Biliary Tract Carcinoma Research Articles

Postoperative adjuvant surufatinib combined with anti-PD-1 antibodies and oral fluoropyrimidines improves surgical outcomes for biliary tract carcinoma with high-risk recurrent factors

Postoperative adjuvant surufatinib combined with anti-PD-1 antibodies and oral fluoropyrimidines improves surgical outcomes for biliary tract carcinoma with high-risk recurrent factors

Targeting the Endothelin-1 pathway to reduce invasion and chemoresistance in gallbladder cancer cells

BackgroundGallbladder cancer (GBC) is a prevalent and deadly biliary tract carcinoma, often diagnosed at advanced stages with limited treatment options. The 5-year survival rate varies widely from 4 to 60%, mainly due to differences in disease stage detection. With only a small fraction of patients having resectable tumors and a high incidence of metastasis, advanced GBC stages are characterized by significant chemoresistance. Identification of new therapeutic targets is crucial, and recent studies have shown that the Endothelin-1 (ET-1) signaling pathway, involving ETAR and/or ETBR receptors (ETRs), plays a crucial role in promoting tumor aggressiveness in various cancer models. Blocking one or both receptors has been reported to reduce invasiveness and chemoresistance in cancers like ovarian, prostate, and colon. Furthermore, transcriptomic studies have associated ET-1 levels with late stages of GBC; however, it remains unclear whether its signaling or its inhibition has implications for its aggressiveness. Although the role of ET-1 signaling in gallbladder physiology is minimally understood, its significance in other tumor models leads us to hypothesize its involvement in GBC malignancy.ResultsIn this study, we investigated the expression of ET-1 pathway proteins in three GBC cell lines and a primary GBC culture. Our findings demonstrated that both ETAR and ETBR receptors are expressed in GBC cells and tumor samples. Moreover, we successfully down-regulated ET-1 signaling using a non-selective ETR antagonist, Macitentan, which resulted in reduced migratory and invasive capacities of GBC cells. Additionally, Macitentan treatment chemosensitized the cells to Gemcitabine, a commonly used therapy for GBC.ConclusionFor the first time, we reveal the role of the ET-1 pathway in GBC cells, providing insight into the potential therapeutic targeting of its receptors to mitigate invasion and chemoresistance in this cancer with limited treatment options. These findings pave the way for further exploration of Macitentan or other ETR antagonists as potential therapeutic strategies for GBC management. In summary, our study represents a groundbreaking contribution to the field by providing the first evidence of the ET 1 pathway's pivotal role in modulating the behavior and aggressiveness of GBC cells, shedding new light on potential therapeutic targets.

Difficulty of adjuvant chemotherapy administration in patients with biliary tract cancer.

This study aimed to elucidate the difficulty of adjuvant chemotherapy administration in patients with biliary tract carcinoma (BTC). Clinical data of patients with BTC who underwent curative-intent surgery were retrospectively analyzed. The eligible patients were stratified into two groups according to the presence or absence of adjuvant chemotherapy administration (adjuvant and non-adjuvant groups), and the clinicopathological features were compared between the two groups. The ratios of adjuvant chemotherapy administration were investigated in each surgical procedure. Independent factors associated with no administration of adjuvant chemotherapy were analyzed using multivariate analyses. Among 168 eligible patients, 141 (83.9%) received adjuvant chemotherapy (adjuvant group), while 27 (16.1%) did not (non-adjuvant group). The most common surgical procedure was pancreaticoduodenectomy in the adjuvant group, and it was hepatectomy with extrahepatic bile duct resection (BDR) in the non-adjuvant group, respectively. The rate of no adjuvant chemotherapy was significantly higher in patients who underwent hepatectomy with BDR than in those who underwent other surgeries (p < 0.001). The most common cause of no adjuvant chemotherapy was bile leak in 12 patients, which occurred after hepatectomy with BDR in ten patients. Multivariate analyses revealed that hepatectomy with BDR and preoperative anemia were independently associated with no adjuvant chemotherapy (p < 0.001 and p < 0.001, respectively). Hepatectomy with BDR and subsequent refractory bile leak can be the obstacle to adjuvant chemotherapy administration in patients with BTC.

