scholarly journals Contemporary Tailored Oncology Treatment of Biliary Tract Cancers

2019 ◽  
Vol 2019 ◽  
pp. 1-15
Author(s):  
Fiona Turkes ◽  
Juliet Carmichael ◽  
David Cunningham ◽  
Naureen Starling
Keyword(s):  
Clinical Trials ◽  
Biliary Tract ◽  
Treatment Options ◽  
Prognostic Significance ◽  
Response To Treatment ◽  
Genomic Profiling ◽  
Biliary Tract Cancers ◽  
Comprehensive Genomic Profiling ◽  
Genomic Aberrations ◽  
Oncology Treatment

Biliary tract cancers (BTCs) are poor prognosis malignancies with limited treatment options. Capecitabine has recently emerged as an effective agent in the adjuvant setting; however, treatment of advanced disease is still limited to first-line cisplatin and gemcitabine chemotherapy. Recent global efforts in genomic profiling and molecular subtyping of BTCs have uncovered a wealth of genomic aberrations which may carry prognostic significance and/or predict response to treatment, and several targeted agents have shown promising results in clinical trials. As such, the uptake of comprehensive genomic profiling for patients with BTCs and the expansion of basket trials to include these patients are growing. This review describes the currently approved systemic therapies for BTCs and provides insight into the emerging targeted and immunotherapeutic agents, as well as conventional chemotherapeutic regimes, currently being investigated in clinical trials.

Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and frequency of clinically relevant genomic alterations.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 4009-4009 ◽  
Author(s):  
Jeffrey S. Ross ◽  
Kai Wang ◽  
Milind M. Javle ◽  
Daniel Virgil Thomas Catenacci ◽  
Rachna T. Shroff ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Biliary Tract Cancers ◽  
Comprehensive Genomic Profiling

Comprehensive genomic profiling of biliary tract cancers to reveal tumor-specific differences and genomic alterations.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. 231-231 ◽  
Author(s):  
Jeffrey S. Ross ◽  
Kai Wang ◽  
Daniel Virgil Thomas Catenacci ◽  
Juliann Chmielecki ◽  
Siraj M. Ali ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Targeted Therapies ◽  
Kras Mutation ◽  
Mutation Frequency ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Extrahepatic Cholangiocarcinoma ◽  
Biliary Tract Cancers ◽  
Comprehensive Genomic Profiling ◽  
Tumor Types

231 Background: Intrahepatic cholangiocarcinoma (IHCCA), extrahepatic cholangiocarcinoma (EHCCA) and gallbladder carcinomas (GBCA) typically present at an advanced stage and systemic chemotherapy provides only modest benefit in most cases. We queried whether comprehensive genomic profiling (GCP) of IHCCA, EHCCA and GBCA would reveal clinically relevant genomic alterations (CRGA) that could lead to targeted therapies. Methods: DNA was extracted from 40µ of FFPE sections from 412 IHCCA, 57 EHCCA and 85 GBCA. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of >600X for 3,230 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer. The CGP assay included base substitutions, INDELs, copy number alterations and fusions/rearrangements. CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: Patient characteristics were similar for all three tumor types. IHCCA and GBCa were more common in females and EHCCA were more common males. CGP revealed the results in the Table. Multiple antitumor responses to targeted therapies in each of the 3 tumor types will be presented. Conclusions: IHCCA, EHCCA and GBCA share GA in cell cycle regulation (CDKN2B) and chromatin remodeling (ARID1A). IHCCA features FGFR fusions, IDH1/2 substitutions, BRAF substitutions and MET amplification with a low KRAS mutation frequency. EHCCA and GBCA feature ERBB2 amplifications (GBCA > EHCCA) and PIK3CA/MTOR pathway alterations. EHCCA has a high KRAS mutation frequency whereas the KRAS GA in GBCA is low. The diverse landscape of CRGA in biliary tract cancers can serve as targets for therapies for patients with CCA, BDCA and GBCA and have the potential to improve outcomes for these aggressive forms of malignancy. [Table: see text]

