PMID: 28487467 (Patient)   Terms: Retrospective Study, retrospective, clinical trial, retrospective study
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0		Overall Survival and Clinical Characteristics of BRCA-Associated Cholangiocarcinoma : A Multicenter Retrospective Study .
1		BACKGROUND :
2		Biliary tract malignancies , in particular cholangiocarcinomas ( CCA ) , are rare tumors that carry a poor prognosis .
3		BRCA2 mutation carriers have an increased risk of developing CCA with a reported relative risk of approximately 5 according to the Breast Cancer Linkage Consortium .
4		In addition to this risk , there are potential therapeutic implications in those harboring somatic and/or germline ( GL ) BRCA mutations .
5		Therefore , it is important to define the clinical characteristics of GL/somatic BRCA1/2 variants in CCA patients .
6		MATERIALS AND METHODS :
7	Μ	We performed a multicenter retrospective analysis of CCA patients diagnosed between January 2000 and December 2013 with GL or somatic variants in BRCA1/2 genes detected by GL mutations testing and/or by tumor next generation sequencing .
8		Cases were identified from clinical databases at participating institutions .
9		Data including demographics , clinical history , surgical procedures , and systemic chemotherapy or radiation were extracted from patients' records .
10		RESULTS :
11	Μ	Overall , 18 cases were identified : 5 carriers of GL BRCA1/2 mutations ( 4 BRCA2 ; 1 BRCA1 ) and 13 harboring somatic variations ( 7 BRCA1 ; 6 BRCA2 ) .
12		Mean age at diagnosis was 60 , SD +/- 10 years ( range 36-75 years ) , with male and female prevalence rates of 61.2% and 38.8% , respectively .
13		Stage at diagnosis was I ( n = 4 ) , II ( n = 3 ) , III ( n = 3 ) , and IV ( n = 8 ) .
14		Six patients had extrahepatic CCA and the rest intrahepatic CCA .
15		Thirteen patients received platinum-based therapy and four were treated with poly ADP ribose polymerase inhibitors , of whom one experienced sustained disease response with a progression-free survival of 42.6 months .
16		Median overall survival from diagnosis for patients with stage I/II in this study was 40.3 months ( 95% confidence interval [CI] , 6.73-108.15 ) and with stages III/IV was 25 months ( 95% CI , 1523-4057 ) .
17		CONCLUSION :
18		BRCA-associated CCA is uncommon .
19		This multicenter retrospective study provides a thorough clinical analysis of a BRCA-associated CCA cohort , which can serve as a benchmark for future development and design of expanded analyses and clinical trials .
20		The Oncologist 2017 ; 22 : 1-7 IMPLICATIONS FOR PRACTICE : BRCA-associated CCA is uncommon but a very important subtype of hepatic malignancies , due to its rising prevalence .
21		Better clinical characterization of this subtype might allow application of targeted therapy for CCA patients with germline or somatic mutations in BRCA1/2 genes , especially due to previously reported success of such therapies in other BRCA-associated malignancies .
22		Thus this study , first of its kind , provides a basis for future multi-centered analyses in larger cohorts , as well as clinical trials .
23		Additionally , this study emphasizes the importance of both germline and somatic genotyping for all CCA patients .

PMID: 26508638 (None)   Terms: , mice
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0		CRISPR/Cas9 somatic multiplex-mutagenesis for high-throughput functional cancer genomics in mice .
1		Here , we show CRISPR/Cas9-based targeted somatic multiplex-mutagenesis and its application for high-throughput analysis of gene function in mice .
2		Using hepatic single guide RNA ( sgRNA ) delivery , we targeted large gene sets to induce hepatocellular carcinoma ( HCC ) and intrahepatic cholangiocarcinoma ( ICC ) .
3	Μ	We observed Darwinian selection of target genes , which suppress tumorigenesis in the respective cellular/tissue context , such as Pten or Cdkn2a , and conversely found low frequency of Brca1/2 alterations , explaining mutational spectra in human ICC/HCC .
4		Our studies show that multiplexed CRISPR/Cas9 can be used for recessive genetic screening or high-throughput cancer gene validation in mice .
5		The analysis of CRISPR/Cas9 -induced tumors provided support for a major role of chromatin modifiers in hepatobiliary tumorigenesis , including that of ARID family proteins , which have recently been reported to be mutated in ICC/HCC .
