Matched targeted therapies (MTT) given alone or in combination with systemic anti-cancer therapies have delivered proven survival benefit for many people with newly diagnosed cancer. However, there is little evidence of their effectiveness in the recurrent or late-stage setting. With this uncertainty, alongside the perception that late-stage cancers are too genetically heterogenous or too mutationally diverse to benefit from matched targeted therapies, next-generation sequencing (NGS) of tumours in people with refractory cancer remains a low priority. As a result, next-generation sequencing testing of recurrent or late-stage disease is discouraged. We lack evidence to support the utility of next generation sequencing in guiding matched targeted therapies in this setting.

To evaluate the benefits and harms of matched targeted therapies in people with advanced cancers in randomised controlled trials.

We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, ClinicalTrials.gov, and the World Health Organisation International Clinical Trials Registry Platform (WHO-ICTRP) search portal up to 30th October 2024. We also screened reference lists of included studies and also the publications that cited these studies.

We included randomised controlled trials (RCTs) that had enroled participants with advanced/refractory solid or haematological cancers who had progressed through at least one line of standard anti-cancer systemic therapy. To be eligible, all participants should have received matched targeted therapy based on next-generation sequencing carried out on their tumour (tumour tissue, blood or bone marrow).

We systematically searched medical databases (e.g. MEDLINE, Embase) and trial registers for randomised controlled trials (RCTs). Outcomes of interest were progression-free survival (PFS), overall survival (OS), overall response rates (ORR), serious (grade 3 or 4) adverse events (AEs) and quality of life (QOL). We used a random-effects model to pool outcomes across studies and compared predefined subgroups using interaction tests. Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment of certainty was used to evaluate the quality of evidence.

We identified a total of 37 studies, out of which 35 studies (including 9819 participants) were included in the meta-analysis. All included studies compared a matched targeted therapy intervention to standard-of-care treatment, non-matched targeted therapies or no treatment (best supportive care): Matched targeted therapy versus standard-of-care treatment Matched targeted therapy (MTT) compared with standard systematic therapy probably reduces the risk of disease progression by 34% (hazard ratio (HR) = 0.66, 95% confidence interval (CI) 0.59 to 0.74; 14 studies, 3848 participants; moderate-certainty evidence). However, MTT might have little to no difference in risk of death (HR = 0.85, 95% CI 0.75 to 0.97; 14 studies, 3848 participants; low-certainty evidence) and may increase overall response rates (low-certainty evidence). There was no clear evidence of a difference in severe (grade 3/4) adverse events between matched targeted therapy and standard-of-care treatment (low-certainty evidence). There was limited evidence of a difference in quality of life between groups (very low-certainty of evidence). Matched targeted therapy in combination with standard-of-care treatment versus standard-of-care treatment alone Matched targeted therapy in combination with standard-of-care treatment compared with standard-of-care treatment alone probably reduces the risk of disease progression by 39% (HR = 0.61, 95% CI 0.53-0.70, 14 studies, 2,637 participants; moderate-certainty evidence) and risk of death by 21% (HR = 0.79, 95% CI 0.70 to 0.89; 11 studies, 2575 participants, moderate-certainty evidence). The combination of MTT and standard-of-care treatment may also increase overall response rates (low-certainty evidence). There was limited evidence of a difference in the incidence of severe adverse events (very low-certainty evidence) and quality of life between the groups (very low-certainty of evidence). Matched targeted therapy versus non-matched targeted therapy Matched targeted therapy compared with non-matched targeted therapy probably reduces the risk of disease progression by 24% (HR = 0.76, 95% CI 0.64 to 0.89; 3 studies, 1568 participants; moderate-certainty evidence) and may reduce the risk of death by 25% (HR = 0.75, 95% CI 0.65 to 0.86, 1307 participants; low-certainty evidence). There was little to no effect on overall response rates between MTT and non-MTT. There was no clear evidence of a difference in overall response rates (low-certainty evidence) and severe adverse events between MTT and non-MTT (low-certainty evidence). None of the studies comparing MTT and non-MTT reported quality of life. Matched targeted therapy versus best supportive care Matched targeted therapy compared with the best supportive care (BSC) i.e. no active treatment probably reduces the risk of disease progression by 63% (HR 0.37, 95% CI 0.28 to 0.50; 4 studies, 858 participants; moderate-certainty evidence). There was no clear evidence of a difference in overall survival between groups (HR = 0.88, 95% CI 0.73 to 1.06, 3 studies, 783 participants; low-certainty evidence). There was no clear evidence of a difference in overall response rates (very low-certainty of evidence) and incidence of severe adverse events (very low-certainty of evidence) between the groups. Quality of life was reported in a single study but did not provide composite scores. Risk of bias The overall risk of bias was judged low for eight studies, unclear for two studies, and the remaining 27 studies were high risk.

