PMID- 26004768 OWN - NLM STAT- MEDLINE DCOM- 20161006 LR - 20181202 IS - 1776-260X (Electronic) IS - 1776-2596 (Print) IS - 1776-2596 (Linking) VI - 10 IP - 4 DP - 2015 Dec TI - 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. PG - 583-96 LID - 10.1007/s11523-015-0369-6 [doi] AB - 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. FAU - Despierre, Evelyn AU - Despierre E AD - Gynecologic Oncology and Leuven Cancer Institute, and Department of Oncology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. evelyndespierre@gmail.com. FAU - Vergote, Ignace AU - Vergote I AD - Gynecologic Oncology and Leuven Cancer Institute, and Department of Oncology, KU Leuven, University Hospitals Leuven, Herestraat 49, 3000, Leuven, Belgium. FAU - Anderson, Ryan AU - Anderson R AD - University of Colorado Cancer Center, Aurora, Colorado, USA. FAU - Coens, Corneel AU - Coens C AD - EORTC Headquarters, Brussels, Belgium. FAU - Katsaros, Dionyssios AU - Katsaros D AD - Azienda Ospedaliera, Presidio Santa Anna, SCDO 3 Ginecologia Oncologica, Universita di Torino, Turin, Italy. FAU - Hirsch, Fred R AU - Hirsch FR AD - University of Colorado Cancer Center, Aurora, Colorado, USA. FAU - Boeckx, Bram AU - Boeckx B AD - Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium. AD - Vesalius Research Center (VRC), VIB, Leuven, Belgium. FAU - Varella-Garcia, Marileila AU - Varella-Garcia M AD - University of Colorado Cancer Center, Aurora, Colorado, USA. FAU - Ferrero, Annamaria AU - Ferrero A AD - Academic Division of Gynecological Oncology, Mauriziano Hospital, Turin, Italy. FAU - Ray-Coquard, Isabelle AU - Ray-Coquard I AD - Departement d'Oncologie Medicale Adulte, Centre Leon Berard, Lyon, France. FAU - Berns, Els M J J AU - Berns EM AD - Erasmus MC Cancer Institute, Rotterdam, The Netherlands. FAU - Casado, Antonio AU - Casado A AD - Hospital Universitario Clinico San Carlos, Servicio de Oncologia Medica, Madrid, Spain. FAU - Lambrechts, Diether AU - Lambrechts D AD - Laboratory for Translational Genetics, Department of Oncology, KU Leuven, Leuven, Belgium. AD - Vesalius Research Center (VRC), VIB, Leuven, Belgium. FAU - Jimeno, Antonio AU - Jimeno A AD - University of Colorado Cancer Center, Aurora, Colorado, USA. CN - European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group (EORTC-GCG) CN - Groupe d'Investigateurs Nationaux pour les Etudes des Cancers de l'Ovaire (GINECO) CN - Austrian Arbeitsgemeinschaft fur Gynakologische Onkologie (A-AGO) CN - National Cancer Research Institute (NCRI) CN - Australia New Zealand Gynaecological Oncology Group (ANZGOG) CN - Mario Negri Gynecologic Oncology group (MaNGO) LA - eng GR - P30 CA046934/CA/NCI NIH HHS/United States GR - P30CA046934/CA/NCI NIH HHS/United States PT - Clinical Trial, Phase III PT - Journal Article PT - Randomized Controlled Trial PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - France TA - Target Oncol JT - Targeted oncology JID - 101270595 RN - 0 (Biomarkers, Tumor) RN - 0 (Organoplatinum Compounds) RN - 0 (Protein Kinase Inhibitors) RN - DA87705X9K (Erlotinib Hydrochloride) RN - EC 2.7.- (Protein Kinases) RN - EC 2.7.10.1 (EGFR protein, human) RN - EC 2.7.10.1 (ErbB Receptors) SB - IM EIN - Target Oncol. 