Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions

Voss, Jesse S.; Holtegaard, Leonard M.; Kerr, Sarah E.; Fritcher, Emily G. Barr; Roberts, Lewis R.; Gores, Gregory J.; Zhang, Jun; Highsmith, W. Edward; Halling, Kevin C.; Kipp, Benjamin R.

doi:10.1016/j.humpath.2012.11.006

Cited by 126 publications

(108 citation statements)

References 34 publications

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“…The PIK3CA mutation rate is of special interest because it is a potential therapeutic target for inhibition of the PIK3CA/Akt pathway. 47,49 Given the very low number of PIK3CA mutations in our study (6% in intraductal tubulopapillary neoplasms and absent in invasive carcinomas), the clinical potential seems to be limited in intraductal tubulopapillary neoplasms. Nuclear accumulation of TP53 was identified in few intraductal tubulopapillary neoplasms.…”

Section: Molecular/immunohistochemical Featuresmentioning

confidence: 72%

Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases

et al. 2015

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Intraductal tubulopapillary neoplasm is a well-established entity in the pancreas. A similar, if not identical, tumor occurs also in the biliary tract. We conducted a multicenter study of 20 such lesions, focusing on their clinicopathologic characteristics and molecular profile. Biliary intraductal tubulopapillary neoplasms were seen in patients in their 60s (mean 62 years). The tumors were intrahepatic 70%, extrahepatic 10%, and perihilar 20%; mean tumor size was 6.9 cm. Histologically, all intraductal tubulopapillary neoplasms showed, in addition to their typical tubular pattern, solid areas (70%) or abortive papillae (50%). Necrosis was common (85%), predominantly focal (40%), and with 'comedocarcinoma-like pattern' in 40%. Immunohistochemically, these neoplasms were characterized by the expression of MUC1 (80%) and MUC6 (30%) and by the absence of MUC2 and MUC5AC. Associated invasive carcinomas were present in 16 (80%), mainly conventional tubular adenocarcinoma (50%). The molecular alterations observed included CDKN2A/p16 (intraductal components 44%, invasive 33%) and TP53 (intraductal components 17%, invasive 9%). Mutations in KRAS (intraductal 6%, invasive 0%), PIK3CA (intraductal 6%, invasive 0%), and loss of SMAD4/DPC4 (intraductal 7%, invasive 0%) were rare. No alterations/mutations were identified in IDH1/2, BRAF, GNAS, EGFR, HER2, and β-catenin. Follow-up information was available for 17 patients (85%) with mean follow-up 44 months. Overall combined survival rates showed favorable prognosis: 1 year 100%, 3 years 90%, and 5 years 90%. In conclusion, despite the relatively high incidence of invasive carcinoma (80%), available follow-up suggests that biliary intraductal tubulopapillary neoplasms have an indolent behavior. Molecular analyses highlight the low prevalence of alterations of common oncogenic signaling pathways in intraductal tubulopapillary neoplasm. Further studies using whole-exome sequencing are required to discover yet unknown molecular changes and to understand the carcinogenesis of intraductal tubulopapillary neoplasms.

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Section: Molecular/immunohistochemical Featuresmentioning

confidence: 72%

Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases

et al. 2015

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“…Our findings are in line with recently published smaller series detecting BRAF mutations in 1% to 4% of evaluated cases. [26][27][28] We cannot confirm the exceedingly high mutation rates detected in early BRAF studies of European cohorts, 29,30 and conclude that the previously assumed regional difference in the genetics of biliary tract cancer in Europe versus the Americas is not existent. 2 Our data further demonstrate that BRAF mutations are restricted to intrahepatic cholangiocarcinomas and account for 3% in this subgroup.…”

