Dataset Information

Molecular detection and clinicopathological characteristics of advanced/recurrent biliary tract carcinomas harboring the FGFR2 rearrangements: a prospective observational study (PRELUDE Study).

ABSTRACT:

Background

Fibroblast growth factor receptor 2 (FGFR2) rearrangement is expected to be a novel therapeutic target in advanced/recurrent biliary tract cancer (BTC). However, efficient detection and the exact frequency of FGFR2 rearrangements among patients with advanced/recurrent BTC have not been determined, and the clinical characteristics of FGFR2 rearrangement-positive patients have not been fully elucidated. We aimed to determine the frequency of FGFR2 rearrangement-positive patients among those with advanced/recurrent BTC and elucidate their clinicopathological characteristics.

Methods

Paraffin-embedded tumor samples from formalin-fixed surgical or biopsy specimens of patients with advanced/recurrent BTC were analyzed for positivity of FGFR2 rearrangement by fluorescent in situ hybridization (FISH). RNA sequencing was performed on samples from all FISH-positive and part of FISH-negative patients.

Results

A total of 445 patients were enrolled. FISH was performed on 423 patients (272 patients with intrahepatic cholangiocarcinoma (ICC), 83 patients with perihilar cholangiocarcinoma (PCC), and 68 patients with other BTC). Twenty-one patients with ICC and four patients with PCC were diagnosed as FGFR2-FISH positive. Twenty-three of the 25 FISH-positive patients (20 ICC and 3 PCC) were recognized as FGFR2 rearrangement positive by targeted RNA sequencing. Younger age (≤ 65 years; p = 0.018) and HCV Ab- and/or HBs Ag-positivity (p = 0.037) were significantly associated with the presence of FGFR2 rearrangement (logistic regression).

Conclusions

FGFR2 rearrangement was identified in ICC and PCC patients, and was associated with younger age and history of hepatitis viral infection.

SUBMITTER: Maruki Y

PROVIDER: S-EPMC7932978 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Similar Datasets

Project description:We posed six clinical questions (CQ) on preoperative biliary drainage and organized all pertinent evidence regarding these questions. CQ 1. Is preoperative biliary drainage necessary for patients with jaundice? The indications for preoperative drainage for jaundiced patients are changing greatly. Many reports state that, excluding conditions such as cholangitis and liver dysfunction, biliary drainage is not necessary before pancreatoduodenectomy or less invasive surgery. However, the morbidity and mortality of extended hepatectomy for biliary cancer is still high, and the most common cause of death is hepatic failure; therefore, preoperative biliary drainage is desirable in patients who are to undergo extended hepatectomy. CQ 2. What procedures are appropriate for preoperative biliary drainage? There are three methods of biliary drainage: percutaneous transhepatic biliary drainage (PTBD), endoscopic nasobiliary drainage (ENBD) or endoscopic retrograde biliary drainage (ERBD), and surgical drainage. ERBD is an internal drainage method, and PTBD and ENBD are external methods. However, there are no reports of comparisons of preoperative biliary drainage methods using randomized controlled trials (RCTs). Thus, at this point, a method should be used that can be safely performed with the equipment and techniques available at each facility. CQ 3. Which is better, unilateral or bilateral biliary drainage, in malignant hilar obstruction? Unilateral biliary drainage of the future remnant hepatic lobe is usually enough even when intrahepatic bile ducts are separated into multiple units due to hilar malignancy. Bilateral biliary drainage should be considered in the following cases: those in which the operative procedure is difficult to determine before biliary drainage; those in which cholangitis has developed after unilateral drainage; and those in which the decrease in serum bilirubin after unilateral drainage is very slow. CQ 4. What is the best treatment for post-drainage fever? The most likely cause of high fever in patients with biliary drainage is cholangitis due to problems with the existing drainage catheter or segmental cholangitis if an undrained segment is left. In the latter case, urgent drainage is required. CQ 5. Is bile culture necessary in patients with biliary drainage who are to undergo surgery? Monitoring of bile cultures is necessary for patients with biliary drainage to determine the appropriate use of antibiotics during the perioperative period. CQ 6. Is bile replacement useful for patients with external biliary drainage? Maintenance of the enterohepatic bile circulation is vitally important. Thus, preoperative bile replacement in patients with external biliary drainage is very likely to be effective when highly invasive surgery (e.g., extended hepatectomy for hilar cholangiocarcinoma) is planned.

