Molecular response to neoadjuvant chemotherapy in high-grade serous ovarian carcinoma

Abstract

Objectives: To prospectively evaluate molecular responses to neoadjuvant chemotherapy in patients with high-grade serous ovarian carcinoma.Methods: Between October 2013 and April 2015, 38 patients with suspected advanced ovarian carcinoma were enrolled in this single institution study. After obtaining informed consent, patients underwent a diagnostic laparoscopy. Eighteen patients were excluded—7 had nonserous histology, 3 were deemed suitable for debulking, and 8 did not have a subsequent specimen collected at interval cytoreduction. Analyses of pre- and posttreatment specimens was performed on the Nanostring platform using the nCounter® PanCancer Pathways Panel. Standard statistical tests were performed. Pathway analysis was performed with Ingenuity Pathway and nSolver Analysis Software (Fold change ³ ±2, P < .05).Results: The analysis included 20 eligible patients with a median age was 74 years (range, 47–85 years). Stage IIIC disease (70%) was predominant, with median pretreatment CA-125 values of 540 (range 33–13,818). Patients received a median of 3 cycles (range, 2–6; mean 3.6) of neoadjuvant chemotherapy before their definitive surgery and collection of their second biospecimen. Based on the Ingenuity Pathway and Network Analysis, the top 5 pathways affected by neoadjuvant chemotherapy are Immune Signaling (P = 1.30E-09), Cell Growth and Proliferation (P = 5.03E-08), Cell-To-Cell Signaling and Interaction (P = 7.49E-06), DNA Damage Response and Repair (P = 1.78E-06), and Checkpoint Signaling (P = 2.54E-06). Upstream regulators of the pathways that were activated included phorbol myristate acetate, TNF, JUN, TGFB1. Consistent with these pathways being significantly altered after neoadjuvant chemotherapy, the top 10 upregulated genes (3-fold to 19-fold change) were NR4A3, NR4A1, DUSP5, FOS, FOSL1, KLF4, OSM, SFRP2, IL12B, and NFATC1, and the top 5 downregulated genes (all 2-fold change) were RAD51, HIST1H3B, HIST1H3G, FANCA, and CCNA2.Conclusions: Genomic differences exist in ovarian cancer biospecimens from before to after therapy. Identification of these changes will be important not only to inform the potential response of targeted therapies, but also to allow improved patient selection for clinical trials. Objectives: To prospectively evaluate molecular responses to neoadjuvant chemotherapy in patients with high-grade serous ovarian carcinoma. Methods: Between October 2013 and April 2015, 38 patients with suspected advanced ovarian carcinoma were enrolled in this single institution study. After obtaining informed consent, patients underwent a diagnostic laparoscopy. Eighteen patients were excluded—7 had nonserous histology, 3 were deemed suitable for debulking, and 8 did not have a subsequent specimen collected at interval cytoreduction. Analyses of pre- and posttreatment specimens was performed on the Nanostring platform using the nCounter® PanCancer Pathways Panel. Standard statistical tests were performed. Pathway analysis was performed with Ingenuity Pathway and nSolver Analysis Software (Fold change ³ ±2, P < .05). Results: The analysis included 20 eligible patients with a median age was 74 years (range, 47–85 years). Stage IIIC disease (70%) was predominant, with median pretreatment CA-125 values of 540 (range 33–13,818). Patients received a median of 3 cycles (range, 2–6; mean 3.6) of neoadjuvant chemotherapy before their definitive surgery and collection of their second biospecimen. Based on the Ingenuity Pathway and Network Analysis, the top 5 pathways affected by neoadjuvant chemotherapy are Immune Signaling (P = 1.30E-09), Cell Growth and Proliferation (P = 5.03E-08), Cell-To-Cell Signaling and Interaction (P = 7.49E-06), DNA Damage Response and Repair (P = 1.78E-06), and Checkpoint Signaling (P = 2.54E-06). Upstream regulators of the pathways that were activated included phorbol myristate acetate, TNF, JUN, TGFB1. Consistent with these pathways being significantly altered after neoadjuvant chemotherapy, the top 10 upregulated genes (3-fold to 19-fold change) were NR4A3, NR4A1, DUSP5, FOS, FOSL1, KLF4, OSM, SFRP2, IL12B, and NFATC1, and the top 5 downregulated genes (all 2-fold change) were RAD51, HIST1H3B, HIST1H3G, FANCA, and CCNA2. Conclusions: Genomic differences exist in ovarian cancer biospecimens from before to after therapy. Identification of these changes will be important not only to inform the potential response of targeted therapies, but also to allow improved patient selection for clinical trials.