Colorectal cancer (CRC), gastroenteropancreatic neuroendocrine neoplasm (GEP-NEN), and cholangiocarcinoma (CCA) exhibit high rates of morbidity and mortality once metastasized to the liver. Liver transplantation (LT) is a viable therapeutic approach for these cancers in highly selected patients; however, their invasive nature at late stages causes many patients to be delisted from transplantation or to require further downstaging. Immunotherapy with immune checkpoint modulators has revolutionized cancer research. Immune checkpoint inhibitors (ICI) leverage the chronic inflammatory state and the overexpression of cytotoxic T lymphocyte antigen 4 (CTLA-4) and programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) by malignant cells and regulatory T cells, to block immune checkpoints and counteract tumor's ability to evade the immune system. However, the interaction between allograft PD-L1 and PD-1 on infiltrating T cells functions as a means of graft tolerance in cases of LT. Therefore, the application of ICIs might block this protective effect and induce graft rejection, a phenomenon particularly observed in PD-1/PD-L1 inhibiting ICIs. The risk of post-LT graft rejection can be mitigated by applying advanced biomarkers and specifying certain mutations that enhance patient selection criteria for pre-LT ICI use. Furthermore, the determination of optimal intervals of ICI administration pre- and post-LT, identification of ICI indications in de novo malignancies occurring after LT, and investigation of biomarkers for early rejection detection, pave the way for more promising LT outcomes in patients with CRC, GEP-NEN, or CCA. Therefore, this review aims to illustrate a comprehensive overview of the role of ICI therapy in the management of non-hepatocellular carcinoma transplant oncology cancers by demonstrating the potential for its application in both pre-and post-LT states, and pathways to reduce or timely detect ICI-associated graft rejection.

The growing interest in post-translational protein modification, particularly in SUMOylation, is driven by its crucial role in cell cycle regulation. SUMOylation affects various cell cycle regulators, including oncogenes, suggesting its relevance in cancer. SUMO E3 ligases are pivotal in this process, exhibiting diverse functionalities through structural domains and subcellular localizations. A less-explored SUMO E3 ligase, RANBP2, a component of the vertebrate nuclear pore complex, emerges as a central player in cellular cycle processes, as well as in tumorigenesis. The current studies illuminate the importance of RANBP2 and underscore the need for more extensive studies to validate its clinical applicability in neoplastic interventions. Our review elucidates the significance of RANBP2 across various types of malignancies. Additionally, it delves into exploring RANBP2 as a prospective therapeutic target for cancer treatment, offering insights into the avenues that scholars should pursue in their subsequent research endeavors. Thus, further investigation into RANBP2's role in solid tumorigenesis is eagerly awaited.

R0 resection is the standard for mass-forming cholangiocarcinoma (MFCCC). R1vasc resection (tumor-vessel detachment) yielded results comparable to R0 and superior to parenchymal-tumor exposure (R1par) for hepatocellular carcinoma and colorectal liver metastases. This study aims to clarify R1vasc outcomes for MFCCC.

Margin status of patients with MFCCC undergoing resection between 2008 and 2022 was assessed to determine the oncological efficacy of R1vasc regarding survival and hepatic recurrence.

The study analyzed 125 patients: 68 (54.4%) R0, 18 (14.4%) R1vasc, 24 (19.2%) R1par, and 15 (12.0%) R1vasc + par. Tumor size was similar between R0 (4.4 cm, range 1.5-19.0) and R1vasc (4.3 cm, range 2.3-14.5, p = 0.754) but larger for R1par (8.2 cm, range 2.5-15.0, p = 0.005) and R1vasc + par (9.0 cm, range 5.0-17.0, p < 0.001). The median overall survival (OS) was comparable for R0 [64.8 months; 95% confidence interval (CI): 50.0-79.6], R1vasc (54.4 months; 95% CI 19.6-89.2; p = 0.932), and R1vasc + par (62.0 months; 95% CI 35.6-88.5; p = 0.989). R1par showed lower OS (26.8 months; 95% CI 16.1-37.6; p = 0.134). Local recurrence was higher for R1par (45.8%, p < 0.0001) compared with R0 (10.3%) and similar for R1vasc (16.6%) and R1vasc + par (20.0%). Survival after hepatic recurrence was higher for R1vasc compared with R1par (p = 0.041).

R1vasc is a valid option for increasing resectability in patients with MFCCC, with OS being comparable to R0. R1vasc + par may be necessary for larger tumors.

Cholangiocarcinoma is a highly lethal disease with a 5-year overall survival rate of 7-20%. A minority of patients present with resectable disease, and relapse rates remain high. Emerging data from next generation sequencing analysis have identified various actionable mutations which drive the different disease courses opening door to precision medicine and targeted therapies. This review focuses on the clinical significance of genetic alterations as well as the role of systemic therapies, immunotherapy and targeted therapies for intrahepatic cholangiocarcinoma.

Hepatobiliary malignancies encompass a spectrum of invasive carcinomas arising in the liver [hepatocellular carcinoma (HCC), bile ducts [intrahepatic cholangiocarcinoma (ICC), and extrahepatic cholangiocarcinoma (EHC)] and the gallbladder. These malignancies represent a growing global health burden, with rising incidence and mortality rates and their overall prognosis remains poor because many patients present with advanced unresectable disease at diagnosis. In recent years, significant advancements in understanding HCC immunogenicity have reshaped the therapeutic scenario of advanced HCC with the immunotherapy revolutionizing the current HCC treatment landscape and patients' prognosis. Moreover, the addition of immunotherapy to chemotherapy has recently established a new standard of care first-line treatment for patients with biliary tract cancers (BTCs) who had historically few therapeutic options. Currently, immunotherapy and immune checkpoint inhibitor (ICI)-based regimens stand as a valuable and practice-changing options in both HCC and BTC management. The mounting recent evidence supporting immunotherapy's survival benefit demands clinicians to stay updated with a rapidly evolving treatment landscape as well as gain knowledge about patient selection, response rate compared with other systemic treatments and immune-mediated adverse events (imAEs) management. A panel of international Experts, comprising hepatologists and oncologists, gathered to explore the challenges in effectively integrating immunotherapy in routine clinical practice. The aim of this review is to present the Experts' insights to inform treatment choice in HCC and BTC with a special emphasis on the role of currently available ICI-based therapies in shifting treatment paradigms and potentially reversing the natural course of these two deadly malignancies.

