title: High EGFR protein expression and exon 9 PIK3CA mutations are independent prognostic factors in triple negative breast cancers.
abstract: BACKGROUND
  Triple negative breast cancers (TNBC) are a more aggressive subset of breast cancer. A better understanding of its biology could allow the rational development of targeted therapies.
  
  
  METHODS
  We extensively analyzed the EGFR/PI3K/PTEN axis in a large, homogeneous population of TNBC to help defining the putative role of anti-EGFR and -PI3K targeted therapies in this setting. EGFR gene amplification, EGFR protein expression, PIK3CA and PTEN gene alterations (two members of EGFR downstream pathways) and their clinicopathological and prognostic implications were analyzed in 204 TNBC samples from European patients.
  
  
  RESULTS
  EGFR amplification was detected in 18 of the 204 TNBC specimens (8.9 %) and was significantly associated with higher EGFR protein levels. Fourteen PIK3CA mutations were identified in exon 9 (6.7 %), and 17 in exon 20 (8.3 %). PIK3CA mutations, especially in exon 9, were significantly associated with grade I-II tumors. PTEN deletions were detected in 43 samples (21.50 %) and were significantly associated with grade III tumors (p < 0.001). Univariate analysis showed a significant association between relapse-free survival (RFS), T and N stage and exon 9 PIK3CA mutations. Overall survival was significantly associated with T stage, N stage and adjuvant chemotherapy, which was administered to 70.3 % of patients. In multivariate analyses, T stage, N stage, presence of exon 9 PIK3CA mutations and high EGFR protein level were independent poor prognostic factors for RFS, while adjuvant chemotherapy was associated with a better outcome.
  
  
  CONCLUSIONS
  High EGFR protein expression and exon 9 PIK3CA activating mutations are independent prognostic factors in TNBC. The efficacy of anti-PI3K targeted therapies needs to be evaluated in this setting.
authors.affiliation: Department of Medical Oncology, Montpellier Cancer Institute Val d'Aurelle, 208, rue des Apothicaires, Montpellier, F-34298, France. william.jacot@icm.unicancer.fr.|Translationnal Research Unit, Montpellier Cancer Institute Val d'Aurelle, 208, rue des Apothicaires, Montpellier, F-34298, France. william.jacot@icm.unicancer.fr.
authors.forename: William
authors.initials: W
authors.lastname: Jacot
authors.affiliation: Biostatistical Research Unit, Montpellier Cancer Institute Val d'Aurelle, 208, rue des Apothicaires, Montpellier, F-34298, France. Caroline.Mollevi@icm.unicancer.fr.
authors.forename: Caroline
authors.initials: C
authors.lastname: Mollevi
authors.affiliation: Department of Oncobiology, Assistance Publique - Hôpitaux de Marseille, Boulevard Pierre Dramard, Marseille, F-13916, France. frederic.fina@ap-hm.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Fina
authors.affiliation: Translationnal Research Unit, Montpellier Cancer Institute Val d'Aurelle, 208, rue des Apothicaires, Montpellier, F-34298, France. evelyne.crapez@icm.unicancer.fr.
authors.forename: Evelyne
authors.initials: E
authors.lastname: Lopez-Crapez
authors.affiliation: Department of Oncobiology, Assistance Publique - Hôpitaux de Marseille, Boulevard Pierre Dramard, Marseille, F-13916, France. martin@chauvet.org.
authors.forename: Pierre-Marie
authors.initials: PM
authors.lastname: Martin
authors.affiliation: Department of Surgical Oncology, Montpellier Cancer Institute Val d'Aurelle, 208, rue des Apothicaires, Montpellier, F-34298, France. Pierre-Emmanuel.Colombo@icm.unicancer.fr.
authors.forename: Pierre-Emmanuel
authors.initials: PE
authors.lastname: Colombo
authors.affiliation: Department of Pathology, Montpellier Cancer Institute Val d'Aurelle, 208, rue des Apothicaires, Montpellier, F-34298, France. frederic.bibeau@icm.unicancer.fr.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Bibeau
authors.affiliation: Department of Medical Oncology, Montpellier Cancer Institute Val d'Aurelle, 208, rue des Apothicaires, Montpellier, F-34298, France. Gilles.Romieu@icm.unicancer.fr.
authors.forename: Gilles
authors.initials: G
authors.lastname: Romieu
authors.affiliation: Department of Oncogenetics, Montpellier Cancer Institute Val d'Aurelle, 208, rue des Apothicaires, Montpellier, F-34298, France. pierre-jean.lamy@icm.unicancer.fr.|Biological Ressources Center, Montpellier Cancer Institute Val d'Aurelle, 208, rue des Apothicaires, F-34298, Montpellier, France. pierre-jean.lamy@icm.unicancer.fr.
authors.forename: Pierre-Jean
authors.initials: PJ
authors.lastname: Lamy
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D058534:Class I Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism*; D005091:Exons; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D051059:PTEN Phosphohydrolase / Q000235:genetics*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics*; D011379:Prognosis; D064726:Triple Negative Breast Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*
chemical_list: D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human