Analysis of the efficacy and factors influencing survival of adjuvant radiotherapy for stage II-III biliary tract carcinoma

BackgroundTo determine the efficacy of adjuvant radiotherapy for stage II–III biliary tract carcinoma.MethodsWe retrospectively analyzed the data of 37 patients who underwent radical resection of biliary tract carcinomas at the Affiliated Hospital of Inner Mongolia Medical University between 2016 and 2020. We analyzed survival differences between patients who did (n = 17) and did not (n = 20) receive postoperative adjuvant radiotherapy by using Kaplan–Meier analysis. The log-rank test and Cox univariate analysis were used. The Cox proportional risk regression model was used for the multifactorial analysis of factors influencing prognosis.ResultsThe median survival time (28.9 vs. 14.5 months) and the 1-year (82.40% vs. 55.0%) and 2-year survival rates (58.8% vs. 25.0%) were significantly higher among patients who received adjuvant radiotherapy than among those who did not (χ2 = 6.381, p = 0.012). Multifactorial analysis showed that pathological tumor type (p = 0.004), disease stage (p = 0.021), and adjuvant radiotherapy (p = 0.001) were independent prognostic factors in biliary tract carcinoma. Subgroup analyses showed that compared to no radiotherapy, adjuvant radiotherapy significantly improved median survival time in patients with stage III disease (21.6 vs. 12.7 months; p = 0.017), positive margins (28.9 vs. 10.5 months; p = 0.012), and T3 or T4 tumors (26.8 vs. 16.8 months; p = 0.037).ConclusionAdjuvant radiotherapy significantly improved the survival of patients with biliary tract carcinoma, and is recommended especially for patients with stage III disease, positive surgical margins, or ≥ T3.

Molecular Analysis of Biliary Tract Cancers with the Custom 3' RACE-Based NGS Panel.

The technique 3' rapid amplification of cDNA ends (3' RACE) allows for detection of translocations with unknown gene partners located at the 3' end of the chimeric transcript. We composed a 3' RACE-based RNA sequencing panel for the analysis of FGFR1-4 gene rearrangements, detection of activating mutations located within FGFR1-4, IDH1/2, ERBB2 (HER2), KRAS, NRAS, BRAF, and PIK3CA genes, and measurement of the expression of ERBB2, PD-L1, and FGFR1-4 transcripts. This NGS panel was utilized for the molecular profiling of 168 biliary tract carcinomas (BTCs), including 83 intrahepatic cholangiocarcinomas (iCCAs), 44 extrahepatic cholangiocarcinomas (eCCAs), and 41 gallbladder adenocarcinomas (GBAs). The NGS failure rate was 3/168 (1.8%). iCCAs, but not other categories of BTCs, were characterized by frequent FGFR2 alterations (17/82, 20.7%) and IDH1/2 mutations (23/82, 28%). Other potentially druggable events included ERBB2 amplifications or mutations (7/165, 4.2% of all successfully analyzed BTCs) and BRAF p.V600E mutations (3/165, 1.8%). In addition to NGS, we analyzed microsatellite instability (MSI) using the standard five markers and revealed this event in 3/158 (1.9%) BTCs. There were no instances of ALK, ROS1, RET, and NTRK1-3 gene rearrangements or MET exon 14 skipping mutations. Parallel analysis of 47 iCCA samples with the Illumina TruSight Tumor 170 kit confirmed good performance of our NGS panel. In conclusion, targeted RNA sequencing coupled with the 3' RACE technology is an efficient tool for the molecular diagnostics of BTCs.

Metabolomics of Duodenal Juice for Biliary Tract Cancer Diagnosis.

The poor prognosis of malignant biliary diseases is partially caused by their difficult early diagnosis. Therefore, many patients are only diagnosed at advanced stages. This study aimed to improve diagnosis by clarifying the differences in the duodenal juice metabolomes of benign and malignant biliary diseases. From October 2021 to January 2023, duodenal juice was obtained from 67 patients with suspected biliary diseases who required endoscopic ultrasonography and endoscopic retrograde cholangiography for diagnosis/treatment. The samples metabolomes were analyzed via nuclear magnet resonance spectroscopy using an 800-MHz spectrometer. Metabolomes of malignant and benign diseases were then compared, and multivariate analysis was performed to determine the relevant factors for malignancy/benignancy. For benignancy, no significant predictors were observed. For malignancy, acetone was a significant predictor, with higher concentrations in the malignant group than in the benign group. Regarding the receiver operating characteristic curve analysis for biliary tract carcinoma diagnosis, the predictive value of acetone in duodenal juice was comparable with serum CA19-9 levels (area under the curve: 0.7330 vs. 0.691, p = 0.697). In conclusion, duodenal juice metabolomics is a feasible method that is available for differential diagnosis in the biliary disease field.

Clinical characteristics of liver injury induced by immune checkpoint inhibitors in patients with advanced biliary tract carcinoma.