Matched targeted therapies guided by next-generation sequencing in people with advanced cancer prolongs the time before cancer progresses compared to standard therapies. However, there is limited evidence to suggest that it prolongs overall survival, improves the quality of life or increases adverse events. Importantly, this review supports equitable access to next-generation sequencing technology for all people with advanced cancer and offers them the opportunity to access genotype-matched targeted therapies.

The plasma lipidome and immune cells are instrumental in shaping the health profile of an organism, and their influence on diseases is profound. However, the intricate interactions between cholangiocarcinoma (CCA) and these physiological components have yet to be comprehensively explored. Employing Mendelian randomization (MR), our study delved into the causal links among immune cells, the lipidome, and CCA. The research design meticulously considered both the direct associations and the mediating roles of immune cells within the complex interplay between the lipidome and CCA. Our analysis uncovered significant correlations between the levels of Sphingomyelin (d34:1), Phosphatidylcholine (0-16:0, 22:5) and Sterol ester (27:1/16:0) and CCA. Moreover, we have pinpointed various immune cells that play a mediating role in the impact of the lipidome on CCA. For example, Sphingomyelin (d34:1) can impact CCA through the IgD on IgD+ CD38- unswitched memory (unsw mem) B cell (B cell panel), IgD on unsw mem (B cell panel) and Naive CD4+ %CD4+ (maturation stages of T cell). The proportion of mediating effects further sheds light on the intricate interplay among the lipidome, immune cells, and their cumulative influence on CCA. Our study illuminates the intricate relationship among the lipidome, immune cells, and CCA. These findings suggest that the lipidome could serve as a promising and potentially effective therapeutic target in the treatment of CCA.

The current state of systemic therapy for advanced biliary tract cancer (BTC) has undergone significant changes. Currently, there are no clinical trials directly comparing various first-line systemic therapy regimens to each other, and these trials are unlikely to be conducted in the future. In this systematic review, after various abstracts and full-text articles published from the establishment of the database until October 2024 were searched, we included and analysed phase 3 clinical trials to evaluate the efficacy of different first-line systemic treatment regimens in advanced BTC. We used the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guidelines and a random effects model to pool the overall effects. Finally, seven low-risk-of-bias trials (with all of the trials representing first-line trials) were included. A total of 4033 patients were included in seven first-line trials. In terms of progression-free survival (PFS), network meta-analysis revealed that durvalumab + gemcitabine + cisplatin (GemCis) triple therapy, S-1 + GemCis triple therapy, and pembrolizumab + GemCis triple therapy were superior to GemCis. In terms of overall survival (OS), network meta-analysis revealed that durvalumab + GemCis triple therapy and pembrolizumab + GemCis triple therapy outperformed GemCis. According to the ranking of the P scores, durvalumab + GemCis triple therapy ranked first in PFS and second in OS. Therefore, the advantages of molecular immunotherapy have gradually become known, which suggests that future trials should focus on other potential combinations and molecular immunotargeted therapies.

Hepatocellular carcinoma (HCC) and biliary tract cancer (BTC) are significant health challenges in China because of their high prevalence and mortality rates. Advances in molecular diagnostics have opened new avenues for personalized treatment strategies. This consensus provides a comprehensive update on the clinical applications of molecular diagnostics in HCC and BTC and addresses the urgent need for personalized treatment strategies tailored to the Chinese population, emphasizing the importance of molecular markers in guiding targeted therapies and immunotherapies. By employing the Delphi method and the Grading of Recommendations Assessment, Development, and Evaluation system, the expert panel formulated evidence-based recommendations for the use of molecular diagnostics in the clinical management of HCC and BTC. Key molecular markers, such as isocitrate dehydrogenase (IDH) 1 and 2, fibroblast growth factor receptor 2 (FGFR2), BRAF V600E, human epidermal growth factor receptor 2 (HER2), rearranged during transfection (RET), and neurotrophic tyrosine receptor kinase (NTRK), are highlighted for their roles in optimizing treatment regimens. The consensus also explores the significance of emerging biomarkers, such as tumor mutation burden and microsatellite instability, in predicting responses to immune checkpoint inhibitors. The recommendations aim to enhance precision medicine approaches, improve patient outcomes, and foster the integration of molecular diagnostics into routine clinical practice.

