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Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy

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An Erratum to this article was published on 08 April 2016

Abstract

Background

In this work, we aimed to identify molecular epidermal growth factor receptor (EGFR) tissue biomarkers in patients with ovarian cancer who were treated within the phase III randomized European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) 55041 study comparing erlotinib with observation in patients with no evidence of disease progression after first-line platinum-based chemotherapy.

Methods

Somatic mutations in KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN were determined in 318 (38 %) and expression of EGFR, pAkt, pMAPK, E-cadherin and Vimentin, and EGFR and HER2 gene copy numbers in 218 (26 %) of a total of 835 randomized patients. Biomarker data were correlated with progression-free survival (PFS) and overall survival (OS).

Results

Only 28 mutations were observed among KRAS, BRAF, NRAS, PIK3CA, EGFR, and PTEN (in 7.5 % of patients), of which the most frequent were in KRAS and PIK3CA. EGFR mutations occurred in only three patients. When all mutations were pooled, patients with at least one mutation in KRAS, NRAS, BRAF, PIK3CA, or EGFR had longer PFS (33.1 versus 12.3 months; HR 0.57; 95 % CI 0.33 to 0.99; P = 0.042) compared to those with wild-type tumors. EGFR overexpression was detected in 93 of 218 patients (42.7 %), and 66 of 180 patients (36.7 %) had EGFR gene amplification or high levels of copy number gain. Fifty-eight of 128 patients had positive pMAPK expression (45.3 %), which was associated with inferior OS (38.9 versus 67.0 months; HR 1.81; 95 % CI 1.11 to 2.97; P = 0.016). Patients with positive EGFR fluorescence in situ hybridization (FISH) status had worse OS (46.1 months) than those with negative status (67.0 months; HR 1.56; 95 % CI 1.01 to 2.40; P = 0.044) and shorter PFS (9.6 versus 16.1 months; HR 1.57; 95 % CI 1.11 to 2.22; P = 0.010). None of the investigated biomarkers correlated with responsiveness to erlotinib.

Conclusions

In this phase III study, increased EGFR gene copy number was associated with worse OS and PFS in patients with ovarian cancer. It remains to be determined whether this association is purely prognostic or is also predictive.

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Acknowledgments

We thank all patients for their participation in the EORTC-GCG 55041 trial. In addition, the active commitment of the EORTC, the study coordinators, and investigators providing tumor tissue is gratefully acknowledged, as it enabled this translational study. We are grateful to Mrs. Katrien Drijkoningen and Mrs. Godelieve Verbist for their expert technical support. This publication was supported by the EORTC Charitable Trust and by an unrestricted educational grant from Roche. Evelyn Despierre was supported by a grant for the NOCI project “Pharmacogenomic and immunohistochemical evaluation of the EGFR pathway in ovarian cancer in patients treated with erlotinib: combined prognostic and predictive assessment on the EORTC 55041-study,” which was competitively selected during the EORTC Groups Annual Meeting in 2009. FISH analyses were supported in part by NCI grant CCSG P30 CA046934 to the University of Colorado Comprehensive Cancer Center.

