P2-12-12: Prognostic Utility of Breast Cancer Index for Late Relapse in Patients with Early Stage Breast Cancer.
Authors: Schnabel CA , Zhang Y , Kesty NC , Erlander MG 
Published: June 2012

Abstract
Background
Residual risk of relapse remains a substantial concern for breast cancer patients as greater than half of recurrences occur beyond the initial 5y of tamoxifen therapy. First generation multigene signatures provide further prognostic information to standard clinical and pathological factors, however, their utility is strongest for predicting early relapse (≤5y post-diagnosis), and they have limited prognostic value for late metastatic risk. Breast Cancer Index (BCI), a continuous risk index based on the combination of HOXB13:IL17BR (H:I) and the molecular grade index (MGI), estimates the individual risk of recurrence in ER+, LN- breast cancer patients. In this study, the prognostic performance of BCI for predicting early versus late relapse (≤5y vs &gt;5y post-diagnosis) was examined.
Methods: Gene expression profiling was performed on RNA extracted from FFPE tumor samples from untreated, postmenopausal, ER+ early stage breast cancer patients in the randomized Stockholm Trial. RT-PCR assay, pre-defined BCI score, H:I and MGI cut-points, and risk group categorization were done as previously described (Jerevall et al., Br J Cancer 2011). Association of gene expression data with the clinical endpoint of time to distant metastasis was assessed by Kaplan-Meier analysis using the log rank test; time-varying coefficient Cox proportional models were used to estimate the time-dependent hazard ratios (HRs).
Results: Analyses included 274 ER+, LN- patients (51% PR+, 87% HER2−, 63% grade 2, 17.7 y median follow-up) who did not receive adjuvant tamoxifen treatment. BCI was significantly associated with 10-year distant metastasis-free survival, with probabilities of 91% (86-96%), 82% (74-91%), and 65% (52-80%) for the low, intermediate, and high-risk BCI groups, respectively (HR high versus low-risk group = 4.31; 95%CI, 2.23−8.33; P=0.00001). Risk stratification for the first 5-y post-diagnosis using time-varying coefficient Cox models showed both MGI and BCI were significantly prognostic with HRs of 6.13 (95% CI: 2.11−17.8; P=0.0009) and 5.77 (95% CI: 2.16−15.39; P=0.0005). For prediction of late relapse in the subset of patients that remained distant metastasis-free for at least 5-y (N=221), MGI decreased in prognostic utility (HR 1.65, 0.76−3.56; P=0.2), consistent with other proliferation-based gene signatures. In comparison, both H:I and BCI were significantly associated with risk of late relapse [HRs 2.89 (1.31−6.36; P=0.009); 3.31(1.3−8.39); P=0.012].

Conclusions: This post-hoc analysis of a randomized clinical trial cohort demonstrates the prognostic utility of BCI to predict disease outcome for both early and late risk of relapse in untreated patients with early stage breast cancer. Given the significant need for predictors of late risk, the stability of BCI prognostic performance may have important implications for the type and duration of treatment for hormone-responsive breast cancer.
Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-12-12.