Biliary tract cancer (BTC) is a heterogeneous group of aggressive malignancies that arise from the epithelium of the biliary tract. Most patients present with locally advanced or metastatic disease at the time of diagnosis. For patients with unresectable BTC, the survival advantage provided by systemic chemotherapy was limited. Over the last decade, immunotherapy has significantly improved the therapeutic landscape of solid tumors. There is an increasing number of studies evaluating the application of immunotherapy in BTC, including immune checkpoint inhibitors (ICIs), cancer vaccines and adoptive cell therapy. The limited response to ICIs monotherapy in unselected patients prompted investigators to explore different combination therapy strategies. Early clinical trials of therapeutic cancer vaccination and adoptive cell therapy have shown encouraging clinical results. However, there still has been a long way to go via validation of therapeutic efficacy and exploration of strategies to increase the efficacy. Identifying biomarkers that predict the response to immunotherapy will allow a more accurate selection of candidates. This review will provide an up-to-date overview of the current clinical data on the role of immunotherapy, summarize the promising biomarkers predictive of the response to ICIs and discuss the perspective for future research direction of immunotherapy in advanced BTC.

Advanced biliary tract cancers (BTCs) have historically been managed with chemotherapy but, in recent years, this treatment paradigm has begun to shift with the introduction of immune checkpoint inhibitors in addition to standard of care chemotherapy. The tumor microenvironment of BTC may be enriched with regulatory T lymphocytes and immune checkpoint expression in some patients. Durvalumab, an anti-programmed death ligand-1 (PD-L1) antibody, in combination with gemcitabine and cisplatin, has now received United States Food and Drug Administration approval for treatment of advanced BTC. Regulatory approval was based on the Phase III, randomized TOPAZ-1 trial that demonstrated survival benefit with addition of durvalumab to gemcitabine plus cisplatin compared to chemotherapy alone. The combination of chemotherapy and immunotherapy was well tolerated, and a subset of patients were able to achieve a durable response, with a 2-year overall survival rate of 23.6%. However, limitations remain in identifying which patients are most likely to benefit from immune checkpoint inhibition. Future study should aim to identify biomarkers predictive of substantial benefit, as well as the role of immune checkpoint inhibition in combination with targeted therapies and radiotherapy in the management of advanced BTC.

Cholangiocarcinomas (CCA) are a heterogeneous group of tumors that are classified as intrahepatic, perihilar, or distal according to the anatomic location within the biliary tract. Each CCA subtype is associated with distinct genomic alterations, including single nucleotide variants, copy number variants, and chromosomal rearrangements or gene fusions, each of which can influence disease prognosis and/or treatment outcomes. Molecular profiling using next-generation sequencing (NGS) is a powerful technique for identifying unique gene variants carried by an individual tumor, which can facilitate their accurate diagnosis as well as promote the optimal selection of gene variant-matched targeted treatments. NGS is particularly useful in patients with CCA because between one-third and one-half of these patients have genomic alterations that can be targeted by drugs that are either approved or in clinical development. NGS can also provide information about disease evolution and secondary resistance alterations that can develop during targeted therapy, and thus facilitate assessment of prognosis and choice of alternative targeted treatments. Pathologists play a critical role in assessing the viability of biopsy samples for NGS, and advising treating clinicians whether NGS can be performed and which of the available platforms should be used to optimize testing outcomes. This review aims to provide clinical pathologists and other healthcare professionals with practical step-by-step guidance on the use of NGS for molecular profiling of patients with CCA, with respect to tumor biopsy techniques, pre-analytic sample preparation, selecting the appropriate NGS panel, and understanding and interpreting results of the NGS test.