BackgroundIntrahepatic cholangiocarcinoma (ICC) presents a significant clinical challenge due to its high fatality rate and limited surgical candidacy. With only 30-40% of patients eligible for surgery upon diagnosis, alternative therapies are imperative. This study assesses the efficacy of Yttrium-90 (Y-90) radioembolization for unresectable ICC patients in a non-university tertiary care center (NUTCC).MethodsA retrospective analysis of 15 unresectable ICC patients treated with Y-90 radioembolization was conducted. Tumor response, survival, and adverse events were evaluated using RECIST criteria.Results60% of patients exhibited partial response, and 20% showed stable disease, with notable tumor size reduction and a median survival of 14 months. Minimal adverse effects were observed, indicating Y-90's favorable safety profile.ConclusionY-90 radioembolization shows potential in reducing tumor burden and enhancing survival rates with minimal adverse effects for unresectable ICC. Larger prospective studies are needed to confirm its efficacy and define its role in ICC treatment protocols.

Induction treatment may be beneficial in patients with unresectable locally advanced perihilar cholangiocarcinoma (LAPCCA). Prospective studies are currently lacking. This study aimed to assess the feasibility and efficacy of gemcitabine and cisplatin as induction treatment in patients with unresectable LAPCCA.

In this prospective single-center registration study, consecutive patients with unresectable LAPCCA who received induction treatment with gemcitabine and cisplatin in an intent to downsize the tumor to allow for resection were included. The primary outcomes were resection rate and overall survival.

Overall, 265 patients with perihilar cholangiocarcinoma were screened between January 2020 and June 2023, of whom 23 patients (9%) with unresectable LAPCCA met the eligibility criteria. Eight patients (35%) became eligible for resection, of whom six ultimately underwent resection (resection rate, 26% (11-42%)). Two out of 23 patients (9%) experienced adverse events grade≥3, forcing one to stop induction treatment. Compared to baseline, CA19.9 levels decreased by 42% (95 % CI, -65 to -5%; P = 0.039) and 8% (-44 to 112%; P = 0.80) at the first and second restaging, respectively. Tumor size did not significantly decrease after chemotherapy. Median overall survival was 19 months (12 to not available (NA)), with NA (19 to NA) in the resected group vs. 15 (11 to NA) in the unresected group (P=0.127). Two-year survival rates were 67% (38 to 100) and 31% (15 to 67), respectively.

Patients with LAPCCA frequently tolerate induction gemcitabine-cisplatin, leading to a 26% resection rate with an improved two-year survival rate of 67%. These findings support routine re-staging after three to six cycles of palliative treatment, and lay the groundwork for future prospective trials in this patient group.

Incidental gallbladder cancer (iGBC) diagnosed post-histopathological examination of gallbladders removed assuming benign gallstone disease constitutes a significant proportion of GBC patients. Most iGBC patients present with early-stage disease. The standard care for localized (non-metastatic) iGBC includes a reoperation for complete extended (radical) cholecystectomy involving liver resection and lymphadenectomy, followed by postoperative adjuvant systemic therapy. However, a major drawback of this approach is the high recurrence rate within six months post-radical surgery, which undermines the benefits of the extensive procedure; notably, most recurrences are distant, highlighting the efficacy of systemic therapy. Similar to other gastrointestinal cancers, there appears to be a potential for neoadjuvant systemic therapy (chemotherapy) before reoperative surgery in iGBC cases. The premise that neoadjuvant systemic therapy aids in selecting diseases with more favorable biological characteristics and addresses micro-metastatic disease appears applicable to iGBC as well. This systematic review examines the current evidence supporting or refuting neoadjuvant therapy and discusses criteria for selecting patients who would derive significant benefit, along with proposing an optimal chemotherapy regimen for iGBC patients. Improved outcomes have been reported in patients undergoing reoperation after 4 to 14 weeks following the initial cholecystectomy compared to immediate reoperation. Limited, yet promising, evidence supports the use of 3 to 4 cycles of gemcitabine-based neoadjuvant chemotherapy prior to reoperative surgery in select high-risk iGBC cases.

The standard regimen of gemcitabine combined with cisplatin offers limited clinical benefits in the treatment of advanced intrahepatic cholangiocarcinoma (ICC) due to intrinsic or acquired resistance. Currently, effective biomarkers to predict and improve chemotherapy resistance in ICC are lacking. Here, it is reported that a long non-coding RNA (lncRNA), PAX8-AS1, reduces the efficacy of standard chemotherapeutic drugs. Mechanistically, PAX8-AS1 activates NRF2 by binding to p62, thereby promoting GPX4 transcription, and stabilizes GPX4 mRNA through interaction with IGF2BP3. The PAX8-AS1/GPX4 axis inhibits ferroptosis and promotes resistance to gemcitabine and cisplatin. In preclinical models, the combination of the GPX4 inhibitor JKE-1674 with gemcitabine and cisplatin exhibits superior antitumor efficacy. These findings suggest a promising therapeutic strategy to improve chemotherapy efficacy in advanced ICC.

Unresectable intrahepatic cholangiocarcinoma (iCCA) is characterized with dismal prognosis. Here, this study aimed to compare the efficacy and safety of hepatic arterial infusion chemotherapy (HAIC) combined with lenvatinib and PD-1 inhibitors versus systemic chemotherapy (SC) for unresectable iCCA.

Patients with histologically confirmed unresectable iCCA from January 2020 to December 2022 at our center were retrospectively enrolled. Propensity score matching (PSM) method was used to balance clinicopathological information between two groups. The primary endpoints were overall survival (OS), progression-free survival (PFS), whereas the secondary endpoints included objective response rate (ORR), disease-control rate (DCR) and safety profiles. Factors affecting the survival were identified through univariate and multivariate analyses.

Eighty-six cases were included in this study. After PSM, there were 30 patients in each group. Compared to SC group, HAIC + Len + PD-1 inhibitor exhibited significantly improved OS (16.91 [95%CI: 11.6-28.4] months vs. 11.06 months [95%CI: 7.8-14.6 months], p = 0.011), PFS (11.17 months [95%CI: 7.0, 26.7] vs. 5.55 months [95%CI: 3.8, NA], p = 0.004), better ORR (56.7% vs. 23.3%, p = 0.008) and DCR (93.3% vs. 70.0%, p = 0.019). Multivariate analysis indicated that treatment arm of SC was a risk factor of worse OS and PFS, while uni-lobe tumor distribution, AST ≤ 40, CA19-9 level ≤ 39 were protective factors of worse OS. All adverse events were comparable and controllable between two groups.

