LAUSR

To the Editor, Cholangiocarcinomas (CCA) consist in an heterogeneous group of cancers developed from biliary cells. According to their anatomical origin along the biliary tree, CCAs are classified into three distinct entities: intrahepatic CCAs (iCCA), hilar or peri‐hepatic tumors, and distal CCAs developed from the extrahepatic bile ducts. iCCA is the second most common liver cancer after hepatocellular carcinoma, and shows a poor overall prognosis with a 5‐year survival less than 10% for patients with advanced disease. For unresectable CCAs, current first‐line therapy is based on gemcitabine plus cisplatin‐based chemotherapy and relapse is a frequent event. Several high‐throughput sequencing studies have identified a number of molecular abnormalities in CCAs that may be targeted, including IDH1/2 mutations, HER2 amplifications or FGFR2, RET and NTRK rearrangements. The identification of such mutations could enable clinicians to use an appropriate targeted therapy for their patients and thus improve patient survival. Currently, several small‐molecule inhibitors are investigated in clinical trials for cholangiocarcinoma patients such as ERK1/2 oral inhibitors (NCT04566393), BRAF inhibitor (NCT04190628), or IDH1 inhibitor (NCT02989857). The Food and Drug Administration, have also recently approved an oral selective FGFR inhibitor, pemigatinib, for second‐line treatment in locally advanced or metastatic CCAs for patients harboring FGFR2 fusions. Altogether, the landscape of therapeutic options is drastically evolving and holds promises to improve the prognosis of this aggressive neoplasm. In this line, we herein report a case of a patient with an iCCA harboring an ALK rearrangement. A 76‐year‐old male patient consulted in our hospital for a prostatic adenocarcinoma, treated by radiotherapy. Follow‐up imaging revealed a 6 cm liver mass associated with elevated serum tumor markers: CA 19.9 150U/mL and ACE 8.5 μg/L. Alpha‐fetoprotein (AFP) plasmatic concentration was 3.3 μg/L. The lesion was biopsied and a microscopic examination showed a glandular architecture, with marked cytological atypia. Immunohistochemical experiments indeed showed high Cytokeratin 7 and 19 expression with lack of PSA, TTF1, CDX2, and PAX8 expression. A diagnosis of iCCA was rendered. The patient further underwent a left hepatectomy. No remote nor nodal metastasis were found. As part of our diagnostic workflow, DNA and RNA were extracted from formalin fixed‐paraffin embeded tumor material and analyzed with the Next Generation Sequencing (NGS) Panel Oncomine Comprehensive Assay v3 using Ion S5 sequencer (ThermoFisher Scientific, Waltham, MA, USA) to look for targetable molecular alterations. Data were interpreted with the Ion Reporter Server. We were able to identify the existence of an EML4‐ALK transcript, and the ALK rearrangement was further confirmed by fluorescence in situ hybridization (FISH), using an ALK break apart probe (ZytoLight SPEC ALK Dual Color Break Apart Probe, Ref. Z‐2124DAKO). We can observe a yellow colocalization signal or red and green signals side by side for nonrearranged cells. By contrast, ALK‐rearranged cells (94 out of 100 nuclei) show a separate red and green signals or an isolated red signal (Figure 1a). Immunohistochemical (IHC) analysis showed strong ALK overexpression by neoplastic cells (Figure 1b). To the best of our knowledge, this is only the third report indicating the occurrence of ALK rearrangement in cholangiocarcinoma. Non‐small cell lung carcinomas tumors harboring ALK or ROS1 rearrangement are sensitive to first, second and third generations of ALK tyrosine kinase inhibitor (TKI). Interestingly, a study reported that a 56‐year‐old patient with cholangiocarcinoma carrying a ROS1 gene fusion (RDX‐ROS1), achieved a durable response to crizotinib, first ALK/ROS1 TKI, with a decreased level of CA19‐9 in serum and a decrease in tumor mass on computed tomography scans. Our patient died of metastatic prostatic cancer and could unfortunately not benefit from crizotinib. To date, three phase 2 clinical trials (NCT02374489, NCT02638909 and NCT02568267) are assessing tyrosine kinase inhibitors (ceritinib and entrectinib) efficacy in solid tumors including ALK, ROS1 or NTRK rearranged cholangiocarcinomas. Phase 1 first results were encouraging, particularly for three out of five patients with cholangiocarcinoma, including one who achieved a complete response for 10.3 months. These results should enable further investigations into the combination of ceritinib and