Background: Combined hepatocellular-cholangiocarcinoma (cHCC-CCA) is a highly aggressive malignancy with a poor prognosis. However, there are no consensus treatment guidelines, and decisions are usually extrapolated from intrahepatic cholangiocarcinoma (ICC) or hepatocellular carcinoma (HCC). Given that cHCC-CCA owns the unequivocal presence of both hepatocytic and cholangiocytic differentiation, a combination regimen of anti-PD1 antibody, multikinase inhibitor, and chemotherapy targeting against both components might be an optimal choice. Case presentation: We present the case of a patient with postoperative metastatic chemotherapy-resistant cHCC-CCA who exhibited a durable response and reasonable tolerability to a combination therapy consisting of the anti-PD1 antibody sintilimab, multikinase inhibitor lenvatinib, and nab-paclitaxel, despite having a low tumor mutational burden (TMB-L), microsatellite stability (MSS), and negative programmed cell death 1 ligand 1 (PD-L1). Conclusion: The combination regimen of immune checkpoint inhibitor sintilimab, multikinase inhibitor lenvatinib, and chemotherapy with nab-paclitaxel, which targets both the HCC and ICC components, may represent a promising treatment option for patients with cHCC-CCA. Further research is warranted to validate these findings in larger patient cohorts.

Therapeutic approaches for extrahepatic cholangiocarcinoma (EHCC) are limited, due to insufficient understanding to biomarkers related to prognosis and drug response. Here, we comprehensively assess the molecular characterization of EHCC with clinical implications.

Whole-exome sequencing (WES) on 37 tissue samples of EHCC were performed to evaluate genomic alterations, tumor mutational burden (TMB) and microsatellite instability (MSI).

Mutation of KRAS (16%) was significantly correlated to poor OS. ERBB2 mutation was associated with improved OS. ERBB2, KRAS, and ARID1A were three potentially actionable targets. TMB ≥10 mutations per megabase was detected in 13 (35.1%) cases. Six patients (16.2%) with MSIsensor scores ≥10 were found. In multivariate Cox analysis, patients with MSIsensor sore exceed a certain threshold (MSIsensor score ≥0.36, value approximately above the 20th percentile as thresholds) showed a significant association with the improved OS (HR = 0.16; 95% CI: 0.056-0.46, p < 0.001), as well as patients with both TMB ≥3.47 mutations per megabase (value approximately above the 20th percentile) and MSIsensor score ≥0.36.

TMB and MSI are potential biomarkers associated with better prognosis for EHCC patients. Furthermore, our study highlights important genetic alteration and potential therapeutic targets in EHCC.

Systemic chemotherapy or chemoradiation therapy has proven to be effective in treating advanced biliary tract carcinoma (BTC). However, its efficacy in the adjuvant setting remains controversial. Therefore, this study aimed to determine the prognostic significance of genomic biomarkers in resected BTC and their potential role in stratifying patients for adjuvant treatment.

We retrospectively reviewed 113 BTC patients who underwent curative-intent surgery and had available tumor sequencing data. Disease-free survival (DFS) was the primary outcome examined and univariate analysis was used to identify gene mutations with prognostic value. Favorable and unfavoratble gene subsets were distinguished from the selected genes through grouping, respectively. Multivariate Cox regression was used to identify independent prognostic factors of DFS.

Our results indicated that mutations in ACVR1B, AR, CTNNB1, ERBB3, and LRP2 were favorable mutations, while mutations in ARID1A, CDKN2A, FGFR2, NF1, NF2, PBRM1, PIK3CA, and TGFBR1 were unfavorable mutations. In addition to age, sex, and node positive, favorable genes (HR = 0.15, 95% CI = 0.04-0.48, p = 0.001) and unfavorable genes (HR = 2.86, 95% CI = 1.51-5.29, p = 0.001) were identified as independent prognostic factors for DFS. Out of the 113 patients, only 35 received adjuvant treatment whereas the majority (78) did not. For patients with both favorable and unfavorable mutations undetected, adjuvant treatment showed negative effect on DFS (median DFS: S441 vs. 956 days, p = 0.010), but there was no significant difference in DFS among those in other mutational subgroups.

Genomic testing might be useful in guiding the decisions regarding adjuvant treatment in BTC.

Biliary tract cancers (BTC) are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens. For more than a decade, the combination of gemcitabine and cis-platin has served as the first-line standard treatment. There are few choices for second-line chemo-therapy. Targeted treatment with fibroblast growth factor receptor 2 inhibitors, neurotrophic tyrosine receptor kinase inhibitors, and isocitrate dehydrogenase 1 inhibitors has had important results. Immune checkpoint inhibitors (ICI) such as pembrolizumab are only used in first-line treatment for microsatellite instability high patients. The TOPAZ-1 trial's outcome is encouraging, and there are several trials underway that might soon put targeted treatment and ICI combos into first-line options. Newer targets and agents for existing goals are being studied, which may represent a paradigm shift in BTC management. Due to a scarcity of targetable mutations and the higher toxicity profile of the current medications, the new category of drugs may occupy a significant role in BTC therapies.

