A Subset of Secreted Proteins in Ascites Can Predict Platinum-Free Interval in Ovarian Cancer

Abstract

The time between the last cycle of chemotherapy and recurrence, the platinum-free interval (PFI), predicts overall survival in high-grade serous ovarian cancer (HGSOC). To identify secreted proteins associated with a shorter PFI, we utilized machine learning to predict the PFI from ascites composition. Ascites from stage III/IV HGSOC patients treated with neoadjuvant chemotherapy (NACT) or primary debulking surgery (PDS) were screened for secreted proteins and Lasso regression models were built to predict the PFI. Through regularization techniques, the number of analytes used in each model was reduced; to minimize overfitting, we utilized an analysis of model robustness. This resulted in models with 26 analytes and a root-mean-square error (RMSE) of 19 days for the NACT cohort and 16 analytes and an RMSE of 7 days for the PDS cohort. High concentrations of MMP-2 and EMMPRIN correlated with a shorter PFI in the NACT patients, whereas high concentrations of uPA Urokinase and MMP-3 correlated with a shorter PFI in PDS patients. Our results suggest that the analysis of ascites may be useful for outcome prediction and identified factors in the tumor microenvironment that may lead to worse outcomes. Our approach to tuning for model stability, rather than only model accuracy, may be applicable to other biomarker discovery tasks.

The role of Piezo1 mechanotransduction in high-grade serous ovarian cancer: Insights from an in vitro model of collective detachment

“…Correlating in vitro concentrations to in vivo settings is challenging, but we would expect that dilution in the ascites would result in lower concentrations. Our prior analysis of 14 patients undergoing primary debulking surgery found a maximum concentration MMP-1 (5 ng/ml) in ascites (57). It is possible that this question could be assessed using a polyethylene glycolbased system with MMP-degradable linkers (58); however, this will likely overestimate any softening relative to the in vivo setting, where surrounding fibroblasts would be depositing matrix at the same time as MMPs are active.…”

Immune environment and antigen specificity of the T cell receptor repertoire of malignant ascites in ovarian cancer

“…Although validation is needed from analyses such as Luminex-based cytokine/chemokine levels in ascites, the elevated expression of regulatory T cells (CD4+FoxP3+) in patients with a good prognosis (Clusters B, C, and D; S2 Fig) may indicate that these cells play a role in suppressing tumor-promoting inflammation. In a recent study of ovarian cancer ascites using multiplex bead-based immunoassays, high concentrations of 2 common inflammatory factors, matrix metalloproteinase 2 and 3, were identified as predictors of shorter platinum-free intervals in patients treated with neoadjuvant chemotherapy or primary debulking surgery [51]. Consistent with the observation, we find that low CD8/Treg in ascites could be a good marker of favorable prognosis in ovarian cancer, along with debulking surgery and TCR characteristics, including high number of productive rearrangements and productive entropy, low productive clonality, maximum productive frequency, top 10 productive frequency, and top 100 productive frequency.…”