PARP Inhibitors in Biliary Tract Cancer: A New Kid on the Block?

Poly adenosine diphosphate-ribose polymerase inhibitors (PARPi) represent an effective therapeutic strategy for cancer patients harboring germline and somatic aberrations in DNA damage repair (DDR) genes. BRCA1/2 mutations occur at 1–7% across biliary tract cancers (BTCs), but a broader spectrum of DDR gene alterations is reported in 28.9–63.5% of newly diagnosed BTC patients. The open question is whether alterations in genes that are well established to have a role in DDR could be considered as emerging predictive biomarkers of response to platinum compounds and PARPi. Currently, data regarding PARPi in BTC patients harboring BRCA and DDR mutations are sparse and anecdotal; nevertheless, a variety of clinical trials are testing PARPi as monotherapy or in combination with other anticancer agents. In this review, we provide a comprehensive overview regarding the genetic landscape of DDR pathway deficiency, state of the art and future therapeutic implications of PARPi in BTC, looking at combination strategies with immune-checkpoint inhibitors and other anticancer agents in order to improve survival and quality of life in BTC patients.

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Immunotherapy for Biliary Tract Cancer in the Era of Precision Medicine: Current Knowledge and Future Perspectives

International Journal of Molecular Sciences ◽

10.3390/ijms23020820 ◽

2022 ◽

Vol 23 (2) ◽

pp. 820

Author(s):

Davide Ciardiello ◽

Brigida Anna Maiorano ◽

Paola Parente ◽

Maria Grazia Rodriquenz ◽

Tiziana Pia Latiano ◽

...

Keyword(s):

Biliary Tract ◽

Current Knowledge ◽

Checkpoint Inhibitors ◽

Target Therapy ◽

Single Agent ◽

Predictive Biomarkers ◽

Therapeutic Options ◽

Future Perspectives ◽

Tract Cancer ◽

Dismal Prognosis

Biliary tract cancers (BTC) represent a heterogeneous and aggressive group of tumors with dismal prognosis. For a long time, BTC has been considered an orphan disease with very limited therapeutic options. In recent years a better understanding of the complex molecular landscape of biology is rapidly changing the therapeutic armamentarium. However, while 40–50% of patients there are molecular drivers susceptible to target therapy, for the remaining population new therapeutic options represent an unsatisfied clinical need. The role of immunotherapy in the continuum of treatment of patients with BTC is still debated. Despite initial signs of antitumor-activity, single-agent immune checkpoint inhibitors (ICIs) demonstrated limited efficacy in an unselected population. Therefore, identifying the best partner to combine ICIs and predictive biomarkers represents a key challenge to optimize the efficacy of immunotherapy. This review provides a critical analysis of completed trials, with an eye on future perspectives and possible biomarkers of response.

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Targeting DNA Damage Repair for Immune Checkpoint Inhibition: Mechanisms and Potential Clinical Applications

Frontiers in Oncology ◽

10.3389/fonc.2021.648687 ◽

2021 ◽

Vol 11 ◽

Author(s):

Wei Sun ◽

Qing Zhang ◽

Runkun Wang ◽

Yang Li ◽

Yue Sun ◽

...

Keyword(s):

Dna Damage ◽

Immune Checkpoint ◽

Kinase Inhibitors ◽

Checkpoint Inhibitors ◽

Dna Damage Repair ◽

Predictive Biomarkers ◽

High Sensitivity ◽

Parp Inhibitors ◽

Combination Strategies ◽

Damage Repair

DNA damage repair (DDR) pathways play an essential role in maintaining genomic integrity. DDR dysfunction leads to accumulated DNA damage, predisposition to cancer, and high sensitivity to chemotherapy and radiotherapy. Recent studies have demonstrated that DDR status is associated with response to immune checkpoint inhibitors (ICIs). Among the DDR pathways, mismatch repair is one of the most recognized predictive biomarkers for ICIs. Furthermore, preclinical and early clinical studies suggest the rationale of combining agents targeting the DDR pathways, such as poly (ADP-ribose) polymerase (PARP) inhibitors, cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, and ataxia telangiectasia and rad3-related (ATR) kinase inhibitors, with ICIs. In the present review, we describe the predictive role of DDR pathways in ICIs and summarize the advances in potential combination strategies of novel agents targeting DDR with ICIs for cancer treatment.

