MSI exploration in patients with biliary tract cancer from the Spanish RETUD Registry.
Authors: Muñoz Martín Andrés J. , Macarulla Teresa , La Casta Adelaida , Adeva Jorge , Castillo Trujillo Oscar Alfredo , Peinado Paloma , Verdaguer Helena , Martinez de Castro Eva , Lobo De Mena Miriam , Granja Ortega Monica , Rodriguez-Alonso Rosa Maria , Fernandez Montes Ana , Vera Ruth , Gallego Javier , Graña Begoña , Ghanem Ismael , Alés Inmaculada , Molina Raquel , Laquente Berta , Aranda Enrique ,   Spanish Cooperative Group for the Treatment of Digestive Tumours (TTD)
Published: January 2023

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Background: Biliary tract cancer (BTC) is a resistant tumor better addressed by targeting molecular alterations. Among described biomarkers, Microsatellite Instability (MSI) is rarely found in BTC patients (pts) (~2%) and therefore, it is scarcely described in literature. Pembrolizumab (PBL) has proved beneficial for MSI-H BTC pts who did not respond to previous treatment. Our aim is to describe outcomes of MSI pt in Spanish daily practice. Methods: This is a descriptive analysis of a cohort of pts from the Spanish RETUD registry diagnosed with BTC between 1 January 2017 and 31 December 2020. All patients recruited at the cut-off date (7 July 2021) were considered in the analysis. Data collected included demographic and clinical characteristics, systemic oncologic treatment and effectiveness (best response and survival outcomes). Pts characteristics were recorded in all MSI-H pts. Survival outcomes and best response were calculated for pts who received systemic oncologic treatment. Descriptive statistic was used to analyze sociodemographic data, tumor characterization, molecular analysis, and best response. Progression-free survival (PFS) and overall survival (OS) were estimated by the Kaplan-Meier method. Results: The registry included 778 evaluable pts. Only 206 pts were tested for MSI and 13 (6.3%) had positive results. Median (interquartile range, IQR) age was 74.5 (68.9-80.8) years, and the male sex (84.6%) was predominant. Primary tumor was 92.3% intrahepatic and 7.7% extrahepatic. Metastatic and locally advanced disease were diagnosed in 3 (23.1%) and 7 (53.8%) pts respectively. Only 4 (30.8%) pts underwent previous surgery. Molecular profile analyses reported 2 (20.0%) BRAF mutations, 1 (10.0%) IDH1 mutations, 2 (20.0%) FGFR2 fusions and 1 (10.0%) HER2 amplification (missing data n=3 pts). One pt was positive to BRAF, IDH1, FGFR2 and HER2 mutations. Eleven pts received systemic oncologic treatment, predominantly frontline therapy with gemcitabine-based combinations (n=9, 81.8%). At the database cut-off, 6 pts died due to disease progression (83.3%) or disease-related complications (16.7%). The median PFS to frontline treatment was 2.7 months (95% Confidence Interval [CI]: 1.5–9.9), and the median OS was 21.0 months (95% CI: 6.5-NA). Five (38.3%) pts received PBL as second-line therapy, with 3 pts responding (1 complete response and 2 partial responses). Median PFS after PBL was 2.6 (95% CI 2.1- NA) months and median OS was 21.0 (19.5-NA) months, in contrast to non-MSI population survival outcomes: PFS= 4.7 (95% CI 4.1-5.2) months, OS=9.0 (95% CI 8.1-9.8) months. Conclusions: This study describes clinical outcomes of the MSI-H pts in a sample of Spanish patients with BTC. Molecular characterization was poorly performed at the time of database cut-off; however, we found a higher presence of MSI-H than expected. PBL, as the second-line strategy, showed a good response.