Publishable Summary - M24 - November 2014

Project context and objectives

Cervical cancer (CC) is the second most common malignancy in women worldwide. While epidemiologists at the recent IGCS meeting in Melbourne (Nov 2014) believe that HPV could be eradicated if all the women were screened, the reality is that regular screening in all women cannot be inforced in highly endemic areas (India) where 84% of women are not aware of screening.


Although CC is a single diagnostic entity and infection of high-risk HPV is recognized as an important initiating event in tumorigenesis, CC exhibits differences in clinical behaviour. Stratification of CC into subclasses for progression and response to targeted 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. Homologous recombination inhibitors start being investigated. There have been recent publications (Ojesina, 2014; Wright, 2013) on high resolution genetic investigations in CC. So far, there has been no prospective assessment on patient outcome based on whole genome/exome sequencing or protein profiling of their tumors together with 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; accepted for publication in Clin Cancer Res).


• We are lacking prognostic and predictive biomarkers for CC treatment 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 in association with standard therapy.
In addition, high throughput screening techniques are performed in CC cell lines to identify new molecules of relevance for CC or CC microenvironment targeting. These molecules are to 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 in cooperation within a network of leading European centres in gynaecologic oncology: EORTC/ENGOT or CCRN (cervical cancer research network. CCRN has been created at the international GC intergroup by Prof Henry Kitchener from Manchester (UK) with the objective to have academic based trials originating from single centres and involving countries with lesser developed structures for screening and treatment of cervical cancer.


Work performed and main results achieved

RAIDs started October 1st, 2012. Consortium members are from 7 European countries (France, Germany, the Netherlands, Serbia, Moldova, Romania and Hungary). The consortium voted the recent integration of a new clinical operations platform, HCTC from Hannover, as a partner with the mission to coordinate the BioRAIDs trial in Germany, Moldova and Romania.


Ethical and regulatory approval of the BioRAIDs (biobanking trial) has now been achieved in all countries. While the first BioRAIDs clinical centre opened in Paris end of July 2013 and while the majority of French centres are today enrolling patients, the first patient inclusions have now started in Serbia, Germany and the Netherlands in November 2014.

Results on quality control aspects
• Teaching and contouring sessions for radiotherapy have already been presented in conferences. 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.).
• Quality control for pathology (percent of tumour cells in biopsy sample and of serum samples) were achieved conjointly by ERASMUS, NKI and SeqOmics.
• Quality control for NMR imaging is in the process of being set up in Serbia.


Ethical and regulatory approval (after submitting revised protocol) of the phase I DNA vaccine (HPV targeted therapy) trial sponsored by NKI in the Netherlands has been achieved
 6 of the 12 planned patients have been accrued within 3 months


The planned trial using Cidofovir (an antiviral reagent) to be sponsored by partner IGR had to be cancelled due to the unavailability of the product by Gilead (pharma) and failing to supply a generic version of Cidofovir from other suppliers.


Contacts have been made with leaders of the EMBRACe platform by ESGO (European society for gynaecological cancer) as well as with the lead from ECCA (European cervical cancer association). ECCA is involved mostly in cancer prevention while RAIDs and ESGO are involved predominantly with treatment. A link to RAIDs has already been established on the most popular Dutch platform for patients (

During the 24 months steering committee meeting a ‘patient advocacy’ workshop was conducted. The clinicians agreed to take turns in replying to the patients’ questions in a drop box that will soon be available on the RAIDs website.
Existing patient information leaflets from participating centres will be inserted into the RAIDs public website following translation into all the languages in the RAIDs consortium.


SCIENTIFIC WORK achieved during the first 24 months
• Exome sequencing on the first tumour samples started at SeqOmics end of October 2014.
• Exome sequencing and drug screening of 23 CC cell lines is finalized and analyses are ongoing. Correlations linking molecular alterations to sensibility/resistance to certain drugs or drug combinations are expected.
• Preclinical mouse models for tumour micro-environmental studies have been developed and published in journals with a high impact factor and early mouse data on combining vaccine and radiotherapy are published.


Expected final results, potential impact and use

RAIDs aims to define a set of stratification criteria based on molecular profiling. Its results will 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 +/- checkpoint inhibition will provide information on predisposing conditions for 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 as well as targeted vaccine trials directed against the HPV
 c) the continuous evaluation of standards of care by comparing standards and outcome in all the RAIDs centres
• to disseminate information on innovative practices in concertation with the help of other international structures, be the clinical trial orientated [EORTC (European Oranisation for Research and Treatment of Cancer) and ENGOT (European Network for Gyneacological Oncology Trials)] centres or international societies such as [ESGO (European Society for Gynaecological Oncology), ESMO (European Society for Medical Oncology) and IGCS (International Gynaecological Cancer Society)].
• to develop new tools and ideas on future treatments using drug combinations which may be exploited and create economic wealth.