6		We have also comprehensively characterized the frequency and size of chromosomal alterations induced by combinatorial sgRNA delivery and describe related limitations of CRISPR/Cas9 multiplexing , as well as opportunities for chromosome engineering in the context of hepatobiliary tumorigenesis .
7		Our study describes novel approaches to model and study cancer in a high-throughput multiplexed format that will facilitate the functional annotation of cancer genomes .

PMID: 26500333 (Patient)   Terms:
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0		Comprehensive genomic profiling of extrahepatic cholangiocarcinoma reveals a long tail of therapeutic targets .
1		AIM :
2	Μ	We queried whether extrahepatic cholangiocarcinoma featured clinically relevant genomic alterations that could lead to targeted therapy .
3		METHODS :
4		Comprehensive genomic profiling by hybridisation capture of up to 315 genes was performed on 99 clinically advanced extrahepatic cholangiocarcinoma .
5		RESULTS :
6		There were 60 male and 39 female patients with a median age of 60.5 years .
7	Μ	A total of 400 alterations were identified ( mean 40 ; range 0-13 ) in 84 genes .
8	Μ	Eighty-two ( 83% ) of extrahepatic cholangiocarcinoma patients featured atleast 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% ) .
9	Μ	BRAF , BRCA2 , CDK4 , CDK6 , FGFR1 , FGFR3 , PTCH1 , RAF1 and STK11 were each altered in a single patient .
10	Μ	No IDH1/2 mutations or FGFR2 gene fusions were identified .
11		CONCLUSIONS :
12		Comprehensive genomic profiling of extrahepatic cholangiocarcinoma differs significantly from intrahepatic cholangiocarcinoma and pancreatic adenocarcinoma , and reveals diverse opportunities for the use of targeted therapies .

PMID: 24563076 (Patient)   Terms:
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0		New routes to targeted therapy of intrahepatic cholangiocarcinomas revealed by next-generation sequencing .
1		BACKGROUND :
2		Intrahepatic cholangiocarcinoma ( ICC ) is a subtype of primary liver cancer that is rarely curable by surgery and is rapidly increasing in incidence .
3		Relapsed ICC has a poor prognosis , and current systemic nontargeted therapies are commonly extrapolated from those used in other gastrointestinal malignancies .
4	Μ	We hypothesized that genomic profiling of clinical ICC samples would identify genomic alterations that are linked to targeted therapies and that could facilitate a personalized approach to therapy .
5		METHODS :
6		DNA sequencing of hybridization-captured libraries was performed for 3,320 exons of 182 cancer-related genes and 36 introns of 14 genes frequently rearranged in cancer .
7		Sample DNA was isolated from 40 mum of 28 formalin-fixed paraffin-embedded ICC specimens and sequenced to high coverage .
8		RESULTS :
9	Μ	The most commonly observed alterations were within ARID1A ( 36% ) , IDH1/2 ( 36% ) , and TP53 ( 36% ) as well as amplification of MCL1 ( 21% ) .
10	Μ	Twenty cases ( 71% ) harbored atleast one potentially actionable alteration , including FGFR2 ( 14% ) , KRAS ( 11% ) , PTEN ( 11% ) , CDKN2A ( 7% ) , CDK6 ( 7% ) , ERBB3 ( 7% ) , MET ( 7% ) , NRAS ( 7% ) , BRCA1 ( 4% ) , BRCA2 ( 4% ) , NF1 ( 4% ) , PIK3CA ( 4% ) , PTCH1 ( 4% ) , and TSC1 ( 4% ) .
11		Four ( 14% ) of the ICC cases featured novel gene fusions involving the tyrosine kinases FGFR2 and NTRK1 ( FGFR2-KIAA1598 , FGFR2-BICC1 , FGFR2-TACC3 , and RABGAP1L-NTRK1 ) .
12		CONCLUSION :
13	Μ	Two thirds of patients in this study harbored genomic alterations that are associated with targeted therapies and that have the potential to personalize therapy selection for to individual patients .

PMID: 9892095 (Patient)   Terms:
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0		Immunoadsorption therapy for paraneoplastic syndromes .
1		Paraneoplastic neurologic syndromes associated with systemic cancer are being increasingly recognized .
2		Although these syndromes are thought to be immunologically mediated treatment with steroids , immunoglobulin and plasmapharesis has been disappointing .
3		Based on our preliminary experience with the treatment of 6 cases of paraneoplastic neurologic syndromes with protein A immunoadsorption , an institutional , open-arm treatment protocol was established .
