A. Rizzo, A. Ricci, G. Gadaleta-Caldarola, G. Brandi
{"title":"胆管癌的精确肿瘤学:临床试验设计和靶向治疗的当前问题","authors":"A. Rizzo, A. Ricci, G. Gadaleta-Caldarola, G. Brandi","doi":"10.1080/23808993.2021.2008144","DOIUrl":null,"url":null,"abstract":"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","PeriodicalId":12124,"journal":{"name":"Expert Review of Precision Medicine and Drug Development","volume":null,"pages":null},"PeriodicalIF":1.0000,"publicationDate":"2021-11-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"1","resultStr":"{\"title\":\"Precision oncology in cholangiocarcinoma: current issues in clinical trial design and access to targeted therapies\",\"authors\":\"A. Rizzo, A. Ricci, G. Gadaleta-Caldarola, G. Brandi\",\"doi\":\"10.1080/23808993.2021.2008144\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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\",\"PeriodicalId\":12124,\"journal\":{\"name\":\"Expert Review of Precision Medicine and Drug Development\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":1.0000,\"publicationDate\":\"2021-11-29\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"1\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Expert Review of Precision Medicine and Drug Development\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1080/23808993.2021.2008144\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"PHARMACOLOGY & PHARMACY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Expert Review of Precision Medicine and Drug Development","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1080/23808993.2021.2008144","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"PHARMACOLOGY & PHARMACY","Score":null,"Total":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
期刊介绍:
Expert Review of Precision Medicine and Drug Development publishes primarily review articles covering the development and clinical application of medicine to be used in a personalized therapy setting; in addition, the journal also publishes original research and commentary-style articles. In an era where medicine is recognizing that a one-size-fits-all approach is not always appropriate, it has become necessary to identify patients responsive to treatments and treat patient populations using a tailored approach. Areas covered include: Development and application of drugs targeted to specific genotypes and populations, as well as advanced diagnostic technologies and significant biomarkers that aid in this. Clinical trials and case studies within personalized therapy and drug development. Screening, prediction and prevention of disease, prediction of adverse events, treatment monitoring, effects of metabolomics and microbiomics on treatment. Secondary population research, genome-wide association studies, disease–gene association studies, personal genome technologies. Ethical and cost–benefit issues, the impact to healthcare and business infrastructure, and regulatory issues.