Clinical utility of comprehensive genomic profiling and targeted therapy in biliary tract cancers: A real-world experience.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e16671-e16671
Author(s):  
Mahum Shahid ◽  
Mohamed A. Abdallah ◽  
Moataz Ellithi ◽  
Hafez Mohammad Abdullah ◽  
Morgan Nelson ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Biliary Tract ◽  
Medical Center ◽  
Genetic Alterations ◽  
Molecular Therapy ◽  
Common Mutation ◽  
Genomic Profiling ◽  
Biliary Tract Cancers ◽  
Comprehensive Genomic Profiling

e16671 Background: Biliary tract cancers (BTC) are a highly aggressive group of malignancies with high mortality and poor prognosis. Chemotherapy is the mainstay of treatment for advanced disease. The role of molecular targeted therapy and immunotherapy using comprehensive genomic profiling (CGP) is evolving. We investigated the role of CGP directed therapy in patients with BTC. Methods: A multi-center retrospective study of CGP done on 35 patients with BTC at Sanford USD Medical Center and Avera McKennan Hospital, Sioux Falls, SD, between 2014 and 2019. 27 patients had cholangiocarcinoma (fifteen intrahepatic, two extrahepatic and ten unclassified), two had gallbladder carcinoma and six had ampullary carcinoma. Results: 22 of 35 BTC (63%) had potentially actionable genetic alterations(GA). Nine of these 22 (41%) received molecular therapy based on CGP. Four patients had microsatellite instability (MSI-H) and two of them received immunotherapy (Table). CDKN2A/B was the most common mutation (23%) followed by PIK3CA (13%), ARID1A (13%) and Tp53(13%). By the end of the follow up period, median overall survival (OS) was 569 days(19 months) for those who received targeted therapy compared to 315 days(10.5 months) for those who did not. (P = 0.051). Conclusions: In this multi-center cohort, 63% of patients had at least one targetable GA. Furthermore, CGP guided treatment decisions in 41% of patients. CGP has the potential to provide clinically meaningful treatment options for patients with BTC. New studies are warranted to further investigate this promising prospect for BTC management. [Table: see text]

scholarly journals Establishment of a Pretreatment Nomogram to Predict the 6-Month Mortality Rate of Patients with Advanced Biliary Tract Cancers Undergoing Gemcitabine-Based Chemotherapy

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3139
Author(s):  
Chiao-En Wu ◽  
Wen-Kuan Huang ◽  
Wen-Chi Chou ◽  
Chia-Hsun Hsieh ◽  
John Wen-Cheng Chang ◽  
...  
Keyword(s):  
Liver Metastasis ◽  
Mortality Rate ◽  
Biliary Tract ◽  
Mortality Risk ◽  
Treatment Options ◽  
Univariate Analysis ◽  
Cytotoxic Agents ◽  
Response To Treatment ◽  
Tract Cancer ◽  
Additional Information

Background: The estimation of mortality risk among patients diagnosed with advanced cancer provides important information for clinicians and patients in clinical practice. Currently, gemcitabine-based chemotherapy regimens are the standard treatment for patients with advanced biliary tract cancer (BTC). We aimed to develop a nomogram to predict the 6-month mortality rate among patients with advanced BTC to help physicians evaluate treatment options and outcomes. Patients: We conducted a retrospective analysis to evaluate the 6-month mortality rate among patients with advanced BTC who underwent gemcitabine-based chemotherapy from 2012 to 2018. Data regarding pretreatment factors and the clinical response to treatment were collected. Univariate and multivariate analyses were performed to identify independent factors for nomogram creation. Results: A total of 202 advanced BTC patients who were treated with gemcitabine-based chemotherapy were included in this analysis. No difference in survival was identified between patients undergoing gemcitabine monotherapy and those treated with gemcitabine combined with other cytotoxic agents. The univariate analysis revealed 10 significant factors, while the multivariate analysis identified four independent factors, including gender, monocyte to lymphocyte ratio (MLR), alkaline phosphatase (ALP), and liver metastasis, which were used to establish the nomogram. The performance of this nomogram for the prediction of 6-month mortality risk was found to be promising and feasible based on logistic regression. Conclusion: A nomogram based on four independent pretreatment factors, including gender, MLR, ALP, and liver metastasis, was established to predict the 6-month mortality risk in patients with advanced BTC; it can provide clinicians and patients with additional information when evaluating treatment outcomes.