Immune-related liver injuries are closely associated with the liver's fundamental state. Patients with advanced biliary tract carcinoma (BTC) have poor liver function. We evaluated the clinical data of immune-related liver injury in patients with advanced BTC and gastric cancer (GC) during immune checkpoint inhibitor (ICI) treatment between February 2019 and July 2022 at Peking University First Hospital. Twenty-five patients with advanced BTC were identified. Fifteen patients (60%) experienced immune-related liver injury during ICI treatment. We also evaluated the clinical status of patients with GC in another group receiving immunotherapy. The results demonstrated that the incidence of immune-related liver injury was higher in patients with BTC than in GC cancer (p=0.040). Multivariate analysis suggested that the type of malignant tumor and baseline liver function status were high-risk factors for grade 2 and higher immune-related liver injuries. Two patients were diagnosed with immune-related cholangitis. Both biliary enzymes can be decreased to a certain degree by corticosteroid and ursodeoxycholic acid (UDCA) therapy but are difficult to reduce to normal levels. Liver function normalized, and symptoms improved after local treatment for cholestasis (stent implantation or PTBD). We observed a higher incidence of immune-related liver injury after ICI treatment in patients with advanced BTC. Effect of baseline liver function on the incidence of liver injury associated with immunotherapy. Interventional therapy provides rapid relief from cholestasis and is an indispensable and effective approach to the treatment of immune-related cholangitis.

Can the sampling method affect the detection of incidental gallbladder carcinoma? Comparative analysis of two sampling methods

Gallbladder cancer (GBC) is the most common biliary tract carcinoma and is commonly diagnosed incidentally in cholecystectomies performed for gallstones. GBC are mostly unrecognizable macroscopically, and sampling is therefore import. This single center study aimed to find out the effect of sampling method on the identification rate of incidental GBC by comparing random sampling and longitudinal full-thickness slice sampling, which was developed in high-incidence areas. A hospital electronic database was searched for cholecystectomy specimens submitted to the pathology department between 01/2000 and 03/2016. Cases with a preoperative clinical and/or radiological suspicion of neoplasia and cases with a macroscopically identified mass were excluded from the study. Two groups were formed according to the sampling method: “random sampling” group (Group 1, n = 10,954) and “full-thickness slice sampling” group (Group 2, n = 5254). In the first group, random samples from the fundus, body and neck were submitted in gallbladders without grossly visible pathology. In the second group, a full-thickness slice sampling protocol was performed, wherein a longitudinal full-thickness slice, including fundus, corpus-neck and the cystic duct margin was submitted for each gallbladder. Statistical comparisons of GBC incidence and clinicopathologic features was performed. In group 1, GBC prevalence was 0.6 % and low grade dysplasia (LGD) was detected in 199 cases (1.8 %). In group 2, GBC prevalence was 1.5 %, LGD was detected in 166 cases (3.2 %). The GBC rate in Group 2 was significantly (p < 0.05) higher than Group 1. The two groups did not show any statistically significant differences in age, sex and presence of gallstones (p > 0.05). In conclusion, this is the largest study comparing two grossing methods in gallbladders without preoperative clinical and/or radiological suspicion of malignancy and macroscopically identified mass. This study demonstrates the importance of systematic and algorithmic sampling in the detection of GBC.

Spatial Patterns of Gallbladder and Biliary Tract Carcinoma in China From 1990 to 2019: An Analysis at the Provincial Level.

Background Despite a high rate of fatal malignancy, little is known regarding the spatial and temporal patterns of the disease burden of gallbladder and biliary tract carcinoma in China, especially at the provincial level. Methodology Using data from the 2019 Global Burden of Diseases, Injuries, and Risk Factors Study, we estimated the temporal trend of the disease burden of gallbladder and biliary tract carcinoma from 1990 to 2019 as well as its incidence, mortality, prevalence, and disability-adjusted life-years (DALYs). We estimated the spatial pattern of the disease burden of gallbladder and biliary tract carcinoma at theprovincial level. Results The disease burden of gallbladder and biliary tract carcinoma significantly increased from 1990 to 2019in China. The age-standardized incidence, prevalence, mortality, and DALYs increased by 28.3%, 50.5%, 13.0%, and 7.0%, respectively. The disease burden of gallbladder carcinoma revealed substantial heterogeneity at the provincial level with a higher disease burden in developed provinces or cities than in developing provinces. The disease burden of gallbladder and biliary tract carcinoma was also heavier among males than among females (e.g., age-standardized DALYs: 42.60 per 100,000 people among males vs. 33.57 per 100,000 people among females in 2019). Conclusions The disease burden of gallbladder and biliary tract carcinoma has shown rapid changes during the past three decades, with a higher burden in economically advantaged regionsthan in disadvantaged regions in China. New public health policies and initiatives are neededto address this rising disease burden.

Prognostic impact of lung recurrence in patients with biliary tract cancer.

