Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets

2015 ◽  
Vol 69 (5) ◽  
pp. 403-408 ◽  
Author(s):  
Hwajeong Lee ◽  
Kai Wang ◽  
Adrienne Johnson ◽  
David M Jones ◽  
Siraj M Ali ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Intrahepatic Cholangiocarcinoma ◽  
Targeted Therapies ◽  
Genomic Profiling ◽  
Gene Fusions ◽  
Single Patient ◽  
Genomic Alterations ◽  
Extrahepatic Cholangiocarcinoma ◽  
Long Tail ◽  
Comprehensive Genomic Profiling

AimWe queried whether extrahepatic cholangiocarcinoma featured clinically relevant genomic alterations that could lead to targeted therapy.MethodsComprehensive genomic profiling by hybridisation capture of up to 315 genes was performed on 99 clinically advanced extrahepatic cholangiocarcinoma.ResultsThere were 60 male and 39 female patients with a median age of 60.5 years. A total of 400 alterations were identified (mean 4.0; range 0–13) in 84 genes. Eighty-two (83%) of extrahepatic cholangiocarcinoma patients featured at least one clinically relevant genomic alterations including KRAS (43%); ERBB2 (9%), PTEN (7%); ATM and NF1 (6%) and CCND1, FBXW7, GNAS, MDM2 and NRAS (all at 5%). BRAF, BRCA2, CDK4, CDK6, FGFR1, FGFR3, PTCH1, RAF1 and STK11 were each altered in a single patient. No IDH1/2 mutations or FGFR2 gene fusions were identified.ConclusionsComprehensive genomic profiling of extrahepatic cholangiocarcinoma differs significantly from intrahepatic cholangiocarcinoma and pancreatic adenocarcinoma, and reveals diverse opportunities for the use of targeted therapies.

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]

scholarly journals The potential role of comprehensive genomic profiling to guide targeted therapy for patients with biliary cancer

2017 ◽  
Vol 10 (6) ◽  
pp. 507-520 ◽  
Author(s):  
Hwajeong Lee ◽  
Jeffrey S. Ross
Keyword(s):  
Targeted Therapy ◽  
Precision Medicine ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Tract Cancer ◽  
Comprehensive Genomic Profiling ◽  
Extrahepatic Bile Ducts ◽  
Associated Risk Factors ◽  
Related Proteins

Remarkable advancements in techniques of genomic profiling and bioinformatics have led to the accumulation of vast amounts of knowledge on the genomic profiles of biliary tract cancer (BTC). Recent largescale molecular profiling studies have not only highlighted genomic differences characterizing tumors of the intrahepatic and extrahepatic bile ducts and gallbladder, but have also revealed differences in genomic profiles pertaining to associated risk factors. Novel genomic alterations such as FGFR2 fusions and IDH1/2 mutations in intrahepatic cholangiocarcinoma (ICC) and ERBB2 alterations in gallbladder cancer (GBCA) are emerging as targeted therapy options capable of advancing precision medicine for the care of these patients. Moreover, variable genomic alterations also appear to impact prognosis and overall disease outcome independent from their therapy selection value. High mutational burden and increased expression of immune checkpoint-related proteins observed in a subset of BTC also show a potential for guidance of immunotherapy. Thus, comprehensive genomic profiling (CGP) is rapidly achieving status as an integral component of precision medicine and is starting to become invaluable in guiding the management of patients with BTC, a rare disease with dismal outcome.

scholarly journals Utility of comprehensive genomic profiling in directing treatment and improving patient outcomes in advanced non-small cell lung cancer

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Shen Zhao ◽  
Zhonghan Zhang ◽  
Jianhua Zhan ◽  
Xin Zhao ◽  
Xinru Chen ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Patient Outcomes ◽  
Targeted Therapies ◽  
Advanced Nsclc ◽  
Clinical Care ◽  
Progression Free Survival ◽  
Targeted Drugs ◽  
Genomic Profiling ◽  
Recent Emergence ◽  
Comprehensive Genomic Profiling