4		Since our original report we have treated an additional 7 patients with this method .
5		The 13 cases were accrued over a 2 year period and included 10 women and 3 men with an average age of 63 .
6		The paraneoplastic syndromes included 6 cases of cerebellar degeneration , 3 cases of opsoclonus/myoclonus , 3 cases of encephalomyelitis and 1 case of Lambert Eaton myasthenic syndrome .
7		Primary cancers included 4 cases of small cell lung cancer , 2 cases of breast cancer , 2 cases of lymphoma and 1 each of acinic cell cancer , cholangiocarcinoma , Merkel cell cancer , pancreatic adenocarcinoma and rectal cancer .
8		Anti-neuronal antibody status , cerebrospinal fluid and neuroimaging studies as well as cancer staging and treatment protocols were reviewed .
9		Neurologic syndromes were clinically separated into component symptoms and signs for assessment of treatment effect .
10		The treatment goal was a total of 6 sessions of protein A immunoadsorption given twice weekly .
11		Twelve of 13 patients completed therapy and one patient developed cutaneous vasculitis during the second session with termination of treatment .
12		Of the remaining patients 3/12 had a complete response of the primary clinical symptom/sign while 6/12 had a partial response for a total response rate of 9/12 ( 75% ) .
13		Toxicity was limited to cutaneous vasculitis in 1 patient and an episode of hemisensory changes in another patient .
14		Current treatment of paraneoplastic neurologic syndromes remains unsatisfactory .
15		Despite the small number of patients in this report , protein A immunoadsorption is a promising therapy which deserves further study in a larger population of patients with paraneoplastic syndromes .

PMID: 2598535 (Patient)   Terms:
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0		[ Metastatic brain tumor in the elderly ] .
1		Authors have reviewed 322 consecutive patients with malignant tumors confirmed by pathological studies between October 1973 and August 1987 in order to determine the frequency , clinical presentation , and lesion localization of metastatic brain tumor in the elderly .
2		Among 322 patients with malignant tumor , 7 patients with primary brain tumor and 21 patients with metastatic brain tumors were found .
3		The over-all frequency of metastases to the brain was 5.8% .
4		This frequency of brain metastasis in the elderly was lower than those of the previous literature which have varied from 9 to 35% .
5		The patients' ages with metastatic brain tumor ranged from 65 to 88 years with a median age of 77.5 years .
6		The primary tumor sites of metastatic brain tumors were limited to 5 kinds of organs .
7		These metastases were found in 27.3% of 11 patients with breast cancer , 17.5% of 80 patients with lung cancer , 6.7% of 15 patients with bile duct system cancer , 5.0% of 20 patients with pancreatic cancer , and 2.0% of 91 patients with gastric cancer .
8		There was no brain metastasis in the other kinds of carcinoma .
9		Among 21 metastatic brain tumors , there were 14 patients with lung cancer , 3 patients with breast cancer , 2 patients with gastric cancer , 1 patient with cholangiocarcinoma , and 1 patient with pancreatic cancer .
10		In this series , the frequency of single and multiple metastases were 13 and 8 cases , respectively .
11		The multiple brain metastases ranged from 2 to 6 nodules .
12		In 21 metastatic brain tumors , there were 42 metastatic nodules in total .

PMID: ASCO_159455-173 (Patient)   Terms: retrospective
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0		Overall survival and clinical characteristics of BRCA germline/somatic cholangiocarcinoma ( CCA ) . .
1		Background : Biliary tract cancers ( BTC ) exhibit a diverse and high frequency of actionable mutations detectable using next generation sequencing ( NGS ) .
2		The Breast Cancer Linkage Consortium reported that BRCA2 mutation carriers are at increased risk for BTC with estimated relative risk of 4.97 , ( 95% CI = 1 50-1652 ) .
3		The purpose of this study was to evaluate the clinical characteristics of germline/somatic BRCA1/2mutations in CCA patients .
4		Methods : Multi-center retrospective analysis of patients with germline/somatic BRCA1/2 - associated CCA diagnosed between January 2000 and December 2013 .
5		Cases were identified from clinical databases at participating institutions .
6		Data including demographics , clinical history , surgical procedures and systemic chemotherapy or radiation were extracted from patient records .
7	Μ	Results : Overall , we identified 18 cases including 5 carriers of germline BRCA1/2 mutations ( 4 BRCA2 ; 1 BRCA1 ) and 13 harboring somatic mutations ( 7 BRCA1 ; 6 BRCA2 ) using a NGS panel testing tumor for 'actionable' mutations .
