Handbook of Targeted Cancer Therapy and Immunotherapy

103 Hepatobiliary In biliary tract cancers (BTCs), approximately 40% to 50% of patients have targetable alterations, and treatment has become more precision oncology driven. Although the sensitivity and concordance between liquid and tissue biopsy have improved in this patient popu lation, now up to 80% to 90% with two samples in driver genes, assay characteristics are still limited for it to serve as a diagnostic tool (29). In patients in whom sufficient cytologic or tissue sampling is not possible for molecular profiling, ctDNA-detected targetable alterations can inform therapy. In BTC, liquid biopsies can also serve as a means for disease monitoring on targeted therapy and detecting acquired resistance mutations through serial measurements in patients who have base line ctDNA positivity (29). Serial liquid biopsies in three patients who were treated with infigratinib, the small molecule FGFR inhibitor, in the phase II clinical trial had shown multiple point mutations in the kinase domain of FGFR2 in postprogression analysis (30). Such serial monitoring can aid in tailoring subsequent therapy to overcome resistance (31). In hepatocellular carcinoma (HCC), cfDNA with alfa-fetoprotein (AFP) in 24 patients with HCC and 62 patients with chronic hepatitis B with varying levels of fibrosis was able to distinguish HCC with a sensitivity and specificity of 87% and 100%, respectively, using what the authors referred to as HCC index (cfDNA, AFP, and age) (32). cfDNA from patients with HCC is more fragmented and shorter than in those with benign liver conditions and patients without liver disease. Methylation patterns, single-nucleotide mutations, and chromosomal rearrangements have been associated with disease detection. The CancerSEEK panel described earlier had shown 98% sensitivity and 99% specificity for distinguishing 44 HCC patients from 812 healthy controls (26). These panels require additional rigorous validation studies with incorporation of benign diseases before they would be ready for clinical practice (33). Challenges to Liquid Biopsies We have outlined the potential uses of ctDNA in various GI malignancies. In most cancer types, studies have shown the ability to distinguish disease from controls with varying sensitivity and specificity. Challenges to bringing these tools to the clinic include the limit of detection of assays

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