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PD-L1, TMB, MSI, and Other Predictors of Response to Immune Checkpoint Inhibitors in Biliary Tract Cancer

Cancers ◽

10.3390/cancers13030558 ◽

2021 ◽

Vol 13 (3) ◽

pp. 558 ◽

Cited By ~ 4

Author(s):

Alessandro Rizzo ◽

Angela Dalia Ricci ◽

Giovanni Brandi

Keyword(s):

Biliary Tract ◽

Anticancer Agents ◽

Biliary Tract Cancer ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Primary Liver Cancer ◽

Tract Cancer ◽

Predictors Of Response ◽

Tumor Mutational Burden

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.

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Predictive and prognostic biomarkers with therapeutic targets in colorectal cancer: A 2021 update on current development, evidence, and recommendation

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211005525 ◽

2021 ◽

pp. 107815522110055

Author(s):

Clement Chung

Keyword(s):

Checkpoint Inhibitors ◽

Therapeutic Targets ◽

Growth Factor Receptor ◽

Predictive Biomarkers ◽

Tumor Location ◽

Prognostic Biomarkers ◽

Her2 Gene ◽

Braf Mutations ◽

Therapeutic Implications ◽

Molecular Alterations

Although therapeutically actionable molecular alterations are widely distributed across many cancer types, only a handful of them show evidence of clinical utility and are recommended for routine clinical practice in the management of cancers of colon and rectum (CRC). This 2021 update aims to provide a succinct summary on the use of prognostic and/or predictive biomarkers (expanded RAS, BRAF, microsatellite-high [MSI-H] or deficient mismatch repair [dMMR], neurotrophic tyrosine receptor kinase [ NTRK] fusion genes, and human epidermal growth factor receptor type II [ HER2] gene amplification) associated with CRC. Therapeutic implications of each relevant predictive or prognostic biomarker for patients with CRC are described, along with discussion on new developments on (1) biomarker-driven therapies such as testing of BRAF, MLH1 promoter methylation and MMR germline genes in differentiating sporadic CRC or hereditary conditions such as Lynch syndrome; (2) first-line use of immune checkpoint inhibitors in metastatic CRC; (3) risk stratification and therapy selection based on primary tumor location (left-sided vs. right-sided colon cancer); (3) atypical BRAF mutations; (4) use of EGFR directed therapy in the perioperative oligometastatic disease setting; (5) re-challenge of EGFR directed therapy and (6) personalizing therapy of fluoropyrimidine and irinotecan based on new evidence in pharmacogenomic testing. Data are collected and analyzed from available systematic reviews and meta-analyses of treatments with known therapeutic targets in CRC, which may be associated with predictive and/or prognostic biomarkers. Discussions are presented in an application-based format, with goal to empower pharmacists or other clinicians to gain awareness and understanding in biomarker-driven cancer therapy issues.

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Hepatic Cancer Stem Cells: Molecular Mechanisms, Therapeutic Implications, and Circulating Biomarkers

Cancers ◽

10.3390/cancers13184550 ◽

2021 ◽

Vol 13 (18) ◽

pp. 4550

Author(s):

