Precision oncology for intrahepatic cholangiocarcinoma in clinical practice

Abstract

Background Advanced cholangiocarcinoma has a poor prognosis. Molecular targeted approaches have been proposed for patients after progression under first-line chemotherapy treatment. Here, molecular profiling of intrahepatic cholangiocarcinoma in combination with a comprehensive umbrella concept was applied in a real-world setting. Methods In total, 101 patients received molecular profiling and matched treatment based on interdisciplinary tumour board decisions in a tertiary care setting. Parallel DNA and RNA sequencing of formalin-fixed paraffin-embedded tumour tissue was performed using large panels. Results Genetic alterations were detected in 77% of patients and included gene fusions in 21 patients. The latter recurrently involved the FGFR2 and the NRG1 gene loci. The most commonly altered genes were BAP1, ARID1A, FGFR2, IDH1, CDKN2A, CDKN2B, PIK3CA, TP53, ATM, IDH2, BRAF, SMARCA4 and FGFR3. Molecular targets were detected in 59% of patients. Of these, 32% received targeted therapy. The most relevant reason for not initiating therapy was the deterioration of performance status. Patients receiving a molecular-matched therapy showed a significantly higher survival probability compared to patients receiving conventional chemotherapy only (HR: 2.059, 95% CI: 0.9817–4.320, P < 0.01). Conclusions Molecular profiling can be successfully translated into clinical treatment of intrahepatic cholangiocarcinoma patients and is associated with prolonged survival of patients receiving a molecular-matched treatment.

BAP1 and PTEN mutations shape the immunological landscape of clear cell renal cell carcinoma and reveal the intertumoral heterogeneity of T cell suppression: a proof-of-concept study

“…DNA was extracted using a Maxwell 16 Research System (Promega, Madison, WI, USA), followed by quantification using the QuBit 2.0 DNA High Sensitivity Kit (Thermo Fisher Scientific, Waltham, MA, USA). Library preparation was performed as previously described [ 15 ]. DNA integrity was assessed using the Genomic DNA ScreenTape Analysis on a 4150 TapeStation System (Agilent Technologies, Santa Clara, CA, USA).…”

First proficiency testing for NGS‐based and combined NGS‐ and FISH‐based detection of FGFR2 fusions in intrahepatic cholangiocarcinoma

“…amplicon‐based assays, which rely on specific primers targeting FGFR2 and the corresponding specific exons of the partner genes, and partner‐agnostic assays (e.g. hybrid capture, single primer extension), which are – by design – able to detect known and unknown (novel) fusion partners [ 14 , 22 ].…”

Overall survival benefit of patients with biliary tract cancer receiving molecular profiling: a real-world multicenter retrospective cohort analysis

“…The main focus of the trial was to demonstrate the e cacy of precision medicine in BTC in routine clinical practice, as the current evidence is predominantly derived from Asian cohorts, patients from phase 1/2 clinical trials, or distinct anatomical subtypes 13,14,23,24 . Recommendations for targeted therapies as proposed, for example, in molecular tumor boards are often hampered by missing availability of the matched treatment due to the lack of cost coverage by insurance companies, clinical deterioration during NGS turnaround times, or low evidence levels in uencing the treating physician or patients 25 .…”

“…It is estimated that up to 50% of BTCs are potential candidates for molecular-informed therapy 9,10 . Several smaller phase I/II trials, basket trials, and case series show the potential of targeted treatment regimens in second-line and beyond [11][12][13][14] . Currently, testing for FGFR2 or NTRK fusion, IDH1 or BRAF hotspot mutations, and HER2/neu ampli cation or microsatellite status is strongly recommended by the new BTC ESMO guidelines 4 .…”

“…Whether the strategy of comprehensive molecular pro ling (NGS, RNA sequencing, immunohistochemistry) of all BTCs, at least in the second-line setting, is e cient in terms of outcome parameters in real-world conditions remains unclear. Although retrospective series suggest a clinical bene t of molecular pro ling, these analyses are hampered by the local availability of targeted treatments, advances in molecular techniques that expand potential molecular vulnerabilities, and ethnic differences in the molecular pro le of BTC 11,13 .…”