This study aimed to evaluate the prognostic impact of the initial recurrence site following resection for biliary tract carcinoma (BTC), focusing on lung recurrence. The clinical data of patients with recurrent BTC who underwent curative intent surgery between March 2009 and December 2021 were retrospectively analyzed. The prognosis of patients with recurrent BTC was investigated in each recurrence site. Eligible patients were classified into two groups according to lung or non-lung recurrence. Clinicopathological factors, survival after recurrence, and overall survival were compared between the two groups. Independent factors associated with survival after recurrence were investigated using multivariate analysis. Of 119 patients, the initial recurrence site was local in 26 (21.8%) patients, liver in 19 (16.8%), peritoneum in 14 (11.8%), lymph node in 12 (10.1%), lung in 11 (9.2%), multiple organs in 32 (26.9%), and others in 5 (4.2%). The survival period after recurrence in patients with lung recurrence was significantly longer than those in patients with other six recurrence patterns. The median survival after recurrence was 34.3 and 9.3 months in lung recurrence and non-lung recurrence groups, respectively (p < 0.0001); that after initial surgery was 50.8 and 26.4 months, respectively (p = 0.0383). Multivariate analysis revealed that lung recurrence and normal albumin level at recurrence were independently associated with survival after recurrence (Hazard Ratio (HR), 0.291; p = 0.0128; HR, 0.476; p = 0.00126, respectively). Survival period after recurrence was significantly longer in patients with lung recurrence.

Mutational spectrum for guiding the decision of adjuvant treatment in patients with resected biliary tract carcinoma.

Systemic chemotherapy or chemoradiation therapy has proven to be effective in treating advanced biliary tract carcinoma (BTC). However, its efficacy in the adjuvant setting remains controversial. Therefore, this study aimed to determine the prognostic significance of genomic biomarkers in resected BTC and their potential role in stratifying patients for adjuvant treatment. We retrospectively reviewed 113 BTC patients who underwent curative-intent surgery and had available tumor sequencing data. Disease-free survival (DFS) was the primary outcome examined and univariate analysis was used to identify gene mutations with prognostic value. Favorable and unfavoratble gene subsets were distinguished from the selected genes through grouping, respectively. Multivariate Cox regression was used to identify independent prognostic factors of DFS. Our results indicated that mutations in ACVR1B, AR, CTNNB1, ERBB3, and LRP2 were favorable mutations, while mutations in ARID1A, CDKN2A, FGFR2, NF1, NF2, PBRM1, PIK3CA, and TGFBR1 were unfavorable mutations. In addition to age, sex, and node positive, favorable genes (HR = 0.15, 95% CI = 0.04-0.48, p = 0.001) and unfavorable genes (HR = 2.86, 95% CI = 1.51-5.29, p = 0.001) were identified as independent prognostic factors for DFS. Out of the 113 patients, only 35 received adjuvant treatment whereas the majority (78) did not. For patients with both favorable and unfavorable mutations undetected, adjuvant treatment showed negative effect on DFS (median DFS: S441 vs. 956 days, p = 0.010), but there was no significant difference in DFS among those in other mutational subgroups. Genomic testing might be useful in guiding the decisions regarding adjuvant treatment in BTC.

EGFR/ERBB2 aberrations in Chinese biliary tract carcinomas.

e16208 Background: Biliary tract carcinoma (BTC) accounts for 3% gastrointestinal cancers in China. BTCs are mainly classified as gallbladder cancer (GBC) and cholangiocarcinomas (CCA) with dismal prognosis. Current chemotherapy regimens for BTC yield poor outcomes. We aimed to describe the genomic landscape of a BTC patient cohort using next-generation sequencing (NGS), focusing on the EGFR/ERBB2 aberrations and exploring the possibility of therapeutic intervention. Methods: We analyzed BTC tissue/blood samples including GBCs and CCAs with targeted sequencing (NGS) for EGFR/ERBB2 activating mutations, copy number amplifications (copy number≥5) and rearrangements (containing the kinase domain). A cohort of 1033 Chinese BTC patients were analyzed including 783 GBC patients and 250 CCA patients. Results: Data analysis revealed EGFR/ERBB2 alteration rates were 9.0% in Chinese BTC patients. The majority of these alterations were in fact ERBB2 alterations at a rate of 15.8% in GBC and 6.4% in CCA（P&lt;0.05). A further subanalysis of ERBB2 mutation types showed that 46.7% in GBC and 64.6% in CCA were activating mutations, 37.8% in GBC and 31.3% in CCA were gene amplifications, 8.9% in GBC and 2.1% in CCA were gene rearrangements and 6.7% of GBC and 2.1% of CCA cases had multiple ERBB2 alterations. The top activating ERBB2 mutation were p.S310F（10/45） followed by p.R678Q(4/45) in GBC and were p.S310F (11/48) followed by p.V777L(5/48) in CCA. EGFR alteration rates were 3.5% in GBC and 1.3% in CCA（P&lt;0.05). Among these, 30% of the GBCs and 60% of the CCAs had an activating EGFR mutation, 70% of the GBCs and 30% of the CCAs had EGFR copy number amplification and 10% of the GBCs and no CCA case had an EGFR rearrangement. Three EGFR activating mutations detected in GBC were p.G719A, p.L861Q, p.A289V. Six EGFR activating mutations detected in CCA were p.G719D, p.E746_S752delinsV, p.L858R, p.N771_H773dup, p.D770_N771insG, p.R222C. Conclusions: We report characteristics of EGFR/ERBB2 alterations in Chinese GBC and CCA patients. In general, 19.4% of GBC and 7.7% CCA may benefit from EGFR/ERBB2 targeted therapy. EGFR/ERBB2 targeted therapies should be further explored in Chinese BTC patients.

