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Research Papers:

Pathogenic mutations and overall survival in 3,084 patients with cancer: the Hellenic Cooperative Oncology Group Precision Medicine Initiative

Elena Fountzilas, Vassiliki Kotoula, Georgia-Angeliki Koliou, Eleni Giannoulatou, Helen Gogas, Christos Papadimitriou, Ioannis Tikas, Jianhua Zhang, Kyriaki Papadopoulou, Flora Zagouri, Christos Christodoulou, Angelos Koutras, Thomas Makatsoris, Sofia Chrisafi, Helena Linardou, Ioannis Varthalitis, George Papatsibas, Evangelia Razis, Pavlos Papakostas, Epaminontas Samantas, Gerasimos Aravantinos, Dimitrios Bafaloukos, Paris Kosmidis, Anna Koumarianou, Amanda Psyrri, Georgios Pentheroudakis, Dimitrios Pectasides, Andrew Futreal, George Fountzilas and Apostolia M. Tsimberidou

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Abstract

Elena Fountzilas1,29,*, Vassiliki Kotoula2,3,*, Georgia-Angeliki Koliou4, Eleni Giannoulatou5,6, Helen Gogas7, Christos Papadimitriou8, Ioannis Tikas3, Jianhua Zhang9, Kyriaki Papadopoulou3, Flora Zagouri10, Christos Christodoulou11, Angelos Koutras12, Thomas Makatsoris12, Sofia Chrisafi3, Helena Linardou13, Ioannis Varthalitis14, George Papatsibas15, Evangelia Razis16, Pavlos Papakostas17, Epaminontas Samantas18, Gerasimos Aravantinos19, Dimitrios Bafaloukos20, Paris Kosmidis21, Anna Koumarianou22, Amanda Psyrri23, Georgios Pentheroudakis24,25, Dimitrios Pectasides26, Andrew Futreal27, George Fountzilas3,28 and Apostolia M. Tsimberidou1

1 The University of Texas MD Anderson Cancer Center, Department of Investigational Cancer Therapeutics, Houston, TX, USA

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

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

4 Section of Biostatistics, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece

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

6 The University of New South Wales, Kensington, NSW, Australia

7 First Department of Medicine, Laiko General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

8 Oncology Unit, Aretaieion Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

9 Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, USA

10 Department of Clinical Therapeutics, Alexandra Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

11 Second Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece

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

13 Oncology Unit, Metropolitan Hospital, Piraeus, Greece

14 First Department of Medical Oncology, Henry Dunant Hospital, Athens, Greece

15 Oncology Department, University General Hospital of Larissa, Larissa, Greece

16 Third Department of Medical Oncology, Hygeia Hospital, Athens, Greece

17 Oncology Unit, Hippokration Hospital, Athens, Greece

18 Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece

19 Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece

20 First Department of Medical Oncology, Metropolitan Hospital, Piraeus, Greece

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

22 Fourth Department of Internal Medicine, Attikon University Hospital, Athens, Greece

23 Section of Medical Oncology, Department of Internal Medicine, Attikon University Hospital, Faculty of Medicine, National and Kapodistrian University of Athens School of Medicine, Athens, Greece

24 Department of Medical Oncology, Medical School, University of Ioannina, Ioannina, Greece

25 Society for Study of Clonal Heterogeneity of Neoplasia (EMEKEN), Ioannina, Greece

26 Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, Athens, Greece

27 The University of Texas MD Anderson Cancer Center, Department of Genomic Medicine, Houston, TX, USA

28 Aristotle University of Thessaloniki, Thessaloniki, Greece

29 Current address: Hellenic Cooperative Oncology Group, Athens, Greece

* These authors contributed equally to this work

Correspondence to:

Elena Fountzilas,email: elenafou@gmail.com

Keywords: actionable gene; next-generation sequencing; pathogenic mutation; precision oncology; prognosis

Received: May 16, 2019     Accepted: October 19, 2019     Published: January 07, 2020

ABSTRACT

Background: We evaluated the association between pathogenic mutations and overall survival (OS) in patients with cancer referred to Hellenic Cooperative Oncology Group–affiliated Departments.

Patients and methods: Patients referred from 12/1980 to 1/2017 had molecular testing (for research) of archival tumor tissue collected at the time of first diagnosis (non-metastatic, 81%; metastatic, 19%). Tumor-specific gene panels (16-101 genes) were used to identify pathogenic mutations in clinically relevant genes. NGS genotyping was performed at the Laboratory of Molecular Oncology, Aristotle University of Thessaloniki. Annotation of mutations was performed at MD Anderson Cancer Center.

Results: We analyzed 3,084 patients (median age, 57 years; men, 22%) with sequencing data. Overall, 1,775 (58% of 3,084) patients had pathogenic mutations. The median follow-up was 7.52 years (95% CI, 7.39-7.61). In patients with non-metastatic tumors, after stratification by tumor type, increasing age, higher grade, and histology other than adenocarcinoma were associated with shorter OS. OS was also shorter in patients with pathogenic TP53 (HR=1.36; p<0.001), MLL3 (HR=1.64; p=0.005), and BRCA1 (HR=1.46; p=0.047) mutations compared to wild-type genes. In multivariate analyses, independent prognostic factors predicting shorter OS were pathogenic mutations in TP53 (HR=1.37, p=0.002) and MLL3 (HR=1.50, p=0.027); increasing age (HR=1.02, p<0.001); and increasing grade (HR=1.46, p<0.001). In patients with metastatic cancer, older age and higher grade were associated with shorter OS and maintained their independent prognostic significance (increasing age, HR=1.03, p<0.001 and higher grade, HR=1.73, p<0.001).

Conclusions: Analysis of molecular data reveals prognostic biomarkers, regardless of tissue or organ of origin to improve patient management.


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