Laura Gramantieri ◽

Catia Giovannini ◽

Fabrizia Suzzi ◽

Ilaria Leoni ◽

Francesca Fornari

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Anticancer Agents ◽

Tumor Heterogeneity ◽

Molecular Mechanisms ◽

Driving Forces ◽

Predictive Biomarkers ◽

Molecular Classification ◽

Circulating Biomarkers ◽

Therapeutic Implications

Hepatocellular carcinoma (HCC) is one of the deadliest cancers. HCC is associated with multiple risk factors and is characterized by a marked tumor heterogeneity that makes its molecular classification difficult to apply in the clinics. The lack of circulating biomarkers for the diagnosis, prognosis, and prediction of response to treatments further undermines the possibility of developing personalized therapies. Accumulating evidence affirms the involvement of cancer stem cells (CSCs) in tumor heterogeneity, recurrence, and drug resistance. Owing to the contribution of CSCs to treatment failure, there is an urgent need to develop novel therapeutic strategies targeting, not only the tumor bulk, but also the CSC subpopulation. Clarification of the molecular mechanisms influencing CSC properties, and the identification of their functional roles in tumor progression, may facilitate the discovery of novel CSC-based therapeutic targets to be used alone, or in combination with current anticancer agents, for the treatment of HCC. Here, we review the driving forces behind the regulation of liver CSCs and their therapeutic implications. Additionally, we provide data on their possible exploitation as prognostic and predictive biomarkers in patients with HCC.

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PARP Inhibitors as a Therapeutic Agent for Homologous Recombination Deficiency in Breast Cancers

Journal of Clinical Medicine ◽

10.3390/jcm8040435 ◽

2019 ◽

Vol 8 (4) ◽

pp. 435 ◽

Cited By ~ 29

Author(s):

Man Keung ◽

Yanyuan Wu ◽

Jaydutt Vadgama

Keyword(s):

Dna Repair ◽

Homologous Recombination ◽

Cancer Cells ◽

Anticancer Agents ◽

Excision Repair ◽

Parp Inhibitor ◽

Predictive Biomarkers ◽

Parp Inhibitors ◽

Homologous Recombination Deficiency ◽

Repair Pathways

Poly (ADP-ribose) polymerases (PARPs) play an important role in various cellular processes, such as replication, recombination, chromatin remodeling, and DNA repair. Emphasizing PARP’s role in facilitating DNA repair, the PARP pathway has been a target for cancer researchers in developing compounds which selectively target cancer cells and increase sensitivity of cancer cells to other anticancer agents, but which also leave normal cells unaffected. Since certain tumors (BRCA1/2 mutants) have deficient homologous recombination repair pathways, they depend on PARP-mediated base excision repair for survival. Thus, inhibition of PARP is a promising strategy to selectively kill cancer cells by inactivating complementary DNA repair pathways. Although PARP inhibitor therapy has predominantly targeted BRCA-mutated cancers, this review also highlights the growing conversation around PARP inhibitor treatment for non-BRCA-mutant tumors, those which exhibit BRCAness and homologous recombination deficiency. We provide an update on the field’s progress by considering PARP inhibitor mechanisms, predictive biomarkers, and clinical trials of PARP inhibitors in development. Bringing light to these findings would provide a basis for expanding the use of PARP inhibitors beyond BRCA-mutant breast tumors.

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PD-L1 expression as a prognostic marker in patients with advanced biliary tract cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.e16679 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. e16679-e16679

Author(s):

Hyera Kim ◽

Jung Yong Hong ◽

Jeeyun Lee ◽

Se Hoon Park ◽

Joon Oh Park ◽

...

