Programmed death-ligand 1 (PD-L1) expression in tumor tissue is under investigation as a candidate biomarker in immuno-oncology dug development. The soluble form of PD-L1 (sPDL1) is suggested to have immunosuppressive activity. In this study, we measured the serum level of sPDL1 and evaluated its prognostic implication in biliary tract cancer (BTC). Blood was collected from 158 advanced BTC patients (68 intrahepatic cholangiocarcinoma, 56 gallbladder cancer, 22 extrahepatic cholangiocarcinoma and 12 ampulla of vater cancer) before initiation of palliative chemotherapy. Serum sPDL1 was measured using an enzyme-linked immunosorbent assay. Clinical data included neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and systemic immune-inflammation index (SII, neutrophil × platelet/lymphocyte). The patients were assigned to two cohorts (training and validation cohort) using a simple random sampling method to validate the cut-off value of each marker. Validation was performed using a twofold cross-validation method. Overall survival (OS) of all patients was 9.07 months (95% CI: 8.20-11.33). Median sPDL1 was 1.20 ng/mL (range 0.03-7.28, mean 1.50, SD 1.22). Median NLR, PLR and SII were 2.60, 142.85 and 584.93, respectively. Patients with high sPDL1 (≥0.94 ng/mL) showed worse OS than patients with low sPDL1 (7.93 vs. 14.10 months, HR 1.891 (1.35-2.65), p<0.001). In multivariate analysis, high sPDL1 and NLR were independent poor prognostic factors. In conclusion, serum sPDL1 can be measured and has significant role on the prognosis of advanced BTC patients treated with palliative chemotherapy.
4520 Background: In aBTC, GemCis is the standard of care as 1st-line treatment. Immunotherapies have shown early promising efficacy in some BTC patients (pts). We assessed D (anti-PD-L1) ± T (anti-CTLA-4) and GemCis in 1L BTC pts, including an extensive biomarker analysis (NCT03046862). Methods: Pts were first enrolled in the biomarker cohort (BMC) to receive 1 cycle of Gem 1000 mg/m2 + Cis 25 mg/m2 on D1 & D8, followed by GemCis + D 1120 mg and T 75 mg, Q3W until disease progression (PD). Subsequent pts were allocated to GemCis + D (3 combo cohort [3C]) or GemCis + D+T (4 combo cohort [4C]) until PD. In all cohorts, tumor biopsies were obtained pre-treatment, after 1 cycle, and at PD. Blood samples for ctDNA were obtained every cycle. Results: 121 pts were enrolled. Median follow-up durations were 28.5 months (m; 95% CI, 26.5-30.5), 11.3 m (95% CI, 9.1-13.5), and 11.9m (95% CI, 8.4-15.4) in the BMC, 3C, and 4C arms, respectively. Efficacy data are shown (Table). The most common adverse events (AEs, any grade) were neutropenia (54.5%), nausea (59.5%), and pruritus (55.44%). The most common grade 3/4 AEs were neutropenia (50.4%), anemia (35.5%), and thrombocytopenia (16.5%). In the BMC cohort, frequent mutations were found in DNA damage repair, cell cycle regulation, and genome instability genes (eg, ATM, BRCA2, POLE, MSH2, CDKN2A). Distinct somatic variants were detected in responders vs non-responders. Baseline tissue TMB did not correlate with PFS or OS. Reductions in ctDNA variant allele frequency (VAF) were more prominent among responders during early D+T cycles. ctDNA VAF on C3, D1 was significantly correlated with ORR ( P< 0.015). Pretreatment PD-L1 expression was not associated with efficacy, but PD-L1 expression after 1st GemCis cycle trended with improved PFS. Conclusions: These are the first clinical data of D±T plus chemotherapy in chemo-naïve aBTC pts. The addition of immunotherapy to chemotherapy was tolerable and showed very promising efficacy. Biomarker analyses show early signs of markers associated with response. The combination of GemCis + D is being investigated in the Phase 3 TOPAZ-1 trial (NCT03875235). Clinical trial information: NCT03046862 . [Table: see text]
Currently, there is no validated therapeutic target for biliary tract cancer (BTC). This study aimed to investigate the pre-clinical and clinical implication of HER2 as a therapeutic target in BTC. We established two novel HER2-amplified BTC cell lines, SNU-2670 and SNU-2773, from gallbladder cancer patients. SNU-2670 and SNU-2773 cells were sensitive to trastuzumab, dacomitinib, and afatinib compared with nine HER2-negative BTC cell lines. Dacomitinib and afatinib led to G1 cell cycle arrest in SNU-2773 cells and apoptosis in SNU-2670 cells. Furthermore, dacomitinib, afatinib, and trastuzumab showed synergistic cytotoxicity when combined with some cytotoxic drugs including gemcitabine, cisplatin, paclitaxel, and 5-fluorouracil. In a SNU-2670 mouse xenograft model, trastuzumab demonstrated a good anti-tumor effect as a monotherapy and in combination with gemcitabine increasing apoptosis. In our clinical data, 13.0% of patients with advanced BTC were defined as HER2-positive. Of these, three patients completed HER2-targeted chemotherapy. Two of them demonstrated a partial response, and the other one showed stable disease for 18 weeks. In summary, these pre-clinical and clinical data suggest that HER2 could be a therapeutic target, and that a HER2-targeting strategy should be developed further in patients with HER2-positive advanced BTC.
Original ArticlePurpose Currently, the DNA damage response (DDR) pathway represents a key target for new cancer drug development. Advanced biliary tract cancer (BTC) has a poor prognosis because of the lack of efficacious treatment options. Although DNA repair pathway alterations have been reported in many patients with BTC, little is known regarding the effects of DDR-targeted agents against BTC. Materials and MethodsIn this study, nine BTC cell lines were exposed to the WEE1 inhibitor (AZD1775). In vitro, MTT assay, colony-forming assay, cell cycle analysis, phospho-histone H3 staining assay, Transwell migration assay, and western blot were performed. Then, to enhance the antitumor effect of AZD1775, the combination treatment of WEE1 inhibitor and ataxia telangiectasia mutated and Rad3 related (ATR) inhibitor (AZD6738) was conducted using MTT assay and comet assay. Finally, HuCCT-1 and SNU2670 xenograft models were established to confirm the anti-tumor effect of AZD1775 alone. Furthermore, the combination treatment was also evaluated in SNU2670 xenograft models. ResultsAZD1775 blocked the phosphorylation of CDC2 and CDC25C in all cell lines, but significantly increased apoptosis and S phase arrest in sensitive cells. However, increased p-ATR and phosphorylated ataxia telangiectasia mutated levels were observed in less sensitive cells. In addition, in vitro and in vivo data illustrated that AZD1775 combined with AZD6738 exerted more potent anti-tumor effects than either drug alone. Although WEE1 inhibition has promising anti-tumor effects in some BTC cells, the addition of ATR inhibitors could enhance its efficacy. ConclusionTaken together, this study supports further clinical development of DDR-targeted strategies as monotherapy or combination regimens for BTC.
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