Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome.
de la Rochefordiere, Anne
Colombo, Pierre Emmanuel
Campo, Eleonor Rivin Del
Feron, Jean Guillaume
von der Leyen, Heiko
Saint-Jorre, Nicolas de
de Koning, Leanne
Reverse phase protein array
Whole exome sequencing
MetadataShow full item record
AbstractBackground: There is a lack of information as to which molecular processes, present at diagnosis, favor tumour escape from standard-of-care treatments in cervical cancer (CC). RAIDs consortium (www.raids-fp7.eu), conducted a prospectively monitored trial, [BioRAIDs (NCT02428842)] with the objectives to generate high quality samples and molecular assessments to stratify patient populations and to identify molecular patterns associated with poor outcome. Methods: Between 2013 and 2017, RAIDs collected a prospective CC sample and clinical dataset involving 419 participant patients from 18 centers in seven EU countries. Next Generation Sequencing has so far been carried out on a total of 182 samples from 377 evaluable (48%) patients, allowing to define dominant genetic alterations. Reverse phase protein expression arrays (RPPA) was applied to group patients into clusters. Activation of key genetic pathways and protein expression signatures were tested for associations with outcome. Findings: At a median follow up (FU) of 22 months, progression-free survival rates of this FIGO stage IB1-IV population, treated predominantly (87%) by chemoradiation, were65•4% [CI95%: 60•2-71.1]. Dominant oncogenic alterations were seen in PIK3CA (40%), while dominant suppressor gene alterations were seen in KMT2D (15%) and KMT2C (16%). Cumulative frequency of loss-of-function (LOF) mutations in any epigenetic modulator gene alteration was 47% and it was associated with PIK3CA gene alterations in 32%. Patients with tumours harboring alterations in both pathways had a significantly poorer PFS. A new finding was the detection of a high frequency of gains of TLR4 gene amplifications (10%), as well as amplifications, mutations, and non-frame-shift deletions of Androgen receptor (AR) gene in 7% of patients. Finally, RPPA protein expression analysis defined three expression clusters. Interpretation: Our data suggests that patient population may be stratified into four different treatment strategies based on molecular markers at the outset. FUND: European Union's Seventh Program grant agreement No 304810.
- Genetic markers and phosphoprotein forms of beta-catenin pβ-Cat552 and pβ-Cat675 are prognostic biomarkers of cervical cancer.
- Authors: Scholl SM, Beal J, de Koning L, Girard E, Popovic M, de la Rochefordière A, Lecuru F, Fourchotte V, Ngo C, Floquet A, Berns EM, Kenter G, Gestraud P, von der Leyen H, Lecerf C, Puard V, Roman SR, Latouche A, Kereszt A, Balint B, Rouzier R, Kamal M
- Issue date: 2020 Nov
- Whole-exome sequencing of cervical carcinomas identifies activating ERBB2 and PIK3CA mutations as targets for combination therapy.
- Authors: Zammataro L, Lopez S, Bellone S, Pettinella F, Bonazzoli E, Perrone E, Zhao S, Menderes G, Altwerger G, Han C, Zeybek B, Bianchi A, Manzano A, Manara P, Cocco E, Buza N, Hui P, Wong S, Ravaggi A, Bignotti E, Romani C, Todeschini P, Zanotti L, Odicino F, Pecorelli S, Donzelli C, Ardighieri L, Angioli R, Raspagliesi F, Scambia G, Choi J, Dong W, Bilguvar K, Alexandrov LB, Silasi DA, Huang GS, Ratner E, Azodi M, Schwartz PE, Pirazzoli V, Stiegler AL, Boggon TJ, Lifton RP, Schlessinger J, Santin AD
- Issue date: 2019 Nov 5
- PIK3CA mutation and CNV status and post-chemoradiotherapy survival in patients with cervical cancer.
- Authors: Martell K, McIntyre JB, Kornaga EN, Chan AMY, Phan T, Köbel M, Enwere EK, Dean ML, Ghatage P, Lees-Miller SP, Doll CM
- Issue date: 2020 Sep
- From prospective biobanking to precision medicine: BIO-RAIDs - an EU study protocol in cervical cancer.
- Authors: Ngo C, Samuels S, Bagrintseva K, Slocker A, Hupé P, Kenter G, Popovic M, Samet N, Tresca P, von der Leyen H, Deutsch E, Rouzier R, Belin L, Kamal M, Scholl S, RAIDs consortium http://www.raids-fp7.eu/.
- Issue date: 2015 Nov 4
- Phase II trial of AKT inhibitor MK-2206 in patients with advanced breast cancer who have tumors with PIK3CA or AKT mutations, and/or PTEN loss/PTEN mutation.
- Authors: Xing Y, Lin NU, Maurer MA, Chen H, Mahvash A, Sahin A, Akcakanat A, Li Y, Abramson V, Litton J, Chavez-MacGregor M, Valero V, Piha-Paul SA, Hong D, Do KA, Tarco E, Riall D, Eterovic AK, Wulf GM, Cantley LC, Mills GB, Doyle LA, Winer E, Hortobagyi GN, Gonzalez-Angulo AM, Meric-Bernstam F
- Issue date: 2019 Jul 5