Evaluation of xenograft alignment with patient tumors to inform treatment studies in uterine carcinosarcoma.

Abstract

e17647 Background: Accurate representation of patient tumors is critical to study the factors affecting treatment response in Uterine Carcinosarcoma (UCS), which is a rare and aggressive uterine malignancy. UCS is categorized as a complex metaplastic carcinoma with sarcomatous component arising from de-differentiation of carcinoma as well as collagen-rich stromal component. Despite the poor prognosis associated with standard chemotherapy, translational efforts to better model UCS architecture and inform therapeutic advancements remain limited. Methods: Primary UCS tumors from the surgical samples of six patients were used to grow patient-derived xenografts (PDXs). Both primary UCS tumor tissue and the matched PDXs underwent dual collagen and hyaluronic acid (HA) staining. High-resolution brightfield images were captured and quantitative spatial parameters, including ECM area fractions, HA : collagen ratios, gray-level co-occurrence matrix (GLCM) texture metrics, and Moran’s I spatial autocorrelation were analyzed. Group comparisons used non-parametric statistics, and principal component analysis (PCA) summarized multivariate ECM signatures. In parallel, patient-derived 3D organoid models are being established from the same frozen UCS tumor specimens. Results: Majority of the patient UCS tumors (n = 5) irrespective of their clinical stage of diagnosis, demonstrated higher collagen area fraction than their matched PDX tumors (0.20 ±0.01 vs 0.05 ±0.04; p<0.05), while HA levels were similar in both. Texture analysis revealed more heterogeneous collagen organization in patient tumors, with higher entropy (8.22 ±0.10 vs 8.07 ±0.02; p<0.05) and lower homogeneity (0.15 ±0.02 vs 0.19 ±0.01; p<0.05). Spatial statistics showed a two-fold increase in collagen Moran’s I in PDX tumors (0.51 ±0.02 vs 0.26 ±0.07; p<0.05), indicating stronger ECM clustering and reduced spatial heterogeneity than the patient tissue. PCA clearly separated patient and PDX samples, driven by HA : collagen imbalance, textural heterogeneity, and spatial metrics. Conclusions: Measurable differences in the stromal profile including reduced collagen content, entropy, and heterogenous organization in PDX tumors, underscore the importance of careful model selection when interpreting treatment-related studies in UCS. Our ongoing efforts of developing the patient-derived 3D organoid models aim to better preserve the UCS features, and will further elucidate factors contributing to the limited clinical benefit observed with standard chemotherapy drugs (carboplatin and paclitaxel) in UCS.