Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome

Suzy Scholl, Marina Popovic, Anne de la Rochefordiere, Elodie Girard, Sylvain Dureau, Aljosa Mandic, Katarina Koprivsek, Nina Samet, Marius Craina, Madalin Margan, Sanne Samuels, Henry Zijlmans, Gemma Kenter, Peter Hillemanns, Sorin Dema, Alis Dema, Goran Malenkovic, Branislav Djuran, Anne Floquet, Delphine Garbay & 34 others Frédéric Guyon, Pierre Emmanuel Colombo, Michel Fabbro, Christine Kerr, Charlotte Ngo, Fabrice Lecuru, Eleonor Rivin del Campo, Charles Coutant, Frédéric Marchal, Nathalie Mesgouez-Nebout, Virginie Fourchotte, Jean Guillaume Feron, Philippe Morice, Eric Deutsch, Pauline Wimberger, Jean-Marc Classe, Noreen Gleeson, Heiko von der Leyen, Mathieu Minsat, Coraline Dubot, Pierre Gestraud, Attila Kereszt, Istvan Nagy, Balazs Balint, Els Berns, Ekaterina Jordanova, Nicolas de Saint-Jorre, Alexia Savignoni, Nicolas Servant, Philippe Hupe, Leanne de Koning, Pierre Fumoleau, Roman Rouzier, Maud Kamal

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: 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.
Original languageEnglish
JournalEBioMedicine
DOIs
Publication statusPublished - 2019

Cite this

Scholl, Suzy ; Popovic, Marina ; de la Rochefordiere, Anne ; Girard, Elodie ; Dureau, Sylvain ; Mandic, Aljosa ; Koprivsek, Katarina ; Samet, Nina ; Craina, Marius ; Margan, Madalin ; Samuels, Sanne ; Zijlmans, Henry ; Kenter, Gemma ; Hillemanns, Peter ; Dema, Sorin ; Dema, Alis ; Malenkovic, Goran ; Djuran, Branislav ; Floquet, Anne ; Garbay, Delphine ; Guyon, Frédéric ; Colombo, Pierre Emmanuel ; Fabbro, Michel ; Kerr, Christine ; Ngo, Charlotte ; Lecuru, Fabrice ; Campo, Eleonor Rivin del ; Coutant, Charles ; Marchal, Frédéric ; Mesgouez-Nebout, Nathalie ; Fourchotte, Virginie ; Feron, Jean Guillaume ; Morice, Philippe ; Deutsch, Eric ; Wimberger, Pauline ; Classe, Jean-Marc ; Gleeson, Noreen ; von der Leyen, Heiko ; Minsat, Mathieu ; Dubot, Coraline ; Gestraud, Pierre ; Kereszt, Attila ; Nagy, Istvan ; Balint, Balazs ; Berns, Els ; Jordanova, Ekaterina ; Saint-Jorre, Nicolas de ; Savignoni, Alexia ; Servant, Nicolas ; Hupe, Philippe ; de Koning, Leanne ; Fumoleau, Pierre ; Rouzier, Roman ; Kamal, Maud. / Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome. In: EBioMedicine. 2019.
@article{6d3899de55104a93a645fa755322c2d8,
title = "Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome",
abstract = "Background: 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.",
author = "Suzy Scholl and Marina Popovic and {de la Rochefordiere}, Anne and Elodie Girard and Sylvain Dureau and Aljosa Mandic and Katarina Koprivsek and Nina Samet and Marius Craina and Madalin Margan and Sanne Samuels and Henry Zijlmans and Gemma Kenter and Peter Hillemanns and Sorin Dema and Alis Dema and Goran Malenkovic and Branislav Djuran and Anne Floquet and Delphine Garbay and Fr{\'e}d{\'e}ric Guyon and Colombo, {Pierre Emmanuel} and Michel Fabbro and Christine Kerr and Charlotte Ngo and Fabrice Lecuru and Campo, {Eleonor Rivin del} and Charles Coutant and Fr{\'e}d{\'e}ric Marchal and Nathalie Mesgouez-Nebout and Virginie Fourchotte and Feron, {Jean Guillaume} and Philippe Morice and Eric Deutsch and Pauline Wimberger and Jean-Marc Classe and Noreen Gleeson and {von der Leyen}, Heiko and Mathieu Minsat and Coraline Dubot and Pierre Gestraud and Attila Kereszt and Istvan Nagy and Balazs Balint and Els Berns and Ekaterina Jordanova and Saint-Jorre, {Nicolas de} and Alexia Savignoni and Nicolas Servant and Philippe Hupe and {de Koning}, Leanne and Pierre Fumoleau and Roman Rouzier and Maud Kamal",
year = "2019",
doi = "10.1016/j.ebiom.2019.03.069",
language = "English",
journal = "EBioMedicine",
issn = "2352-3964",
publisher = "Elsevier BV",

