cancers Article Impact of Pathological Stratification on the Clinical Outcomes of Advanced Well-Differentiated/Dedifferentiated Liposarcoma Treated with Trabectedin Chiara Fabbroni 1 , Giovanni Fucà 1 , Francesca Ligorio 1 , Elena Fumagalli 1 , Marta Barisella 2 , Paola Collini 2 , Carlo Morosi 3 , Alessandro Gronchi 4 , Angelo Paolo Dei Tos 5,6 , Paolo Giovanni Casali 1,7 and Roberta Sanfilippo 1, *   Citation: Fabbroni, C.; Fucà, G.; Ligorio, F.; Fumagalli, E.; Barisella, M.; Collini, P.; Morosi, C.; Gronchi, A.; Dei Tos, A.P.; Casali, P.G.; et al. Impact of Pathological Stratification on the Clinical Outcomes of Advanced Well-Differentiated/ Dedifferentiated Liposarcoma Treated with Trabectedin. Cancers 2021, 13, 1453. https://doi.org/10.3390/ cancers13061453 Academic Editors: Armita Bahrami and Brian A. Van Tine Received: 4 February 2021 Accepted: 18 March 2021 Published: 22 March 2021 Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affil- iations. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). 1 Adult Mesenchymal Tumour Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; chiara.fabbroni@istitutotumori.mi.it (C.F.); giovanni.fuca@istitutotumori.mi.it (G.F.); francesca.ligorio@istitutotumori.mi.it (F.L.); Elena.fumagalli@istitutotumori.mi.it (E.F.); paolo.casali@istitutotumori.mi.it (P.G.C.) 2 Department of Pathology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; marta.barisella@istitutotumori.mi.it (M.B.); paola.collini@istitutotumori.mi.it (P.C.) 3 Department of Radiology, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; carlo.morosi@istitutotumori.mi.it 4 Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, 20133 Milan, Italy; alessandro.gronchi@istitutotumori.mi.it 5 Department of Pathology and Molecular Genetics, Treviso General Hospital, 31100 Treviso, Italy; angelo.deitos@unipd.it 6 Department of Medicine, University of Padova School of Medicine, 35128 Padova, Italy 7 Oncology and Hemato-Oncology Department, University of Milan, 20122 Milan, Italy * Correspondence: roberta.sanfilippo@istitutotumori.mi.it; Tel.: +39-02-2390-2638 Simple Summary: The treatment options for advanced well differentiated liposarcoma (WDLPS) and dedifferentiated liposarcoma (DDLPS) are scant, especially after the failure of first-line, anthracycline- based treatment, when trabectedin is one of the most active agents currently approved. Thus, the identification of biological characteristics allowing an efficient patients stratification in this setting appears mandatory. Here, applying a grading-based stratification, we showed that trabectedin may be more active against low-grade LPS (i.e., WDLPS and low-grade DDLPS) than in high-grade LPS (i.e., high-grade DDLPS). If confirmed, our data might allow the implementation of grading as a tool patients’ stratification in this setting. Abstract: Background. We previously showed that grading can prognosticate the outcome of retroperitoneal liposarcoma (LPS). In the present study, we aimed to explore the impact of pathologi- cal stratification using grading on the clinical outcomes of patients with advanced well-differentiated LPS (WDLPS) and dedifferentiated LPS (DDLPS) treated with trabectedin. Patients: We included patients with advanced WDLPS and DDLPS treated with trabectedin at the Fondazione IRCCS Istituto Nazionale dei Tumori between April 2003 and November 2019. Tumors were categorized in WDLPS, low-grade DDLPS, and high-grade DDLPS according to the 2020 WHO classification. Patients were divided in two cohorts: Low-grade (WDLPS/low-grade DDLPS) and high-grade (high-grade DDLPS). Results: A total of 49 patients were included: 17 (35%) in the low-grade cohort and 32 (65%) in the high-grade cohort. Response rate was 47% in the low-grade cohort versus 9.4% in the high-grade cohort (logistic regression p = 0.006). Median progression-free survival (PFS) was 13.7 months in the low-grade cohort and 3.2 months in the high-grade cohort. Grading was confirmed as an independent predictor of PFS in the Cox proportional-hazards regression multi- variable model (adjusted hazard ratio low-grade vs. high-grade: 0.45, 95% confidence interval: 0.22–0.94; adjusted p = 0.035). Conclusions: In this retrospective case series, sensitivity to trabectedin was higher in WDLPS/low-grade DDLPS than in high-grade DDLPS. If confirmed in larger series, grading could represent an effective tool to personalize the treatment with trabectedin in patients with advanced LPS. Cancers 2021, 13, 1453. https://doi.org/10.3390/cancers13061453 https://www.mdpi.com/journal/cancers