Current and novel therapeutic opportunities for systemic therapy in biliary cancer

Marin, José J.G.; Prete, Maria Giuseppina; Lamarca, Ángela; Tavolari, Simona; Landa-Magdalena, Ana; Brandi, Giovanni; Segatto, Oreste; Vogel, Arndt; Macı́as, Rocı́o I.R.; Rodrigues, Pedro M.; Casta, Adelaida La; Mertens, Joachim C.; Rodrigues, Cecília M.P.; Fernández‐Barrena, Maite G.; Ruivo, Ana Da Silva; Marzioni, Marco; Mentrasti, Giulia; Acedo, Pilar; Munoz‐Garrido, Patricia; Cardinale, Vincenzo; Bañales, Jesús M.; Valle, Juan W.; Bridgewater, John; Braconi, Chiara

doi:10.1038/s41416-020-0987-3

Cited by 41 publications

(35 citation statements)

References 137 publications

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“…Despite their identification, the presence of these mutations in a tumour is not a strong predictor of therapeutic outcome (17)(18)(19) and for approximately 30% of ICC patients a driver mutation cannot be identified (20,21).…”

Section: Resultsmentioning

confidence: 99%

In vivo modelling of patient genetic heterogeneity identifies concurrent Wnt and PI3K activity as a potent driver of invasive cholangiocarcinoma growth

Younger

Wilson

Jarman

et al. 2021

Preprint

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Intrahepatic cholangiocarcinoma (ICC) is an aggressive and lethal malignancy of the bile ducts within the liver characterised by high levels of genetic heterogeneity. In the context of such genetic variability, determining which oncogenic mutations drive ICC growth has been difficult and developing modes of patient stratification and targeted therapies remains challenging. As a result, survival rates following a diagnosis with ICC have remained static since the late 1970s, whilst incidence of ICC has increased. Here, we performed the first functional in vivo study into the role that genetic heterogeneity plays in driving ICC via modelling of interactions between rare mutations with more common driver genes. By leveraging human ICC sequencing data to stratify and then model genetic heterogeneity in the mouse, we uncovered numerous novel tumour suppressors which, when lost, cooperate with the RAS oncoprotein to drive ICC growth. In this study, we specifically focus on a set of driver mutations that interact with KRAS to initiate aggressive, sarcomatoid-type ICC. We show that tumour growth of this cancer relies on both Wnt and PI3K signalling to drive proliferation and suppress apoptosis. Finally, we demonstrate that pharmacological co-inhibition of Wnt and PI3K in vivo substantially impedes the growth of ICC, regardless of mutational profile. As such, Wnt and PI3K activity should be considered as a signature by which patients can be stratified for treatment and inhibitors of these pathways should be levied as a treatment for patients diagnosed with ICC.

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Section: Resultsmentioning

confidence: 99%

In vivo modelling of patient genetic heterogeneity identifies concurrent Wnt and PI3K activity as a potent driver of invasive cholangiocarcinoma growth

Younger

Wilson

Jarman

et al. 2021

Preprint

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“…Therapy with IDH-1 inhibitors can only work in patients with corresponding mutations [ 31 , 32 ], and therapy with FGFR2 inhibitors is only effective in patients with a gene fusion or gene rearrangement [ 33 , 34 ]. These new data underline the high dynamics with which the clinical management of patients with cholangiocarcinoma is currently evolving [ 35 , 36 ]. The concept of biomarker analysis for therapy management and stratification of patients according to their prognosis will undoubtedly gain importance in the coming 5 years.…”

Section: Discussionmentioning

confidence: 99%

Levels of Circulating PD-L1 Are Decreased in Patients with Resectable Cholangiocarcinoma

