Comparison of the Ability of Different Clinical Treatment Scores to Estimate Prognosis in High-Risk Early Breast Cancer Patients: A Hellenic Cooperative Oncology Group Study.
OBJECTIVE
Early breast cancer is a heterogeneous disease, and, therefore, prognostic tools have been developed to evaluate the risk for distant recurrence. In the present study, we sought to develop a risk for recurrence score (RRS) based on mRNA expression of three proliferation markers in high-risk early breast cancer patients and evaluate its ability to predict risk for relapse and death. In addition the Adjuvant! Online score (AOS) was also determined for each patient, providing a 10-year estimate of relapse and mortality risk. We then evaluated whether RRS or AOS might possibly improve the prognostic information of the clinical treatment score (CTS), a model derived from clinicopathological variables.


METHODS
A total of 1,681 patients, enrolled in two prospective phase III trials, were treated with anthracycline-based adjuvant chemotherapy. Sufficient RNA was extracted from 875 samples followed by multiplex quantitative reverse transcription-polymerase chain reaction for assessing RACGAP1, TOP2A and Ki67 mRNA expression. The CTS, slightly modified to fit our cohort, integrated the prognostic information from age, nodal status, tumor size, histological grade and treatment. Patients were also classified to breast cancer subtypes defined by immunohistochemistry. Likelihood ratio (LR) tests and concordance indices were used to estimate the relative increase in the amount of information provided when either RRS or AOS is added to CTS.


RESULTS
The optimal RRS, in terms of disease-free survival (DFS) and overall survival (OS), was based on the co-expression of two of the three evaluated genes (RACGAP1 and TOP2A). CTS was prognostic for DFS (p<0.001), while CTS, AOS and RRS were all prognostic for OS (p<0.001, p<0.001 and p = 0.036, respectively). The use of AOS in addition to CTS added prognostic information regarding DFS (LR-Δχ2 8.7, p = 0.003), however the use of RRS in addition to CTS did not. For estimating OS, the use of either AOS or RRS in addition to CTS added significant prognostic information. Specifically, the use of both CTS and AOS had significantly better prognostic value vs. CTS alone (LR-Δχ2 20.8, p<0.001), as well as the use of CTS and RRS vs. CTS alone (LR-Δχ2 4.8, p = 0.028). Additionally, more patients were scored as high-risk by AOS than CTS. According to immunohistochemical subtypes, prognosis was improved in the Luminal A (LR-Δχ2 7.2, p = 0.007) and Luminal B (LR-Δχ2 8.3, p = 0.004) subtypes, in HER2-negative patients (LR-Δχ2 23.4, p<0.001) and in patients with >3 positive nodes (LR-Δχ2 23.9, p<0.001) when AOS was added to CTS.


CONCLUSIONS
The current study has shown a clear benefit in predicting overall survival of high-risk early breast cancer patients when combining CTS with either AOS or RRS. The combination of CTS and AOS adds significant prognostic information compared to CTS alone for DFS, while the combination of CTS with either AOS or RRS has better prognostic value than CTS alone for OS. These findings could possibly add on the information needed for the best risk prediction strategy in high-risk early breast cancer patients in a rather simple and inexpensive way, especially in Luminal A and B subtypes, HER2-negative patients and those with >3 positive nodes.
Third Department of Medical Oncology, "Hygeia" Hospital, Athens, Greece.
Flora
F
Stavridi
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.|Translational Research Section, Hellenic Cooperative Oncology Group, Data Office, Athens, Greece.
Konstantine T
KT
Kalogeras
Oncology Section, Second Department of Internal Medicine, "Hippokration" Hospital, Athens, Greece.
Kyriaki
K
Pliarchopoulou
STRATIFYER Molecular Pathology GmbH, Cologne, Germany.
Ralph M
RM
Wirtz
Department of Biostatistics, Health Data Specialists Ltd, Athens, Greece.
Zoi
Z
Alexopoulou
Department of Clinical Therapeutics, "Alexandra" Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
Flora
F
Zagouri
STRATIFYER Molecular Pathology GmbH, Cologne, Germany.
Elke
E
Veltrup
Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece.
Eleni
E
Timotheadou
First Department of Medicine, "Laiko" General Hospital, National and Kapodistrian University of Athens School of Medicine, Athens, Greece.
Helen
H
Gogas
Division of Oncology, Department of Medicine, University Hospital, University of Patras Medical School, Patras, Greece.
Angelos
A
Koutras
Department of Medical Oncology, "Papageorgiou" Hospital, Aristotle University of Thessaloniki, School of Health Sciences, Faculty of Medicine, Thessaloniki, Greece.
Georgios
G
Lazaridis
Second Department of Medical Oncology, "Metropolitan" Hospital, Piraeus, Greece.
Christos
C
Christodoulou
Department of Medical Oncology, Ioannina University Hospital, Ioannina, Greece.
George
G
Pentheroudakis
First Department of Medical Oncology, "Metropolitan" Hospital, Piraeus, Greece.
Apostolos
A
Laskarakis
Department of Pathology, Micromedica Labs, Athens, Greece.
Petroula
P
Arapantoni-Dadioti
Department of Pathology, Ioannina University Hospital, Ioannina, Greece.
Anna
A
Batistatou
Department of Pathology, "Alexandra" Hospital, Athens, Greece.
Maria
M
Sotiropoulou
Second Department of Medical Oncology, "Agii Anargiri" Cancer Hospital, Athens, Greece.
Gerasimos
G
Aravantinos
Oncology Unit, "Hippokration" Hospital, Athens, Greece.
Pavlos
P
Papakostas
Second Department of Medical Oncology, "Hygeia" Hospital, Athens, Greece.
Paris
P
Kosmidis
Oncology Section, Second Department of Internal Medicine, "Hippokration" Hospital, Athens, Greece.
Dimitrios
D
Pectasides
Laboratory of Molecular Oncology, Hellenic Foundation for Cancer Research/Aristotle University of Thessaloniki, Thessaloniki, Greece.|Aristotle University of Thessaloniki, Thessaloniki, Greece.
George
G
Fountzilas
D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D015415:Biomarkers; D001943:Breast Neoplasms / Q000175:diagnosis / Q000401:mortality* / Q000628:therapy*; D017024:Chemotherapy, Adjuvant; D017326:Clinical Trials, Phase III as Topic; D003131:Combined Modality Therapy; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D009364:Neoplasm Recurrence, Local; D009367:Neoplasm Staging; D011379:Prognosis; D012372:ROC Curve; D015203:Reproducibility of Results; D012189:Retrospective Studies; D016019:Survival Analysis; D016896:Treatment Outcome
D015415:Biomarkers
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