Abstract Background With the identification of new targetable drivers and the recent emergence of novel targeted drugs, using comprehensive genomic profiling in lieu of the routine testing for classic drivers in the clinical care for advanced NSCLC has been increasingly advocated. However, the key assumption justifying this practice, that comprehensive genomic profiling could lead to effective anticancer therapies and improve patient outcomes, remains unproved. Methods Comprehensive genomic profiling was prospectively applied in 1564 advanced NSCLC patients to identify potentially actionable genomic alterations. Patients were assigned to genotype-matched targeted therapies or nonmatched therapies based on the profiling results. Its utility in directing treatments was determined by the proportion of patients receiving genotype-matched targeted therapies and the proportion of patients being enrolled into genotype-matched clinical trials. Its impacts on patient outcomes were assessed by comparing progression-free survival (PFS) and overall survival (OS) between patients who received a genotype-matched and nonmatched therapy. Results From October 2016 to October 2019, tumor genomic profiles were established in 1166 patients, leading to a matched targeted therapy in 37.7% (n = 440) and a genotype-matched trial enrollment in 20.9% of patients (n = 244). Potentially actionable alterations were detected in 781 patients (67.0%). For these patients, a genomic profiling-directed matched therapy significantly improved PFS (9.0 months vs 4.9 months, P < 0.001) and OS (3.9 years vs 2.5 years, P < 0.001) compared with a nonmatched therapy. Excluding patients with standard targeted therapies, genomic profiling led to a matched targeted therapy in 16.7% (n = 24) and a matched trial enrollment in 11.2% (n = 16) of patients. No PFS (4.7 months vs 4.6 months, P = 0.530) or OS (1.9 years vs 2.4 years, P = 0.238) benefit was observed with the use of genotype-matched targeted therapies in this population. Conclusions Comprehensive genomic profiling is of clinical utility in assisting treatment selection, facilitating clinical trial enrollment, and improving patient outcomes in advanced NSCLC. However, for patients carrying alterations without standard-of-care targeted drugs, the interpretation of genomic profiling results should be careful given the low likelihood of benefit from the investigational or off-label use of targeted therapies in this population in the current treatment landscape. Trial registration ChiCTR1900027582 (retrospectively registered on 19 November 2019)

In search of novel synthetic lethality anti-cancer drug targets in intrahepatic cholangiocarcinoma: MTAP genomic loss.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 337-337
Author(s):  
Jeffrey S. Ross ◽  
Alexa Betzig Schrock ◽  
Russell Madison ◽  
Natalie Danziger ◽  
Dean Pavlick ◽  
...  
Keyword(s):  
Intrahepatic Cholangiocarcinoma ◽  
Drug Targets ◽  
Synthetic Lethality ◽  
Parp Inhibitor ◽  
Suppressor Gene ◽  
Cancer Drug ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Comprehensive Genomic Profiling ◽  
Tumor Mutational Burden

