Abstract 7610: Predictive biomarkers for immuno-chemotherapy response in biliary tract malignancies

Abstract

Abstract Background: Biliary tract cancers (BTCs) refer to invasive malignancies of the biliary tree. Lack of specific symptoms in early-stages frequently leads to late-stage diagnosis, reducing therapeutic options. Surgical resection remains the only curative option for early-stage disease; instead, patients with advanced disease usually receive chemotherapy (cisplatin plus gemcitabine) in combination with durvalumab as first-line treatment and mFOLFOX-6 as second-line, but effects are limited and only a small proportion of patients respond to treatment. Recent advances in molecular characterization of BTCs allowed the identification of several alterations (e.g. IDH1/2 mutations, FGFR2 rearrangement) for which targeted agents are now available in second line setting but only for a small subset of patients. However, prognosis for patients with advanced stage disease remains poor. Treatment failure depends on several factors such as intra- and inter-tumor heterogeneity and the complex immunological landscape. Therefore, the identification of predictive biomarkers able to individuate patients that will benefit from immuno-chemotherapy will be crucial. Methods: BTC patients at any stage were enrolled in two arms: A) BTCs undergoing surgery; B) advanced/relapsed BTCs. For this study, patients belonging to arm B were selected, in particular those who received first-line immuno-chemotherapy. Blood samples were collected before and after three months of therapy. Ascites samples were collected for patients with advanced disease who underwent paracentesis during therapy. DEPArray NxT (Menarini Silicon Biosystems) was used for phenotypic analysis and single ascites-derived cell isolation. The Ampli1 Lowpass kit was used for copy number aberration (CNA) profiling. Extracellular vesicles (EVs) were isolated from plasma at baseline and after three months of immuno-chemotherapy by size-exclusion chromatography and analyzed for size distribution and concentration using Nanosight NS300. Surface EV markers were analyzed by flow cytometry using the MACSPlex Exosome Kit human (MiltenyiBiotec). Results: We enrolled 43 patients starting from August 2022: 14 in arm A and 29 in B. 23 patients from arm B received immuno-chemotherapy and 3 underwent paracentesis during therapy. Patient-derived organoids (PDOs) were successfully established from tumor cells recovered from ascites of these patients. Epithelial cells recovered from ascites displayed aberrant CNA profiles with gains in chromosomes 1q, 8q, 10, 12p, 20, and losses in 1q, 3q, 4, 8q, 9 and X. EV size distribution and concentration were similar before and after treatment as well as surface markers exposure. Further analyses in correlation with clinical features of patients will be performed. Conclusions: Our approach will contribute to identify potential predictive factors associated with response/resistance to immuno-chemotherapy in BTCs. Citation Format: Michele Zanoni, Tania Rossi, Martina Valgiusti, Giuliano La Barba, Michela Cortesi, Sara Bandini, Giulia Bartolini, Alessandra Dubini, Paolo Di Gioia, Chiara Gallio, Luca Esposito, Alessandra Virga, Giorgia Gurioli, Sara Bravaccini, Giovanni Martinelli, Paola Ulivi, Giovanni Luca Frassineti, Giorgio Ercolani, Ilario Giovanni Rapposelli. Predictive biomarkers for immuno-chemotherapy response in biliary tract malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 7610.