We acknowledge all collaborators who actively contributed to this study, including C. Abraham (Hôpital André Mignot, Le Chesnay, France), F. Amant (University Hospital Leuven, Leuven, Belgium), R. Anderson (University of Colorado, Boulder, CO, USA), A. Azzedine (Centre Hospitalier, Avignon, France), C. Benedetto (University of Turin, Turin, Italy), G. Bertelli (Singelton Hospital, Swansea, UK), P. Berteloot (University Hospital Leuven, Leuven, Belgium), D. Berton-Rigaud (Centre René Gauducheau, Saint-Herblain, France), N. Biglia (University of Turin, Turin, Italy), N. Bonichon-Lamichhane (Clinique Tivoli, Bordeaux, France), P. Bougnoux (Centre Hospitalier Universitaire [CHU], Tours, France), E. Bourbouloux (Centre René Gauducheau, Saint-Herblain, France), C. Bourcier (Centre Hospitalier Départemental [CHD] Les Oudairies, La Roche-Sur-Yon, France), M. Buck (Sir Charles Gairdner Hospital, Nedlands, Australia), M. Campone (Centre René Gauducheau, Saint-Herblain, France), E.M. Canuto (University of Turin, Turin, Italy), A. Casado Herraez (Hospital Universitario San Carlos, Madrid, Spain), I. Cauvin (Centre Hospitalier, Chambéry, France), L. Chauvenet (Hôpital Hôtel-Dieu, Paris, France), A. Chevalier-Place (Centre Oscar Lambret, Lille, France), P.-H. Cottu (Institut Curie, Paris, France), J. Cretin (Clinique de Valdegour, Nîmes, France), I. Cumin (Centre Hospitalier de Bretagne Sud, Lorient, France), H. Curé (Institut Jean Godinot, Reims, France), F. Dalenc (Institut Claudius Régaud, Toulouse, France), S. Danese (University of Turin, Turin, Italy), A. Davis (The Canberra Hospital, Garran (woden), Australia), P. Debruyne (AZ St. Augustinus, Kortrijk, Belgium), G. Delplanque (Groupe Hospitalier Saint-Joseph, Paris, France), R. Delva (Centre Paul Papin, Angers, France), De Valk (Onze Lieve Vrouw Gasthuis, Amsterdam), V. D'Hondt (Hôpitaux Universitaires Jules Bordet), D. Dramais (Centre Hospitalier, Valence, France), X. Durando (Centre Jean Perrin, Clermont-Ferrand, France), C. El Kouri (Centre Catherine de Sienne, Nantes, France), C. Esteban (Hospital Virgen de la Salud, Toledo, Spain), M. Fabbro (Institut du Cancer de Montpellier Val d'Aurelle, Montpellier, France), C. Falandry (Centre Hospitalier Lyon Sud, Pierre-Bénite, France), B. Filleul (Hopital de Jolimont, Haine-Saint-Paul, Belgium), A. Floquet (Institut Bergonie, Bordeaux, France), P. Fumoleau (Centre Georges François Leclerc, Dijon, France), M. Garcia-Varella (University of Colorado, Boulder, CO, USA), C. Garnier (Groupe Hospitalier Mutualiste, Institut Daniel Hollard, Grenoble, France), E. Gilby (Royal United Hospital, Bath, UK), L. Gladieff (Centre Claudius Regaud, Toulouse, France), F. Goffin (Centre Hospitalier Regional de la Citadelle, Liège, Belgium), M.-C. Gouttebel (Centre Hospitalier, Valence, France), J.A. Green (Clatterbridge Cancer Centre NHS Foundation Trust, Bebington, Wirral, UK), J.-P. Guastalla (Centre Léon Bérard, Lyon, France), A.-C. Hardy-Bessard (Clinique Armoricaine de Radiologie, Saint-Brieuc, France), F. Hirsch (University of Colorado, Boulder, CO, USA), A. Hughes (Gateshead Hospitals, Queen Elizabeth Hospital, Gateshead, UK), D. Jaubert (Clinique Tivoli, Bordeaux, France), M.-C. Kaminsky (Centre Alexis Vautrin, Vandoeuvre-lès-Nancy, France), D. Katsaros (Clinica Universita, Torino, Italy), Frederic Kridelka (Centre Hospitalier Regional de la Citadelle, Liège, Belgium), R. Largillier (Centre Antoine Lacassagne, Nice, France), D. Lebrun-Jezekova (Institut Jean Godinot, Reims, France), B. Leduc (Centre Hospitalier, Brive-la-Gaillarde, France), M. Leheurteur (Centre Jean Perrin, Clermont-Ferrand, France), A. Lesoin (Centre Oscar Lambret, Lille, France), K. Leunen (University Hospital Leuven, Leuven, Belgium), N. Levasseur (Groupe Hospitalier Saint-Joseph, Paris, France), C. Leyronnas (Groupe Hospitalier Mutualiste, Institut Daniel Hollard, Grenoble, France), J.-F. Llory (Institut d'Oncologie Hartmann, Levallois Perret, France), A. Lortholary (Centre Catherine de Sienne, Nantes, France), F. Mayer (Centre Georges Francois Leclerc, Dijon, France), D. Mayeur (Hôpital André Mignot, Le Chesnay, France), C. Mendiola (Hospital Universitario 12 de Octubre, Madrid, Spain), L. Mignot (Institut Curie, Paris, France), J. Morgan (Ipswich Hospital NHS Trust, Ipswich, Suffolk, UK), M.-A. Mouret-Reynier (Centre Jean Perrin, Clermont-Ferrand, France), P. Neven (University Hospital Leuven, Leuven, Belgium), Paola Modaffari (Ospedale Mauriziano Umberto I, Torino, Italy),T. Petit (Centre Paul Strauss, Strasbourg, France),E. Picardo (University of Turin, Turin, Italy), J. Plaza (Centre Hospitalier Général, Montbelliard, France), M. Pluvio-Coronado (Universitario San Carlos Madrid, Madrid, Spain), F. Priou (CHD Les Oudairies, La Roche-Sur-Yon, France), E. Pujade-Lauraine (Hôpital Hôtel-Dieu, Paris, France), I. Ray Coquard (Centre Leon Berard, Lyon, France), N. Reed (NHS Greater Glasgow and Clyde Beatson West of Scotland Cancer Centre-Gartnavel General Hospital, Glasgow, UK), I. Rigault de la Longrais (University of Turin, Turin, Italy), S. Scholl (Institut Curie, Paris, France), I. Sillet-Bach (Centre Hospitalier, Brive-La-Gaillarde, France),C. Steer (Murray Valley Private Hospital, Wodonga, Australia), J. Summers (Mid Kent Oncology Centre, Maidstone, Kent, UK), V. Trillet-Lenoir (Centre Hospitalier Lyon Sud, Pierre-Bénite, France), P. Van Dam (AZ St. Augustinus, Wilrijk, Belgium), M.E.L. Van Der Burg (Erasmus Medical Center, Rotterdam, the Netherlands), E. Vanlerenberghe (Centre Oscar Lambret, Lille, France), J.-M. Vannetzel (Institut d'Oncologie Hartmann, Levallois Perret, France),I. Vergote (University Hospital Leuven, Leuven, Belgium), J.A. Vidart Aragon (Universitario San Carlos Madrid, Madrid, Spain), J. Waters (East Kent Hospitals University NHS Foundation Trust, Queen Elizabeth The Queen Mother Hospital, Margate, UK), B. Weber (Centre Alexis Vautrin, Vandoeuvre-Les-Nancy, France), G. Yazbek (Institut Jean Godinot, Reims, France), P. Zola (Ospedale Mauriziano Umberto I, Torino, Italy).