Whether irAEs can predict the efficacy of PD-1 inhibitors in cholangiocarcinoma (CCA) has not been assessed. Therefore, this study aims to investigate the correlation between irAEs and the therapeutic effect of PD-1 inhibitors combination therapy in patients with advanced CCA.

All patients with CCA who were consecutively admitted to the inpatient unit of our hospital and received PD-1 inhibitors combination therapy between September 2020 and April 2022 were screened. In total, 106 patients with CCA were screened out. We then followed up these patients until October 2022. Due to perioperative use (n=28), less than 2 cycles of PD-1 inhibitor therapy (n=9), incomplete data (n=8) and no pathological report (n=2), 59 patients were included in the final analysis. The patients were divided into the irAEs cohort and the non-irAEs cohort according to whether they experienced irAEs or not. The Log-Rank test was performed to compare the difference in survival time between these two cohorts. We then applied multivariate COX regression analysis to investigate whether irAEs were independent prognostic factors for survival in patients with advanced CCA.

Finally, 32 patients were included in the irAEs cohort and 27 patients in the non-irAEs cohort. A total of 32 patients (54.2%) had any-grade irAEs, of which 4 patients (6.8%) had grade 3-4 irAEs. The most common irAEs were thyroid toxicity (30.5%) and dermatologic toxicity (30.5%). There were no notable differences in demographics and clinical characteristics between the irAEs and non-irAEs cohorts, except for total bilirubin level (P=0.026) and relapse (P=0.016). The disease control rate (DCR) in the irAEs cohort was higher than in the non-irAEs cohort (90.6% vs 70.4%, P=0.047). Median overall survival (OS) and median progression-free survival (PFS) were better in the irAEs cohort than in the non-irAEs cohort (OS: 21.2 vs 10.0 months, P<0.001; PFS: 9.0 vs 4.4 months, P=0.003). Multivariate COX regression analysis showed that irAEs were independent prognostic factors for OS and PFS (OS: HR=0.133, 95% CI: 0.039-0.452, P=0.001; PFS: HR=0.435, 95% CI: 0.202-0.934, P=0.033).

IrAEs correlated with improved DCR, OS, and PFS in advanced CCA patients receiving PD-1 inhibitors combination therapy.

Cholangiocarcinoma consists of a heterogeneous group of malignancies with generally poor prognoses. Immunotherapy has emerged in the treatment landscape of many tumors, offering survival benefits, but data regarding the use of immunotherapy for cholangiocarcinoma remain vague. In this review, the authors analyze differences in the tumor microenvironment and various immune escape mechanisms and discuss available immunotherapy combinations with other agents among completed and ongoing clinical trials, such as chemotherapy, targeted agents, antiangiogenic drugs, local ablative therapies, cancer vaccines, adoptive cell therapy and PARP and TGF-β inhibitors. Ongoing research to identify appropriate biomarkers is warranted.

Cholangiocarcinomas (CCAs) are a heterogenous group of epithelial malignancies originating at any level of the biliary tree and are subdivided according to their location into intrahepatic (iCCA) and extrahepatic (eCCA).

This review provides an updated analysis of studies of genetic characterization of CCA at the level of gene mutation profiling, copy number alterations and gene expression, with definition of molecular subgroups and identification of some molecular biomarkers and therapeutic targets.

With the development of genetic sequencing, several driver mutations have been identified and targeted as novel therapeutic approaches, including FGFR2, IDH1, BRAF, NTRK, HER2, ROS, and RET. Furthermore, identification of the cellular and molecular structure of the tumor microenvironment has contributed to the development of novel therapies, such as tumor immunotherapy. Combination therapies of chemotherapy plus targeted molecules or immunotherapy are under evaluation and offer the unique opportunity to improve the outcomes of CCA patients with advanced disease.

The previous year's worldview for cancer treatment has advanced from general to more precise therapeutic approaches. Chemotherapies were first distinguished as the most reliable and brief therapy with promising outcomes in cancer patients. However, patients could also suffer from severe toxicities resulting from chemotherapeutic drug usage. An improved comprehension of cancer pathogenesis has led to new treatment choices, including tumor-targeted therapy and immunotherapy. Subsequently, cancer immunotherapy and targeted therapy give more hope to patients since their combination has tremendous therapeutic efficacy. The immune system responses are also initiated and modulated by targeted therapies and cytotoxic agents, which create the principal basis that when targeted therapies are combined with immunotherapy, the clinical outcomes are of excellent efficacy, as presented in this review. This review focuses on how immunotherapy and targeted therapy are applicable in cancer management and treatment. Also, it depicts promising therapeutic results with more extensive immunotherapy applications with targeted therapy. Further elaborate that immune system responses are also initiated and modulated by targeted therapies and cytotoxic agents, which create the principal basis that this combination therapy with immunotherapy can be of great outcome clinically.

