Prognostic Impact of Src, CDKN1B, and JAK2 Expression in Metastatic Breast Cancer Patients Treated with Trastuzumab

Panagiota Economopoulou; Vassiliki Kotoula; Georgia-Angeliki Koliou; Kyriaki Papadopoulou; Christos Christodoulou; George Pentheroudakis; Georgios Lazaridis; Petroula Arapantoni-Dadioti; Angelos Koutras; Dimitris Bafaloukos; Pavlos Papakostas; Helen Patsea; Kitty Pavlakis; Dimitrios Pectasides; Athanasios Kotsakis; Evangelia Razis; Gerasimos Aravantinos; Epaminondas Samantas; Konstantine T Kalogeras; Theofanis Economopoulos; Amanta Psyrri; George Fountzilas

doi:10.1016/j.tranon.2019.02.010

Prognostic Impact of Src, CDKN1B, and JAK2 Expression in Metastatic Breast Cancer Patients Treated with Trastuzumab

Transl Oncol. 2019 May;12(5):739-748. doi: 10.1016/j.tranon.2019.02.010. Epub 2019 Mar 14.

Authors

Panagiota Economopoulou¹, Vassiliki Kotoula², Georgia-Angeliki Koliou³, Kyriaki Papadopoulou⁴, Christos Christodoulou⁵, George Pentheroudakis⁶, Georgios Lazaridis⁷, Petroula Arapantoni-Dadioti⁸, Angelos Koutras⁹, Dimitris Bafaloukos¹⁰, Pavlos Papakostas¹¹, Helen Patsea¹², Kitty Pavlakis¹³, Dimitrios Pectasides¹⁴, Athanasios Kotsakis¹⁵, Evangelia Razis¹⁶, Gerasimos Aravantinos¹⁷, Epaminondas Samantas¹⁸, Konstantine T Kalogeras¹⁹, Theofanis Economopoulos²⁰, Amanta Psyrri²¹, George Fountzilas²²

Affiliations

¹ Second Department of Internal Medicine, Attikon University Hospital, 1 Rimini St 12462, Haidari, Athens, Greece. Electronic address: panagiota_oiko@hotmail.com.
² Department of Pathology, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, University Campus, Building 17B, 54006, Thessaloniki, Greece; Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, University Campus, Building 17B, 54006, Thessaloniki, Greece. Electronic address: vkotoula@auth.gr.
³ Section of Biostatistics, Hellenic Cooperative Oncology Group, 18 Hatzikonstanti St, 11524, Athens, Greece. Electronic address: g_koliou@hecog.ondsl.gr.
⁴ Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, University Campus, Building 17B, 54006, Thessaloniki, Greece. Electronic address: kyriakipapadopoulou@hotmail.com.
⁵ Second Department of Medical Oncology, Metropolitan Hospital, 9 Ethnarchou Makariou St, 185 47, Piraeus, Greece. Electronic address: c_christodoulou@yahoo.gr.
⁶ Department of Medical Oncology, Ioannina University Hospital, Leof. Stavrou Niarchou, 45500, Ioannina, Greece. Electronic address: gpenther@cc.uoi.gr.
⁷ Department of Medical Oncology, Papageorgiou Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Ring Road, Nea Efkarpia, 56450, Thessaloniki, Greece.
⁸ Department of Pathology, Henry Dunant Hospital, 107 Mesogion Av, 11526, Athens, Greece.
⁹ Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Panepistimioupoli Patron, 26504, Patras, Greece. Electronic address: angkoutr@otenet.gr.
¹⁰ First department of Medical Oncology, Metropolitan Hospital, 9 Ethnarchou Makariou St, 185 47, Piraeus, Greece. Electronic address: dimmp@otenet.gr.
¹¹ Oncology Unit, Hippokration Hospital, 114 Vasilissis Sofias Av, 11527, Athens, Greece. Electronic address: p.papakostas@gmail.com.
¹² Department of Pathology, IASSO General Hospital, 264 Mesogion Av, 15562, Athens, Greece.
¹³ Pathology Department, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
¹⁴ Oncology Section, Second Department of Internal Medicine, Hippokration Hospital, 114 Vasilissis Sofias Av, 11527, Athens, Greece. Electronic address: pectasid@otenet.gr.
¹⁵ Department of Medical Oncology, University General Hospital of Heraklion, Voutes, 71110, Crete, Greece. Electronic address: thankotsakis@hotmail.com.
¹⁶ Third Department of Medical Oncology, Hygeia Hospital, 4 Erithrou Stavrou St, Marousi, 15123, Athens, Greece. Electronic address: e.razis@hygeia.gr.
¹⁷ Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece.
¹⁸ Third Department of Medical Oncology, Agii Anargiri Cancer Hospital, Timiou Stavrou, 14564, Kifisia, Athens, Greece. Electronic address: epsam@otenet.gr.
¹⁹ Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, University Campus, Building 17B, 54006, Thessaloniki, Greece; Translational Research Section, Hellenic Cooperative Oncology Group, 18 Hatzikonstanti St, 11524, Athens, Greece. Electronic address: k_kalogeras@hecog.ondsl.gr.
²⁰ Second Department of Internal Medicine, Attikon University Hospital, 1 Rimini St 12462, Haidari, Athens, Greece. Electronic address: economopoulosth@ath.forthnet.gr.
²¹ Second Department of Internal Medicine, Attikon University Hospital, 1 Rimini St 12462, Haidari, Athens, Greece. Electronic address: psyrri237@yahoo.com.
²² Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, University Campus, Building 17B, 54006, Thessaloniki, Greece; Aristotle University of Thessaloniki, 54124, Thessaloniki, Greece. Electronic address: fountzil@auth.gr.

Abstract

Background: Src, CDKN1B, and JAK2 play a crucial role in the coordination of cell signaling pathways. In the present study, we aim to investigate the prognostic significance of these biomarkers in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab (T).

Methods: Formalin-fixed paraffin-embedded tumor tissue samples from 197 patients with HER2-positive MBC treated with T were retrospectively collected. All tissue samples were centrally assessed for ER, PgR, Ki67, HER2, and PTEN protein expression; EGFR gene amplification; PI3KCA mutational status; and tumor-infiltrating lympocytes density. Src, CDKN1B, and JAK2 mRNA expression was evaluated using quantitative reverse transcription-polymerase chain reaction.

Results: Only 133 of the 197 patients (67.5%) were found to be HER2-positive by central assessment. CDKN1B mRNA expression was strongly correlated with Src (rho = 0.71) and JAK2 (rho = 0.54). In HER2-positive patients, low CDKN1B conferred higher risk for progression [hazard ratio (HR) = 1.58, 95% confidence interval (CI) 1.08-2.32, P = .018]. In HER2-negative patients, low Src was associated with longer survival (HR = 0.56, 95% CI 0.32-0.99, P = .045). Upon multivariate analyses, only low CDKN1B and JAK2 mRNA expression remained unfavorable factors for PFS in de novo and relapsed (R)-MBC patients, respectively (HR = 2.36, 95% CI 1.01-5.48, P = .046 and HR = 1.76, 95% CI 1.01-3.06, P = .047, respectively).

Conclusions: Low CDKN1B and JAK2 mRNA expressions were unfavorable prognosticators in a cohort of T-treated MBC patients. Our results suggest that CDKN1B and JAK2, if validated, may serve as prognostic factors potentially implicated in T resistance, which seems to be associated with distinct pathways in de novo and R-MBC.