In conclusion, HAIC combined with lenvatinib and PD-1 blockade yields better tumor control and survival outcomes over SC for unresectable iCCA, with manageable adverse events as well.

Ampullary carcinoma (AC) is a rare disease with an abysmal prognosis and few treatment options. The molecular landscape and its therapeutic implications remain inadequately understood. This study aims to provide a clinical and genomic characterization of AC and explore opportunities for precision oncology.

We carried out a retrospective analysis of clinical and genomic features in patients with AC treated in our institution. Gene mutations were categorized into molecular pathways, and potentially targetable alterations were classified according to the European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of Molecular Targets (ESCAT). Key molecular findings were validated in an external cohort.

We included 78 patients with a median age of 66 years; 51.6% were women, and most were treated with surgery (81.2%). Histologically, they were classified as pancreaticobiliary (58.3%), intestinal (INT, 33.3%), and mixed (8.3%). The percentages of patients diagnosed at stages I, II, III, and IV disease were 18.8%, 23.4%, 32.8%, and 25.0%, respectively. Of note, the INT subtype was enriched in transforming growth factor-β pathway alterations (25.9% versus 6.1%, P = 0.03). Potentially actionable molecular alterations were found in 52% of the patients. Importantly, KRASWT tumors were enriched in potentially targetable alterations ESCAT I-IIIA both in our cohort (37.2% versus 9.4%, P = 0.006) and external validation cohort (23.0% versus 9.3%, P = 0.01), including 25.6% ERBB2 amplification/mutation, 14.0% homologous recombination deficiency status, and 7.4% microsatellite instability status. Six patients received matched targeted therapies after progression to chemotherapy, with a response rate of 50% and two patients surviving for >1 year.

AC patients are enriched in targetable alterations, especially KRASWT tumors, and could particularly benefit from precision oncology-based approaches.

Cholangiocarcinoma (CCA) is a type of cancer with few effective systemic therapies. Elucidation of the molecular landscape of the disease from genomic studies based on next-generation sequencing (NGS) has contributed to the introduction of new targeted therapies. One of these treatments consists of a class of small molecules that target members of the fibroblast growth factor receptors (FGFRs) family of receptor tyrosine kinases. We report here on a patient with a cholangiocarcinoma bearing an FGFR2 mutation. The patient was treated with 2 different FGFR inhibitors, as the first caused ocular toxicity. She obtained clinical benefits from both. This case illustrates the efficacy of FGFR inhibitors on cholangiocarcinoma with specific point mutations.

Liver transplantation for cancer indications has gained momentum in recent years. This review is intended to optimize the care setting of liver transplant candidates by highlighting current indications, technical aspects and barriers with available solutions to facilitate the guidance of available strategies for healthcare professionals in specialized centres.

A review of the most recent relevant literature was conducted for all the cancer indications of liver transplantation including colorectal cancer liver metastases, hilar cholangiocarcinoma, intrahepatic cholangiocarcinoma, neuroendocrine tumours, hepatocellular carcinoma and hepatic epitheloid haemangioendothelioma.

Transplant benefit from the best available evidence, including SECA I, SECA II, TRANSMET studies for colorectal liver metastases, various preoperative protocols for cholangiocarcinoma patients, standard, extended selection criteria for hepatocellular carcinoma and neuroendocrine tumours, are discussed. Innovative approaches to deal with organ shortages, including machine-perfused deceased grafts, living donor liver transplantation and RAPID procedures, are also explored.

Cancer indications for liver transplantation are here to stay, and the selection criteria among all cancer groups are likely to evolve further with improved prognostication of tumour biology using adjuncts such as radiomics, cancer genomics, and circulating DNA and RNA status. International prospective registry-based studies could overcome the limitations of smaller patient cohorts and lack of level 1 evidence.

Patients with cholangiocarcinoma (CCA) have poor prognosis. Current cisplatin-based first-line chemotherapy offers limited survival benefits. Cisplatin induces single-strand DNA breaks, activating DNA repair mechanisms that diminish its effectiveness. Here, we present the design, chemical synthesis, and therapeutic evaluation of a new generation of chemotherapeutic agents (Aurkines) with unique polyelectrophilic properties. These agents cause a high frequency of double-strand DNA breaks, bypassing DNA repair, and promoting cancer cell death.

Two novel compounds, Aurkine 16 and Aurkine 18, were designed and evaluated for their antitumor effects in both naïve and cisplatin-resistant CCA cells, cancer-associated fibroblasts (CAFs), healthy cholangiocytes, and in vivo models.

Aurkines effectively induced double-strand DNA breaks, leading to increased DNA damage and elevated levels of reactive oxygen species, resulting in greater cytotoxicity than cisplatin in CCA cells. Phosphoproteomic and molecular analysis revealed that cisplatin activates DNA repair pathways, while Aurkines primarily induce apoptosis. Importantly, Aurkines also triggered apoptosis in cisplatin-resistant CCA cells and CAFs without harming healthy cholangiocytes. Additionally, Aurkines demonstrated cytotoxicity in other cisplatin-resistant cancers, such as breast and ovarian cancer. This tumor selectivity results from reduced uptake, increased efflux, and compact chromatin structure in normal cells, limiting Aurkine-DNA interactions. In vivo, Aurkines inhibited the growth of subcutaneous naïve and cisplatin-resistant CCA tumors, as well as orthotopic tumors in immunocompetent mice promoting antitumor immune cell recruitment, without any adverse events. Transport studies revealed that Aurkines were selectively taken up by OCT1, OCT3, CTR1, and OATP1A2, whereas only CTR1 transported cisplatin.

Aurkines represent promising therapeutic drugs for both naïve and cisplatin-resistant cancers due to their unique polyelectrophilic properties and selective targeting of malignant cells.

This study introduces a novel therapeutic strategy designed to induce frequent double-strand DNA breaks selectively in both naïve and cisplatin-resistant cancer cells, without evident toxic side effects at therapeutic doses. This approach may settle the basis for new strategies to overcome the critical challenge of drug resistance in cancer treatment, and has the potential to be a breakthrough not only for the treatment of biliary tumors but also for other cancers.

Intrahepatic cholangiocarcinoma (ICC) remains one of the most lethal malignancies with an increasing incidence worldwide. Gemcitabine has been considered the standard first-line chemotherapeutic agent for ICC but the therapeutic response is unsatisfactory due to the development of chemoresistance. Caspase-3-mediated pyroptosis has been reported to play significant roles in chemotherapeutic response but the relevant therapeutic strategy remains unstated due to the unclear molecular mechanisms under pyroptosis in ICC.

