Abstract
Background and purpose
There are scarce data available on the prognostic/predictive value of p-Akt and p-mTOR protein expression in patients with high-risk early breast cancer.
Patients and methods
Formalin-fixed paraffin-embedded (FFPE) tumor tissue samples from 997 patients participating in two adjuvant phase III trials were assessed for EGFR, PTEN, p-Akt, p-mTOR protein expression, and PIK3CA mutational status. These markers were evaluated for associations with each other and with selected patient and tumor characteristics, immunohistochemical subtypes, disease-free survival (DFS), and overall survival (OS).
Results
p-mTOR protein expression was negatively associated with EGFR and positively associated with PTEN, with p-Akt473, and with the presence of PIK3CA mutations. EGFR expression was positively associated with p-Akt473, p-Akt308, and PIK3CA wild-type tumors. Finally, p-Akt308 was positively associated with p-Akt473 expression. In univariate analysis, EGFR (p = 0.016) and the coexpression of EGFR and p-mTOR (p = 0.015) were associated with poor OS. Among patients with p-Akt308-negative or low-expressing tumors, those treated with hormonal therapy were associated with decreased risk for both relapse and death (p = 0.013 and p < 0.001, respectively). In the subgroup of patients with locoregional relapse, positive EGFR and mTOR protein expression was found to be associated with increased (p = 0.034) and decreased (p < 0.001) risk for earlier relapse, respectively. In multivariate analysis, low levels of p-Akt308 and the coexpression of EGFR and p-mTOR retained their prognostic value.
Conclusion
Low protein expression of p-Akt308 was associated with improved DFS and OS among patients treated with hormonal therapy following adjuvant chemotherapy. Coexpression of EGFR and p-mTOR was associated with worse OS.
Zusammenfassung
Hintergrund
Geringe Daten existieren über den prognostischen/prädiktiven Wert der p-Akt- und p-mTOR-Proteinexpression bei Patienten mit “High-risk”-Mammakarzinom im Frühstadium.
Patienten und Methoden
Formalinfixierte und in Paraffin eingebettete (FFPE) Tumorgewebeproben von 997 Patienten, welche im Rahmen von 2 adjuvanten Phase-III-Studien zytostatisch behandelt wurden, wurden auf EGFR, PTEN, p-Akt, pmTOR und PIK3CA-Mutationsstatus untersucht. Diese Marker wurden in Assoziation mit ausgewählten Patienten- und Tumorcharakteristika, immunhistochemischen Mammakarzinomsubtypen, dem krankheitsfreien Überleben (DFS) sowie dem Gesamtüberleben (OS) evaluiert.
Ergebnisse
Die Expression von p-mTOR war negativ mit der Expression von EGFR, jedoch signifikant positiv mit PTEN und p-Akt473 sowie dem Nachweis von PIK3CA-Mutationen assoziiert. Die EGFR-Expression war signifikant positiv mit der Proteinexpression von p-Akt473 und p-Akt308 sowie PIK3CA-Wildtyp-Tumoren assoziiert. Die p-Akt308-Expression war ebenfalls signifikant positiv mit der Expression von p-Akt473 assoziiert. In der univariaten Analyse war sowohl die EGFR (p = 0,016), als auch die Koexpression von EGFR und p-mTOR (p = 0,015) mit einem schlechteren OS assoziiert. Unter den Patienten mit p-Akt308-negativen oder gering exprimierenden Tumoren konnte bei denjenigen, die mit einer Hormontherapie behandelt wurden, ein signifikant vermindertes Risiko für ein Rezidiv als auch für den Tod (jeweils p = 0,013 und p < 0,001) nachgewiesen werden. In der Subgruppenanalyse von Patienten mit lokoregionärem Rezidiv konnte eine Assoziation von positivem EGFR-Status sowie mTOR-Expression mit einem jeweils erhöhten (p = 0,034) bzw. verminderten (p < 0,001) Risiko für das Auftreten von Frührezidiven nachgewiesen werden. In der multivariaten Analyse behielten die niedrigen p-Akt308-Werte und die Koexpression von EGFR und p-mTOR ihren prognostischen Wert.
Fazit
Eine niedrige Expression von p-Akt308 bei Patienten, die eine Hormontherapie nach einer adjuvanten Chemotherapie erhielten, war mit einem verbesserten DFS und OS assoziiert. Die Koexpression von EGFR und p-mTOR war mit einem schlechteren OS assoziiert.
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Acknowledgments
The authors are indebted to all patients and their families for their trust and participation in the HE10/97 and HE10/00 trials and for the provision of biological material for research purposes. The authors also wish to thank all HeCOG personnel (data managers, research assistants, and monitors) for their dedication, M. Moschoni for data coordination, T. Spinari for collection of FFPE tissue blocks, and S. Dallidou for secretarial assistance.
Conflict of interest
G. Lazaridis, S. Lambaki, G. Karayannopoulou, A.G. Eleftheraki, I. Papaspirou, M. Bobos, I. Efstratiou, G. Pentheroudakis, N. Zamboglou, and G. Fountzilas state they are supported by an internal Hellenic Cooperative Oncology Group (HeCOG) translational research grant (HE TRANS_BR).
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The first two authors contributed equally to this work.
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Lazaridis, G., Lambaki, S., Karayannopoulou, G. et al. Prognostic and predictive value of p-Akt, EGFR, and p-mTOR in early breast cancer. Strahlenther Onkol 190, 636–645 (2014). https://doi.org/10.1007/s00066-014-0620-6
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DOI: https://doi.org/10.1007/s00066-014-0620-6