8		One patient presented with two different somatic mutations in the BRCA2gene .
9		Mean age at diagnosis was 60 years ( range 36-75 ) , male : females ( 612% versus 388% , respectively ) .
10		Stage at diagnosis : I ( n = 4 ) , II ( n = 3 ) , III ( n = 3 ) and IV ( n = 8 ) .
11		Six patients had extrahepatic CAA ; twelve patients had intrahepatic CCA .
12		Prior therapy in 13 patients included platinum-based therapy with one patient receiving prior olaparib .
13		Median overall survival for patients with stage I/II is 34.7 months ( 95% CI , 706-629 ) and for stages III/IV is 25 months ( 95% CI , 1202-3584 ) .
14		Conclusions : BRCA associated CCA may have an enhanced therapeutic sensitivity to DNA damaging agents .
15		This needs confirmation in a larger cohort of patients .

PMID: AACR_2016-1293 (Patient)   Terms: xenograft, tumor growth in preclinical models, mouse models, mouse, mice
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0		JQ1 sensitivity of patient-derived xenograft models of cholangiocarcinoma .
1		Cholangiocarcinoma ( CCA ) is a lethal malignancy arising from cholangiocytes in any part of the biliary tree .
2		The incidence of CCA has been on the rise worldwide , and the prognosis and clinical outcome have remained essentially unchanged for 30 years .
3		The majority of patients are diagnosed at late stage , and surgery continues to be the only cure .
4		Patients receive systemic chemotherapy with the first - line combination therapy comprising gemcitabine and cisplatin .
5		Median survival for these patients is <12 months , emphasizing the need to improve current treatment .
6		A step toward improving outcome is the pre-clinical evaluation of novel therapeutics .
7		Recently the bromodomain and extra-terminal domain ( BET ) inhibitor JQ1 has been shown to suppress tumor growth in preclinical models of multiple tumor types .
8		The therapeutic effect of JQ1 has been attributed , atleast in part , to its ability to inhibit c-Myc expression. 95% of CCA tumors express c-Myc and its down-regulation has been shown to reduce the invasive potential of CCA cells , suggesting that c-Myc contributes to CCA phenotype .
9		Our lab recently evaluated the efficacy of the BET inhibitor JQ1 in CCA patient-derived xenograft mouse models .
10		JQ1 suppressed CCA tumor growth in 2 of the 3 models .
11		To determine gene products whose upregulation or downregulation is responsible for the differences in sensitivity to JQ1 among our CCA models , we generated expression profiles of tumors from vehicle control and JQ1 treated mice using NanoString technology ( nCounter PanCancer Pathways panel ) .
12		Our data demonstrate that JQ1 inhibited the expression of c-Myc to a greater extent in the sensitive models than in the insensitive model .
13		Expression array data showed further that gene products involved in cell cycle and DNA repair pathways were also decreased by JQ1 .
14		Of particular interest were two transcriptional targets of c-Myc , Chk1 and BRCA2 , each of which is involved in DNA damage response .
15		Immunohistochemistry staining confirmed expression profile analyses .
16		We conclude that the inhibition of cell cycle and DNA repair genes may contribute to the mechanism of action of JQ1 in CCA tumors .

PMID: ASCO_140039-158 (Patient)   Terms:
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0		Tumor profiling of biliary tract carcinomas to reveal distinct molecular alterations and potential therapeutic targets. .
1		Background : Extrahepatic cholangiocarcinoma ( EHCC ) , intrahepatic cholangiocarcinoma ( IHCC ) , and gallbladder carcinoma ( GBCA ) are rare tumors with poor prognosis that tend to be chemo-resistant .
2		The underlying molecular alterations and their correlation with altered responses to therapies are not well understood .
3		We hypothesized that delineation of different molecular alterations in the cancer types might potentially yield different therapeutic options .
4		Methods : 815 cases ( 126 EHCC , 434 IHCC , 244 GBCA , 11 NOS ) were tested by a commercial multiplatform profiling service ( Caris Life Sciences , Phoenix , AZ ) .
5		Tests included sequencing ( Sanger , NGS ) , gene amplification ( CISH/FISH ) , and protein expression (IHC) .
6		Results : 24 of 47 genes tested had mutations , with the highest rates in TP53 ( 28% ) , KRAS ( 18% ) , IDH1 ( 9% ) , and SMAD4 ( 6% ) .