Genomic profiling of biliary tract carcinomas by their location.

e16175 Background: Historically, biliary tract cancers have had a poor prognosis. Genomic profiling allows identification of alterations in genes with FDA-approved matched therapies either in these cancers ( FGFR2/3 fusions, certain IDH1 missense mutations), in all solid tumors (e.g. BRAF V600E mutations), or in other cancers (e.g. BRCA1/2 loss-of-function mutations) that could inform treatment. Here we examine the frequency of matched therapies in biliary tract carcinomas and the association with tumor location. Methods: All biliary tract carcinoma patient samples receiving the OncoExTra assay between April 2018 and November 2022 were included. The assay uses tumor-normal, whole-exome, whole-transcriptome sequencing to identify genomic alterations. Alterations in genes with FDA-approved matched therapies in any cancer, with matched clinical trials, or with evidence in cancer guidelines or the literature for possible matched therapies were recorded. Results: A total of 155 patient samples were processed: 92 intrahepatic CCA, 34 gall bladder carcinomas, 9 extrahepatic CCA, and 20 ampulla of Vater carcinomas. Targetable alterations were found in 153 (98.7%) samples; 31 (20.3%) had FDA-approved matched therapies, including 5 (3.3%) with microsatellite unstable and/or tumor mutational burden-high (eligible for immunotherapy) and 7 (4.6%) homologous recombinational repair deficient. Alterations of several genes showed a significant association with tumor type (Table). Cancers in the ampulla of Vater were enriched for KRAS, APC and ARID2 alterations; TP53 alterations were less frequent in biliary tract/intrahepatic cancers. Among the 15 FGFR1/2/3 alterations, there were 3 amplifications (1 FGFR1, 1 FGFR2, 1 FGFR3), 3 missense FGFR2 mutations, and 9 FGFR2 fusions. Conclusions: Comprehensive genomic profiling of biliary tract cancers identifies numerous targetable alterations. The distribution of altered genes varies, suggesting that appropriate therapies may differ by location, reflecting different lineage types. [Table: see text]

A phase IIa/IIb, open-label trial of BI 907828, an MDM2–p53 antagonist, in patients with locally advanced/metastatic biliary tract carcinoma or pancreatic ductal adenocarcinoma: Brightline-2.

TPS4179 Background: Biliary tract cancer (BTC) and pancreatic ductal adenocarcinoma (PDAC) carry a median survival of one year in the advanced stages, and effective therapies are urgently needed. Mouse double minute 2 (MDM2) is amplified in ~5–6% of cases of BTC and ~1% of PDAC. MDM2, an E3 ubiquitin ligase, is an endogenous negative regulator of p53. Aberrations affecting MDM2 may drive oncogenesis, and indeed, preclinical as well as emerging clinical data suggest blocking MDM2 in TP53 wild-type tumors may be a potential therapeutic strategy. BI 907828 is an MDM2–p53 antagonist that binds to MDM2 and blocks its interaction with p53, thereby restoring p53 function, leading to cell-cycle arrest and apoptosis in TP53 wild-type tumor cells. In ongoing Phase I studies, BI 907828 has demonstrated initial signs of activity in selected advanced/metastatic solid tumors, including BTC and PDAC. Methods: Brightline-2 is a Phase IIa/IIb, open-label, single-arm, multicenter study (~60 sites) that aims to assess the efficacy, safety, and tolerability of BI 907828 monotherapy in patients with locally advanced, unresectable, or metastatic MDM2-amplified, TP53 wild-type BTC (adenocarcinoma histology; Cohort 1; n=~90) or PDAC (Cohort 2; n=~10) [NCT05512377]. Cohorts for other solid tumors may be added via protocol amendment. All patients will receive BI 907828 45mg orally once every 3 weeks. Key inclusion criteria include: ≥18 years of age; locally advanced/metastatic, histologically confirmed unresectable BTC/PDAC; progression or intolerance to standard therapies; local test indicating MDM2 amplification or MDM2 copy number ≥8 and TP53 wild-type (liquid biopsy not permitted); ≥1 measurable target lesion (RECIST v1.1); and ECOG PS 0/1. A key exclusion criterion is prior treatment with an MDM2–p53 antagonist. Treatment will continue until disease progression, unacceptable toxicity, or withdrawal of consent. The primary endpoint is objective response rate (ORR; based on blinded central independent review). Secondary endpoints are duration of response, progression-free survival, overall survival, disease control, occurrence of adverse events, and patient-reported health-related quality of life. In Phase IIa, an interim futility analysis will be performed after the initial 30 patients in Cohort 1 have either been followed for ≥12 weeks or have discontinued. If the cohort passes the non-binding interim futility boundary (ORR = 20%), the study will enter Phase IIb, and 60 additional patients will be enrolled onto Cohort 1, totaling 100 patients planned across Cohorts 1 and 2. The final primary analysis will be performed after all treated patients have been followed for ≥12 weeks or until study discontinuation. As of 13 December 2022, 1 patient has been enrolled. Clinical trial information: NCT05512377 .

