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

Abstract

Cholangiocarcinoma is a very heterogenous cancer and "target-rich" disease. While the current classifications are based on the anatomic location of these tumors (intrahepatic cholangiocarcinoma, extrahepatic cholangiocarcinoma, and gallbladder cancer), tumors within and across these disease groups have unique and often mutually exclusive molecular aberrations. Amongst these, fibroblast growth factor receptor 2 (FGFR2) fusion is one of the first amongst the list of "actionable" targets for which the US Food and Drug Administration just approved pemigatinib. This is for patients with cholangiocarcinoma who have received prior treatment and have FGFR2 fusion or another rearrangement. This was based on the results from the clinical trial FIGHT-202 (NCT02924376). At present, several FGFR inhibitors are actively being tested in several agnostic and tumor-specific clinical trials. Patients also have had the opportunity of getting access to some of these oral drugs through compassionate use programs. As a consequence, these patients have more options in addition to chemotherapy. These all tend to have "good" initial responses and improvement in performance status and later "acquired" mechanisms of resistance. The latter tend to often be gatekeeper mutations that bypass the inhibitory effects of these selective FGFR inhibitors and/or cause steric hindrance. These tumors, therefore, evolve on selective pressure (temporal heterogeneity). This can be captured noninvasively using "liquid biopsies" (circulating tumor DNA testing). Here we present cases (several years into treatment on average) showing the feasibility of using liquid biopsies (ctDNA testing) as well as the gain and later potential loss of intratumoral and tempo

A Pancancer Analysis of the Expression Landscape and Clinical Relevance of Fibroblast Growth Factor Receptor 2 in Human Cancers

“…A previous study reported that FGFR2 fusions are observed mostly in cholangiocarcinoma, occurring in 10-16% of patients (24,44,45). In our study, we found that cholangiocarcinoma had the highest frequency of FGFR2 alteration, and fusion accounted for the major proportion.…”

Comparative Genomic Analysis of Intrahepatic Cholangiocarcinoma: Biopsy Type, Ancestry, and Testing Patterns

“…Liquid biopsy followed by sequencing of circulating tumor DNA (ctDNA) allows for noninvasive mutational profiling, and recently published studies suggest that Lbx profiling can interrogate tumor heterogeneity in cholangiocarcinoma and other gastrointestinal cancers, as well as acquired resistance mutations to FGFRis [29, 30]. Additionally, clinical responses to FGFRis solely based on Lbx profiling have been reported [30, 31]. However, discordance between Pbx and Lbx in small datasets has been observed, which can be caused by a variety of factors including baiting differences between assays and usage preferences [32, 33].…”

Sustained response on sequential anti-FGFR therapy in metastatic gall bladder cancer: a case report and literature review

“…Previously published data points towards the potential role of sequential anti-FGFR therapy in CCA. [23][24][25] As gallbladder cancer shares several clinical and pathological characteristics of CCA, it is reasonable to assume that a similar effect would likely be seen in these patients.…”