Breast Cancer Research and Treatment

, Volume 158, Issue 2, pp 307–321 | Cite as

Effects of TP53 and PIK3CA mutations in early breast cancer: a matter of co-mutation and tumor-infiltrating lymphocytes

  • Vassiliki Kotoula
  • Vasilios Karavasilis
  • Flora Zagouri
  • George Kouvatseas
  • Eleni Giannoulatou
  • Helen Gogas
  • Sotiris Lakis
  • George Pentheroudakis
  • Mattheos Bobos
  • Kyriaki Papadopoulou
  • Eleftheria Tsolaki
  • Dimitrios Pectasides
  • Georgios Lazaridis
  • Angelos Koutras
  • Gerasimos Aravantinos
  • Christos Christodoulou
  • Pavlos Papakostas
  • Christos Markopoulos
  • George Zografos
  • Christos Papandreou
  • George Fountzilas
Clinical trial


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.


TP53 PIK3CA Co-mutation Tumor-infiltrating lymphocytes P53 immunohistochemistry Adjuvant 



The authors wish to thank Mrs. Emily Daskalaki for excellent technical assistance with MPS and Ms. Maria Moschoni, and Mrs. Stella Dallidou for secretarial assistance.


This study was supported by an internal Hellenic Cooperative Oncology Group (HeCOG) translational research grant (HE TRANS_BR). The funders played no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. This study was also partly supported by the Greek General Secretary for Research and Technology (GSRT) Program, Research in Excellence II, funded by 75 % from the European Union, and the Operational Program ‘‘Education & Lifelong Learning’’ ESPA-THALIS#266 of the Ministry of Education, Lifelong Learning & Religious Affairs.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Supplementary material

10549_2016_3883_MOESM1_ESM.doc (316 kb)
Supplementary material 1 (DOC 315 kb)
10549_2016_3883_MOESM2_ESM.xls (78 kb)
Supplementary material 2 (XLS 78 kb)


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Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • Vassiliki Kotoula
    • 1
    • 2
  • Vasilios Karavasilis
    • 3
  • Flora Zagouri
    • 4
  • George Kouvatseas
    • 5
  • Eleni Giannoulatou
    • 6
    • 7
  • Helen Gogas
    • 8
  • Sotiris Lakis
    • 2
  • George Pentheroudakis
    • 9
  • Mattheos Bobos
    • 2
  • Kyriaki Papadopoulou
    • 2
  • Eleftheria Tsolaki
    • 2
  • Dimitrios Pectasides
    • 10
  • Georgios Lazaridis
    • 3
  • Angelos Koutras
    • 11
  • Gerasimos Aravantinos
    • 12
  • Christos Christodoulou
    • 13
  • Pavlos Papakostas
    • 14
  • Christos Markopoulos
    • 15
  • George Zografos
    • 16
  • Christos Papandreou
    • 17
  • George Fountzilas
    • 2
    • 18
  1. 1.Department of Pathology, School of Health Sciences, School of Medicine, Faculty of MedicineAristotle University of ThessalonikiThessalonikiGreece
  2. 2.Faculty of Medicine, Laboratory of Molecular OncologyHellenic Foundation for Cancer Research/Aristotle University of ThessalonikiThessalonikiGreece
  3. 3.Department of Medical Oncology, Papageorgiou Hospital, Faculty of Medicine, School of Health SciencesAristotle University of ThessalonikiThessalonikiGreece
  4. 4.Department of Clinical Therapeutics, Alexandra HospitalNational and Kapodistrian University of Athens School of MedicineAthensGreece
  5. 5.Department of BiostatisticsHealth Data Specialists LtdAthensGreece
  6. 6.Victor Chang Cardiac Research InstituteDarlinghurstAustralia
  7. 7.The University of New South WalesKensingtonAustralia
  8. 8.First Department of Medicine, Laiko General HospitalNational and Kapodistrian University of Athens School of MedicineAthensGreece
  9. 9.Department of Medical OncologyIoannina University HospitalIoanninaGreece
  10. 10.Oncology Section, Second Department of Internal MedicineHippokration HospitalAthensGreece
  11. 11.Division of Oncology, Department of MedicineUniversity Hospital, University of Patras Medical SchoolPatrasGreece
  12. 12.Second Department of Medical OncologyAgii Anargiri Cancer HospitalAthensGreece
  13. 13.Second Department of Medical OncologyMetropolitan HospitalPiraeusGreece
  14. 14.Oncology UnitHippokration HospitalAthensGreece
  15. 15.Second Department of Prop. SurgeryLaiko General Hospital, National and Kapodistrian University of Athens School of MedicineAthensGreece
  16. 16.Breast UnitNational and Kapodistrian University of Athens School of MedicineAthensGreece
  17. 17.Department of Medical OncologyUniversity Hospital of Larissa, University of Thessaly School of MedicineLarissaGreece
  18. 18.Aristotle University of ThessalonikiThessalonikiGreece

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