Abstract 22P
Background
Considerable efforts have been made to understand the leading causal mechanisms behind the development of platinum resistance in relapsed High Grade Serous ovarian Cancer (HGSC) patients. Accumulating evidence shows that epigenetic alterations play an important role in the emergence of platinum-resistant disease. To assess their subsequent effect on the transcriptome, we extracted and sequenced RNA from formalin-fixed, paraffin-embedded (FFPE) paired tumor samples in order to perform Differentially Gene Expression Analysis (DGEA) between diagnosis and platinum-resistant relapse.
Methods
FFPE samples from chemo-naïve patients (diagnosis) and matched platinum-resistant recurrence (at the time of surgery for bowel obstruction) were used for RNA extraction (QIAGEN RNeasy FFPE Kit). DGEA was subsequently conducted to identify potential changes in the transcriptome (through RNA sequencing) that may elucidate the development of platinum-resistance.
Results
We collected 25 samples (8 patients), each with at least 2 biopsies taken at diagnosis (from both the ovary and peritoneum) and 2 at relapse (either nodal or peritoneal one). Only 2 out of 8 patients’ biopsies clustered together at diagnosis. Surprisingly, patients with similar gene expression at diagnosis (who were also the only two BRCA1/2 mutation carriers) maintained their similarity at relapse. All comparisons (diagnosis versus relapse, primary site versus distant site at diagnosis, and distant site at diagnosis versus relapse) revealed that relapse/metastases are associated with an enrichment in acute inflammatory response genes and well-established cancer pathways (Wnt signalling/PI3K-Akt). Additionally, we consistently found an enrichment in neuronal biological processes. These findings support our previous results obtained from preclinical models, where primary cell cultures from chemo-naïve patients were treated with multiple pulses of 6-hour exposure to 50uM Carboplatinum.
Conclusions
New pathways implicated in chemotherapy failure may offer novel therapeutic approaches; Wnt signalling and PI3K-Akt may be evaluated as possible targeted strategies.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
R. Ergasti: Financial Interests, Personal, Invited Speaker: GSK. G. Giannone: Financial Interests, Personal, Other: ESMO, AIRC. A. Fagotti: Financial Interests, Personal, Funding: AstraZeneca, MSD; Financial Interests, Personal, Other: Johnson and Johnson; Financial Interests, Personal, Invited Speaker: Menarini. G. Scambia: Financial Interests, Personal, Other: Covidien, AstraZeneca, MSD, Olympus, Baxter, GSK, Healthcare, Intuitive Surgical Inc. I. McNeish: Financial Interests, Personal, Other: Clovis Oncology, AZ, GSK, Roche, Scancell, OncoC4, Theolytics. All other authors have declared no conflicts of interest.