{'fraction_non_alphanumeric': 0.0273224043715847, 'fraction_numerical': 0.011514441842310695, 'mean_word_length': 5.536989795918367, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
Precision oncology in cholangiocarcinoma: current issues in clinical trial design and access to targeted therapies

Cholangiocarcinomas (CCAs) include a heterogeneous group of hepatobiliary tumors accounting for approximately the 10–15% of primary liver cancers [1]. Unfortunately, most of these tumors are diagnosed at an advanced stage, and more than ten years after the publication of the landmark phase III ABC-02 trial establishing gemcitabine-cisplatin as first-line standard for metastatic CCA, the prognosis of this patient population remains grim [2]. In fact, most of patients treated with front-line treatment fail to achieve a response or responses are short lived [3]. Recent years have witnessed the advent of molecular profiling in this setting, and new techniques and technologies have led to the identification of a variety of molecular alterations in CCA [4]. Over the last decade, several potentially actionable genetic aberrations have been highlighted, and precision oncology approaches have been evaluated and are under investigation in these hepatobiliary malignancies (Figure 1). A large number of anticancer agents are currently in development, including Fibroblast Growth Factor Receptor (FGFR) 2, Isocitrate Dehydrogenase 1 (IDH-1), and BRAF inhibitors [5]. FGFR2 aberrations have been reported in approximately the 20% of intrahepatic cholangiocarcinomas (iCCAs), with these alterations highlighted as most common in female patients and young adults [6]. Of note, FGFR2 aberrations are mainly represented by fusions, while mutations are detected only in a minority of patients. As regards IDH-1, missense mutations are the most frequent aberrations, involving a single residue in the active site of the enzyme [7]; typically, IDH-1 missense mutations have been reported to be more common in small duct type iCCAs and in poorly differentiated or undifferentiated forms [8]. Several other molecular aberrations have been observed in CCA patients, including BRCA mutations, NTRK fusions, and BRAF V600E mutations [9,10]. Nonetheless, several questions remain unanswered, and the adoption of precision oncology in CCA patients remains still far from everyday clinical practice, with some important exceptions. Among current obstacles, a crucial point to highlight is the limited access to anticancer treatments. For example, although the final overall survival (OS) analysis of the ClarIDHy phase III trial has been presented and on 25 August 2021 the FDA approved ivosidenib use in IDH-1 mutant iCCA, the IDH-1 inhibitor is not available in several countries, according to different choices by the regulatory agencies [11]. Second, biopsy samples are often inadequate for molecular profiling since tissue sampling has reported low sensitivity in the diagnosis of malignant biliary strictures; in fact, the highly desmoplastic nature of CCA severely limits the accuracy of pathological and cytological methodologies. On the basis of these premises, it is urgent to develop in this scenario novel strategies aimed at anticipating the diagnosis by detecting CCA at an early, resectable stage, as well as to obtain adequate material to perform genomic analysis. Among these strategies, liquid biopsy may represent a fundamental tool, although the use of this technique is still limited and has to be implemented in the near future [12]. A long-standing issue is also represented by the genomic diversity of CCAs that also mirrors anatomical, epidemiological, and therapeutical differences. In fact, it is currently well known that these malignancies should not be considered as a single entity but a group of tumors with heterogeneous features. However, several trials still group together different anatomical CCA subgroups, such as iCCA, perihilar CCA, and distal CCA, something that represents a ‘historical’ issue in clinical trial design in these hepatobiliary malignancies. Stratification of patients according to CCA subgroup should always be present in studies on these tumors, also considering that distinct subgroups are associated to different molecular features, clinical outcomes and prognosis. In our opinion, another landmark topic in this setting is represented by clinical trial enrollment, something that remains a priority in CCA due to the difficulties encountered in enrolling patients with these rare hepatobiliary tumors. For example, the ClarIDHy and the FIGHT-202 trials on ivosidenib and pemigatinib, respectively, enrolled more than a hundred CCA patients, requiring important efforts in terms of screening and enrollment [13–15]. Similarly, the investigators of the phase II, singlearm, ROAR trial evaluating dabrafenib plus trametinib in BRAF V600E-mutated CCAs, had to prescreen 626 subjects to enroll 43 CCA patients, a figure that highlights the difficulties in completing such a trial [16]. Conducting clinical studies in rare CCA subgroups with genetic aberrations remains a compelling challenge, and international collaborations are of pivotal importance in this setting. This is even more important in CCA patients whose disease has progressed following first-line or