Prognostication of individual risk for distant recurrence and death for patients with ER+
breast cancer treated only with adjuvant endocrine therapy continues to be a challenge given that approximately 75% of these patients remain disease-free at 15 years [1
]. In addition, the Oxford overview of a meta-analysis of 34,873 women reports the low recurrence rate of 2.2% per year for ER+
patients receiving tamoxifen alone [16
]. Furthermore, 12-year follow-up of 1,536 patients who had ER+
breast cancer and who were randomly assigned to tamoxifen versus tamoxifen plus chemotherapy had recurrence-free survival rates of 79% and 89%, respectively, and overall survival rates of 83% and 87%, respectively, and absolute chemotherapy benefits of 10% for recurrence-free survival and 4% for overall survival. A large proportion of ER+
patients are disease-free more than 10 years after diagnosis when treated with endocrine therapy alone and, therefore, could forgo chemotherapy and the associated toxicities. Prognostic indices, which identify low-risk patients, can be used to generate information to aid in the treatment decision process for determining optimal adjuvant therapy for ER+
Early breast cancer assessment tools for prognosis such as the St Gallen breast cancer consensus guidelines and the AO assess risks and benefits associated with adjuvant therapy [13
]. For AO, the selection criteria for withholding chemotherapy is based primarily on the integration of clinicopathological correlates (tumor grade, nodal status, tumor size, and ER status) and comorbidities, all of which have inherent limitations in assessment or measurement [3
]; however, correct assessment is of major importance in order to avoid unnecessary toxic side effects associated with chemotherapy [18
Here, we report the prognostic performance of the gene expression-based BCI within a clinical case series of patients with ER+ LN- breast cancer and demonstrate that BCI is a highly significant predictor of distant metastasis and death in patients treated with adjuvant tamoxifen, with or without chemotherapy. With categorical stratification, BCI identified more than 50% of the patients with low risk with a 10-year rate of recurrence of 6.6% and breast cancer-specific mortality rate of 3.8%. In a multivariate model that includes clinicopathological covariates, BCI remained a significant factor associated with recurrence risk and mortality.
Prognostic gene expression signatures have the capability to offer objective and reproducible predictive risk assessments beyond the traditional criteria used for AO to guide adjuvant treatment selection. The overall correlation between BCI and AO for individual 10-year risk of recurrence assessment was low (r = 0.2), and AO risk was higher for most patients. For example, of the study's 226 patients who were defined by AO as having at least a 10% risk of recurrence at 10 years, 51% were classified by BCI as low-risk, 22% as intermediate-risk, and 27% as high-risk. Actual recurrence rates for these three groups were 10%, 14%, and 34%, respectively.
Proportional hazards models that include both AO and BCI demonstrate that both factors are highly significant predictors for outcome. Furthermore, iAUC analyses demonstrate that the addition of BCI to AO increases the probability for concordance between survival time and predicted risks from 67% to 75% globally for 10-year outcome for ER+ LN- patients receiving tamoxifen only. Time-dependent ROC analysis enables further granulation of the additive effect of BCI to AO for predicting recurrence. The addition of BCI has its greatest accuracy benefit 4 to 10 years after diagnosis; for patients treated with tamoxifen only, BCI + AO had a recurrence prediction of 81% versus 65% for AO only.
A potential reason for the observed additive accuracy effect of BCI after 4 years may be that tumor grade, a clinicopathological covariate used in calculating AO, has its greatest prognostic strength 0 to 5 years after diagnosis; specifically, high-grade tumors are associated with increased recurrence risk. In contrast, a retrospective study (n
= 2,838 patients) designed to identify factors associated with residual risk of recurrence (> 5 years) reported that only low-grade tumors were significantly associated with recurrence for patients receiving adjuvant therapy and disease-free for 5 years [19
]. This suggests that accurate prediction of recurrence throughout the entire 10 years requires not only assessment of tumor differentiation and tumor proliferation for predicting early recurrences (that is, 0 to 5 years) but also prediction of recurrences more than 5 years by identifying the subset of low-grade or 'indolent appearing' tumors with high potential to metastasize. BCI is a score that integrates two prognostics: MGI, an index highly correlative with tumor grade [7
], and H:I, which has a low correlation with tumor grade [11
]. Studies are ongoing to further examine the potential differing prognostic contributions of MGI and H:I for early and late recurrences, respectively.
Current gene expression-based signatures such as the 21-gene, 70-gene, 76-gene, and 97-gene genomic grade derive a significant amount of their prognostic and predictive strength from the expression measurement of genes associated with tumor differentiation and proliferation [20
]. For example, a multi-institutional study of 198 LN-
patients without systemic adjuvant therapy demonstrated that the 70-gene, 76-gene, and 97-gene genomic grade signatures had similar prognostic performance; in all three signatures, the genes controlling tumor differentiation and proliferation had the greatest prognostic discriminatory strength [20
]. In addition, among the four different gene groups of the 21-gene signature, only the proliferative gene group is significantly associated with chemotherapy benefit in the ER+
patient cohort randomly assigned to tamoxifen or tamoxifen plus chemotherapy [21
]. Furthermore, time dependence of the prognostic performance of the 76-gene was examined over a period of 15 years to predict distant metastasis and overall survival and was compared with AO; for both risk assessments, the HRs decline over time [24
]. The prognostic performance of the 21-gene signature has been compared with AO and is consistent with our findings that prediction of the risk of recurrence with the assay is independent of that with AO [25