This study was designed to comprehensively explore the crucial role and underlying mechanisms of NRXN3 in pyroptosis and chemosensitivity of ICC.

We performed genome-scale CRISPR-Cas9 screen integrated with transcriptomic analysis to identify key regulators of pyroptosis and gemcitabine sensitivity in ICC. In vitro and in vivo experiments were employed to investigate the effects of NRXN3 on gemcitabine-induced pyroptosis. RNA-seq and IP-MS were conducted to explore the mechanisms of NRXN3-regulated pyroptosis and chemosensitivity.

NRXN3 was identified to be a critical contributor to pyroptosis and chemosensitivity in ICC. Low NRXN3 expression correlates with poor prognosis and worse therapeutic response. Mechanistically, NRXN3 competitively blocks caspase-3 binding to the RSK1 serine/threonine-protein kinase, thereby inhibiting RSK1-dependent phosphorylation of caspase-3 at T152. Inhibition of caspase-3 phosphorylation impairs its interaction with the ubiquitin ligase component FBXO1 and enhances its stability, thus facilitating caspase-3/GSDME-dependent pyroptotic cell death and chemosensitivity. Furthermore, administration of an RSK1 inhibitor or caspase-3 activator boosts the efficacy of gemcitabine in murine models of ICC.

NRXN3 plays a crucial role in maintaining chemotherapy-induced pyroptosis in ICC. Targeting the NRXN3/RSK1/FBXO1/caspase-3 axis emerges as a promising strategy for ICC treatment, with the potential to improve chemosensitivity and survival.

Biliary tract cancers (BTCs) include intrahepatic, perihilar, distal cholangiocarcinoma, gallbladder cancer, and sometimes papillary Vater cancer. The incidence of BTCs varies worldwide (0.3-85.0/100,000 population). In Japan, the incidence is lowest, but it is increasing (22,000 cases/ year). The 5-year overall survival (OS) in patients with localized BTC is approximately 60%, which is better than that in liver or pancreatic cancer, but is < 5% in patients with metastatic cancers. Surgery requires liver and pancreas surgery with vascular reconstruction, and is associated with a high perioperative mortality rate (> 2%) relative to other cancer surgeries (< 1%). As an adjuvant therapy, fluorouracil prodrugs are effective for improving OS (hazard ratio [HR] 0.69-0.81); however, in patients who receive major hepatectomy, the completion rate is reportedly low (60%). Since 2010, gemcitabine + cisplatin (GC) has become the first-line therapy for unresectable lesions. Subsequently, in 2023-2024 three triplet regimens were reported: GC + S-1(tegafur-gimeracil-oteracil), GC + durvalumab (an anti-PD-L1 antibody), and GC + pembrolizumab (an anti-PD-1 antibody). HRs for OS were 0.79-0.83, objective response rates were 27-42% (GC, 15-29%), and tumor control rates were 75-85% (GC, 62-83%) with small increases in adverse events. In this review, considering the eligibility criteria of currently ongoing neoadjuvant studies, we report two borderline resectable cases with a discussion on resectability. Owing to the high-risk nature of the surgery and to avoid early recurrence due to subclinical metastasis during postoperative recovery, these three triplet regimens for unresectable tumors may change the concept of resectability in BTC.

Chemoresistance contributes to poor outcomes in patients with intrahepatic cholangiocarcinoma (ICC). This study aimed to explore the mechanisms underlying chemotherapy resistance and to develop strategies that can sensitize the chemotherapy. Patient derived organoids (PDOs) drug screening and Lipidomics profiling were performed to investigate the chemoresistance mechanism. Through multi-strategy analysis, we found that SENP3 enhanced chemotherapy sensitivity in a SUMO system dependent manner. Mechanistically, chemotherapy resistance increased METTL3 expression, which regulated SENP3 mRNA stability through YTHDF2-dependent m6A methylation modifications. SENP3 interacted with HADHA and catalyzed its deSUMOylation at two lysine residues. Specifically, SUMOylation and ubiquitination exhibited crosstalk at the same modification sites on HADHA, influencing its protein stability and, consequently, regulating fatty acid oxidation (FAO) levels. The physical interaction of SENP3, HADHA, and USP10 provides a novel molecular mechanism for the abnormal activation of FAO pathway. The lipid metabolism-targeting drug could be a promising therapeutic strategy for sensitizing ICC to chemotherapy.

Hepatobiliary cancers are heterogeneous and molecularly complex. Recent advances in next-generation sequencing (NGS) have enhanced the understanding of their molecular landscape and enabled deployment of biomarker-based gene- and immune-targeted therapies. This review examines the role of molecular testing and targeted therapies in these malignant neoplasms.

Patients with hepatobiliary cancers have poor outcomes. Precision oncology studies have shown that while many common molecular alterations are not currently targetable in hepatocellular carcinoma (HCC), a large number of actionable alterations characterize biliary tract cancers (BTCs), with several therapies now approved by the US Food and Drug Administration. Immunotherapy is increasingly adopted in clinical practice, either as monotherapy or combined with cytotoxic chemotherapy, for both HCC and BTCs. Moreover, multiple solid cancer tumor-agnostic therapies are approved (larotrectinib, entrectinib, and repotrectinib for NTRK fusions; selpercatinib for RET fusions; dabrafenib and trametinib combination for BRAF V600E mutations; dostarlimab or pembrolizumab for tumors with high microsatellite instability and pembrolizumab for tumor mutation burden ≥10 mutations/megabase), highlighting the need for NGS as well as ERBB2 (formerly HER2) immunohistochemistry (IHC) (with the recent approval of solid tissue-agnostic deruxtecan trastuzumab for ERBB2-positive [IHC 3+] cancer) across cancers. N-of-1 clinical trials using customized drug combinations matched to the tumor's molecular profile have yielded encouraging results and provide a promising framework for future clinical trial design.

Molecular testing and gene- and immune-targeted therapies are transforming hepatobiliary cancer treatment. Tumor-agnostic and N-of-1 clinical trials have challenged traditional clinical trial paradigms and provide the foundation for truly personalized oncology for patients with these aggressive cancers. Further work is needed to determine how to leverage these novel approaches into the management of operable disease.

Mass-forming intrahepatic cholangiocarcinoma (MF-ICC) is the second most common primary liver cancer and liver resection offers the best chance of possible cure. This study aimed to assess treatment outcomes and prognostic factors for long-term survival in patients who underwent curative-intent liver resection.

