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.
[en] [en] 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.
Disciplines :
Oncology
Author, co-author :
Despierre, Evelyn; Gynecologic Oncology and Leuven Cancer Institute, and Department of Oncology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. evelyndespierre@gmail.com
Vergote, Ignace; Gynecologic Oncology and Leuven Cancer Institute, and Department of Oncology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium
Anderson, Ryan; University of Colorado Cancer Center, Aurora, Colorado, USA
Katsaros, Dionyssios; Azienda Ospedaliera, Presidio Santa Anna, SCDO 3 Ginecologia Oncologica, Università di Torino, Turin, Italy
Hirsch, Fred R; University of Colorado Cancer Center, Aurora, Colorado, USA
Boeckx, Bram; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium ; Vesalius Research Center (VRC), VIB, Leuven, Belgium
Varella-Garcia, Marileila; University of Colorado Cancer Center, Aurora, Colorado, USA
Ray-Coquard, Isabelle; Département d'Oncologie Médicale Adulte, Centre Leon Bérard, Lyon, France
Berns, Els M J J; Erasmus MC Cancer Institute, Rotterdam, The Netherlands
Casado, Antonio; Hospital Universitario Clínico San Carlos, Servicio de Oncologia Medica, Madrid, Spain
Lambrechts, Diether; Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium ; Vesalius Research Center (VRC), VIB, Leuven, Belgium
Jimeno, Antonio; University of Colorado Cancer Center, Aurora, Colorado, USA
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)
Mario Negri Gynecologic Oncology group (MaNGO)
Goffin, Frédéric ; Centre Hospitalier Universitaire de Liège - CHU > > Service de gynécologie-obstétrique (CHR) ; Member of European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG),
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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