Improved prediction of disease-free survival in tamoxifen-treated patients using an expression signature of estrogen-regulated genes as compared to progesterone receptor

Abstract

535 Background: Progesterone receptor (PR) is a direct downstream target of activated estrogen receptor (ER) and its expression is a marker of estrogen signaling within breast tumors. Studies suggest the absence of PR predicts the likelihood of distant recurrence in patients treated with hormonal therapies such as tamoxifen, but better clinical measures are needed. Methods: Through analysis of public mRNA expression profiling datasets, we identified 36 genes with the following expression patterns similar to PR: (1) induced by 17β-estradiol (E2) in estrogen receptor (ER)-positive breast cancer cell lines in vitro, (2) under-expressed in ER-negative compared to ER-positive breast tumors, and (3) correlated with PR expression in ER-positive tumors. The average expression of these 36 genes was used as a “risk index” for assessing disease-specific survival in two independent tumor profile datasets of 60 and 67 patients treated with tamoxifen (these data not having been used to initially select the 36 genes), with a high risk group in each dataset defined as those with the bottom 25% of risk index values. Results: The Kaplan-Meier estimates of the rates of distant recurrence at 10 years in the low-risk and high-risk groups were 24% and 64% in the one dataset and 32% and 72% in the other dataset. In both validation datasets, the rate in the low-risk group was significantly lower than that in the high-risk group (P=0.008 and P=0.006 by log-rank, respectively), whereas patient groups defined by histologically-assigned PR status did not show significant risk differences (P=0.70 and P=0.94, respectively). In a univariate Cox model, the risk index combined across both validation datasets provided significant predictive power (P=0.03). Conclusions: Through RT-PCR assay of a larger independent cohort of breast tumor samples, we are currently validating the prognostic value of individual genes within the 36-gene signature. No significant financial relationships to disclose.