Comprehensive geriatric assessment based multidisciplinary team intervention for hospitalized frail patients in oncology: COMPASS-ONCO/KCSG AL21-13.

TPS12138 Background: Comprehensive geriatric assessment (CGA) is a multidimensional, interdisciplinary assessment for evaluating older patients’ medical, psychological, physical functions and social status. CGA-based multidimensional intervention is the gold standard in geriatric oncology to identify patients at high risk of adverse outcomes and optimize cancer and overall management. Numerous studies have demonstrated that CGA could modify oncologic treatment decision. However, little is known about the treatment outcomes of a multidisciplinary team intervention based on CGA. Methods: The COMPASS study is the first pragmatic multicentre trial within a cohort comprising three randomized controlled trials focusing on focusing on CGA and multidisciplinary intervention for hospitalised elderly patients in various healthcare settings of Korea. COMPASS-ONCO compares the effect of an oncologist-led multidisciplinary team intervention based on the CGA to that of conventional treatment for older cancer patients without the involvement of geriatricians. The patients will be randomised into the intervention or control groups in a 1:1 ratio. The inclusion criteria are as follows: (1) 65 years of age or older, (2) prefrail or frail status assessed by Korean version of the Fatigue, Resistance, Ambulation, Illnesses and Loss of Weight scale questionnaire, (3) having two or more of the following diseases; hypertension, diabetes, ischaemic heart disease, chronic lung disease, arthritis, stroke, depression, chronic kidney disease and dementia. (4) living at home for more than 3 months before hospitalization, (5) subject to palliative chemotherapy and (6) histologically confirmed gastric, colorectal, lung, pancreatic or biliary tract carcinoma. The intervention includes CGA and CGA-based multidisciplinary interventions by oncologists, nurses, nutritionists and pharmacists. The multidisciplinary intervention includes nutritional support, medication review and adjustment, rehabilitation, early discharge planning and prevention of geriatric syndromes (falls, delirium, pressure sore and urinary retention). The analysis will be based on an intention-to-treat principle. The primary outcome is overall treatment utility which is a clinical outcome incorporating objective and subjective measures of anticancer efficacy, tolerability and acceptability. Additionally, recognition of advance directives, changes in body composition and validity of anticancer drug toxicity prediction model will also be assessed. Approximately 1040 patients will be required for COMPASS study, and 260 will be enrolled in the COMPASS-ONCO substudy at five hospitals in Korea. Participants have been recruited from 2 November 2021, and recruitment will continue until December 2024. Clinical trial information: KCT0006270 .

MSI analysis in patients with GIST with lynch syndrome.

e23510 Background: Lynch Syndrome due to mutations in one of DNA mismatch repair (MMR) genes, is found in patients with colon cancer (3%).The mutations in these DNA repair genes induce genetic instability and development of ovarian, endometrial, urothelial, gastrointestinal and biliary tract carcinoma. Methods: In our center, 31 patients with Lynch syndrome are followed in Oncology Department in multidisciplinary team according to regional diagnostic therapeutic assistance paths and international guidelines. Immunohistochemical staining (IC) for mismatch repair proteins (MLH1, MSH2, MSH6, PMS2) and microsatellite instability testing (MSI) by PCR real time easyPGX were performed in colon cancer, genetic testing has been preceded by genetic counseling. When GIST diagnosis occurred in patients with colon cancers and Lynch syndrome, IC and MSI were performed in GIST too. Results: MSI-H has been detected in synchronous colo-rectal cancer in 2 patients with GIST. Pathogenetic germline mutations in MSH2 gene were observed in both patients. In 1 female patient with gist of duodenum (very low risk according to Miettinen classification) with previous endometrial cancer and sincronous PT3N0 rectal cancer, we observed MSI-stable in IC and PCR, KIT/PDGFRα wild type in Next GenSequencing analysis, BRAF wild type (PCR-real time), SDH-B + (IC), NTRK 1 (exon 9-10, exon 1-12 del, exon 12), NTRK 2 (exon 12-15.exon 16-17), exon 14, NTRK 3 (exon 14, exon 15) no gene fusion by PCR-real time (CE.IVD kit easy NTRK). In 1 male patient with ileal GIST (intermediate risk according to Miettinen classification ) with ileal adenocarcinoma pT3N0, we observed KIT exon 11 mutated, MSI-stable in IC, when we repeated the analysis using PCR real time EasyPGX, we observed high instability of microsatellites. Conclusions: For the first time we observed in Lynch Syndrome MSH2 mutated, simolutaneous GIST and colon cancer in the same site of ileum and PCR analisys detected a rare exemple of microsatellite instability in GIST.

