Research Papers:

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

George Fountzilas _, Eleni Giannoulatou, Zoi Alexopoulou, Flora Zagouri, Eleni Timotheadou, Kyriaki Papadopoulou, Sotiris Lakis, Mattheos Bobos, Christos Poulios, Maria Sotiropoulou, Aggeliki Lyberopoulou, Helen Gogas, George Pentheroudakis, Dimitrios Pectasides, Angelos Koutras, Christos Christodoulou, Christos Papandreou, Epaminontas Samantas, Pavlos Papakostas, Paris Kosmidis, Dimitrios Bafaloukos, Charisios Karanikiotis, Meletios-Athanassios Dimopoulos and Vassiliki Kotoula

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Oncotarget. 2016; 7:32731-32753. https://doi.org/10.18632/oncotarget.9022

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George Fountzilas1,2,*, Eleni Giannoulatou3,4, Zoi Alexopoulou5, Flora Zagouri6, Eleni Timotheadou7, Kyriaki Papadopoulou1, Sotiris Lakis1, Mattheos Bobos1, Christos Poulios8, Maria Sotiropoulou9, Aggeliki Lyberopoulou1, Helen Gogas10, George Pentheroudakis11, Dimitrios Pectasides12, Angelos Koutras13, Christos Christodoulou14, Christos Papandreou15, Epaminontas Samantas16, Pavlos Papakostas17, Paris Kosmidis18, Dimitrios Bafaloukos19, Charisios Karanikiotis20, Meletios-Athanassios Dimopoulos4, Vassiliki Kotoula1,8,*

1Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece

2Aristotle University of Thessaloniki, Thessaloniki, Greece

3Victor Chang Cardiac Research Institute, Darlinghurst, NSW, Australia

4The University of New South Wales, NSW, Australia

5Department of Biostatistics, Health Data Specialists Ltd, Athens, Greece

6Department of Clinical Therapeutics, “Alexandra” Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

7Department of Medical Oncology, “Papageorgiou” Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece

8Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece

9Department of Pathology, “Alexandra” Hospital, Athens, Greece

10First Department of Medicine, “Laiko” General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

11Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece

12Oncology Section, Second Department of Internal Medicine, “Hippokration” Hospital, Athens, Greece

13Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece

14Second Department of Medical Oncology, “Metropolitan” Hospital, Piraeus, Greece

15Department of Medical Oncology, University Hospital of Larissa, University of Thessaly School of Medicine, Larissa, Greece

16Third Department of Medical Oncology, “Agii Anargiri” Cancer Hospital, Athens, Greece

17Oncology Unit, “Hippokration” Hospital, Athens, Greece

18Second Department of Medical Oncology, Hygeia Hospital, Athens, Greece

19First Department of Medical Oncology, “Metropolitan” Hospital, Piraeus, Greece

20Department of Medical Oncology, 424 Army General Hospital, Thessaloniki, Greece.

*These authors contributed equally to this work

Correspondence to:

George Fountzilas, email: [email protected]

Keywords: early breast cancer, TP53 mutations, PIK3CA mutations, p53 immunohistochemistry, trastuzumab

Received: November 26, 2015     Accepted: March 28, 2016     Published: April 26, 2016


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).

Materials and 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.

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