Abstract
The majority of patients with high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy; however, most will develop chemotherapy resistance. Gene signatures may change with the development of chemotherapy resistance in this population, which is important as it may lead to tailored therapies. The objective of this study was to compare tumor gene expression profiles in patients before and after treatment with neoadjuvant chemotherapy (NACT). Tumor samples were collected from six patients diagnosed with HGSOC before and after administration of NACT. RNA extraction and whole transcriptome sequencing was performed. Differential gene expression, hierarchical clustering, gene set enrichment analysis, and pathway analysis were examined in all of the samples. Tumor samples clustered based on exposure to chemotherapy as opposed to patient source. Pre-NACT samples were enriched for multiple pathways involving cell cycle growth. Post-NACT samples were enriched for drug transport and peroxisome pathways. Molecular subtypes based on the pre-NACT sample (differentiated, mesenchymal, proliferative and immunoreactive) changed in four patients after administration of NACT. Multiple changes in tumor gene expression profiles after exposure to NACT were identified from this pilot study and warrant further attention as they may indicate early changes in the development of chemotherapy resistance.
Highlights
About 85% of patients with high-grade serous ovarian cancer (HGSOC) will achieve a clinical remission with a combination of surgery and platinum-based chemotherapy despite presenting with advanced stage disease [1]
Tumor purity and chemotherapy response score (CRS) scores were evaluated by an expert clinical pathologist specializing in ovarian cancer (Figure 1 and Table 1)
When using all 770 genes, the samples did not cluster based on pre- and post-neoadjuvant chemotherapy (NACT) status in the Arend study, while in our study, clustering using an expanded set of 6748 genes did result in separation (Figure 2)
Summary
About 85% of patients with high-grade serous ovarian cancer (HGSOC) will achieve a clinical remission with a combination of surgery and platinum-based chemotherapy despite presenting with advanced stage disease [1]. To elucidate the mechanisms underlying platinum resistance several groups have generated chemoresistant versions of established ovarian cancer cell lines and compared gene expression between the chemoresistant line and its chemosensitive parental line [2,3,4,5]. These studies provide insight into changes that occur as cells adapt to high levels of chemotherapy, but the genes identified in these studies are inconsistent between studies and the mechanisms of in vitro resistance could very likely be different from those arising in human tumors [6]. Patch et al compared matched samples taken from patients at initial debulking and at recurrence [8], suggesting that gene profiles in the latter may represent a chemoresistant gene signature
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