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Checkpoint Inhibitors ◽

Univariate Analysis ◽

Group Analysis ◽

Progression Free Survival ◽

Tumor Location ◽

Tract Cancer ◽

Positive Score ◽

Combined Positive Score

e16679 Background: Biliary tract cancer (BTC) is associated with poor prognosis because of its aggressive and heterogeneous nature. Programmed death ligand 1 (PD-L1) has been considered as a novel biomarker for prognosis and response of immune checkpoint inhibitors in various tumors. However, there are limited data reporting on the role of PD-L1 in advanced BTC patients. Methods: We analyzed 186 patients with advanced BTC who received palliative gemcitabine and platinum between May 2010 and December 2019. All patients were evaluated for PD-L1 expression by combined positive score (CPS) positivity. Results: In all 186 patients, the median age was 62 years (range 38-82), and the primary tumor location was intrahepatic cholangiocarcinoma (IH-CCC) in 72 patients (38.7%), extrahepatic (EH)-CCC in 90 (48.4%), and gallbladder (GB) cancer in 24 (12.9%). There were 158 (84.9%) patients with recurrent disease and 28 (15.1%) with metastatic disease. Among the 186 patients, 53 (28.5%) had PD-L1 CPS positivity, and 133 were CPS negative. The median overall survival (OS) of patients with PD-L1 CPS positivity or negativity was 12.1 and 15.4 months, respectively. The median progression-free survival (PFS) in patients with PD-L1 positivity or negativity was 5.7 and 7.1 months, respectively. The OS and PFS were not statistically different between groups. In sub-group analysis, EH-CCC patients with PD-L1 negativity had more favorable OS (17.2 vs. 11.6 months, p= 0.002) and PFS (7.8 vs. 5.4 months, p= 0.005) than those that were PD-L1 negative. However, this finding was not reproduced in patients with IH-CCC or GB cancer. Univariate analysis of the association between PD-L1 expression and OS in patients with advanced BTC indicated that PD-L1 CPS positivity has a prognostic role in sub-populations older than 60 years (HR 1.743, CI 1.001-3.034, p = 0.050), those with EH-CCC (HR 2.449, CI 1.355-4.426, p = 0.003), and those with liver metastasis (HR 2.511, CI 1.362-4.626, p = 0.003). Conclusions: This study demonstrated that PD-L1 expression might be a novel prognostic biomarker in patients with EH-CCC but not for patients with IH-CCC or GB cancer.

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Biomarker exploration for SHR-1210 plus GEMOX as first-line treatment in advanced biliary tract cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.4_suppl.536 ◽

2020 ◽

Vol 38 (4_suppl) ◽

pp. 536-536 ◽

Cited By ~ 1

Author(s):

Xiaofeng Chen ◽

Hao Wu ◽

Xiaofeng Wu ◽

Qianwen Shao ◽

Feipeng Zhu ◽

...

Keyword(s):

Gene Mutation ◽

Biliary Tract ◽

Biliary Tract Cancer ◽

Lymphocyte Count ◽

Gene Mutations ◽

Predictive Biomarkers ◽

Wild Type ◽

Tissue Samples ◽

Tract Cancer ◽

Hla Dr

536 Background: We conducted a trial to evaluate the efficacy and safety of SHR-1210 (a humanized anti-programmed cell death receptor 1 antibody) plus gemcitabine and oxaliplatin (GEMOX) as in untreated patients (pts) with biliary tract cancer (BTC) (NCT03486678). This study is to explore the predictive biomarkers for efficacy. Methods: Baseline lymphocyte count and lactate dehydrogenase (LDH) level were obtained from routine tests. Gene mutation and tumor mutation burden (TMB) from baseline tissue and blood samples were tested by the next generation sequencing (NGS) with a 425-gene panel. The expressions of PD-L1 and markers for lymphocyte, natural killer cells, and macrophages in baseline tumor tissue samples were analyzed by immunohistochemistry (IHC). Results: The median progression free survival (PFS) and overall survival (OS) in this trial was 6.2m and 12.1m, respectively. Firstly, pts with normal LDH level (≤271 U/L) had a tendency for longer PFS (6.2m vs 5.0m, p = 0.053) and significantly longer OS (p = 12.6m vs 6.8m, p < 0.001) than those with elevated LDH ( > 271 U/L). Low baseline lymphocyte count (≤ 1.1×109/L) was related to worse OS (12.6m vs 6.9m, p < 0.001) and PFS (6.2m vs 3.9m, p = 0.021). Secondly, baseline tissue and ctDNA gene mutations were detected in 33 and 30 pts, respectively. Tissue analysis showed that pts with STK11 (p = 0.0254), CTNNB1 (p < 0.001) and SMARCA4 (p = 0.0181) wild type showed significantly longer PFS than those with mutations. Pts with ARID1A gene wild type showed a tendency for longer PFS (p = 0.0634) and significantly longer OS (p = 0.0149). Gene mutations from baseline ctDNA revealed that pts with wild type SMARCA4, CTNNB1, STK11, and NF1 had longer PFS than those with mutations. Lastly, IHC meant that PD-L1 positivity may be related to longer PFS (TPS > 1%, p = 0.08; IPS > 1%, p = 0.05). Besides, pts with CD68+ HLA-DR+ macrophages > 0.01%, CD68+ HLA-DR- macrophages>2.5%, and CD56bright>1.7% and CD56dim > 0.05 also got PFS benefits (all p < 0.05). TMB (cutoff = 7 muts/mbp) was not associated with PFS. Conclusions: Despite limited sample size, biomarkers from routine blood test, gene mutation and immune microenvironment can be helpful to stratify pts who are sensitive to immunotherapy in advanced BTC. Clinical trial information: NCT03486678.