7		BRCA1/2 mutations were seen in 3/41 ( 73% ) and 5/40 ( 125% ) cases .
8	Μ	Overall , IHC showed high TOPO1 , TOP2A , PD-1 , SPARC and PD-L1 in 56% , 49% , 40% , 39% and 15% of cases and low RRM1 , ERCC1 and TS in 82% , 72% and 79% , respectively , suggesting potential utility of chemotherapeutic and immunomodulatory agents targeting these alterations in selected cases .
9		Mutually exclusive protein loss of chromatin modifiers BAP1 and PBRM1 were seen in 17% and 27% .
10	Μ	ROS1 break-apart FISH showed negative results in 16 cases tested .
11	✓	Comparing the three carcinomas ( EHCC , IHCC and GBCA , Table ) , EHCC had the highest KRAS mutation rate ; IHCC had the highest IDH1 mutation ; GBCA and EHCC had significantly higher TP53 mutation and HER2 amplification than IHCC .	GM-ASS-DS
12	✓	IDH1 and TP53 mutations were mutually exclusive , and IDH1-mutated IHCC had higher P-glycoprotein expression than TP53-mutated IHCC ( 82% vs. 37% ) .	GE-ASS-DS
13		GBCA had high TOP2A by FISH and IHC , and a high loss of PBRM1 ( all p < 0.05 ) .
14		Conclusions : Multiplatform cancer profiling reveals distinctbiomarker characteristics of biliary tract carcinomas , offering insights into disease biology and suggests potential sensitivity to novel and conventional therapies .
15		Further analyses with clinical correlation are warranted .

PMID: AACR_2016-4493 (Patient)   Terms:
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0		Germline findings in targeted tumor sequencing using matched normal DNA .
1		Background : The promise of precision medicine is vast and efforts are needed to increase utilization of precision oncology tests .
2		Studies have suggested that mutations in cancer predisposition are more common than previously thought .
3		Herein , we investigated germline alterations in cancer patients undergoing tumor profiling to identify the potential genetic predisposing factors as well as therapeutically relevant germline variants .
4		Methods : Comprehensive genomic profiling was performed on tumor samples from 67 patients from 24 cancer types with ages ranging 23-77 years .
5		We performed targeted exome sequencing of 562 genes in tumor and paired normal DNA which included 116 genes that have been associated with cancer predisposition syndromes .
6		In addition to identifying the somatic changes , we characterized germline mutations in select 116 genes using public databases ( ClinVar , Ensembl ) .
7	Μ	Results : Pathogenic germline mutations were found in 17.91% ( 12/67 ) of cases , which included 10 unique variants in 8 genes , the majority of which included DNA repair genes ( ATM , BRCA2 , ERCC4 , NBN , PSM2 , MUTYH , XPC and AR ) .
8	Μ	Likely pathogenic mutations were found in 23% ( 16/67 ) of the cases and 12% ( 8/67 ) were predicted pathogenic by SIFT/PolyPhen .
9		In select cases we found existence of a 2nd hit which may have an impact on certain targeted therapeutics such as PARP inhibitors .
10		All of the cases profiled carried either benign or variants of unknown significance ( VUS ) mutations .
11		Germline findings in cancer susceptibility genes that were concordant with the individual's cancer type included ATM (R2227C) in HER2+ breast cancer patient ; BRCA2 missense mutation (K944X) in peritoneal cancer and HER2+ breast cancer ; BRCA2 ( W1692MfsX3 , I2588YfsX60 ) in patients with pancreatic and breast cancer respectively and PMS2 (L729QfsX6) in colorectal cancer ( CRC ) .
12		Germline pathogenic findings in cancer susceptibility genes that were dis-concordant with the individual's cancer type included ERCC4 (R799W) in endometrial cancer ; XPC (P334H) in CRC ; MUTYH (G393D) in esophageal and CRC ; NBN (K219NfsX16) in HER2+ breast cancer and AR (A646D) mutation in CRC .
13	✓	Interestingly , FLT4 (R1324L) mutation which is associated with decreased response and toxicity to sunitinib in renal cell cancer was found across several tumor types including lung adenocarcinoma ( n = 3 ) , pancreatic cancer ( n = 3 ) , HER2+ breast cancer ( n = 2 ) , CRC ( n = 2 ) and n = 1 in gallbladder carcinoma , cholangiocarcinoma and endometrial adenocarcinoma .	GM-ASS-RO
14		The comparison of somatic to germline mutation will be presented .
15		Conclusion : Germline data analysis of a small cohort of advanced cancer patients revealed that unselected cancer patients may benefit from germline evaluation which may influence the evaluation and care of the patient or the patient's family members .
