Abstract
BackgroundIntraperitoneal chemotherapy is used to treat peritoneal cancer. The pattern of gene expression changes of peritoneal cancer during intraperitoneal chemotherapy has not been studied before. Pressurized intraperitoneal aerosol chemotherapy is a new form of intraperitoneal chemotherapy using repeated applications and allowing repeated tumor sampling during chemotherapy. Here, we present the analysis of gene expression changes during pressurized intraperitoneal aerosol chemotherapy with doxorubicin and cisplatin using a 22-gene panel.MethodsTotal RNA was extracted from 152 PC samples obtained from 63 patients in up to six cycles of intraperitoneal chemotherapy. Quantitative real-time PCR was used to determine the gene expression levels. For select genes, immunohistochemistry was used to verify gene expression changes observed on the transcript level on the protein level. Observed (changes in) expression levels were correlated with clinical outcomes.ResultsGene expression profiles differed significantly between peritoneal cancer and non- peritoneal cancer samples and between ascites-producing and non ascites-producing peritoneal cancers. Changes of gene expression patterns during repeated intraperitoneal chemotherapy cycles were prognostic of overall survival, suggesting a molecular tumor response of peritoneal cancer. Specifically, downregulation of the whole gene panel during intraperitoneal chemotherapy was associated with better treatment response and survival.ConclusionsIn summary, molecular changes of peritoneal cancer during pressurized intraperitoneal aerosol chemotherapy can be documented and may be used to refine individual treatment and prognostic estimations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-016-2668-4) contains supplementary material, which is available to authorized users.
Highlights
Intraperitoneal chemotherapy is used to treat peritoneal cancer
Local and regional treatment strategies such as peritonectomy, peritonectomy combined with hyperthermic intraperitoneal chemoperfusion (HIPEC), and various modalities of intraperitoneal chemotherapy (IPC), including pressurized intraperitoneal aerosol chemotherapy (PIPAC), have been reported to achieve objective treatment responses in patients with Peritoneal carcinomatosis (PC) of various origins [6,7,8,9]
Peritoneal metastases had copy number aberrations that differed from those found in the primary tumor: a six gene expression signature including EFTUD1, CALB2, TIMP3, CYP1B1, IL7R, and RARRES2 distinguished primary from metastatic tumors and predicted overall survival [11]
Summary
The pattern of gene expression changes of peritoneal cancer during intraperitoneal chemotherapy has not been studied before. Verhaak et al used a 100 gene signature including RB1, NFKBIB, and RXRB for molecular subtyping of advanced ovarian cancer specimens with peritoneal metastases [10]. Others have used gene expression patterns to characterize the molecular pathway highlighting the transition of primary ovarian tumors to peritoneal metastases. In a similar study of 47 epithelial ovarian cancers, microarray analysis using an Affymetrix platform identified a 56 gene set with differential expression discriminating the primary tumor from peritoneal metastases [12]. Matte et al studied gene expression changes in human peritoneal mesothelial cells (HPMCs) exposed to malignant ascites from ovarian cancer with PC [13]. We felt it is reasonable to investigate whether tumor samples with contact to ascites would have different gene expression patterns compared to tumor samples without such exposure
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