Biliary tract cancers (BTCs) comprise a heterogeneous group of aggressive malignancies with unfavorable prognoses. The benefit of chemotherapy seems to have reached a bottleneck and, therefore, new effective therapeutic strategies for advanced BTCs are needed. Molecularly targeted therapies in selected patients are rapidly changing the situation. However, the low frequency of specific driver alterations in BTCs limits their wide application. Recently, immunotherapeutic approaches are also under active investigation in BTCs, but the role of immunotherapy in BTCs remains controversial.

PubMed, Web of Science, and meeting resources were searched for relevant articles published from January 2017 to May 2022. The search aimed to identify current and emerging immunotherapeutic approaches for BTCs. Information on clinical trials was obtained from https://clinicaltrials.gov/ and http://www.chictr.org.cn/.

Immunotherapy in BTC patients is currently under investigation, and most of the investigations focused on the application of immune checkpoint inhibitors (ICIs). However, only a subgroup of BTCs with microsatellite-instability high (MSI-H)/DNA mismatch repair-deficient (dMMR) or tumor mutational burden-high (TMB-H) benefit from monotherapy of ICIs, and limited activity was observed in the second or subsequent settings. Nevertheless, promising results come from studies of ICIs in combination with other therapeutic approaches, including chemotherapy, in advanced BTCs, with a moderate toxicity profile. Recent studies demonstrated that compared to GEMCIS alone, durvalumab plus GEMCIS significantly improved patient survival (TOPAZ-1 trial) and that ICIs-combined chemoimmunotherapy is poised to become a new frontline therapy option, regardless of TMB and MMR/MSI status. Adoptive cell therapy and peptide- or dendritic-based cancer vaccines are other immunotherapeutic options that are being studied in BTCs. Numerous biomarkers have been investigated to define their predictive role in response to ICIs, but no predictive biomarker has been validated, except MSI-H/dMMR.

The role of immunotherapy in BTCs is currently under investigation and the results of ongoing studies are eagerly anticipated. Several studies have demonstrated the safety and efficacy of ICIs in combination with chemotherapy in treatment-naive patients, such as the phase III TOPAZ-1 trial, which will change the standard care of first-line chemotherapy for advanced BTCs. However, further research is needed to understand the best combination with immunotherapy and to discover more predictive biomarkers to guide clinical practice.

The advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic options of hepatobiliary malignancies. However, the clinical benefit provided by immunotherapy seems limited to a small subgroup of patients with hepatobiliary malignancies. The identification of reliable predictors of the response to immunotherapy is urgently needed.

Literature search was conducted in PubMed for relevant articles published up to May 2022. Information of clinical trials was obtained from https://clinicaltrials.gov/.

Biomarkers for ICI response of hepatobiliary malignancies remain in the exploration stage and lack compelling evidence. Tumor programmed death-ligand 1 (PD-L1) expression is the most widely studied biomarker in hepatocellular carcinoma (HCC) and biliary tract cancers (BTCs), but there are conflicting results on its predictive potential. Tumor mutational burden (TMB) is generally low both in HCC and BTCs, and the clinical trials of TMB are rare in hepatobiliary malignancies. Promisingly, mismatch repair deficiency (dMMR)/high microsatellite instability (MSI-H) may be a predictive biomarker of response to anti-PD-1 therapy in BTCs. Furthermore, some emerging biomarkers, such as gut microbiota, show predictive potential in the preliminary studies. Radiomics and liquid-biopsy biomarkers, including circulating tumor cells, circulating tumor DNA (ctDNA) and exosomal PD-L1 provide a quick and non-invasive approach for monitoring the ICI response, showing a new promising direction.

Multiple potential biomarkers for predicting ICI response of hepatobiliary malignancies have been explored and tried to apply in clinic. Yet there is no robust evidence to prove their clinical value in predicting immunotherapeutic response for patients with hepatobiliary malignancies. The identification of predictors for response to ICIs is an urgent need and major challenge. Further studies are warranted to validate the role of emerging biomarkers in predicting immunotherapeutic responses.