16	Μ	Even though majority of germline mutations were VUS , several mutations were identified which may be amenable to targeted therapeutic strategies .

PMID: AACR_2016-2750 (Patient)   Terms:
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0		Mutations on the homologous recombination pathway in 13 cancer types .
1		Homologous recombination ( HR ) is important in DNA double - strand break repair .
2		HR defects promote carcinogenesis and are associated with selective sensitivity to PARP-inhibitors and DNA-damaging agents .
3		We collected 1029 tumor samples in 13 cancer types and used next-generation sequencing ( NGS ) to survey genes in the HR pathway .
4		NGS on 591 genes was performed using formalin-fixed paraffin-embedded samples on the Illumina NextSeq platform ( Caris Life Sciences , AZ ) .
5	Μ	Mutations in as low as 5% of cells can be detected with > 99% confidence .
6	Μ	Deletions larger than 27bp may not be detected by this method .
7		Pathogenic or presumed pathogenic variants are counted as mutations .
8		The table summarizes mutation rates of 7 key genesATM , BRCA1 , BRCA2 , CHEK1 , CHEK2 , PALB2 and PTENincluded in this pilot study .
9		Another 17 HR genesATR , ATRX , BARD1 , BLM , BRIP1 , FANCA , FANCC , FANCD2 , FANCE , FANCF , FANCG , FANCL , MRE11A , NBN , RAD50 , RAD51 , and RAD51Bwere also analyzed .
10		PTEN mutations were seen in 6.3% of tumors , ATM in 5% , BRCA1 in 2% , BRCA2 in 2% , PALB2 in 1% , and CHEK2 in 1% .
11	Μ	No CHEK1 mutations were observed .
12		Overall , 15% of tumors carry atleast one mutation in any of the 7 key genes .
13		The highest mutation rates were seen in endometrial ( 43% ) , glioblastoma ( 34% ) , and gastric cancers ( 23% ) .
14		The highest rates of ATM ( 97% ) , BRCA2 ( 65% ) , and PALB2 ( 65% ) were seen in gastric cancer , while the highest CHEK2 ( 56% ) , BRCA1 ( 73% ) and PTEN ( 44% ) mutations were seen in cholangiocarcinoma , ovarian and endometrial tumors , respectively .
15	Μ	One 53-year old pt with metastatic poorly-differentiated gastric adenocarcinoma experienced ongoing radiographic partial response and dramatic symptom relief following 4 cycles of FOLFOX without surgery ; tumor analysis revealed a nonsense PALB2 ( S326* ) gene mutation , while the other 23 HR genes were wild type .
16	Μ	ERCC1 showed intact expression by IHC .

PMID: ASCO_193846-199 (Patient)   Terms: prospective, NCT01775072, Prospective
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0		A prospective analysis of germline alterations ( GA ) in biliary tract cancer ( BTC ) . .
1		Background : The incidence of hereditary cancer predisposition syndromes in patients ( pts ) with BTC is unknown .
2		Cholangiocarcinoma has been reported in pts with germline mutations in BAP1 , BRCA1/2 , and mismatch repair genes .
3		These associations are poorly characterized to date and the majority of pts do not undergo clinical germline analysis ( CGA ) .
4		Methods : Pts with BTC were offered consent to CGA between 01/2016 and 01/2017 under an IRB approved protocol ( NCT01775072 ) .
5	Μ	Using the MSK-IMPACT platform , 76 genes associated with hereditary cancer predisposition were analyzed for germline variants and matched tumor samples were analysed for somatic alterations in > 340 genes .
6		Demographic and clinical data were collected .
7		Results : 78 patients were accrued : Intrahepatic = 52 , extrahepatic = 13 , gallbladder = 13 .
8		Median age at diagnosis was 57 years ( range 21-80 ) , 45 ( 58% ) had a positive family history of cancer in atleast one 1st degree or two 2nd degree relatives. 7 patients had a personal history of cancer .
9		A pathogenic or likely pathogenic GA was identified in 16 pts ( 20% ) .
10		( See table ) .
11		Conclusions : Prospective analysis of GAs in pts with BTC , unselected by family history or age , revealed potentially actionable findings in 20% of pts .