Improvements in access to cancer clinical trials facilitated by comprehensive genomic profiling in non-small cell lung cancer.

2021 ◽  
Vol 39 (28_suppl) ◽  
pp. 59-59
Author(s):  
Woojung Lee ◽  
Scott Spencer ◽  
Josh John Carlson ◽  
Tam Dinh ◽  
Victoria Dayer ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Clinical Trials ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Genetic Alterations ◽  
Small Cell ◽  
Genomic Profiling ◽  
Small Cell Lung ◽  
Eligibility Criteria ◽  
Comprehensive Genomic Profiling

59 Background: The use of comprehensive genomic profiling (CGP) in cancer patients could lead to additional enrollment in clinical trials that study novel genetic biomarkers, potentially reducing treatment costs for payers and improving health outcomes for patients. Our objective was to estimate the number of additional clinical trials in which patients with non-small cell lung cancer (NSCLC) could potentially enroll due to the use of CGP vs. a comparator panel of 50 genes or less. Methods: Clinical trials in NSCLC that started between 2015 - 2020 were identified from the Aggregate Analysis of ClinicalTrials.gov (AACT) database. Trials with unknown status or study sites outside the United States only were excluded. We abstracted information on required genetic alterations based on the study eligibility criteria. We calculated the incremental number of trials available to patients due to results generated by CGP (FoundationOne CDx, 324 genes) vs. a commercially available comparator panel that was 50 genes or less (Oncomine Dx Target Test, 23 genes) by phase and calendar year. The additional trials were characterized by disease severity, type of therapy, and setting. Results: Enrollment eligibility was dependent on genetic variant status in 35% (250/709) of all identified NSCLC trials. There were 29 (248 vs. 219) additional clinical trials available to patients through the use of CGP, 12% of all gene-specific trials for NSCLC. We identified 45 uses of genetic markers in the 29 additional clinical trials. The most frequent genetic marker in the incremental trials was microsatellite instability, accounting for 44% of all identified markers (20/45). The incremental number of trials available to patients due to the use of CGP did not vary significantly over time but varied by phase – most of the additional clinical trials were in phase 1 or 2 (28/29, 97%). Most of the incremental trials were in metastatic disease (22/29, 76%) and were conducted in academic or advanced community settings (18/29, 62%). The most frequently studied type of intervention in these studies was targeted monotherapy (8/29, 28%), followed by immuno-monotherapy (7/29, 24%). Conclusions: Clinical trials in NSCLC initiated over the past 5 years have consistently included CGP-specific genes or markers in eligibility criteria. Patients with NSCLC have the potential to benefit from the use of CGP as compared to smaller gene panels through improved access to clinical trials.[Table: see text]

scholarly journals Molecular and Immunological Characterization of Biliary Tract Cancers: A Paradigm Shift Towards a Personalized Medicine

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2190 ◽  
Author(s):  
Ines Malenica ◽  
Matteo Donadon ◽  
Ana Lleo
Keyword(s):  
Biliary Tract ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Ampulla Of Vater ◽  
Current Treatment ◽  
Medical Community ◽  
Small Subset ◽  
Molecular Heterogeneity ◽  
Biliary Tract Cancers

Biliary tract cancers (BTCs) are a group of rare cancers that account for up to 3–5% of cancer patients worldwide. BTCs include cholangiocarcinoma (CCA), gallbladder cancer (GBC), and ampulla of Vater cancer (AVC). They are frequently diagnosed at an advanced stage when the disease is often found disseminated. A late diagnosis highly compromises surgery, the only potentially curative option. Current treatment regimens include a combination of chemotherapeutic drugs gemcitabine with cisplatin that have a limited efficiency since more than 50% of patients relapse in the first year. More recently, an inhibitor of fibroblast growth factor receptor 2 (FGFR2) was approved as a second-line treatment, based on the promising results from the NCT02924376 clinical trial. However, novel secondary treatment options are urgently needed. Recent molecular characterization of CCA and GBC highlighted the molecular heterogeneity, etiology, and epidemiology in BTC development and lead to the classification of the extrahepatic CCA into four types: metabolic, proliferating, mesenchymal, and immune type. Differences in the immune infiltration and tumor microenvironment (TME) have been described as well, showing that only a small subset of BTCs could be classified as an immune “hot” and targeted with the immunotherapeutic drugs. This recent evidence has opened a way to new clinical trials for BTCs, and new drug approvals are highly expected by the medical community.