Roderburg

Loosen

Bednarsch

et al. 2021

IJMS

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Tumor resection represents the only curative treatment option for patients with biliary tract cancers (BTCs), including intrahepatic cholangiocarcinoma (CCA), perihilar and extrahepatic CCA and gallbladder cancer. However, many patients develop early tumor recurrence and are unlikely to benefit from surgery. Therefore, markers to identify ideal surgical candidates are urgently needed. Circulating programmed cell death 1 ligand 1 (PD-L1) has recently been associated with different malignancies, including pancreatic cancer which closely resembles BTC in terms of patients’ prognosis and tumor biology. Here, we aim at evaluating a potential role of circulating PD-L1 as a novel biomarker for resectable BTC. Methods: Serum levels of PD-L1 were analyzed by ELISA in 73 BTC patients and 42 healthy controls. Results: Circulating levels of preoperative PD-L1 were significantly lower in patients with BTC compared to controls. Patients with low PD-L1 levels displayed a strong trend towards an impaired prognosis, and circulating PD-L1 was negatively correlated with experimental markers of promalignant tumor characteristics such as CCL1, CCL21, CCL25 and CCL26. For 37 out of 73 patients, postoperative PD-L1 levels were available. Interestingly, after tumor resection, circulating PD-L1 raised to almost normal levels. Notably, patients with further decreasing PD-L1 concentrations after surgery showed a trend towards an impaired postoperative outcome. Conclusion: Circulating PD-L1 levels were decreased in patients with resectable BTC. Lack of normalization of PD-L1 levels after surgery might identify patients at high risk for tumor recurrence or adverse outcome.

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“…1,2,3,4 One of the reasons for the dismal prognosis of advanced BTC is that efficient systemic chemotherapy is limited. 5,6 Gemcitabine plus cisplatin (GC) combination chemotherapy is the standard first-line regimen for BTC. 7,8,9 Recently, gemcitabine plus oral fluoropyrimidine S-1 therapy has been proven to be non-inferior to GC therapy.…”

Section: Introductionmentioning

confidence: 99%

Success rate of microsatellite instability examination and complete response with pembrolizumab in biliary tract cancer

et al. 2021

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Background and Aim: The success rate of microsatellite instability (MSI) examination in biliary tract cancer (BTC) and the treatment outcomes of pembrolizumab in patients with MSI-high (MSI-H) BTC have not been fully investigated. We examined the success rate of MSI examination and the rate of MSI-H status in patients with BTC as well as the treatment outcomes of patients with MSI-H status who underwent pembrolizumab treatment. Methods: We retrospectively reviewed 60 consecutive patients with unresectable or postoperative recurrent BTC who underwent MSI examination in a Japanese cancer referral center between January 2019 and September 2020. Results: The study included 24 intrahepatic cholangiocarcinomas, 12 hilar cholangiocarcinomas, 4 distal cholangiocarcinomas, 16 gallbladder carcinomas, and 4 ampullary carcinomas. The methods of cancer tissue sampling were percutaneous liver tumor biopsy in 26 cases, surgery in 15 cases, endoscopic ultrasound fine-needle aspiration in 12 cases, transpapillary bile duct biopsy in 5 cases, and others in 2 cases. The success rate of MSI examination was 98.3% (59 of 60). MSI examination failed in only one case using a surgical specimen due to time-dependent degradation of DNA. The frequency of MSI-H BTC was 3.3% (2 of 60 cases). One patient with MSI-H intrahepatic cholangiocarcinoma achieved a complete response with pembrolizumab treatment. Conclusions: MSI examinations in BTC were successful in almost all cases, regardless of tissue sampling methods. We experienced a case in which pembrolizumab resulted in a complete response to MSI-H BTC. Since pembrolizumab for MSI-H BTC could prolong survival time, MSI examination should be performed proactively to increase treatment options.

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Current and novel therapeutic opportunities for systemic therapy in biliary cancer

Abstract: On behalf of the working group 6 of the COST-action 18122 (Euro-Cholangio-NET) as part of the European Network for the study of Cholangiocarcinoma (ENSCCA)

Cited by 41 publications

References 137 publications

In vivo modelling of patient genetic heterogeneity identifies concurrent Wnt and PI3K activity as a potent driver of invasive cholangiocarcinoma growth

In vivo modelling of patient genetic heterogeneity identifies concurrent Wnt and PI3K activity as a potent driver of invasive cholangiocarcinoma growth

Levels of Circulating PD-L1 Are Decreased in Patients with Resectable Cholangiocarcinoma

Success rate of microsatellite instability examination and complete response with pembrolizumab in biliary tract cancer

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