The combination of gemcitabine-based chemotherapy and immune checkpoint inhibitors has a good efficacy in advanced biliary tract cancer (BTC). The multi-target TKI lenvatinib and NGS-guided targeted therapy are also promising in BTC treatment. This study aimed to explore the performance of GemOX plus sintilimab and TKI (either lenvatinib or by NGS-guided targeted therapy) for local advanced or metastatic BTCs.

This prospective single-arm study included patients with local advanced or metastatic BTCs and applied intravenous infusion of standard GemOX plus sintilimab and lenvatinib (no targetable gene alterations) or targeted therapy based on NGS (olaparib for BRCA1/2 mutation, dasatinib for IDH1/2 mutation, afatinib for EGFR amplification, lenvatinib for PDGFR and KIT mutation, and lenvatinib for FGFR/KIT mutation).

From November 2020 to December 2021, 22 patients BTCs (6 GBC, 14 iCCA, 1 pCCA and 1 dCCA cases) were enrolled, with an average age of 58.4 years. Partial response (PR) was achieved in 10 cases, stable disease (SD) in 9 cases and progression disease (PD) in 3 cases (13.6%). The objective response rate (ORR) was 45.5%, and the disease control rate (DCR) was 86.4%. During the treatment, the incidence of adverse reactions was 81.8%, and the incidence of grade 3/4 adverse events was 9.09%. For 14 patients with NGS, 5 patients were treated by targeted therapy and there were 1 SD and 4 PR cases. For four patients with positive PD-L1 expression, the ORR was 100%. While among the three patients with super-progression markers such as RET, MDM2 and FGF14/STK24, there were two SD and one PD cases.

In patients with advanced BTCs, the combination of GemOX plus sintilimab and lenvatinib or NGS-guided targeted therapy showed promising ORR and DCR, especially for the patients with positive PD-L1 expression and targetable gene alterations.

Biliary tract cancers (BTCs) are frequently diagnosed in advanced stages and are highly lethal. Immunotherapy may play a role in the treatment of these patients. Promising results come from monotherapy or combination therapy studies in pretreated patients. In addition, several studies have demonstrated the safety and efficacy of immune checkpoint inhibitors (ICIs) in combination with chemotherapy in treatment-naive patients. Numerous biomarkers have been investigated to define their predictive role in response to ICIs. However, the full extent of the benefit of immunotherapies has not yet been fully established and, except for high microsatellite instability status, no other biomarkers were uniquely predictive of response to ICIs.

Cholangiocarcinoma (CCA), which consists of intrahepatic CCA (iCCA), perihilar CCA (pCCA), and distal CCA (dCCA), is an aggressive malignancy worldwide. PCCA and dCCA are often classified as extrahepatic CCA (exCCA). However, the differences in mutational characteristics between pCCA and dCCA remain unclear.

Deep sequencing targeting of 450 cancer genes was performed for genomic alteration detection. The tumor mutational burden (TMB) was measured by an algorithm developed in-house. Correlation analysis was conducted using Fisher's exact test.

FGFR2 and ERBB2 mutations mainly occurred in iCCA and exCCA, respectively. In exCCA, the frequencies of PIK3CA, FAT4, KDM6A, MDM2, and TCF7L2 mutations were significantly higher in pCCA compared to dCCA, while the frequencies of TP53 and KRAS mutations were markedly lower in pCCA than those in dCCA. The prognosis-related mutations were different among the CCA subtypes. NF1 mutation was associated with short disease-free survival (DFS) and overall survival (OS), and ERBB2 mutation was associated with short DFS in dCCA patients. Meanwhile, MAP2K4 mutation was associated with long DFS and OS, and TERT mutation was associated with short DFS in pCCA. A series of mutations in genes, including ARID1A, ARID2, SMAD4, TERT, TP53, and KRAS, were found to be associated with the TMB.

In this study, we investigated the comprehensive genomic characterizations of CCA patients, identified the significant alterations in each subtype, and identified potential biomarkers for prognosis prediction. These results provide molecular evidence for the heterogeneity of CCA subtypes and evidence for further precision targeted therapy of CCA patients.