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Genomic alterations in biliary tract cancer predict prognosis and immunotherapy outcomes

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2021-003214 ◽

2021 ◽

Vol 9 (11) ◽

pp. e003214

Author(s):

Xiaofeng Chen ◽

Deqiang Wang ◽

Jing Liu ◽

Jingrong Qiu ◽

Jun Zhou ◽

...

Keyword(s):

Biliary Tract ◽

Biliary Tract Cancer ◽

Poor Prognosis ◽

Immune Cell ◽

Checkpoint Inhibitors ◽

Early Stage ◽

Chinese Patients ◽

Genomic Alterations ◽

Early Stage Disease ◽

Tract Cancer

BackgroundRecently, immunotherapy with immune checkpoint inhibitors (ICIs) has shown promising efficacy in biliary tract cancer (BTC), which includes gallbladder cancer (GBC) and cholangiocarcinoma (CHOL). Understanding the association between immunotherapy outcomes and the genomic profile of advanced BTC may further improve the clinical benefits from immunotherapy.MethodsGenomic tumor DNA was isolated from 98 Chinese patients with advanced BTC and used for targeted next-generation sequencing of 416 cancer-related genes to identify the genomic alterations common to advanced BTC. Thirty-four patients had received ICI camrelizumab plus gemcitabine and oxaliplatin (from the NCT03486678 trial) as a first-line treatment. Tumor-infiltrating immune cells were evaluated using immunofluorescence staining.ResultsKRAS and TP53 mutations were much more frequent in the advanced-stage BTC cohort than in other cohorts with mostly early stage disease. Specifically, KRAS-TP53 co-mutations were favored in advanced CHOL, with a favorable response to immunotherapy, while single KRAS mutations predicted poor prognosis and immunotherapy outcomes for CHOL. Compared with GBC, CHOL had more mutations in genes involved in KRAS signaling; a high mutation load in these genes correlated with poor immunotherapy outcomes and may subsequently cause inferior immunotherapy outcomes for CHOL relative to GBC. Furthermore, a genomic signature including 11 genes was developed; their mutated subtype was associated with poor prognosis and immunotherapy outcomes in both CHOL and GBC. Transcriptome analyses suggested immune dysfunction in the signature mutated subtype, which was validated by tumor microenvironment (TME) evaluation based on detection of immune cell infiltration. Importantly, the signature wild-type subtype with favorable TME may be an advantageous population of immunotherapy.ConclusionsGenomic alterations in advanced BTC were associated with specific prognosis and immunotherapy outcomes. Combining genomic classification with TME evaluation further improved the stratification of immunotherapy outcomes.

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