12		CGA in pts with BTC may benefit patients and their families in view of screening and therapeutic implications .
13		GeneAlterationPenetranceSiteSexageEthnicityFamily hx cancerPersonal hx cancerAPCp .
14		I1307KLowGBM53AJYNAPCp .
15		I1307KLowEHCF57AJYNAPCI1307KLowIHCF71AJYNATMp .
16		L1224*ModerateIHCF36WHITEYNBRCA2p .
17		L1072*HighIHCM49INDIANnNBRCA2p .
18		D1868EFS*4HighGBM50INDIANYNBRCA2p .
19		N1377-T1378INSHighIHCF55WHITEyBreastBRCA2p .
20		S1982RFS*22HighGBF61AJYOvaryFHp .
21		K477DUPRecessiveIHCM60WHITEUKNMITFp .
22		E419KModerateIHCF52WHITEyNMUTYHp .
23		G393DLowIHCM39WHITEYNMUTYHp .
24		E466DELLowIHCM42WHITEYNMUTYHY90*LowEHCM66WHITEYNNBNp .
25		L128*ModerateGBF48INDIANNNPALB2p .
26		Y1183*HighIHCF43WHITEUKNTSC2p .

PMID: ASCO_169730-176 (Patient)   Terms: clinical trial
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0		Comprehensive profiling of biliary tract cancers ( BTC ) to reveal molecular heterogeneity with implications for matched targeted therapies ( MTT ) . .
1		Background : BTC is an heterogeneous disease that includes intrahepatic cholangiocarcinoma ( IHC ) , extrahepatic cholangiocarcinoma ( EHC ) , gallbladder carcinomas ( GBC ) and ampulloma ( AM ) , typically present an advanced stage at diagnosis and chemotherapy ( chemo ) has limited efficacy .
2		We describe potentially targetable genomic alterations ( ptGA ) of BTC and impact of MTT in these patients ( pts ) .
3		Methods : From 2011 to 2015 , 104 chemorefractory patients ( pts ) with BTC ( 62 IHC , 23 EHC , 15 GBC , 4 AM ) were referred to molecular profiling at our institution .
4		Archived tumor samples were analyzed using different panels ( FoundationOne in 27 , Amplicon-MiSeq in 25 , MassARRAY-Sequenom in 23 , Fusion-Nanostring in 31 and protein expression in 13 ) and pts were offered MTT in Phase 1 trials according to specific eligibility criteria and logistics .
5		Results : Median age was 57 y ( 27-82 ) ; metastatic sites were liver ( 81% ) , nodes ( 43% ) and lung ( 21% ) ; median time to progression on first - line chemo was 5.1 months (m) ( CI95% 41-63 ) ; 27% received 2 or more chemo lines .
6		At least one ptGA was detected in 49% of the samples , with proportional increase according to the size and spectrum of gene alterations tested ( p < 0001 ) .
7		Type of ptGA differed across tumor types ( see Table ) .
8		Additional ptGA in IHC ( BRAF D594 , ERBB2 S310 , RNF43 and BRCA2 mut ) and EHC ( BRAF G469 and ERBB2 S310 mut ) were found in single cases .
9		A total of 22 pts were enrolled in Phase 1 trials , 13 of them with a direct MTT ( 5 PI3K , 2 MEK , 2 MET , 2 IDH1 , 1 ERBB2 and 1 FGFR inhibitor [inh] ) .
10		Partial response was observed in 1 case ( MET ampl IHC with MET inh ) and prolonged stable disease in 3 pts ( 1 FGFR2 fusion IHC with FGFR inh ; 1 IDH1 mut IHC with IDH1 inh ; 1 NRAS mut GBC with MEK inh ) .
11		Conclusions : The diverse landscape of ptGA in BTC is a rich source for MTT in early clinical trials , and has the potential to improve outcomes of individual pts .
12	Μ	Expanding gene panels to identify these driver alterations ( mut , ampl and fusions ) is key for precision medicine in BTC .

PMID: ASCO_160309-173 (Patient)   Terms:
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0		PD-1/PD-L1 expression and molecular associations in HPB malignancies. .
1		Background : Cholangiocarcinoma ( CC ) , hepatocellular carcinoma ( HCC ) , and pancreatic ductal adenocarcinoma ( PDAC ) are all devastating malignancies .
2		Limited data exists about PD-1 and PDL1 expression in these cancers .
3		We assessed expression of PD1/PDL1 in a large cohort of patients with hepato-pancreatico-biliary ( HPB ) cancers and explored the existence of accompanying genomic mutations associated with expression of PD-1/PD-L1 .