A retrospective analysis was conducted on prospectively collected data from patients with MF-ICC managed at the Royal North Shore/North Shore Private Hospital from January 1998 to October 2023. Baseline, peri-operative and long-term outcomes have been analysed, including an overall survival (OS) and disease-free survival (DFS) analysis.

During the 25-year study period, 47 patients underwent curative-intent liver resection for primary MF-ICC at a median age of 70 years. The median OS was 36 months, with a 5-year OS of 33%. Multiple liver tumours (HR = 2.84; 95% CI = 1.24-6.48; P = 0.013) and a positive resection margin (HR = 2.46; 95% CI = 1.10-5.52; P = 0.029) were identified as independent predictors of poor long-term OS. Recurrence occurred in 62% of patients after a median DFS of 16 months, with poor tumour differentiation (HR = 3.93; 95% CI = 1.62-9.54; P = 0.002) and elevated tumour markers (HR = 3.47; 95% CI = 1.53-7.87; P = 0.003) as independent predictors of poor DFS.

Liver resection can offer a significant chance for prolonged survival in a highly selected population of patients with MF-ICC. However, the surgical challenges inherent in treating this rare disease are evident, emphasizing the need for a multimodal approach and continued exploration of additional therapies to enhance personalized treatment strategies.

The efficacy and safety of pemigatinib in advanced cholangiocarcinoma (aCCA) were presented in phase I-II trials and retrospective reports, with small sample sizes and variable results.

A systematic literature search included studies investigating the efficacy/safety of pemigatinib in aCCA harboring FGFR fusions/rearrangements. Primary outcomes were objective response rate (ORR) and treatment-related adverse events (AEs). A pooled proportion meta-analysis was performed.

Three hundred and twenty-seven patients in eight studies were included (three phase-II, one phase-I/II, two phase-I, and two retrospective). In the pooled analyses, the median age was 58.9 years (95% confidence interval (CI): 51.9-65.8); 33.4% (95% CI: 28.1-39.0) were male. Pemigatinib was the second-line treatment in 58.5% (95% CI: 52.7-64.1) and was beyond second-line in the remaining. ORR was 42.2% (95% CI: 35.9-48.7) (I2:48.4%) and disease control rate (DCR) was 86.5% (95% CI: 81.6-90.5) (I2: 58.8%). Median progression-free survival (PFS) was 7.8 months (95% CI: 6.2-9.4) (I2: 11.6%). Two studies reported overall survival (OS) (median 17.5 and 17.1 months). The most common AEs (any grade) were hyperphosphatemia (46%), dysgeusia (33.2%), alopecia (31.4%), fatigue (30.9%), stomatitis (28.5%), and diarrhea (27.5%). Cumulative eye and nail toxicities were observed in 32.5% and 40.9%, and retinal detachment in 5.5%.

This analysis emphasizes the FGFR alteration testing and pemigatinib use in the second-line and beyond treatment of aCCA.

CRD42024627459.

The prognosis for patients with advanced biliary tract cancer (BTC) who have not responded to gemcitabine and cisplatin (GP)-based therapy is dismal. Fluorouracil (5-FU)-based chemotherapy could be considered for those patients who are refractory to GP-based treatments. Our study aimed to evaluate the real-world efficacy and safety of 5-FU-based chemotherapy for BTC patients who had progressed after gemcitabine-based treatment.

This study analyzed patients from Seoul St. Mary's Hospital and St. Vincent's Hospital with advanced BTC who had previously failed treatment with GP-based chemotherapy. From June 2020 and May 2024, these patients received 5-FU-based chemotherapy as a second-line treatment. The 5-FU-based systemic treatments encompassed 5-FU, leucovorin, and oxaliplatin (FOLFOX); 5-FU, leucovorin, and liposomal irinotecan (Nal-IRI/FL); and 5-FU, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX). Our investigation focused on evaluating the survival outcomes and safety profiles of each regimen within this cohort.

In our analysis of 147 patients, the primary tumor sites were distributed with 56 (38.1%) having intrahepatic cholangiocarcinoma, 51 (34.7%) with extrahepatic cholangiocarcinoma, and 40 (27.2%) with gallbladder cancer. Regarding the 5-FU-based regimens, 57 patients (38.8%) were treated with FOLFOX, 56 (38.1%) with Nal-IRI/FL, and 34 (23.1%) with FOLFIRINOX. The median progression-free survival (PFS) and overall survival (OS) were 2.3 months (95% confidence interval (CI), 2.0-2.6) and 4.8 months (95% CI, 3.8-5.8), respectively. Poor performance status and higher histologic grade were associated with worse PFS and OS, while female gender and prior surgery were linked to improved OS. FOLFOX and Nal-IRI/FL demonstrated comparable efficacy, with a median OS of 5.4 months (95% CI, 3.5-7.3) for FOLFOX and 4.7 months (95% CI, 2.6-6.9) for Nal-IRI/FL, and no significant differences were observed across subgroups. Grade 3 or higher neutropenia and biliary events were less frequent with FOLFOX, which also showed a lower incidence of adverse events and higher relative dose intensity than Nal-IRI/FL or FOLFIRINOX.

In patients with advanced BTC who failed GP treatment, the FOLFOX regimen demonstrated comparable efficacy, and a more favorable safety profile compared to other 5-FU-based treatments. Given its favorable toxicity profile in a real-world setting, FOLFOX should be considered a standard second-line treatment option.

Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer whose incidence is increasing globally. However, the high tumor heterogeneity of ICC restricts the efficacy of available systematic therapies. We aim to dissect the tumor heterogeneity of ICC utilizing high-resolution single-cell RNA sequencing to identify novel therapeutic targets.

We performed single-cell RNA sequencing (scRNA-seq) of 26 tumor samples from 23 ICC patients and spatial transcriptomic sequencing of six tumor sections from six ICC patients. Bulk RNA-seq data from two public datasets were used for validation. Additionally, immunohistochemical staining and multiplex immunofluorescence staining were conducted to validate the infiltration and distribution of cells in the tumor microenvironment.

We discovered that malignant cells in ICC samples exhibited a remarkably high degree of tumor heterogeneity. We identified a basal-like tumor cell subpopulation characterized by the expression of basal epithelial related genes including KRT5, KRT6A, and KRT17. The basal-like tumor subpopulation was characterized by activation of MET signaling and extracellular matrix organization associated with tumor invasion and correlated with poor prognosis. Cell-cell communication analysis further showed significant HGF-MET interaction between inflammatory cancer-associated fibroblasts (iCAFs) and basal-like tumor cells. We found that iCAFs were the major source of HGF in tumor environment and contributed to the basal-like phenotype formation of tumor cells by HGF-MET axis.

