Cholangiocarcinoma With FGFR Genetic Aberrations: A Unique Clinical Phenotype

Abstract

Purpose FGFR genetic aberrations (GAs) occur in an estimated 10% to 16% of intrahepatic cholangiocarcinomas (CCAs). The natural history of CCA with FGFR GAs, the prognostic role of coexisting GAs, and the outcome with FGFR-targeted inhibitors are unknown. Patients and Methods Patients with CCA with FGFR GAs were identified using next-generation sequencing or fluorescence in situ hybridization from four tertiary cancer centers and compared with FGFR wild-type counterparts. Data reviewed included demographic, treatment, overall survival (OS), and GA data. Fisher’s exact test, Kaplan-Meier plots, and log-rank tests were used for statistical analysis. Results Three hundred seventy-seven patients with CCA were identified, and 95 had FGFR GAs. FGFR2 GA was most common (n = 74, with 63 fusions) and seen in intrahepatic CCA. In patients with CCA, FGFR GAs occurred more frequently in younger patients (≤ 40 years; 20%) compared with older patients (> 40 years; 6.7%; P < .001), presented at an earlier stage (TNM stage I/II v III/IV: 35.8% v 22%, respectively; P = .001), and were associated with a longer OS compared with patients without FGFR GAs (37 v 20 months, respectively; P < .001). This difference remained significant after excluding 36 patients treated with FGFR inhibitors. There was no OS difference ( P = .60) between CCA with FGFR2 fusions (n = 63) versus other FGFR GAs (n = 29). Patients with FGFR GAs had a better OS with FGFR-targeted therapy compared with standard treatment ( P = .01). BAP1 mutation was the most common coexisting mutation without prognostic impact, whereas TP53 ( P = .04) and CDKN2A/B ( P = .04) were correlated with a shorter OS. Conclusion CCA with FGFR GAs represents a unique subtype occurring in younger patients with an indolent disease course. FGFR-targeted therapy may have a positive impact on OS in this subgroup.

Use of an Integrated Pan-Cancer Oncology Enrichment Next-Generation Sequencing Assay to Measure Tumour Mutational Burden and Detect Clinically Actionable Variants

“…An additional advantage of panel-based designs is the ability to enrich RNA targets. Recent studies have shown the importance of RNA fusions such as the TMPRSS-ERG fusion in prostate cancer [16], the FGFR2 fusion in cholangiocarcinoma [17] and the NTRK fusion in lung and other cancers [18]. These fusions are either targetable with molecularly targeted agents (e.g.…”

Molecular targeted therapies: Ready for “prime time” in biliary tract cancer

“…136 Even though BICC1 is one of the most frequent fusion companions for FGFR2, multiple other partners have been identified. 84,92,94,132,137,138 It seems clear that FGFR2 fusions are more relevant than mutations when it comes to the treatment of iCCA. 139 Whether specific partners have any relevance in terms of carcinogenesis or response to therapy is still to be elucidated.…”

“…139,140 FGFR2 fusionpositive tumours seem to present with concomitant mutations in BAP1 90 and have been shown to be associated with indolent disease and a better prognosis. 91,92,138,141 Some research groups have also seen an association between BAP1 mutations and skeletal bone metastases. 92 FGFR aberrations were initially targeted with non-selective multi-TKIs such as dovitinib, ponatinib, lucitanib, lenvatinib, pazopanib and regorafenib that, in addition to targeting FGFR, also inhibited other tyrosine kinases including c-kit, FLT3, vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-SRC and RET.…”

“…The vast majority of patients included in the studies with FGFR inhibitors (>90%) were iCCA. This, together with the fact that FGFR aberrations have been shown to be associated with a more indolent disease course and better prognosis, 91,92,138,141 makes results even more difficult to compare and put into context in the absence of a randomised phase III clinical trial.…”

Liver resection and transplantation for intrahepatic cholangiocarcinoma

“…77 This type of genetic signature likely contributes to a more favourable biological behaviour, 76 as patients with FGFR had significantly higher overall survival (37 months vs. 20 months) compared to non-mutated patients. 78 In such a context, infigratinib, derazantinib and pemigatinib showed overall response rates of 19%, 21% and 36%, and disease control rates of 83%, 83% and 82%, respectively, even though progression-free survival remains around 6 months, mainly due to primary and secondary resistance. [79][80][81] These small molecules evaluated in phase II trials for advanced iCCA may possibly represent future alternative options in the adjuvant setting in light of premiminary data on their manageable toxicity.…”