}

Scholl, S, Popovic, M, de la Rochefordiere, A, Girard, E, Dureau, S, Mandic, A, Koprivsek, K, Samet, N, Craina, M, Margan, M, Samuels, S, Zijlmans, H, Kenter, G, Hillemanns, P, Dema, S, Dema, A, Malenkovic, G, Djuran, B, Floquet, A, Garbay, D, Guyon, F, Colombo, PE, Fabbro, M, Kerr, C, Ngo, C, Lecuru, F, Campo, ERD, Coutant, C, Marchal, F, Mesgouez-Nebout, N, Fourchotte, V, Feron, JG, Morice, P, Deutsch, E, Wimberger, P, Classe, J-M, Gleeson, N, von der Leyen, H, Minsat, M, Dubot, C, Gestraud, P, Kereszt, A, Nagy, I, Balint, B, Berns, E, Jordanova, E, Saint-Jorre, ND, Savignoni, A, Servant, N, Hupe, P, de Koning, L, Fumoleau, P, Rouzier, R & Kamal, M 2019, 'Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome' EBioMedicine. https://doi.org/10.1016/j.ebiom.2019.03.069

Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome. / Scholl, Suzy; Popovic, Marina; de la Rochefordiere, Anne; Girard, Elodie; Dureau, Sylvain; Mandic, Aljosa; Koprivsek, Katarina; Samet, Nina; Craina, Marius; Margan, Madalin; Samuels, Sanne; Zijlmans, Henry; Kenter, Gemma; Hillemanns, Peter; Dema, Sorin; Dema, Alis; Malenkovic, Goran; Djuran, Branislav; Floquet, Anne; Garbay, Delphine; Guyon, Frédéric; Colombo, Pierre Emmanuel; Fabbro, Michel; Kerr, Christine; Ngo, Charlotte; Lecuru, Fabrice; Campo, Eleonor Rivin del; Coutant, Charles; Marchal, Frédéric; Mesgouez-Nebout, Nathalie; Fourchotte, Virginie; Feron, Jean Guillaume; Morice, Philippe; Deutsch, Eric; Wimberger, Pauline; Classe, Jean-Marc; Gleeson, Noreen; von der Leyen, Heiko; Minsat, Mathieu; Dubot, Coraline; Gestraud, Pierre; Kereszt, Attila; Nagy, Istvan; Balint, Balazs; Berns, Els; Jordanova, Ekaterina; Saint-Jorre, Nicolas de; Savignoni, Alexia; Servant, Nicolas; Hupe, Philippe; de Koning, Leanne; Fumoleau, Pierre; Rouzier, Roman; Kamal, Maud.

In: EBioMedicine, 2019.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Clinical and genetic landscape of treatment naive cervical cancer: Alterations in PIK3CA and in epigenetic modulators associated with sub-optimal outcome

AU - Scholl, Suzy

AU - Popovic, Marina

AU - de la Rochefordiere, Anne

AU - Girard, Elodie

AU - Dureau, Sylvain

AU - Mandic, Aljosa

AU - Koprivsek, Katarina

AU - Samet, Nina

AU - Craina, Marius

AU - Margan, Madalin

AU - Samuels, Sanne

AU - Zijlmans, Henry

AU - Kenter, Gemma

AU - Hillemanns, Peter

AU - Dema, Sorin

AU - Dema, Alis

AU - Malenkovic, Goran

AU - Djuran, Branislav

AU - Floquet, Anne

AU - Garbay, Delphine

AU - Guyon, Frédéric

AU - Colombo, Pierre Emmanuel

AU - Fabbro, Michel

AU - Kerr, Christine

AU - Ngo, Charlotte

AU - Lecuru, Fabrice

AU - Campo, Eleonor Rivin del

AU - Coutant, Charles

AU - Marchal, Frédéric

AU - Mesgouez-Nebout, Nathalie

AU - Fourchotte, Virginie

AU - Feron, Jean Guillaume

AU - Morice, Philippe

AU - Deutsch, Eric

AU - Wimberger, Pauline

AU - Classe, Jean-Marc

AU - Gleeson, Noreen

AU - von der Leyen, Heiko

AU - Minsat, Mathieu

AU - Dubot, Coraline

AU - Gestraud, Pierre

AU - Kereszt, Attila

AU - Nagy, Istvan

AU - Balint, Balazs

AU - Berns, Els

AU - Jordanova, Ekaterina

AU - Saint-Jorre, Nicolas de

AU - Savignoni, Alexia

AU - Servant, Nicolas

AU - Hupe, Philippe

AU - de Koning, Leanne

AU - Fumoleau, Pierre

AU - Rouzier, Roman

AU - Kamal, Maud

PY - 2019

Y1 - 2019

N2 - Background: 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.

AB - Background: 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.

UR - https://www.scopus.com/inward/record.uri?partnerID=HzOxMe3b&scp=85063719850&origin=inward

UR - https://www.ncbi.nlm.nih.gov/pubmed/30952619

U2 - 10.1016/j.ebiom.2019.03.069

DO - 10.1016/j.ebiom.2019.03.069

M3 - Article

JO - EBioMedicine

JF - EBioMedicine

SN - 2352-3964

ER -