scholarly journals Systemic treatment options for advanced biliary tract carcinoma

2020 ◽  
Vol 55 (10) ◽  
pp. 944-957
Author(s):  
Changqing Xie ◽  
Nicole A. McGrath ◽  
Cecilia Monge Bonilla ◽  
Jianyang Fu
Keyword(s):  
Clinical Trials ◽  
Targeted Therapy ◽  
Biliary Tract ◽  
Treatment Options ◽  
Single Agent ◽  
Current Status ◽  
Dna Mismatch ◽  
First Line Therapy ◽  
Molecular Landscape ◽  
Line Setting

Abstract Advanced biliary tract cancers (BTC) include a diverse collection of rare and heterogenous tumors with poor prognosis. The combination of gemcitabine and cisplatin is the established first-line therapy for advanced BTC. There are no accepted standard treatments in the second line setting, though there are several ongoing clinical trials that implement chemotherapy as a therapeutic strategy. The understanding of the molecular landscape of BTC has offered hope of targeted therapies to the identified actionable genomic aberrations, such as FGFR2 gene fusions, mutations of IDH1/2, HER2, BRAC1/2 and BRAF. Pembigatinib has become the first approved targeted therapy for BTC with FGFR2 fusion or other rearrangements. Recent immunotherapy has opened new therapy avenues in BTC with pembrolizumab approved for either microsatellite instability high (MSI-H) or DNA mismatch repair deficient (dMMR) advanced solid tumors, including BTC. The combination of immunotherapy with other modalities is currently being evaluated in different clinical trials, since single agent immunotherapy appears to provide modest benefits in advanced BTC. In this review, we summarize the current status of treatment options, including systemic chemotherapy, targeted therapy, immunotherapy, and various combinations in advanced BTC.

Tumor mutational burden (TMB) and co-existing actionable mutations in biliary tract cancers (BTC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4086-4086 ◽  
Author(s):  
Apurva Jain ◽  
Rachna T. Shroff ◽  
Mingxin Zuo ◽  
Jacqueline Weatherly ◽  
Funda Meric-Bernstam ◽  
...  
Keyword(s):  
Dna Repair ◽  
Biliary Tract ◽  
Checkpoint Inhibitors ◽  
Repair Pathway ◽  
Biliary Tract Cancers ◽  
Mutational Burden ◽  
Study Results ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Brca1 Brca2

4086 Background: Mutations in DNA repair pathway were identified in 13% of Biliary Tract Cancers (BTC) [ Cancer2016;122:3838–3847]. High TMB tumors including melanoma, lung cancer and those with microsatellite instability (MSI-H) are associated with susceptibility to immune blockade using checkpoint inhibitors. TMB data in BTC is limited and its association with actionable somatic mutation (mut) profiles in BTC is unknown. Methods: Comprehensive genomic profiling (CGP) of 309 FFPE tissue blocks of BTC pts with a hybrid capture of all coding exons of 236 cancer-related genes and 47 introns of 19 genes rearranged in cancer was done using FoundationOne. Base substitutions, indels, gene fusion/rearrangements, TMB, and MSI status were assessed. TMB was calculated by counting mutations across a 1.25Mb region and classified into high (TMBH; ≥20 mut/Mb), intermediate (TMBI; 6 - 19mut/Mb) and low (TMBL; < 6mut/Mb). MSI high (MSIH) and Stable (MSS) status was assigned by a computational algorithm examining 114 intronic homopolymer loci. Patients with TMB ≥6 mut/Mb (N = 60) were included in the clinical correlative portion of this study. Results: Sixty patients with TMB ≥6 mut were identified out of 309 pts of which 9 (15%) were TMBH and 51 (85%) were TMBI. These included 3 (5%) MSIH and 18 (30 %) MSS. The median age was 59 years (range: 29-86), 35 (58%) were females, majority were intrahepatic cholangiocarcinoma (n = 31; 52%) and 28 (47%) presented with advanced disease at diagnosis. Twenty three (38%) pts had received radiation therapy, 28 (47%) surgery and 3 (5%) received immunotherapy. Most frequent co-existing mut seen was TP53 (N = 35; 58%). APC mut was seen in 7 (12%) pts. DNA repair pathway muts ( MSH6, BRCA1, BRCA2, ATM, MLH1, or MSH2 genes) were identified in 78% of TMBH versus 16% in TMBI cases (p < 0.0001). Frequency of PIK3CA mut differed significantly between TMBH and TMBI (44% vs 10%, p < 0.0001). Pts with TMBI had a significantly better median OS (110 weeks) as compared to TMBH (43 weeks) (p = 0.003). Conclusions: DNA repair pathway and PIK3CA mut maybe associated with TMBH in BTC. A better understanding of TMB and associated actionable mutations in BTC may be of value for the management of BTC patients with targeted agents and immunotherapy.

