title: Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes.
abstract: The purpose of this study is to investigate whether the outcome of breast cancer (BC) patients treated with adjuvant chemotherapy is affected by co-mutated TP53 and PIK3CA according to stromal tumor-infiltrating lymphocytes (TILs). Paraffin tumors of all clinical subtypes from 1661 patients with operable breast cancer who were treated within 4 adjuvant trials with anthracycline-taxanes chemotherapy were informative for TP53 and PIK3CA mutation status (semiconductor sequencing genotyping) and for stromal TILs density. Disease-free survival (DFS) was examined. TP53 mutations were associated with higher (p < 0.001) and PIK3CA with lower (p = 0.004) TILs in an ER /PgR-specific manner (p < 0.001). Mutations did not affect the favorable DFS of patients with lymphocyte-predominant (LP) BC. Within non-LPBC, PIK3CA-only mutations conferred best, while TP53-PIK3CA co-mutations (6 % of all tumors) conferred worst DFS (HR 0.59; 95 % CI 0.44-0.79; p = 0.001 for PIK3CA-only). TP53-only mutations were unfavorable in patients with lower TILs, while patients with lower TILs performed worse if their tumors carried TP53-only mutations (interaction p = 0.046). Multivariate analysis revealed favorable PIK3CA-only mutations in non-LPBC (HR 0.64; 95 % CI 0.47-0.88; p = 0.007), and unfavorable TP53 mutations in ER/PgRpos/HER2neg (HR 1.55; 95 % CI 1.07-2.24; p = 0.021). Mutations did not interact with TILs in non-LP triple-negative and HER2-positive patients. TP53 and PIK3CA mutations appear to have diverse effects on the outcome of early BC patients, according to whether these genes are co-mutated or not, and for TP53 according to TILs density and ER/PgR-status. These findings need to be considered when evaluating the effect of these two most frequently mutated genes in the context of large clinical trials.
authors.affiliation: Department of Pathology, School of Health Sciences, School of Medicine, Faculty of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece. vkotoula@auth.gr.|Faculty of Medicine, Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece. vkotoula@auth.gr.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kotoula
authors.affiliation: Department of Medical Oncology, Papageorgiou Hospital, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Vasilios
authors.initials: V
authors.lastname: Karavasilis
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 Biostatistics, Health Data Specialists Ltd, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Kouvatseas
authors.affiliation: Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia.|The University of New South Wales, Kensington, NSW, Australia.
authors.forename: Eleni
authors.initials: E
authors.lastname: Giannoulatou
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: Faculty of Medicine, 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: Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Pentheroudakis
authors.affiliation: Faculty of Medicine, 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: Faculty of Medicine, 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: Faculty of Medicine, Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Eleftheria
authors.initials: E
authors.lastname: Tsolaki
authors.affiliation: Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece.
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Pectasides
authors.affiliation: Department of Medical Oncology, Papageorgiou Hospital, Faculty of Medicine, School of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece.
authors.forename: Georgios
authors.initials: G
authors.lastname: Lazaridis
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, Agii Anargiri Cancer Hospital, Athens, Greece.
authors.forename: Gerasimos
authors.initials: G
authors.lastname: Aravantinos
authors.affiliation: Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Christodoulou
authors.affiliation: Oncology Unit, Hippokration Hospital, Athens, Greece.
authors.forename: Pavlos
authors.initials: P
authors.lastname: Papakostas
authors.affiliation: Second Department of Prop. Surgery, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
authors.forename: Christos
authors.initials: C
authors.lastname: Markopoulos
authors.affiliation: Breast Unit, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
authors.forename: George
authors.initials: G
authors.lastname: Zografos
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: Faculty of Medicine, 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
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D018943:Anthracyclines / Q000494:pharmacology / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics; D017024:Chemotherapy, Adjuvant; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics*; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000473:pathology*; D008875:Middle Aged; D009154:Mutation; D011446:Prospective Studies; D012189:Retrospective Studies; D016019:Survival Analysis; D043823:Taxoids / Q000494:pharmacology / Q000627:therapeutic use*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*; D055815:Young Adult
chemical_list: D018943:Anthracyclines; C495901:TP53 protein, human; D043823:Taxoids; D016159:Tumor Suppressor Protein p53; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human
keywords: Adjuvant; Co-mutation; P53 immunohistochemistry; PIK3CA; TP53; Tumor-infiltrating lymphocytes