Abstract 434: Rational molecular assessment and innovative drug selection (RAIDs): exome data from cervical cancer
Authors: Scholl Suzy , Kamal Maud , Berns Els , Balint Balzs , Kereszt Attila , de Koning Leanne , Jeannot Emmanuelle , Luscap-rondof Windy , Sibut Vonick , Hupe Philippe , Kenter Gemma , Samuels Sanne , Jordanova Katja , Blanchet Sandrine , Lafanachere Laurence , Billaud Marc ,   RAIDs consortium
Published: July 2016

Abstract
Background Recent retrospective data1,2 identified major molecular alterations in cervical cancer (CC), but so far there has been no prospective assessment on patient outcome using a complete molecular profiling with quality control evaluation of treatment. The Cetuxicol (phase 2) clinical trial showed that the addition of Cetuximab over a 6 week period, did not improve DFS. PI3K pathway mutations in the tumor in the Cetuximab treatment arm led to a worse DFS3. 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.
Methodology RAIDs (http://www.raids-fp7.eu) is a multidisciplinary co-operation between academic clinical centers, SMEs and translational research platforms in seven European countries. It includes: 1) a cognitive cohort study (BioRAIDs)4, one of the first prospective trials intended to define patient stratification for targeted therapies, 2) a targeted clinical trial using an HPV directed vaccine and 3) preclinical studies aiming at assessing new treatment strategies. Molecular analysis on quality controlled tumor and sera samples from 500 patients enrolled in BioRAIDs combine Next Generation Sequencing at SeqOmics (Hungary), PIK3CA mutations detection in circulating tumor (ct) DNA at ERASMUS (The Netherlands), Reverse Phase Protein array and HPV insertion sites analyses at Institut Curie (France). Bioinformatics pipelines to detect somatic mutations and clustering methods were developed in order to stratify the patients into different subtypes. Following quality control, the pharmacological profiling of a panel of 20 CC cell lines using a panel of drugs which may potentially synergize with “standard treatment” has been completed. Drugs were chosen so as to interfere with different signaling pathways.
Results Molecular profiles including exome sequencing and ctDNA analyses on 48 quality controlled samples from the BioRAIDs patients and 20 CC cell lines will be presented. Preliminary results on HPV insertion sites in tumor and serum will be reported. Somatic and DNA copy number alterations from exome sequencing profiles confirm PI3K pathway mutations to be a dominant feature in CC. Stratifications of patients’ tumors based on their mutation profiles show that some cell lines cluster similarly to patients’ tumors, suggesting that they will be helpful for the prediction of response to drugs for patients within the same cluster.
Conclusions The identification of predictive tumor/blood based biomarkers will permit the definition of new strategies for precision medicine in CC. A bioinformatics analysis which will assess drug responsiveness in CC cell lines in relation to specific genomic alterations is ongoing. Its results should permit to select treatments according to genetic “constellations” of the tumors.
Citation Format: Suzy Scholl, Maud Kamal, Els Berns, Balzs Balint, Attila Kereszt, Leanne de Koning, Emmanuelle Jeannot, Windy Luscap-rondof, Vonick Sibut, Philippe Hupe, Gemma Kenter, Sanne Samuels, Katja Jordanova, Sandrine Blanchet, Laurence Lafanachere, Marc Billaud, RAIDs consortium. Rational molecular assessment and innovative drug selection (RAIDs): exome data from cervical cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 434.