Targeted therapy for HER2 driven colorectal cancer.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 3583-3583 ◽  
Author(s):  
Jeffrey S. Ross ◽  
Siraj Mahamed Ali ◽  
Julia Andrea Elvin ◽  
Alexa Betzig Schrock ◽  
James Suh ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trials ◽  
Genomic Profiling ◽  
Hybrid Capture ◽  
Mutational Burden ◽  
Precision Therapy ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden ◽  
Upper Gastrointestinal ◽  
Colonic Adenocarcinomas

3583 Background: ERBB2 ( HER2) genomic alterations (GA) are evolving therapy taregets in metastatc coorectal cancer (mCRC). Methods: Hybrid capture based comprehensive genomic profiling (CGP) was performed on 8874 (9.6%) mCRC including both colonic adenocarcinomas (7587 cases; 85%) and rectal adenocarcinomas (1287 cases, 15%) Tumor mutational burden (TMB) was calculated from a minimum of 1.2 Mb of sequenced DNA. Results: ERBB2 amplifications or a short variant (SV) alterations or both were found in 433 (4.9%) of the total mCRC. 195 (45%) of the ERBB2 positive mCRC were female and 238 (55%) were male. Median age was 54 years (range 22 to 88 years). The most frequently co-altered genes were SV GA in TP53 (82%), APC (70%), KRAS (26%), SMAD4 (15%) and PIK3CA (13%). Clinically relevant GA significantly under-represented in ERBB2-altered CRC included significantly reduced GA in KRAS at 26% (p = 0.001) and BRAF at 4% (p = 0.003) as well as other kinases at 1% including EGFR, KIT, MET and RET. The frequency of TMB at > 10 mut/Mb (p < 0.0001), but at > 20 mut/Mb mCRC cases demonstrated virtually the same results regardless to ERBB2 status at a frequency of x%. The overall ERBB2 GA frequency at 5.3% in rectal mCRC is slightly higher than that seen in colonic mCRC at 4.9%, (p = 0.36). The frequency of TMB > 10 mut/Mb in ERBB2 WT mCRC is greater in the colonic mCRC than the rectal mCRC (p < 0.0001 for both comparisons). When > 20 mut/Mb is used as the cut-off, the greater frequency of TMB in colonic mCRC versus rectal mCRC remains significant (p < 0.0001). When the ERBB2altered mCRC cases are evaluated, the greater frequency of TMB > 10 mu/Mb in colonic mCRC versus rectal mCRC remains significant (p = 0.009), but the greater frequency in colonic verses rectal mCRC at the > 20 mut/Mb is not significant (p = 0.37). Conclusions: Although lower than observed in breast and upper gastrointestinal carcinomas where anti-HER2 therapies are approved indications, the frequency of ERBB2 GA in CRC at 4.9% is significant. Importantly, nearly half of CRC ERBB2 alterations are SVs, not detectable by routine IHC and FISH testing. However, the success of anti-HER2 therapies shown here and progress in on-going clinical trials indicates that targeting ERBB2 has potential to become an approved advance in precision therapy for mCRC patients.

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