We identified an aggressive basal-like tumor cell subpopulation, which correlated with poor prognosis in ICC. The MET pathway contributes to the aggressiveness of basal-like tumor cells and serves as a novel therapeutic target for ICC.

Chemotherapy (CT) is the standard of care for patients presenting with unresectable advanced gallbladder carcinoma (GBC) but their prognosis remains poor. The value of consolidation CT and radiation therapy (RT) after initial CT is uncertain. We, therefore, conducted a single-center open-label randomized trial evaluating consolidation CTRT versus observation after 4 cycles of CT in patients whose disease did not progress during CT (partial responders/stable disease).

Responders to 4 cycles of CT were randomized (1:1) to CTRT versus observation (n = 135). CTRT was delivered using 3-dimensional-conformal RT (Field in the field when required) along with concurrent capecitabine. The dose of RT was 45 Gy in 25 fractions to GBC and lymphatics followed by a boost of 9 Gy in 5 fractions to the GBC. The primary endpoint was overall survival (OS) which was calculated from the date of randomization.

A total of 67 patients were randomized to observation and 68 to CTRT. Consolidation CTRT led to an improvement in median OS from 4 to 10 months (hazard ratio, 0.43; 95% CI, 0.32-0.62; P < .001). The actual median OS from accrual was 7 months (95% CI, 6.114-7.88 months) versus 13 months (95% CI, 11.13 -14.84 months). Adverse events (grade 3 or higher) because of CTRT were nausea (3%), anemia (9%), gastrointestinal bleeding (5.8%), and hepatotoxicity (13%). Functional Assessment of Cancer Therapy-General score and the Functional Assessment of Cancer Therapy-Hepatobiliary score did not deteriorate because of CTRT compared with observation (P values, .053 and .097).

To our knowledge, this is the first-ever randomized study in a low-middle-income country setting to demonstrate that consolidation CTRT significantly prolonged OS without deterioration in quality of life and should be the alternative standard of care in advanced unresectable GBC.

Recent years have witnessed significant advances in the imaging, molecular profiling, and systemic treatment of cholangiocarcinoma (CCA). Despite this progress, the early detection, precise classification, and effective management of CCA remain challenging. Owing to recent developments and the significant differences in CCA subtypes, EASL commissioned a panel of experts to draft evidence-based recommendations on the management of extrahepatic CCA, comprising distal and perihilar CCA. Particular attention is given to the need for accurate classification systems, the integration of emerging molecular insights, and practical strategies for diagnosis and treatment that reflect real-world clinical scenarios.

Liquid biopsy has already proven effective in aiding diagnosis, risk stratification and treatment personalization in several malignancies, and it could represent a practice-changing tool also in biliary tract cancer, even though clinical applications are currently still limited. It is promising for early diagnosis, especially in high-risk populations, and several studies on circulating free DNA (cfDNA), circulating tumour cells and differential microRNA (miRNA) profiles in this setting are ongoing. Circulating tumour DNA (ctDNA) also appears as a feasible noninvasive biomarker in the curative setting, in detecting minimal residual disease after resection and in monitoring disease recurrence. As of today, it can be particularly valuable in biliary tract cancer for genomic profiling, with a good concordance with tissue samples for most molecular alterations. CtDNA analysis may especially be considered in clinical practice when the tumour tissue is not sufficient for next-generation sequencing, or when urgent therapeutic decisions are needed. Moreover, it offers the possibility of providing a real-time picture to monitor treatment response and dynamically identify resistance mutations, potentially representing a way to optimize treatment strategies.

Gallbladder cancer (GBC) arises from the malignant transformation of epithelial cells that line the gallbladder mucosa. The likelihood of developing GBC escalates with advancing age, and the condition generally presents a dismal prognosis. Despite this, there is a limited amount of research focusing on the prognostic determinants linked to GBC. As a result, this study sought to create a nomogram for evaluating GBC prognostic factors.

In this investigation, a total of 8,615 cases of GBC from the Surveillance, Epidemiology, and End Results (SEER) database spanning from 2000 to 2020 were collected. In a 7:3 ratio, these instances were randomly assigned to one of two groups: training or internal validation. To assess the impact of clinical variables on overall survival (OS) in patients with GBC, both univariate and multivariate Cox regression analyses were utilized. The clinical criteria established were used to develop a nomogram. The effectiveness of the nomogram was evaluated through several approaches, such as receiver operating characteristic (ROC) curves, decision curve analysis (DCA), calibration curves, and Kaplan-Meier (KM) analysis.

To predict the prognosis of GBC patients, a nomogram was created based on the following criteria: sex, rural-urban continuum, marital status, nodes, histology, radiation, chemotherapy, metastasis, age, surgery, and grade. The training set had an area under the curve for 1-year, 3-year, and 5-year OS of 0.79, 0.78, and 0.78, respectively. The DCA curves demonstrated that the model was clinically useful and well-corrected. Patients with GBC were categorized into high-risk and low-risk groups based on the median risk score. KM curves revealed a significantly lower survival rate for the high-risk group in comparison with the low-risk group (P < 0.001).

Our model demonstrated strong predictive capabilities for the prognosis of GBC patients, thereby aiding in the refinement of treatment strategies for these individuals.

Pembrolizumab has been introduced to solid cancers with microsatellite instability (MSI)-high cases; however, its clinical experience for cholangiocarcinoma remains very limited. Here, we present a case who successfully underwent conversion surgery following pembrolizumab treatment for MSI-high perihilar cholangiocarcinoma, which pathologically exhibited complete response.