2016 Jun;11(3):429. PMID: 27056749 MH - Adult MH - Aged MH - Aged, 80 and over MH - Antineoplastic Combined Chemotherapy Protocols/therapeutic use MH - Biomarkers, Tumor/genetics/metabolism MH - Disease Progression MH - Disease-Free Survival MH - ErbB Receptors/genetics/*metabolism MH - Erlotinib Hydrochloride/*therapeutic use MH - Female MH - Humans MH - Middle Aged MH - Mutation MH - Organoplatinum Compounds/administration & dosage MH - Ovarian Neoplasms/*drug therapy/enzymology/genetics MH - Protein Kinase Inhibitors/*therapeutic use MH - Protein Kinases/genetics/metabolism PMC - PMC4661131 MID - NIHMS730161 FIR - Abraham, C IR - Abraham C FIR - Chesnay, Le IR - Chesnay L FIR - Amant, F IR - Amant F FIR - Anderson, R IR - Anderson R FIR - Azzedine, A IR - Azzedine A FIR - Benedetto, C IR - Benedetto C FIR - Bertelli, G IR - Bertelli G FIR - Berteloot, P IR - Berteloot P FIR - Berton-Rigaud, D IR - Berton-Rigaud D FIR - Biglia, N IR - Biglia N FIR - Bonichon-Lamichhane, N IR - Bonichon-Lamichhane N FIR - Bougnoux, P IR - Bougnoux P FIR - Bourbouloux, E IR - Bourbouloux E FIR - Bourcier, C IR - Bourcier C FIR - Buck, M IR - Buck M FIR - Campone, M IR - Campone M FIR - Canuto, E M IR - Canuto EM FIR - Casado Herraez, A IR - Casado Herraez A FIR - Cauvin, I IR - Cauvin I FIR - Chauvenet, L IR - Chauvenet L FIR - Chevalier-Place, A IR - Chevalier-Place A FIR - Cottu, P -H IR - Cottu P- FIR - Cretin, J IR - Cretin J FIR - Cumin, I IR - Cumin I FIR - Cure, H IR - Cure H FIR - Dalenc, F IR - Dalenc F FIR - Danese, S IR - Danese S FIR - Davis, A IR - Davis A FIR - Debruyne, P IR - Debruyne P FIR - Delplanque, G IR - Delplanque G FIR - Delva, R IR - Delva R FIR - D'Hondt, V IR - D'Hondt V FIR - Dramais, D IR - Dramais D FIR - Durando, X IR - Durando X FIR - El Kouri, C IR - El Kouri C FIR - Esteban, C IR - Esteban C FIR - Fabbro, M IR - Fabbro M FIR - Falandry, C IR - Falandry C FIR - Filleul, B IR - Filleul B FIR - Floquet, A IR - Floquet A FIR - Fumoleau, P IR - Fumoleau P FIR - Garcia-Varella, M IR - Garcia-Varella M FIR - Garnier, C IR - Garnier C FIR - Gilby, E IR - Gilby E FIR - Gladieff, L IR - Gladieff L FIR - Goffin, F IR - Goffin F FIR - Gouttebel, M -C IR - Gouttebel M- FIR - Green, J A IR - Green JA FIR - Guastalla, J -P IR - Guastalla J- FIR - Hardy-Bessard, A -C IR - Hardy-Bessard A- FIR - Hirsch, F IR - Hirsch F FIR - Hughes, A IR - Hughes A FIR - Jaubert, D IR - Jaubert D FIR - Kaminsky, M -C IR - Kaminsky M- FIR - Katsaros, D IR - Katsaros D FIR - Largillier, R IR - Largillier R FIR - Lebrun- Jezekova, D IR - Lebrun- Jezekova D FIR - Leduc, B IR - Leduc B FIR - Leheurteur, M IR - Leheurteur M FIR - Lesoin, A IR - Lesoin A FIR - Leunen, K IR - Leunen K FIR - Levasseur, N IR - Levasseur N FIR - Leyronnas, C IR - Leyronnas C FIR - Llory, J -F IR - Llory J- FIR - Lortholary, A IR - Lortholary A FIR - Mayer, F IR - Mayer F FIR - Mayeur, D IR - Mayeur D FIR - Mendiola, C IR - Mendiola C FIR - Mignot, L IR - Mignot L FIR - Morgan, J IR - Morgan J FIR - Mouret-Reynier, M -A IR - Mouret-Reynier M- FIR - Neven, P IR - Neven P FIR - Petit, T IR - Petit T FIR - Picardo, E IR - Picardo E FIR - Plaza, J IR - Plaza J FIR - Pluvio-Coronado, M IR - Pluvio-Coronado M FIR - Priou, F IR - Priou F FIR - Pujade-Lauraine, E IR - Pujade-Lauraine E FIR - Coquard, I Ray IR - Coquard I FIR - Reed, N IR - Reed N FIR - Rigault de la Longrais, I IR - Rigault de la Longrais I FIR - Scholl, S IR - Scholl S FIR - Sillet-Bach, I IR - Sillet-Bach I FIR - Steer, C IR - Steer C FIR - Summers, J IR - Summers J FIR - Trillet-Lenoir, V IR - Trillet-Lenoir V FIR - Van Dam, P IR - Van Dam P FIR - Van Der Burg, M E L IR - Van Der Burg ME FIR - Vanlerenberghe, E IR - Vanlerenberghe E FIR - Vannetzel, J -M IR - Vannetzel J- FIR - Vergote, I IR - Vergote I FIR - Aragon, J A Vidart IR - Aragon JA FIR - Waters, J IR - Waters J FIR - Weber, B IR - Weber B FIR - Yazbek, G IR - Yazbek G FIR - Zola, P IR - Zola P EDAT- 2015/05/26 06:00 MHDA- 2016/10/08 06:00 PMCR- 2016/12/01 CRDT- 2015/05/26 06:00 PHST- 2015/05/26 06:00 [entrez] PHST- 2015/05/26 06:00 [pubmed] PHST- 2016/10/08 06:00 [medline] PHST- 2016/12/01 00:00 [pmc-release] AID - 10.1007/s11523-015-0369-6 [pii] AID - 10.1007/s11523-015-0369-6 [doi] PST - ppublish SO - Target Oncol. 2015 Dec;10(4):583-96. doi: 10.1007/s11523-015-0369-6.