337 Background: The association of BRCA tumor suppressor gene (TSG) inactivation and PARP inhibitor efficacy through a mechanism of synthetic lethality (SL) is now well-established. Recently, the PRMT5 arginine methyltransferase dependence in cells with MTAP (S-methyl-5'-thioadenosine phosphorylase) genomic alterations (GA) has been proposed as a new SL based anti-tumor strategy and under consideration for development for intrahepatic cholangiocarcinoma (IC). Methods: 2,170 cases of clinically advanced IC were submitted for comprehensive genomic profiling (CGP) to detect genomic alterations (GA), tumor mutational burden (TMB) and microsatellite instability (MSI) using a hybrid capture based assay (F1CDx). PD-L1 expression in tumor cells (Dako 22C3) was measured by IHC and scored using the tumor proportion score (TPS) method. Results: 328 (15%) ICs featured MTAP inactivation (MTAP-IC). 48% of MTAP-IC cases were female and 52% were male with a median age of 66 years (range 26-93 years). MTAP-IC featured 6.3 GA per sample. The median TMB was 2.5 mut/Mb with only 2% of cases with TMB ≥10 mut/Mb. No (0%) MTAP-IC cases were MSI-high. Of 112 MTAP-IC IHC stained for PD-L1, 4% were PD-L1 high (> 50%), 14% were PD-L1 low (1-49%) and 82% were PD-L1 negative. 99% of MTAP inactivation was by copy number (CN) loss and 1% was due to non-CN mutation. In MTAP-IC, 99% featured CDKN2A loss and 95% featured CDKN2B loss (9p21 co-deletion). TP53 was mutated in 31% and KRAS in 24% (3% G12C). Other currently non-targetable GA included ARID1A (19%), BAP1 (16%) and SMAD4 (13%). Among potentially targetable GA, the MTAP-IC featured 12% FGFR2 GA (8% rearrangements), 10% BRAF (8% V600E), 7% IDH1, 7% PIK3CA, 4% BRCA2, 4% ERBB2 (2% amplification) and 3% MET. Conclusions: Comprehensive genomic profiling elucidated that MTAP GA are frequent in IC and features relatively high GA/tumor, including 9p21 co-deletion, but relatively low TMB and PD-L1 expression. Isolated MTAP deletion without CDKN2A/B co-deletion was extremely rare. In addition to the potential targeting of PRMT5 in MTAP-IC tumors, co-altered genes known to be targets in IC such as FGFR2, IDH1 and BRAF are still prevalent in MTAP-IC, indicating potential for combining targeted therapies in some MTAP-IC patients.

Comprehensive genomic profiling of 443 cases of renal cell carcinoma to reveal frequent clinically relevant genomic alterations.

2015 ◽  
Vol 33 (7_suppl) ◽  
pp. 433-433 ◽  
Author(s):  
Sumanta Kumar Pal ◽  
Siraj M. Ali ◽  
Zachary Chalmers ◽  
Jose A. Karam ◽  
Julia Andrea Elvin ◽  
...  
Keyword(s):  
Targeted Therapies ◽  
Collecting Duct ◽  
Medullary Carcinoma ◽  
Patient Specific ◽  
Genomic Profiling ◽  
Genomic Alterations ◽  
Medical Need ◽  
Comprehensive Genomic Profiling ◽  
Metastatic Sites

433 Background: Despite the availability of targeted therapy, effective management of advanced RCC is an unmet medical need as treatment is not personalized and is not guided by patient-specific genomic alterations (GAs). To assess the spectrum of clinically relevant GAs (CRGAs) in advanced RCC, comprehensive genomic profiling (CGP) of clinical RCC samples was performed with the goal of informing use of existing and novel targeted therapies. Methods: DNA was extracted from 40 microns of FFPE sections from 443 consecutive patients with relapsed/metastatic RCC. CGP was performed on hybridization-captured, adaptor ligation based libraries to a mean coverage depth of 646X 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 (SUB), INDELs, copy number alterations (CNA) and fusions/rearrangements. CRGA were defined as GA linked to drugs on the market or under evaluation in mechanism driven clinical trials. Results: There were 73% male and 27% female patients with a mean age of 56 years, and the majority of cases were advanced stage with 198/443 specimens (44.6%) from metastatic sites. 400/443 patients (89%) had at least 1 GA on CGP with a mean 3.1 GA/case. 396/400 RCC harboring GA had at least 1 CRGA involving 111 individual genes with a mean of 1.32 CRGA/UC. The most common novel CRGA in order of frequency were: CDKN2A (21%), BAP1 (12%), ATM (11%), PTEN(8.5%), TSC1(8.3%), mTOR (7%), MET (6.5%), AR (5.3%), DNMT3A (5%) and TSC2 (5%). Moreover, VHL harbored a diversity of GA’s in in 49% of cases. Collecting duct carcinomas harbored an enrichment of NF2 truncating alterations (>40%), distinct from renal medullary carcinoma which did not harbor such GA. Multiple clinical antitumor responses to targeted therapies will be presented. Conclusions: Using a CGP assay capable of detecting all classes of GA simultaneously, a high frequency of CRGA was identified in a large series of patients with advanced RCC. The diversity of CRGA suggests opportunities for the rational application of existing and investigational targeted therapies, and for possible deeper characterization of histological types of RCC.

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