A 69-year-old male with Bismuth IV perihilar cholangiocarcinoma with bulky lymphadenopathy was referred, who initially required left hepatic trisectionectomy, caudate lobectomy, bile duct resection, and portal vein resection and reconstruction (H123458-B-PV). During the waiting period after preoperative portal vein embolization, the right hepatic artery was involved by rapid tumor progression, needing a modification of the initially scheduled surgical procedure to additional hepatic artery resection and reconstruction (H123458-B-PV-HA). We revised the surgical decision of resectable to locally unresectable disease. He received systemic chemotherapy with gemcitabine and cisplatin as first-line, showing the best effect of stable disease followed by slight tumor progression and re-elevation of tumor marker after 5 courses of treatment. Cancer multi-gene panel analysis using percutaneous biopsy specimen showed the nature of MSI-high. Therefore, he received pembrolizumab treatment as second-line therapy, leading to a drastic downsize >30% in tumor diameter and normalization of the tumor marker as well after only 2 cycles of administration. After confirmation of keeping tumor shrinkage during 22 courses of pembrolizumab treatment without any severe adverse events, we decided to perform conversion surgery and performed left trisectionectomy, caudate lobectomy, and bile duct resection with portal vein resection (H123458-B-PV). Although the right hepatic artery was extensively fibrotic, there was no evidence of malignancy by frozen section histologic diagnosis. The pathological findings showed pathological complete response with no residual tumor cells. The patient is under periodical checkup without adjuvant chemotherapy, and no tumor recurrence was observed at 4 months postoperatively.

We experienced clinical partial response but pathological complete response after second-line pembrolizumab treatment for unresectable locally advanced perihilar cholangiocarcinoma with a biologic nature of MSI-high. Conversion surgery may be considered as a promising option for such effective case, whereas there is a possibility to avoid resection in the MSI-high setting.

Biliary tract cancers (BTCs) are classified on the basis of their anatomical origin, and the feasibility of surgical resection depends on the tumor location and extent of progression. However, for unresectable BTCs, systemic therapy has been uniformly applied. Gemcitabine and cisplatin (GC) therapy and GC-based therapies were established as the first-line standard BTC treatment. However, no highly effective second-line therapy has been established, and the prognosis remains poor, highlighting the need for further therapeutic advancements. Meanwhile, the era of precision medicine has expanded the use of genetic testing, leading to the identification of actionable molecular targets in BTC. Several targeted therapies, including FGFR inhibitors and IDH1 inhibitors, have been developed, offering new second-line treatment options and the potential for first-line use in appropriate cases. Notably, the frequency of these genetic alterations varies depending on the tumor location, demonstrating the molecular heterogeneity of BTC. Therefore, it has been recognized that a tailored treatment approach for each BTC patient may be more effective than uniform systemic therapy. Consequently, although routine genetic testing before initiating systemic treatment is currently limited by the medical environment (e.g., cost, accessibility, regional differences), it is recommended in ESMO guideline and might be increasingly advocated. However, BTC harbors a wide range of genetic alterations, and numerous targeted therapies are being developed accordingly. This review provides an overview of the reported genetic alterations in BTC, the frequencies of these alterations, and the corresponding targeted therapies, emphasizing the evolving role of precision medicine in BTC treatment.

The KEYNOTE-966 study demonstrated that pembrolizumab combined with chemotherapy is more effective than chemotherapy alone as first-line treatment for patients with advanced biliary tract cancer (BTC). However, the cost-effectiveness of pembrolizumab combined with chemotherapy in the USA and China remains uncertain.

This study aimed to evaluate the cost-effectiveness of pembrolizumab plus chemotherapy compared with placebo plus chemotherapy from the perspective of US and Chinese payers.

Markov models with three health states were developed to simulate the process of advanced BTC. Cost data were obtained from available databases and published literature in the US scenario, and from local institutions from the China scenario. Utility values were derived from previous studies.

Primary outcomes included quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs).

In the US scenario, pembrolizumab plus chemotherapy increased costs by US$97,222.13, compared with chemotherapy alone, with a gain of 0.12 QALYs, resulting in an ICER of US$810 184.42 per QALY. In the China scenario, the ICER was $360 933.50 per QALY. Sensitivity analyses indicated the costs of pembrolizumab had the greatest impact on the model in both scenarios. Further analyses suggested that the optimal price of pembrolizumab in the USA would be nearly US$10.33 /mg, while a price reduction of over 90% would be required for the combined therapy to be cost-effective for patients in China.

Based on the willingness-to-pay threshold set at three times the gross domestic product per capita, pembrolizumab plus chemotherapy is not a cost-effective option for patients with advanced BTC in either the USA or China. Significant price reduction for pembrolizumab may be necessary to achieve an acceptable ICER.

NCT04003636; postresults.

The prevalence of intrahepatic cholangiocarcinoma (ICC) is increasing globally. Despite advancements in comprehending this intricate malignancy and formulating novel therapeutic approaches over the past few decades, the prognosis for ICC remains poor. Owing to the high degree of malignancy and insidious onset of ICC, numerous cases are detected at intermediate or advanced stages of the disease, hence eliminating the chance for surgical intervention. Moreover, because of the highly invasive characteristics of ICC, recurrence and metastasis postresection are prevalent, leading to a 5-year survival rate of only 20%-35% following surgery. In the past decade, different methods of treatment have been investigated, including transarterial chemoembolization, transarterial radioembolization, radiotherapy, systemic therapy, and combination therapies. For certain patients with advanced ICC, conversion treatment may be utilized to facilitate surgical resection and manage disease progression. This review summarizes the definition of downstaging conversion treatment and presents the clinical experience and evidence concerning conversion treatment for advanced ICC.

The diagnosis of cholangiocarcinoma (CCA) remains challenging. Although new technologies have been developed and validated, their routine use in clinical practice is needed. Conventional cytology obtained during endoscopic retrograde cholangiopancreatography-guided brushings is the first-line technique for the diagnosis of CCA, but it has shown limited sensitivity when combined with endoscopic ultrasound-guided biopsy. Other diagnostic tools have been proposed for the diagnosis of CCA, with their respective advantages and limitations. Cholangioscopy with biopsy or cytology combined with FISH analysis, intraductal biliary ultrasound and confocal laser microscopy have made significant advances in the last decade. More recently, developments in the analytical "omics" sciences have allowed the mapping of the microbiota of patients with CCA, and liquid biopsy with proteomic and extracellular vesicle analysis has allowed the identification of new biomarkers that can be incorporated into the predictive diagnostics. Furthermore, in the preoperative setting, radiomics, radiogenomics and the integrated use of artificial intelligence may provide new useful foundations for integrated diagnosis and personalized therapy for hepatobiliary diseases. This review aims to evaluate the current diagnostic approaches and innovative translational research that can be integrated for the diagnosis of CCA.

Intrahepatic cholangiocarcinoma (iCCA) is the second most common liver malignancy with poor prognosis and limited treatment options.

To identify the most effective drug for transarterial chemoembolization (TACE) in cholangiocarcinoma and evaluate the efficacy and safety of combining it with gemcitabine and cisplatin (GemCis) for unresectable iCCA.

