title: TP53 mutations and protein immunopositivity may predict for poor outcome but also for trastuzumab benefit in patients with early breast cancer treated in the adjuvant setting.
abstract: BACKGROUND
  We investigated the impact of PIK3CA and TP53 mutations and p53 protein status on the outcome of patients who had been treated with adjuvant anthracycline-taxane chemotherapy within clinical trials in the pre- and post-trastuzumab era.
  
  
  RESULTS
  TP53 and PIK3CA mutations were found in 380 (21.5%) and 458 (25.9%) cases, respectively, including 104 (5.9%) co-mutated tumors; p53 immunopositivity was observed in 848 tumors (53.5%). TP53 mutations (p < 0.001) and p53 protein positivity (p = 0.001) were more frequent in HER2-positive and triple negative (TNBC) tumors, while PIK3CA mutations were more frequent in Luminal A/B tumors (p < 0.001). TP53 mutation status and p53 protein expression but not PIK3CA mutation status interacted with trastuzumab treatment for disease-free survival; patients with tumors bearing TP53 mutations or immunopositive for p53 protein fared better when treated with trastuzumab, while among patients treated with trastuzumab those with the above characteristics fared best (interaction p = 0.017 for mutations; p = 0.015 for IHC). Upon multivariate analysis the above interactions remained significant in HER2-positive patients; in the entire cohort, TP53 mutations were unfavorable in patients with Luminal A/B (p = 0.003) and TNBC (p = 0.025); p53 immunopositivity was strongly favorable in patients treated with trastuzumab (p = 0.009).
  
  
  METHODS
  TP53 and PIK3CA mutation status was examined in 1766 paraffin tumor DNA samples with informative semiconductor sequencing results. Among these, 1585 cases were also informative for p53 protein status assessed by immunohistochemistry (IHC; 10% positivity cut-off).
  
  
  CONCLUSIONS
  TP53 mutations confer unfavorable prognosis in patients with Luminal A/B and TNBC tumors, while p53 immunopositivity may predict for trastuzumab benefit in the adjuvant setting.
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.|Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Fountzilas
authors.affiliation: Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.|The University of New South Wales, NSW, Australia.
authors.forename: Eleni
authors.initials: E
authors.lastname: Giannoulatou
authors.affiliation: Department of Biostatistics, Health Data Specialists Ltd, Athens, Greece.
authors.forename: Zoi
authors.initials: Z
authors.lastname: Alexopoulou
authors.affiliation: Department of Clinical Therapeutics, "Alexandra" Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
authors.forename: Flora
authors.initials: F
authors.lastname: Zagouri
authors.affiliation: Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece.
authors.forename: Eleni
authors.initials: E
authors.lastname: Timotheadou
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Kyriaki
authors.initials: K
authors.lastname: Papadopoulou
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Sotiris
authors.initials: S
authors.lastname: Lakis
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Mattheos
authors.initials: M
authors.lastname: Bobos
authors.affiliation: Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Poulios
authors.affiliation: Department of Pathology, "Alexandra" Hospital, Athens, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Sotiropoulou
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Aggeliki
authors.initials: A
authors.lastname: Lyberopoulou
authors.affiliation: First Department of Medicine, "Laiko" General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
authors.forename: Helen
authors.initials: H
authors.lastname: Gogas
authors.affiliation: Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Pentheroudakis
authors.affiliation: Oncology Section, Second Department of Internal Medicine, "Hippokration" Hospital, Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pectasides
authors.affiliation: Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece.
authors.forename: Angelos
authors.initials: A
authors.lastname: Koutras
authors.affiliation: Second Department of Medical Oncology, "Metropolitan" Hospital, Piraeus, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Christodoulou
authors.affiliation: Department of Medical Oncology, University Hospital of Larissa, University of Thessaly School of Medicine, Larissa, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Papandreou
authors.affiliation: Third Department of Medical Oncology, "Agii Anargiri" Cancer Hospital, Athens, Greece.
authors.forename: Epaminontas
authors.initials: E
authors.lastname: Samantas
authors.affiliation: Oncology Unit, "Hippokration" Hospital, Athens, Greece.
authors.forename: Pavlos
authors.initials: P
authors.lastname: Papakostas
authors.affiliation: Second Department of Medical Oncology, Hygeia Hospital, Athens, Greece.
authors.forename: Paris
authors.initials: P
authors.lastname: Kosmidis
authors.affiliation: First Department of Medical Oncology, "Metropolitan" Hospital, Piraeus, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Bafaloukos
authors.affiliation: Department of Medical Oncology, 424 Army General Hospital, Thessaloniki, Greece.
authors.forename: Charisios
authors.initials: C
authors.lastname: Karanikiotis
authors.affiliation: The University of New South Wales, NSW, Australia.
authors.forename: Meletios-Athanassios
authors.initials: MA
authors.lastname: Dimopoulos
authors.affiliation: Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.|Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kotoula
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000074322:Antineoplastic Agents, Immunological / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000032:analysis / Q000235:genetics*; D017024:Chemotherapy, Adjuvant; D016009:Chi-Square Distribution; D058534:Class I Phosphatidylinositol 3-Kinases / Q000032:analysis / Q000235:genetics; D002986:Clinical Trials as Topic; D004252:DNA Mutational Analysis; D018450:Disease Progression; D018572:Disease-Free Survival; D005260:Female; D020022:Genetic Predisposition to Disease; D006115:Greece; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D008875:Middle Aged; D015999:Multivariate Analysis; D009154:Mutation; D018579:Patient Selection; D010641:Phenotype; D011237:Predictive Value of Tests; D016016:Proportional Hazards Models; D011446:Prospective Studies; D012189:Retrospective Studies; D012307:Risk Factors; D013997:Time Factors; D000068878:Trastuzumab / Q000627:therapeutic use*; D016896:Treatment Outcome; D064726:Triple Negative Breast Neoplasms / Q000737:chemistry / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000032:analysis / Q000235:genetics*; D055815:Young Adult
chemical_list: D000074322:Antineoplastic Agents, Immunological; D014408:Biomarkers, Tumor; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D000068878:Trastuzumab
keywords: PIK3CA mutations; TP53 mutations; early breast cancer; p53 immunohistochemistry; trastuzumab