Publishable Summary - M18 - May 2014

Project context and objectives

Cervical cancer (CC) is the second most common malignancy in women worldwide. Although CC is a single diagnostic entity and infection of high-risk HPV is recognized as an important initiating event in tumourogenesis, CC exhibits differences in clinical behaviour.

  • Stratification of CC into subclasses for progression and response to treatment remains to be defined. At present, the dominant targets under scrutiny for innovative CC treatments are the following: EGFR/PI3K pathway, proliferation/DNA checkpoint and angiogenesis inhibition as well as anti-HPV vaccines. There have been recent publications (Ojesina, 2014; Wright, 2013) on high resolution genetic investigations in CC, but so far there has been no prospective assessment on patient outcome using whole genome/exome sequencing or protein profiling and quality control evaluation of patient treatment. Early prospective data is available from a small phase 2 clinical trial by Institut Curie, the coordinators centre (n=78; submitted for publication).

  • We are lacking prognostic and predictive biomarkers in CC and there is a growing need for the development of biomarkers to follow up the course of the disease.

RAIDs is a multidisciplinary co-operation between academic clinical centres, SMEs and translational research platforms. It combines Next Generation Sequencing (NGS) and Reverse Phase Protein array (RPPA) in a large patient population prior to standard therapy. It includes:

  • a cognitive cohort study (BioRAIDs) intended to define patient stratification for targeted therapies,
  • as well as targeted clinical trials using an HPV directed vaccine trial or direct viral targeting in association with standard therapy.

In addition, high throughput screening techniques will be performed in CC cell lines to identify new molecules of relevance for CC or CC microenvironment targeting. These molecules will be validated in preclinical mouse models.


The main objectives of RAIDs as stated in the DoW are:

  • To identify prognostic and predictive biomarkers for standard and targeted therapy in cervical cancer patients using high throughput genomic and proteomic approaches in order to improve treatment response for the individual patient;

  • To define a set of stratification criteria for therapy in patients with cervical cancer based on the tumour’s molecular profile;

  • To identify underlying mechanisms causing immune tolerance of the viral transmitted disease allowing innovative clinical interventions by vaccination studies (together with anti-micro-environmental reagents and/or checkpoint inhibitors);

  • To improve clinical outcome of patients with cervical cancer by conducting interventional targeted therapy-based trials, which will be carried out by a network of leading European centres in gynaecologic oncology: (EORTC/ENGOT).

Work performed and main results achieved

RAIDs started October 1st, 2012 and involves 7 European countries (France, Germany, the Netherlands, Serbia, Moldova, Romania and Hungary).

  • The main efforts during the first 18 months were dedicated to

A) regulatory and ethical submission and acceptance of 2 finalized protocols  with numerous administrative and legal hurdles related to the European dimension and the multicentre aspect of the clinical trials
B) set up of quality control aspects for biobanking, for data reporting and for data integration.

  • BioRAIDs biobanking trial.

A) The first BioRAIDs clinical centre opened in Paris end of July 2013. Four additional French centres opened immediately prior to the 18 months meeting in April 2014 and 30 patients are included in France at the time of submission
B) Regulatory and ethical approval was achieved and insurances have been contracted by The Netherlands, Germany and Serbia; accrual of patients is imminent in these countries.
C) Regarding Moldova and Romania, we are still actively working on administrative issues related to delegation contracts with our partner ECRIN.
D) Results on quality control aspects

  1. Teaching and contouring sessions for radiotherapy have already been published. Educational tools consisted in web based tumour contouring workshops with expert guidance. (Rivin del Campo et al. 2014 Quality input of an Online Delineation Workshop in Advanced Stage Cervical Cancer.).

  2. Quality control for pathology (percent of tumour cells in biopsy sample) will be run conjointly by Amsterdam and Seqomics,

  3. Quality control for NMR imaging is in the process of being set up in Serbia.

  • The DNA vaccine (HPV targeted therapy) sponsored by NKI in the Netherlands received approval after several protocol modifications and we expect patients’ accrual as of June 2014.
  • The virus targeting Cidofovir trial sponsored by partner IGR is delayed due to 1st the unavailability of the product over a period of 12 months at the level of Gilead (pharma) and 2nd to the subsequent failing of KEOCYT to provide available generic versions of Cidofovir from other suppliers. This protocol has been reviewed internally and is ready for submission to regulatory/ethical committees pending definition of the source of the product.
  • Standard operating procedures (SOPs) for biopsy and blood collections are established and documents are translated in English and French as well as in Romanian/Moldovian and Serbian.
  • Members from IOV and Curie have participated in a patient advocacy session at the ESGO annual meeting in Liverpool in Oct 2013 which reported on patient’s requests. Access for patients to the ESGO website has also been arranged. Our plan is to cooperate with ENGAGe, add a link between ENGAGe and our RAIDs website.
  • Clinical data information is being collated in an electronic Clinical report file (CRF) which has been validated by the Curie clinical research team and the RAIDs consortium. Electronic controls have been introduced by data managers from Curie and Quanticsoft assuring that the data will be accurate and that the need to send out queries for data validation can be kept to a minimum.
  • A seamless information system that covers all the requirements needed for the RAIDs project ranging from data traceability, data analysis, query and visualisation has been developed by the bio informatics department of Institut Curie in collaboration with Quanticsoft. The centralized information system KDI (Knowledge and Data Integration) is ready to collect all the data that will be generated within the consortium.
  • Sequencing  tests by SeqOmics to evaluate the different strategies of exome capture on tumour cell lines prior to the analysis of the first tumour biopsies are completed. A pilot study on the first batch of tumour samples will start in June 2014.
  • CC cell lines: we have accrued a set of 19 cell lines (of which 2 could not be included in the analysis due to mycoplasma infection) and 6 more cell lines have been received from a RAIDs partner (Institut Curie, Paris) and are going to be analyzed: early results on single or combined drug sensitivity studies are available. Cell lines from Berlin (3) and from Manchester (4-6) may become available.
  • Preclinical mouse models for tumour micro-environmental studies have been developed and early mouse data on combining vaccine and radiotherapy are also now available.


Expected final results, potential impact and use

RAIDs aims to define a set of stratification criteria based on molecular profiling. Its results should give insight into dominant genomic and protein signalling pathway alterations, enabling the identification of prognostic and predictive biomarkers for standard or targeted therapy in CC. Immunological data from trials involving vaccine or direct viral targeting will provide information on immune rejection or tolerance of this virally transmitted disease.

The RAIDs consortium aims

  • to provide a safer and more efficient therapy for the individual patient;

  • to raise awareness in countries with lesser screening practices;

  • to improve the quality of life for women with cancer via:
    a) the acquisition of defined molecular data for better treatment decisions,
    b) targeted pilot trials directed at specific alterations and
    c) the continuous evaluation of standards of care by comparing standards and outcome in all the RAIDs centres in concertation with other (EORTC and ENGOT) centres and international societies [ESGO (European society for gynaecological oncology) and IGCS (International gynae cancer society)] who may wish to join this initiative in Europe.