Abstract P3-10-07: T5 Is a New Molecular Predictor of Distant Recurrence in Estrogen Receptor-Positive, HER2-Negative Breast Cancer
Authors: Filipits M , Rudas M , Jakesz R , Dubsky P , Singer CF , Dietze O , Greil R , Jelen A , Sevelda P , Freibauer C , Fitzal F , Müller V , Jänicke F , Schmidt M , Kölbl H , Rody A , Kaufmann M , Schroth W , Schwab M , Brauch H , Weber K , Feder I , Hennig G , Gehrmann M , Gnant MFX. 
Published: April 2011

Background: Molecular tests predicting outcome of breast cancer patients may be useful for treatment decisions in addition to standard clinicopathologic features.

Methods: Using human genome HG-U133A array and qRT-PCR datasets, we developed and validated a gene-expression signature predicting the likelihood of distant recurrence in postmenopausal, early-stage breast cancer patients with estrogen receptor-positive, HER2-negative tumors treated with adjuvant endocrine therapy. RNA levels assessed by qRT-PCR in formalin-fixed paraffin-embedded tumor specimens were used to calculate a risk score (T5) and to determine a risk group (low or high) for each patient. The prospectively defined T5 risk score was then validated independently in patients from two large randomized phase III trials. Distant recurrence-free survival and overall survival were analyzed with Cox models adjusted for clinicopathological factors. The primary endpoint was time to distant recurrence.

Results: In a training set of 964 tumors, we identified a gene-expression signature consisting of three proliferation-related genes (BIRC5, UBE2C, DHCR7), five estrogen-regulated genes (RBBP8, IL6ST, AZGP1, MGP, STC2), and three reference genes (CALM2, OAZ1, RPL37A). For the validation, RNA analysis was possible in 1702 of 1725 (99%) tumors of both validation sets. Women were classified as having low risk (n=832; 49%) or high risk (n=870; 51%) by the T5 risk score. The T5 risk score provided prognostic information independent from clinicopathologic risk as estimated by Adjuvant!Online or Ki67 labeling index. Patients with a higher T5 risk score had a significantly shorter time to distant recurrence (adjusted hazard ratio, 1.24; 95% confidence interval [CI], 1.15 to 1.33; P&lt;0.001) and overall survival (adjusted hazard ratio, 1.13; 95% CI, 1.06 to 1.19; P&lt;0.001) compared to patients with a lower T5 risk score. The addition of the risk characterized by the T5 risk score to the clinicopathological risk resulted in 10-year distant recurrence-free survival rates of 95% in combined low risk patients and 82% in combined high risk patients (P&lt;0.001).

Conclusions: Using formalin-fixed paraffin-embedded tumor specimens, the multigene T5 risk score provides prognostic information independent of Adjuvant!Online or Ki67 labeling index. By combining the T5 risk score with clinicopathological risk, we were able to accurately identify breast cancer patients with low risk or high risk for distant recurrence. Using this new easy-to-use multigene tool in clinical practice will assist in optimizing adjuvant therapy by reducing both undertreatment and overtreatment and thus improves outcome and quality of life of patients with early-stage breast cancer.

Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P3-10-07.