BioRAIDs is a supervised longitudinal collection of tumor and blood together with clinical outcome data in 419 primary cervical cancer patients from 7 European countries (NCT02428842).
Molecular analysis [Next Generation Sequencing (NGS) at SeqOmics (Hungary) & Reverse Phase Protein array (RPPA) at Institut Curie] was performed on quality-controlled primary tumor samples in 295 patients (70%) who subsequently had received primary radio chemotherapy (RCT). Integrative bioinformatics analyses were performed to identify pathway activations suggesting the need for additional/different therapies.
NGS demonstrated driver Tyrosine Kinase Receptor/ PI3 kinase (TKR/PI3K) pathway mutations in 27%; TKR/PI3K + epigenetic pathway alterations (MLL2, MLL3) in 32 % and epigenetic alterations alone in 13% of patients. At a median follow up of 19 months [2-38], tumors for which no mutations in relevant genes from the TKR/PI3K pathways nor alterations in genes involved in epigenetic signaling appeared to be associated with a significantly better prognostic profile: HR = 2.4 [95% CI: 1.1 – 5.2]. RPPA analysis was carried out separating patients in 3 subgroups according to signaling pathway activation [EMT (epithelial mesenchymal transition), DNA damage and MAPK/PI3K], none of which was associated with bad prognosis.
The high frequency of epigenetic alterations with or without TKR/PI3K pathway mutations, suggests that epigenetically acting drugs (VorinostatR) may be relevant for patients whose tumors have genetic mutations of significance in epigenetically acting enzymes. Relevance of copy number alterations and of other frequently mutated genes (CSMD3, SYNE1), needs to be integrated and cross validated in a larger complementary dataset.
Clinical trial identification
Legal entity responsible for the study
This project has received founding from the European Union’s Seventh Program for research, technological development and demonstration under grant agreement No 304810.
All authors have declared no conflicts of interest.