Conflict of Interest

Marileila Varella-Garcia is co-inventor on a patent held by the University of Colorado to use EGFR copy number as biomarker for selection of lung cancer patients for targeted therapy. Evelyn Despierre, Ignace Vergote, Ryan Anderson, Corneel Coens, Dionyssios Katsaros, Fred R. Hirsch, Bram Boeckx, Annamaria Ferrero, Isabelle Ray-Coquard, Els MJJ Berns, Antonio Casado, Diether Lambrechts, and Antonio Jimeno declare no conflict of interest.

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Authors and Affiliations

  1. Gynecologic Oncology and Leuven Cancer Institute, and Department of Oncology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium

    Evelyn Despierre & Ignace Vergote

  2. University of Colorado Cancer Center, Aurora, Colorado, USA

    Ryan Anderson, Fred R. Hirsch, Marileila Varella-Garcia & Antonio Jimeno

  3. EORTC Headquarters, Brussels, Belgium

    Corneel Coens

  4. Azienda Ospedaliera, Presidio Santa Anna, SCDO 3 Ginecologia Oncologica, Università di Torino, Turin, Italy

    Dionyssios Katsaros

  5. Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium

    Bram Boeckx & Diether Lambrechts

  6. Vesalius Research Center (VRC), VIB, Leuven, Belgium

    Bram Boeckx & Diether Lambrechts

  7. Academic Division of Gynecological Oncology, Mauriziano Hospital, Turin, Italy

    Annamaria Ferrero

  8. Département d’Oncologie Médicale Adulte, Centre Leon Bérard, Lyon, France

    Isabelle Ray-Coquard

  9. Erasmus MC Cancer Institute, Rotterdam, The Netherlands

    Els M. J. J. Berns

  10. Hospital Universitario Clínico San Carlos, Servicio de Oncologia Medica, Madrid, Spain

    Antonio Casado

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  1. Evelyn Despierre
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  2. Ignace Vergote
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  3. Ryan Anderson
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  8. Marileila Varella-Garcia
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  14. Antonio Jimeno
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Consortia

on behalf of the European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG), Groupe d’Investigateurs Nationaux pour les Etudes des Cancers de l’Ovaire (GINECO), Austrian Arbeitsgemeinschaft für Gynäkologische Onkologie (A-AGO), National Cancer Research Institute (NCRI), Australia New Zealand Gynaecological Oncology Group (ANZGOG), and the Mario Negri Gynecologic Oncology group (MaNGO)

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Correspondence to Evelyn Despierre.

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Despierre, E., Vergote, I., Anderson, R. et al. Epidermal Growth Factor Receptor (EGFR) Pathway Biomarkers in the Randomized Phase III Trial of Erlotinib Versus Observation in Ovarian Cancer Patients with No Evidence of Disease Progression after First-Line Platinum-Based Chemotherapy. Targ Oncol 10, 583–596 (2015). https://doi.org/10.1007/s11523-015-0369-6

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