Combined immune checkpoint inhibition with durvalumab and tremelimumab with and without radiofrequency ablation in patients with advanced biliary tract carcinoma.

e16158 Background: The prognosis of advanced bile tract cancer (BTC) is unfavorable with a 5-year overall survival (OS) rate of less than 10%. Durvalumab has been approved in the first line setting in combination with chemotherapy (gemcitabine with cisplatin) for advanced BTC. Monotherapy with immune checkpoint inhibitors (ICI) in BTC in the second line is suboptimal with ORR reported in the 5-15% range. The purpose of this study was to explore the efficacy of an anti-PD-L1 (durvalumab) agent in combination with an anti-CTLA4 (tremelimumab) agent with and without radio frequency ablations (RFA) in advanced BTC. Methods: Eligible patients with advanced BTC who had received or refused at least one prior line of systemic therapy were treated with tremelimumab 75 mg intravenously (IV) and durvalumab 1500 mg (IV) for 4 combined doses followed by monthly durvalumab 1500 mg IV alone until progression of disease or unacceptable toxicity. Objective response was assessed through CT or MRI by Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1) every 8 weeks. Adverse events (AEs) were recorded and managed. The primary endpoint was 6-month progression free survival (PFS). All patients underwent a pretreatment and on treatment biopsy. Results: 22 patients with advanced BTC were enrolled in this study; 10 patients were treated with durvalumab and tremelimumab (Durva/ Treme -Arm A) and 12 patients were treated with the combination of durvalumab and tremelimumab and an ablative procedure (Durva/ Treme/ RFA -Arm B). A total of 18 patients were evaluable (10 in Arm A and 8 in Arm B). The best clinical response in Arm A were as follows: PR (n=8), SD (n=1), PD (n=1) and in Arm B: SD (n=3), PD (n=5). The median progression free survival (PFS) in the Durva/ Treme Arm A was 3.3 months (95% CI: 1.9-3.9) and Durva/ Treme/ RFA Arm was 2 months (95% CI: 1.3-2.5)). The median overall survival (OS) in the Durva/ Treme Arm A was 6.1 months (95% CI: 3.5-7.4) and Durva/ Treme/ RFA Arm was 5.7 months (95% CI: 2.9-7.6). The most common study hematologic related Grade 3-4 adverse events (AEs) were lymphopenia (n=6) and anemia (n=3) and the most common non hematologic AEs included increased AST (n=9), increased alk phos (n=7) and increased total bilirubin (n=6). Conclusions: Combined ICI with Durva/ Treme with and without RFA is well tolerated; Durva/ Treme alone showed promising activity in this small early-stage study, with an ORR of 80%, in patients with advanced BTC. Clinical trial information: NCT02821754 .

Single-cell transcriptome analysis revealed the immune profile of PD-1 blockade in gallbladder carcinoma liver metastasis.

Gallbladder carcinoma is the most common cancer of the biliary tract, and the immune checkpoint blockade showed promising efficacy in the treatment of advanced gallbladder carcinoma. However, the underlying mechanisms remain unknown. Single-cell RNA sequencing was used to reveal immune cell dynamics in an anti-PD-1 responder with gallbladder carcinoma liver metastases. Gene set variation analysis, pseudotime analysis, single-cell regulatory network inference and clustering analysis, and CellChat analysis were used to identify the functions of each cell cluster. Immunohistochemistry and multicolored immunohistochemistry analysis were applied to confirm the intratumoral cell types, and the prognostic value of CXCL13+CD8+T cells in patients with gallbladder carcinoma liver metastases with immunotherapy was evaluated. Four biliary tract carcinoma and 3 immunotherapy bulk RNA-seq datasets were analyzed to investigate the prognostic value of CXCL13+CD8+T cells and SPP1+TAMs. A total of 19,648 high-quality single-cell transcriptome data were obtained from liver metastasis before and after aPD-1 therapy. We discovered improved cytotoxic activity in CD8+T cells and enhanced proinflammatory phenotypes in myeloid cells. The identified SPP1+TAMs were related to poor prognosis. The increased effector/memory T cells represented characteristics similar to exhausted T cells in transitory status after aPD-1therapy, which may play a crucial role in the antitumor immune response. We further revealed that CXCL13+T cells in a high subtype of biliary tract carcinoma were characterized as a 'hot tumor' profile with high immune scores, correlated to the immunostimulatory context with favorable survival, and can predict effective responses to immunotherapy. Our study provided an overview of immune cell dynamics in gallbladder carcinoma liver metastases after aPD-1 treatment and highlighted the importance of CXCL13+T cells in biliary tract carcinoma and effective responses to immunotherapy, which would advance the understanding and treatment of the disease.

