles of 38 pairs of bile and plasma from 38 patients with PBCA. Finally, we investigated 87 bile and 38 plasma for the ability to detect druggable mutations. Results:The amount of DNA was significantly lower in plasma than in bile (p < .001).Oncogenic mutations were identified in 21 of 38 (55%) patients in bile and nine (24%) in plasma samples (p = .005). Bile was significantly more sensitive than plasma in identifying druggable mutations (p = .032). The authors detected 23 drugmatched mutations in combined bile and plasma, including five ERBB2, four ATM, three BRAF, three BRCA2, three NF1, two PIK3CA, one BRCA1, one IDH1, and one PALB2.Conclusions: Liquid biopsy using bile may be useful in searching for therapeutic agents, and using the obtained genomic information may improve the prognoses of patients with PBCA.

Bile as a liquid biopsy matrix: potential applications and limitations

“…Most of the studies reported above compare the performance obtained with paired tissue and bile samples, and all concur in that more genomic alterations could be detected in bile than in the corresponding tissue, in agreement with the fact that LB recapitulates tumor heterogeneity better than tissue biopsy [22,55,56,112]. In addition, the better sensitivity for cancer detection obtained in bile than in plasma is well demonstrated [21,22,55].…”

“…Most of the studies reported above compare the performance obtained with paired tissue and bile samples, and all concur in that more genomic alterations could be detected in bile than in the corresponding tissue, in agreement with the fact that LB recapitulates tumor heterogeneity better than tissue biopsy [22,55,56,112]. In addition, the better sensitivity for cancer detection obtained in bile than in plasma is well demonstrated [21,22,55]. All in all, the increased sensitivity of new technologies, as well as the possibility to assess the presence of druggable-mutations, has boosted the potential utility of bile for both diagnosis of malignancy and targeting therapy.…”

“…Moreover, its relatively confined nature and location reduce the possibility of detecting aberrant biomarkers coming from another diseased organ, increasing the specificity of the results. In fact, in this context, as a tumor-adjacent fluid, several studies have shown that the analysis of bile outperforms that of blood, and in addition has the potential to recapitulate tumor heterogeneity [20][21][22][23].…”

Promise of bile circulating tumor DNA in biliary tract cancers

“…Further work in this field will need to determine the etiology of the differences in oncogenic mutations between bile and plasma ctDNA and establish the clinical settings for when each will be most informative. The work from Ohyama et al 8 . is an important step in this progression.…”

“…In this issue of Cancer , Ohyama and colleagues 8 report a prospective study evaluating the performance of both plasma and bile cfDNA in 87 patients (59 cholangiocarcinoma [CC], 12 gallbladder cancer [GBC], and 16 PC). They found that bile had a higher sensitivity for the identification of oncogenic mutations than plasma (56% vs. 24%, respectively), and the variant allele frequency was overall higher in bile than plasma.…”