4		Methods : 524 patients with HPB cancers ( 354 PDAC , 58 HCC , 54 intrahepatic ( ICC ) , 18 extrahepatic ( ECC ) , and 40 gallbladder ( GBC ) ) were included in the study and tumors tested centrally at a CLIA lab ( Caris Life Sciences , Phoenix , AZ ) .
5		Tests included one or more of the following : gene sequencing ( next generation sequencing , Illumina TruSeq ) , protein expression ( immunohistochemistry [IHC] ) and gene amplification ) .
6		PD-1 (SP142 antibody) and PD-L1 (MRQ-22 antibody) status was tested in all samples .
7		Two-tailed Fisher's exact test was performed to test where proportions of positive results were different by subgroup ( p005 ) .
8		Results : Among those with PDAC , HCC , ICC , ECC , and GBC , rates of PD1 expression on tumor infiltrating lymphocytes ( TILs ) and PD-L1 expression on tumor cells is detailed in the Table .
9		In PD-1+ , compared with PD-1 - HPB cancers , mutations in the following were more prevalent , though not statistically significant : BRCA2 , ATM , CTNNB1 , and PIK3CA .
10		Among all theranostic biomarkers tested , TOP2A expression (IHC) was significantly increased in PD-L1+ versus PD-L1 - tumors ( 82% versus 60% ; p = 00083 ) .
11		Conclusions : HPB tumors express PD-L1 at a frequency of 4-18% , and PD-1 at a frequency of 29-45% .
12	Μ	A statistically significant association of mutations with PD-1+ or PD-L1+ tumors was not identified in this group of tumors .
13		PD-L1 expression associates with TOP2a expression , a marker of proliferation and also anthracycline sensitivity .
14		Further evaluation of this correlation and PDL1/PD-1 + anthracycline combination therapy may be warranted .

PMID: ASCO_190853-199 (Patient)   Terms:
Sent#	Symbols	Sentence	Mnemonics
0		Tumor mutational burden ( TMB ) and co-existing actionable mutations in biliary tract cancers ( BTC ) . .
1	Μ	Background : Mutations in DNA repair pathway were identified in 13% of Biliary Tract Cancers ( BTC ) [Cancer2016 ; 122 : 38383847] .
2		High TMB tumors including melanoma , lung cancer and those with microsatellite instability ( MSI-H ) are associated with susceptibility to immune blockade using checkpoint inhibitors .
3		TMB data in BTC is limited and its association with actionable somatic mutation ( mut ) profiles in BTC is unknown .
4		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 .
5		Base substitutions , indels , gene fusion/rearrangements , TMB , and MSI status were assessed .
6		TMB was calculated by counting mutations across a 1.25Mb region and classified into high ( TMBH20 mut/Mb ) , intermediate ( TMBI ; 6 - 19mut/Mb ) and low ( TMBL< 6mut/Mb ) .
7		MSI high ( MSIH ) and Stable ( MSS ) status was assigned by a computational algorithm examining 114 intronic homopolymer loci .
8		Patients with TMB 6 mut/Mb ( N = 60 ) were included in the clinical correlative portion of this study .
9		Results : Sixty patients with TMB 6 mut were identified out of 309 pts of which 9 ( 15% ) were TMBH and 51 ( 85% ) were TMBI .
10		These included 3 ( 5% ) MSIH and 18 ( 30 % ) MSS .
11		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 .
12		Twenty three ( 38% ) pts had received radiation therapy , 28 ( 47% ) surgery and 3 ( 5% ) received immunotherapy .
13		Most frequent co-existing mut seen was TP53 ( N = 35 ; 58% ) .
14		APC mut was seen in 7 ( 12% ) pts .
15		DNA repair pathway muts ( MSH6 , BRCA1 , BRCA2 , ATM , MLH1 , or MSH2 genes ) were identified in 78% of TMBH versus 16% in TMBI cases ( p < 00001 ) .
16		Frequency of PIK3CA mut differed significantly between TMBH and TMBI ( 44% versus 10% , p < 00001 ) .
17		Pts with TMBI had a significantly better median OS ( 110 weeks ) as compared to TMBH ( 43 weeks ) ( p = 0003 ) .
18		Conclusions : DNA repair pathway and PIK3CA mut maybe associated with TMBH in BTC .
19		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 .