Molecular Response to Neoadjuvant Chemotherapy in High-Grade Serous Ovarian Carcinoma

Abstract

While high-grade serous ovarian carcinoma (HGSOC) is the most common histologic subtype of ovarian cancer, significant tumor heterogeneity exists. In addition, chemotherapy induces changes in gene expression and alters the mutational profile. To evaluate the notion that patients with HGSOC could be better classified for optimal treatment based on gene expression, we compared genetic variants [by DNA next-generation sequencing (NGS) using a 50 gene Ion Torrent panel] and gene expression (using the NanoString PanCancer 770 gene Panel) in the tumor from 20 patients with HGSOC before and after neoadjuvant chemotherapy (NACT). NGS was performed on plasma cell free DNA (cfDNA) on a select group of patients (n ¼ 14) to assess the utility of using cfDNA to monitor these changes. A total of 86 genes had significant changes in RNA expression after NACT. Thirty-eight genetic variants (including SNPs) from 6 genes were identified in tumors pre-NACT, while 59 variants from 19 genes were detected in the cfDNA. The number of DNA variants were similar after NACT. Of the 59 variants in the plasma pre-NACT, only 6 persisted, whereas 33 of 38 specific variants in the tumor DNA remained unchanged. Pathway analysis showed the most significant alterations in the cell cycle and DNA damage pathways.Implications: Gene expression profiles at the time of interval debulking provide additional genetic information that could help impact treatment decisions after NACT; although, continued collection and analysis of matched tumor and cfDNA from multiple time points are needed to determine the role of cfDNA in the management of HGSOC. Mol Cancer Res; 16(5); 813-24. Ó2018 AACR.

Clonal Evolution and Timing of Metastatic Colorectal Cancer

“…Genome doubling was calculated based on the mean ploidy of the sample. If the mean ploidy reported by FACETS was greater than 3, the sample was termed to have undergone genome doubling [ 56 ].…”

Orthogonal proteomic platforms and their implications for the stable classification of high-grade serous ovarian cancer subtypes

“…Although HGSOC is the most common histological subtype of ovarian cancer, there is a considerable amount of tumor heterogeneity (Arend et al, 2018), thus underscoring the need for comprehensive characterization of the molecular subtypes of this lethal disease. Previous studies have shown that somatic mutations (Wiegand et al, 2010), genetic (Gates et al, 2010) and environmental risk factors (Goode et al, 2010), and the clinical response rates to platinum- or taxane-based therapy (Sugiyama et al, 2000) vary considerably among the HGSOC molecular subtypes.…”

Prediction of the treatment response in ovarian cancer: a ctDNA approach

“…Additionally, these BRCA1/2 reversion mutations could be detected by ctDNA sequencing analysis in the patients who received platinum and/or PARP inhibitors [116]. Rebecca et al [117] compared the genetic variants of a panel of 50 genes between tumor and ctDNA among 20 patients diagnosed with the high-grade ovarian carcinoma during neoadjuvant chemotherapy (NACT). Notably, 38 genetic variants out of six genes (TP53, KIT, KDR, KRAS, PIK3CA, and PTEN) were identified in tumors pre-NACT, while 59 variants out of 19 genes were detected in the ctDNA.…”

“…Most of the mutations found in ctDNA were not present in tumor resulting from the amplifying of ctDNA. Besides, the heterogeneity in the tumor can be detected in ctDNA, in contrast with tumor tissue [117].…”