Biliary tract cancer (BTC) is a highly malignant tumor with limited treatment options and poor prognosis. Our study aimed to evaluate camrelizumab plus oxaliplatin-based chemotherapy as first-line therapy for advanced BTC. In this multicenter, open-label, phase 2 trial conducted in China (ClinicalTrials.gov, NCT03092895), untreated patients with advanced BTC were given camrelizumab (3 mg/kg iv drip injection, every 2 weeks) plus typical FOLFOX4 (Cam-FOLFOX4 group; infusional 5-fluorouracil, leucovorin and oxaliplatin) or GEMOX (Cam-GEMOX group; infusional gemcitabine and oxaliplatin). The primary endpoint was objective response rate (ORR). Ninety-two patients were enrolled: 29 received Cam-FOLFOX4 and 63 received Cam-GEMOX. The confirmed ORR and disease control rate were 16.3% (95% confidence interval [CI] = 9.4-25.5) and 75.0% (95% CI = 64.9-83.4), respectively. Median duration of response was 8.7 months (95% CI = 5.1-not reached). Median progression-free survival and overall survival were 5.3 months (95% CI = 3.7-5.7) and 12.4 months (95% CI = 8.9-16.1), respectively. Grade ≥3 treatment-related adverse events (TRAEs) occurred in 82.8% of patients receiving Cam-FOLFOX4 and in 68.3% receiving Cam-GEMOX, with no unexpected effects observed. Six (6.5%) patients discontinued treatment due to TRAE. Camrelizumab plus FOLFOX4 or GEMOX as first-line treatment was effective and tolerable for Chinese patients with advanced BTC, warranting phase 3 trials.

Cholangiocarcinomas (CCAs) are heterogeneous biliary tract malignancies with dismal prognosis, mainly due to tumor aggressiveness, late diagnosis, and poor response to current therapeutic options. High-throughput technologies have been used as a fundamental tool in unveiling CCA molecular landscape, and several molecular classifications have been proposed, leading to various targeted therapy trials. In this review, we aim to analyze the critical issues concerning the status of precision medicine in CCA, discussing molecular signatures and clusters, related to both anatomical classification and different etiopathogenesis, and the latest therapeutic strategies. Furthermore, we propose an integrated approach comprising the CCA molecular mechanism, pathobiology, clinical and histological findings, and treatment perspectives for the ultimate purpose of improving the methods of patient allocations in clinical trials and the response to personalized therapies.

Biliary tract cancer (BTC) represents the second most frequently diagnosed primary liver cancer worldwide following hepatocellular carcinoma, and the overall survival of patients with unresectable disease remains poor. In recent years, the advent of immune checkpoint inhibitors (ICIs) has revolutionized the therapeutic landscape of several malignancies with these agents, which have also been explored in advanced BTC, as monotherapy or in combination with other anticancer agents. However, clinical trials evaluating ICIs in BTC have shown conflicting results, and the clinical benefit provided by immunotherapy seems limited to a small subgroup of BTC patients. Thus, the identification of reliable predictors of the response to immunotherapy represents a significant challenge in this setting. This review provides an overview of the available evidence on the biomarkers predictive of the response to ICIs in patients with advanced BTC, especially focusing on programmed death-ligand 1 (PD-L1), tumor mutational burden (TMB), microsatellite instability (MSI), and other emerging biomarkers.

Cholangiocarcinoma (CCA), a group of malignancies that originate from the biliary tract, is associated with a high mortality rate and a concerning increase in worldwide incidence. In Thailand, where the incidence of CCA is the highest, the socioeconomic burden is severe. Yet, treatment options are limited, with surgical resection being the only form of treatment with curative intent. The current standard-of-care remains adjuvant and palliative chemotherapy which is ineffective in most patients. The overall survival rate is dismal, even after surgical resection and the tumor heterogeneity further complicates treatment. Together, this makes CCA a significant burden in Southeast Asia. For effective management of CCA, treatment must be tailored to each patient, individually, for which an assortment of targeted therapies must be available. Despite the increasing numbers of clinical studies in CCA, targeted therapy drugs rarely get approved for clinical use. In this review, we discuss the shortcomings of the conventional clinical trial process and propose the implementation of a novel concept, co-clinical trials to expedite drug development for CCA patients. In co-clinical trials, the preclinical studies and clinical trials are conducted simultaneously, thus enabling real-time data integration to accurately stratify and customize treatment for patients, individually. Hence, co-clinical trials are expected to improve the outcomes of clinical trials and consequently, encourage the approval of targeted therapy drugs. The increased availability of targeted therapy drugs for treatment is expected to facilitate the application of precision medicine in CCA.