Section: Discussionmentioning

confidence: 59%

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

et al. 2014

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BRAF mutations have emerged as an important predictive biomarker for metastasized melanoma. Other types of cancer may also benefit from BRAF mutation-targeted therapies. In biliary tract cancer, reported BRAF mutation rates are highly controversial, ranging from 0 to 33% in adenocarcinoma of the gallbladder and 0 to 22% in cholangiocarcinoma. We here analyzed tissue microarrays of a large cohort of biliary tract cancer (n ¼ 377) including 159 intrahepatic cholangiocarcinomas, 149 extrahepatic cholangiocarcinomas, and 69 adenocarcinomas of the gallbladder for BRAF V600E mutation using a highly sensitive immunohistochemical screening approach implementing the BRAF V600E protein-specific antibody VE1. All VE1-positive cases as well as 42 VE1-negative cases were additionally analyzed by Sanger sequencing. In total, only 5 VE1-positive cases were detected (5/377; 1%). BRAF V600E mutation was confirmed by direct sequencing in all cases. All 5 mutated cases were intrahepatic cholangiocarcinomas (5/159; 3%). None of the extrahepatic cholangiocarcinomas and adenocarcinomas of the gallbladder were VE1 positive. Apart from the subtype restriction of BRAF V600E mutation to intrahepatic cholangiocarcinoma and a female predominance (4 female, 1 male), no significant correlation with clinicopathological data and patient outcome was detected. In conclusion, we demonstrate that BRAF V600E mutation is a rare event in biliary tract cancer, accounting for only 1% of all subtypes, and is restricted to intrahepatic cholangiocarcinoma. In addition, we demonstrate that VE1 immunohistochemistry is a feasible approach to routinely screen for BRAF V600E mutation in biliary tract cancer patients, thereby facilitating the detection of rare patients who may benefit from BRAF mutation-targeted therapies.

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“…These include activating mutations in PIK3CA (4–7%) (Nakamura et al ., 2015; Riener et al ., 2008), inactivating mutations in PIK3R1 (4%), TSC1 (3%), TSC2 (1%) and amplifications in AKT3 (3%) (Nakamura et al ., 2015). Finally, 5–30% of BTCs harbour mutations, amplifications and fusions in receptor tyrosine kinases of the Erb and FGFR families, and c‐MET (Hezel et al ., 2010; Li et al ., 2014; Nakamura et al ., 2015; Voss et al ., 2013), which can all activate signalling through the PI3K/AKT/mTOR pathway.…”

Section: Introductionmentioning

confidence: 99%

K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

et al. 2017

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Advanced biliary tract cancer (BTC) has a poor prognosis and limited treatment options. The PI3K/Akt/mTOR signalling pathway is hyperactivated in a subset of BTCs, and clinical activity of the mTOR inhibitor everolimus has been observed in some patients with BTC. The goal of this study was to identify biomarkers predictive of everolimus response. Twenty BTC cell lines were assessed for everolimus sensitivity with a spectrum of growth inhibitory responses observed. Molecular biomarkers of sensitivity and resistance were identified by interrogation of the activation status of the Ras/MAPK and PI3K/Akt/mTOR pathways. K‐Ras mutations and/or amplifications were identified in 45% of cell lines and were associated with resistance to everolimus. Activating mutations in PIK3CA or loss of PTEN was not predictive of everolimus response; however, high basal levels of pAKT were associated with sensitivity, independent of Ras/MAPK pathway activation status. Notably, everolimus inhibited mTOR signalling to a similar extent in sensitive and resistant cell lines, suggesting that relative dependence on the mTOR pathway rather than the magnitude of pathway inhibition determines everolimus response. Consistent with the known limitations of rapalogs, everolimus induced feedback‐mediated activation of AKT in BTC cell lines, which could be overcome by cotreatment with an AKT inhibitor or ATP‐competitive mTORC1/mTORC2 inhibitors. However, both approaches failed to induce greater apoptosis compared to everolimus, and mTORC1/mTORC2 kinase inhibitors induced compensatory activation of pERK, identifying an inherent limitation of these agents in BTC cell lines. These findings suggest that future trials of everolimus in BTC would benefit from preselecting patients based on their K‐Ras and PI3K/mTOR pathway activation status. The study also identifies strategies for enhancing inhibition of the PI3K/mTOR pathway in BTC cell lines.

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Molecular profiling of cholangiocarcinoma shows potential for targeted therapy treatment decisions

Cited by 126 publications

References 34 publications

Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases

Intraductal tubulopapillary neoplasms of the bile ducts: clinicopathologic, immunohistochemical, and molecular analysis of 20 cases

BRAF V600E-specific immunohistochemistry reveals low mutation rates in biliary tract cancer and restriction to intrahepatic cholangiocarcinoma

K‐Ras mutation and amplification status is predictive of resistance and high basal pAKT is predictive of sensitivity to everolimus in biliary tract cancer cell lines

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