Project description:Intraductal carcinoma (IC) is the World Health Organization designation for lesions previously called low-grade cribriform cystadenocarcinoma. The relationship of IC to salivary duct carcinoma (SDC) is controversial, but currently these are considered distinct entities. It is hypothesized that IC and SDC should have different genomic signatures that may be identifiable by next-generation sequencing. A total of 23 ICs were identified: 14 pure IC and 9 invasive carcinomas with an intraductal component. Five invasive carcinomas were subjected to next-generation paired-end RNA sequencing. Data analysis was performed using FusionSeq and Mutation detection algorithms (MuTect and VarScan) for variant callers. Gene fusion candidates were validated by fluorescence in situ hybridization and reverse transcription polymerase chain reaction, and mutations by Sanger sequencing. Among the 9 invasive carcinomas, all except 1 were apocrine SDCs with an intraductal component. The remaining case showed typical intercalated duct type IC with invasive adenocarcinoma. The 14 pure ICs had typical intercalated duct features (2 showed hybrid intercalated/apocrine features). RNA sequencing predicted a NCOA4-RET fusion, confirmed by reverse transcription polymerase chain reaction, in the intercalated duct type IC invasive component. Six additional cases of pure IC showed RET rearrangement by fluorescence in situ hybridization (7/15=47%). No apocrine carcinomas showed RET rearrangement. RNA sequencing and Sanger sequencing identified PIK3CA (p.E545K/p.H1047R) and/or HRAS (p.Q61R) hotspot mutations in 6 of 8 (75%) apocrine carcinomas. In conclusion, 2 distinctive types of intraductal lesions are emerging based on molecular analysis. Classic intercalated type ICs commonly harbor fusions involving RET and rarely show widespread invasion. Apocrine intraductal lesions are typically associated with widespread invasion with no pure examples and show similar PIK3CA and HRAS mutations to SDC.

Project description:The purpose of radiation therapy for unresectable biliary tract cancer is to prolong survival or prolong stent patency, and to provide palliation of pain. For unresectable bile duct cancer, there are a number of studies showing that radiation therapy is superior to the best supportive care. Although radiation therapy is used in many institutions, no large randomized controlled trials (RCTs) have been performed to date and the evidence level supporting the superiority of this treatment is low. Because long-term relief of jaundice is difficult without using biliary stenting, a combination of radiation therapy and stent placement is commonly used. As radiation therapy, external-beam radiation therapy is usually performed, but combined use of intraluminal brachytherapy with external beam radiation therapy is more useful for making the treatment more effective. There are many reports demonstrating improved response rates as well as extended survival and time to recurrence achieved by this combination therapy. Despite the low level of the evidence, this combination therapy is performed at many institutions. It is expected that multi-institutional RCTs will be carried out. Unresectable gallbladder cancer with a large focus is usually extensive, and normal organs with high radio sensitivity exist contiguously with it. Therefore, only limited anticancer effects are to be expected from external beam radiation therapy for this type of cancer. The number of reports on ampullary cancer is small and the role of radiation therapy in this cancer has not been established. Combination treatment for ampullary cancer consists of either a single use of intraoperative radiation therapy, postoperative external beam radiation therapy or intraluminal brachytherapy, or a combination of two or three of these therapies. Intraoperative radiation therapy is superior in that it enables precise irradiation to the target site, thereby protecting adjacent highly radiosensitive normal tissues from irradiation. There are reports showing extended survival, although not significant, in groups undergoing intraoperative or postoperative radiation therapy compared with groups without radiation therapy. To date, there are no reports of large RCTs focusing on the significance of radiation therapy as a postoperative adjuvant treatment, so its usefulness as a postoperative adjuvant treatment is not proven. An alternative treatment is photodynamic therapy. There is an RCT demonstrating that, in unresectable bile duct cancer, extended survival and improved quality of life (QOL) have been achieved through a combination of photodynamic therapy and biliary stenting, compared with biliary stenting alone. Results from large RCTs are desired.

Project description:The only curative treatment in biliary tract cancer is surgical treatment. Therefore, the suitability of curative resection should be investigated in the first place. In the presence of metastasis to the liver, lung, peritoneum, or distant lymph nodes, curative resection is not suitable. No definite consensus has been reached on local extension factors and curability. Measures of hepatic functional reserve in the jaundiced liver include future liver remnant volume and the indocyanine green (ICG) clearance test. Preoperative portal vein embolization may be considered in patients in whom right hepatectomy or more, or hepatectomy with a resection rate exceeding 50%-60% is planned. Postoperative complications and surgery-related mortality may be reduced with the use of portal vein embolization. Although hepatectomy and/or pancreaticoduodenectomy are preferable for the curative resection of bile duct cancer, extrahepatic bile duct resection alone is also considered in patients for whom it is judged that curative resection would be achieved after a strict diagnosis of its local extension. Also, combined caudate lobe resection is recommended for hilar cholangiocarcinoma. Because the prognosis of patients treated with combined portal vein resection is significantly better than that of unresected patients, combined portal vein resection may be carried out. Prognostic factors after resection for bile duct cancer include positive surgical margins, especially in the ductal stump; lymph node metastasis; perineural invasion; and combined vascular resection due to portal vein and/or hepatic artery invasion. For patients with suspected gallbladder cancer, laparoscopic cholecystectomy is not recommended, and open cholecystectomy should be performed as a rule. When gallbladder cancer invading the subserosal layer or deeper has been detected after simple cholecystectomy, additional resection should be considered. Prognostic factors after resection for gallbladder cancer include the depth of mural invasion; lymph node metastasis; extramural extension, especially into the hepatoduodenal ligament; perineural invasion; and the degree of curability. Pancreaticoduodenectomy is indicated for ampullary carcinoma, and limited operation is also indicated for carcinoma in adenoma. The prognostic factors after resection for ampullary carcinoma include lymph node metastasis, pancreatic invasion, and perineural invasion.