28P - Collagen-activated signalling pathway is significantly hypermethylated in high-grade serous ovarian cancer (HGSOC) patients treated with platinum-containing neoadjuvant chemotherapy (NACT)

Background

Epigenetic changes can induce resistance to different CT agents. The aim of our study was to identify those epigenetic changes in high-grade ovarian cancer patients (HGOC) that have been treated with 3-4 previous cycles of neoadjuvant platinum-containing CT (NACT).

Methods

We obtained tumor tissue from HGOC that were considered candidates for NACT with carboplatin +/- paclitaxel. Tumor tissue from diagnostic biopsy and then from the remaining tissue in the interval cytoreductive surgery (ICS) were obtained. A quality control of the data was performed in order to reject those samples in which hybridization was not adequate. Thereafter data were normalized. Quality control and data processing were done with the packet minfi. Thereafter an analysis of differential methylation positions (DMPs) was performed with the packet limma. CpG probe were considered significant with a FDR<0.05. A differential methylation regions (DMRs) analysis and a overrepresentation analysis (ORA) of functional enrichment of KEGG and GO pathways were done.

Results

16 samples from 12 different patients (10 from diagnostic biopsy and 6 from ICS sample tissue after exposure to 3-4 cycles of carboplatin containing CT) were obtained. Mean age was 61.25 years. All patients had a HGSOC diagnosis. Most patients were BRCA wild type (8 pts), unknown in 3 patients and only 1 had a somatic BRCA1 mutation. FIGO stage was III (66.6%) and IV (33.3%). All patients were treated with carboplatin+paclitaxel but one that received carboplatin single agent. The number of NACT cycles were 3 in 30% and 4 in the 70%. 100% had a partial response before ICS. 1459 CpG probe and 169 DMR were significantly different between. Cluster heatmap created classified both groups. The number of DMR hypomethylated were 81 and the hypermethylated were 88. From the significant DMRs the ORA test identified 2 enriched BO biological processes, the collagen-activated (CA) tyrosine kinase receptor signalling pathway and the CA signalling pathway due in part to the existence of DMR significant in the genes COL1A1, DDR1 and DDR2.

Conclusions

An epigenetic enrichment of the collagen-activated pathways was observed after response to carboplatin NACT.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

INCLIVA.

Funding

GEICO.

Disclosure

J.A. Perez Fidalgo: Financial Interests, Personal, Invited Speaker: AstraZeneca, Clovis, GSK, PharmaMar, AstraZeneca, Artios Pharma; Financial Interests, Personal, Advisory Board: AstraZeneca, GSK, Clovis, PharmaMar, Roche, Abilify Pharma; Financial Interests, Personal, Full or part-time Employment, Associate Professor: University of Valencia; Financial Interests, Institutional, Research Grant: GSK, PharmaMar; Financial Interests, Institutional, Invited Speaker: Novartis, AstraZeneca; Financial Interests, Institutional, Funding: GSK; Non-Financial Interests, Personal, Project Lead, Coordinating PI Phase III trial in breast cancer: Novartis; Non-Financial Interests, Personal, Member, Member of the Early Drug Development working group: ENGOT; Non-Financial Interests, Personal, Leadership Role, Member of the Executive Committee and Head of the Scientific Committee: GEICO; Non-Financial Interests, Personal, Leadership Role, Member of the Executive Committee and co-coordinator of Uterine Sarcoma Group: GEIS; Non-Financial Interests, Personal, Leadership Role, Co-chair Phase 2 group: GCIG; Non-Financial Interests, Personal, Member: BIG; Non-Financial Interests, Personal, Member, Adolescent and Young Adults working group: SEOM. B. Pineda Merlo: Financial Interests, Institutional, Research Grant: AstraZeneca, PharmaMar. All other authors have declared no conflicts of interest.