Discovery of candidate tumor biomarkers for treatment with intraperitoneal chemotherapy for ovarian cancer

Abstract

Tumor mRNA expression was used to discover genes associated with worse survival or no survival benefit after intraperitoneal (IP) chemotherapy. Data for high grade serous ovarian cancer patients treated with IP (n = 90) or IV-only (n = 398) chemotherapy was obtained from The Cancer Genome Atlas. Progression free survival (PFS) and overall survival (OS) were compared between IP and IV groups using Kaplan-Meier analysis and Cox regression. Validations were performed by analyses of microarray and RNA-Seq mRNA expression data. PFS and OS were compared between IP and IV groups by permutation testing stratified by gene expression. P-values are two-tailed. IP chemotherapy increased PFS (26.7 vs 16.0 months, HR 0.43 (0.28–0.66), p = 0.0001) and OS (49.6 vs 38.2 months, HR 0.46 (0.25–0.83), p = 0.01). Increased expression of NCAM2 and TSHR and decreased expression of GCNT1 was associated with decreased PFS and OS after IV chemotherapy (p < 0.05). High tumor expression of LMAN2, FZD4, FZD5, or STT3A was associated with no significant PFS increase after IP compared to IV chemotherapy. Low expression of APC2 and high expression of FUT9 was associated with 5.5 and 7.2 months, respectively, decreased OS after IP compared to IV chemotherapy (p ≤ 0.007).

Wnt Signaling and Survival of Women With High-Grade Serous Ovarian Cancer: A Brief Report

“…4 Patients who received adjuvant IP/IV (n = 90) or IV (n = 398) chemotherapy were included, and these cohorts were previously described. 2 Cox proportional hazards regression of OS and PFS by mRNA expression with inclusion of covariates age, surgical stage, and histological grade was performed for 26 Wnt pathway genes (APC/APC2, AXIN1/2, CTNNB1, DVL1/2/3, FZD1/2/3/4/5/6/7/8/9/10, GSK3B, LRP5/6, and WNT1/2/3/4/ 5A) with microarray data. For multivariate Cox regression (microarray) of OS and PFS for IP patients (n = 90), 30 and 18 cases, respectively, were omitted because of missing data; for IV patients (n = 398), 121 and 90 cases, respectively, were omitted because of missing data.…”

“…2 Restricted mean survival times are the areas under the Cox regression adjusted survival curves of OS and PFS using a restriction time of 60 months and represent mean survival times of patients given a particular relative mRNA expression level. 5,6 Permutation testing (10,000 permutations) was performed to test the significance of the difference in mean OS and PFS between patients treated with IP versus IV chemotherapy given a specified range of gene expression.…”

“…This null hypothesis is consistent with the large OS and PFS benefits of IP chemotherapy observed in the TCGA cohort of patients with OvCa. 2 Findings from permutation testing with microarray expression data were validated by identical permutation testing using RNA-Seq data. Any gene for which the null hypothesis is rejected by both expression data sets is considered a candidate biomarker.…”

“…2 Recently, investigators also reported that patients with endometrioid OvCa with increased membrane A-catenin protein expression had decreased PFS and increased platinum resistance. 3 To further evaluate Wnt pathway genes as potential biomarkers for OvCa survival and chemotherapy response, we analyzed associations of Wnt pathway genes with survival outcomes among patients with high-grade serous OvCa treated with IP or IV chemotherapy.…”

Specific features of current intraperitoneal therapy in patients with ovarian cancer

“…Важным моментом является то, что высокая концентрация лекарства в брюшной полости не предусматривает автоматически его боль-шую эффективность из-за ограничений проникнове-ния агента в саму перитонеальную опухоль [14], од-нако пролонгирование в / б концентрации может обеспечивать высокую интенсивность его действия и изменение профиля побочных явлений. Высокая концентрация препарата в брюшной полости по срав-нению с плазмой (соотношение концентраций) пока-зана в виде AUC (рис.…”