Cholangiocarcinoma cell lines (RBE, HuCC-T1) were treated with 10 chemotherapeutic drugs, and cytotoxicity was assessed by cell counting kit-8 assays. Tumor-bearing nude mice were treated with idarubicin or GemCis, and tumor growth was monitored. Clinical data from 85 iCCA patients were analyzed to evaluate the efficacy and safety of idarubicin-TACE combined with GemCis.

Idarubicin demonstrated the highest cytotoxicity, significantly outperforming GemCis, the standard first-line therapies. In tumor-bearing mouse models, idarubicin and GemCis treatments significantly slowed tumor growth, with idarubicin showing particularly pronounced effects on days 12 and 15 (P < 0.05). In retrospective analysis, the median overall survival (OS) and progression-free survival (PFS) in the combination therapy group were significantly longer than those in the GemCis alone group (median OS, 16.23 months vs 10.07 months, P = 0.042; median PFS, 7.73 months vs 6.30 months, P = 0.023). Additionally, major grade 3/4 adverse events (AEs) in the combination therapy group were abdominal pain (26.3% vs 6.5%, P = 0.049) and elevated transaminases (42.1% vs 12.9%, P = 0.038). Most AEs were mild to moderate and manageable.

Idarubicin demonstrated higher cytotoxicity than GemCis, significantly inhibiting tumor growth in tumor-bearing mouse models. Preliminary clinical results suggest that local idarubicin-TACE combined with GemCis may offer improved survival outcomes for iCCA patients with a manageable safety profile.

The survival rate of patients with intrahepatic cholangiocarcinoma (ICC) is extremely low mainly because of its high metastatic characteristic, pushing us to explore effective targets inhibiting the metastasis of ICC.

To explore potential therapeutical targets to restrict the metastasis of ICC.

The potential targets were screened via RNA sequencing and verified in cells and tissues. The prognostic value of TMEM158 was explored in ICC patients. The abilities of TMEM158 on affecting the metastasis of ICC were detected in cells and mice models. The cell actin skeleton stiffness was measured by phalloidin staining. The effect of TMEM158 on lactic acid (LA) generation was explored via metabolic flow and relative mechanism was detected by co-immunoprecipitation and immunofluorescence. The relationship between HIF-1A and TMEM158 was explored by dual luciferase reporter gene experiment.

TMEM158 was identified as a potential candidate over-expressed in ICC, especially with metastasis, that is linked to reduced overall survival. Besides, functional studies indicated that TMEM158 silencing inhibits ICC metastasis in vivo and in vitro through decreasing cell actin skeleton stiffness of ICC cells, and visa versa. Moreover, mechanically, lactic acid (LA) is validated as the bridge connecting TMEM158 and skeleton stiffness and TMEM158 induces the generation of LA via interaction with and activating Ras protein and subsequently enhancing glucose transporter 3 (Glut3) mediated glycolysis in ICC cells. Finally, HIF-1A directly targets the promoter region of TMEM158 and thus increases its level in ICC.

TMEM158 reduced the actin skeleton stiffness of ICC cells through activating Ras protein mediated generation of LA, which finally results in enhanced metastasis of ICC. Our work provides a preclinical evidence of concept for TMEM158 as a novel candidate inhibiting the metastasis of ICC.

The current standard first-line treatment for patients with advanced biliary tract cancer (BTC) is a combination chemotherapy regimen. However, whether the efficacy of combination therapy is superior to that of monotherapy in older patients with BTC remains unclear. Therefore, in this study, we aimed to compare the efficacy and safety of monotherapy with those of combination therapy in such patients.

We retrospectively enrolled 157 patients with unresectable or recurrent BTC aged ≥ 75 years who received systemic chemotherapy between August 2011 and November 2020. We compared the efficacy and safety of combination therapy (gemcitabine [GEM] + cisplatin and GEM + S-1) with those of monotherapy (GEM or S-1 alone). We assessed patients' characteristics, survival, adverse events, and dose intensity. Statistical significance was set at p < 0.05.

Patients who received monotherapy were older and had worse performance status (PS), lower albumin levels, and higher carcinoembryonic antigen (CEA) levels than those who received combination therapy. The median overall survival (OS) was 16.4 and 12.8 months in the combination therapy and monotherapy groups, respectively (Hazard ratio [HR], 0.69; 95% confidence interval [CI], 0.47-1.01), with a trend towards longer OS observed with combination therapy. However, multivariable analysis did not show superior OS with combination therapy (HR, 1.05; 95% CI, 0.66-1.68). Multivariable analysis also revealed gallbladder cancer, CEA, neutrophil-to-lymphocyte ratio (NLR), and C-reactive protein (CRP) levels as prognostic factors for OS. Regarding safety, the incidence of grade ≥ 3 adverse events was significantly higher in the combination therapy group than in the monotherapy group (79% vs. 53%, p = 0.001); however, the rate of treatment discontinuation was approximately 10% in both groups, with no treatment-related deaths, suggesting that toxicities are manageable even in older patients.

Combination therapy is not necessarily recommended for older patients with BTC. Selecting an appropriate chemotherapy regimen based on an individual's condition is important.

Advanced biliary tract cancers (ABCs) are a heterogeneous group of rare malignancies of the bile ducts and gall-bladder with a poor prognosis and limited treatment options. Cisplatin-gemcitabine (CISGEM) chemotherapy plus immunotherapy (durvalumab or pembrolizumab) is the current first-line standard of care (1L-SoC). ABCs frequently harbour actionable molecular alterations that suggest a high potential for benefit from molecular targeted therapies (MTTs). However, the assessment of potential first-line MTT treatments is hindered by the scarcity of ABCs harbouring a specific alteration and the time required to carry out tumour molecular profiling.

We detail here the design of SAFIR-ABC10, an international, randomised, phase III umbrella trial comparing the efficacy of sequential matched targeted therapy after four cycles (12 weeks) of 1L-SoC versus continued 1L-SoC in patients with ABC and an actionable molecular alteration [European Society for Medical Oncology (ESMO) Scale for Clinical Actionability of molecular Targets (ESCAT) tier I or II]. The primary study endpoint is progression-free survival. Besides initial tumour and circulating DNA next-generation sequencing analysis, sequential blood and tumour sampling will be carried out to identify biomarkers of prognosis, response and acquired resistance.

SAFIR-ABC10 is, to our knowledge, the first randomised, umbrella trial assessing the concept of precision medicine in ABC, the ideal setting for addressing this question with a high rate of targetable alterations.