Abstract 6482: CLDN18.2 expression is associated with clinicopathological features and prognosis of Chinese patients with digestive system cancers: a retrospective analysis

Abstract Importance: CLDN18.2 was a promising therapeutic target in solid tumors, whereas the clinicopathological features of Chinese CLDN18.2-positive cancer patients were rarely elucidated. Objective: This study aimed to explore the association between CLDN18.2 expression and clinicopathological features of Chinese patients with CLDN18.2-positive digestive system cancers. Methods: This retrospective study included digestive system cancer patients from June 2019 to April 2021 who were screened for two clinical trials of CT041 (an anti-CLDN18.2 CAR-T cell, NCT03874897, and NCT04581473), which were initiated at our center. Results: A total of 875 digestive system cancer patients were included. CLDN18.2 expression was observed in 73.1% GC patients, 61.8% pancreatic cancer (PC) patients, 10.6% colorectal cancer (CRC) patients, and 65.6% biliary tract carcinoma (BTC) patients. In GC, CLDN18.2 expression was associated with age, sex, and Lauren phenotype (all P&amp;lt;0.01). CLDN18.2-positive GC patients had a higher incidence of uterine adnexa metastasis (6.4% vs. 20.8%, P&amp;lt;0.001), and a lower incidence of liver metastasis (22.2% vs. 35.7%, P&amp;lt;0.001). In PC, CLDN18.2-positive cases had a higher proportion of tumors with moderate/high differentiation (46.1% vs. 19.0%, P&amp;lt;0.001), compared with CLDN18.2-negative patients. Additionally, compared with CLDN18.2-negative patients, the proportion of right colon cancer was higher in CLDN18.2-positive patients (40% vs. 18.1%, P=0.028). Conclusions: The results of this study suggested that CLDN18.2-positive tumors had unique clinicopathological features, which provided a theoretical basis for the treatment of CLDN18.2 positive tumors. Citation Format: Chong XiaoYi, Changsong Qi, Jifang Gong, Miao Zhang, Mingyang Ma, keren Jia, Ting Zhou, Li Jian, Zhi Peng, Jun Xiao, Xiaohui Peng, Zhen Liu, Zonghai Li, Xiaotian Zhang, Lin Shen. CLDN18.2 expression is associated with clinicopathological features and prognosis of Chinese patients with digestive system cancers: a retrospective analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6482.

A retrospective cohort study on the efficacy and safety for combination therapy of immunotherapy, targeted agent, and chemotherapy versus immunochemotherapy or chemotherapy alone in the first-line treatment of advanced biliary tract carcinoma.

A paucity of effective treatment for biliary tract carcinoma (BTC) has necessitated the investigation into new therapies. As combinations of targeted therapy with immunotherapy are well-established in hepatocellular carcinoma, the GEMOX chemotherapy (gemcitabine and oxaliplatin) is the standard treatment for BTC. This study aimed to evaluate the efficacy and safety of immunotherapy in combination with targeted agent and chemotherapy in advanced BTC. Patients who were pathologically identified advanced BTC and had received gemcitabine-based chemotherapy alone or in combination with anlotinib, and/or anti-programmed cell death protein-1 (PD-1)/programmed death ligand 1 (PD-L1) inhibitors such as camrelizumab as first-line treatment were retrospectively screened from The First Affiliated Hospital of Guangxi Medical University from February 2018 to August 2021. The outcomes included objective response rate (ORR), median overall survival (OS), and median progressive-free survival (PFS). Adverse events (AEs) were assessed according to the NCI-CTCAE v. 4.03. Patients were followed up weekly. A total of 35 patients were enrolled in this study: 11 patients treated with PD-1/PD-L1 inhibitor plus anlotinib and gemcitabine (arm A), 12 patients with the GEMOX combined with PD-1/PD-L1 inhibitor (arm B), and 12 patients with GEMOX (arm C). With a median follow-up time of 31.9 months (range, 23.8-39.7 months), the median OS was 16.8 months [95% confidence interval (CI): 7.0-not reached], 11.8 months (95% CI: 7.2-31.7 months), and 11.6 months (95% CI: 7.3-18.0 months) in arms A, B, and C, respectively (P=0.298). The median PFS was 16.8 months (95% CI: 7.0-NR), 6.0 months (95% CI: 5.1-8.7 months), and 6.3 months (95% CI: 4.6-7.0 months) in arms A, B, and C, respectively. The ORR were 63.6% in arm A, 33.3% in arm B, and 25.0% in arm C. AEs of all grades occurred in 33 (94.3%) patients. Grade 3-4 AEs in all patients included neutrophil count decrease (14.3%), aspartate aminotransferase increase (8.6%), alanine aminotransferase increase (8.6%), fatigue (5.7%), and blood bilirubin increase (5.7%). Anti-PD-1/PD-L1 immunotherapy in combination with anlotinib and gemcitabine showed promising efficacy and an acceptable safety profile for the BTC patients included in this study.