Comprehensive analysis integrating both clinicopathological and gene expression data in more than 1500 samples: Proliferation captured by gene expression grade index appears to be the strongest prognostic factor in breast cancer (BC)

Sotiriou C, Wirapati P, Loi S, Haibe-Kains B, Desmedt C, Tutt A., Ellis P., Buyse M, Delorenzi M, Piccart M

Background: Although, the development of high-throughput gene expression technologies has allowed the identification of several molecular signatures predicting clinical outcome, no attempt has been made yet to perform a comprehensive analysis integrating both clinicopathological, and gene expression data. Here, we aim to elucidate the relationship between clinical parameters and tumor markers, with gene expression patterns and their interaction with prognosis.

Methods: We analyzed gene expression and clinical data from several published studies, including more than 1500 BC patients. We developed several gene expression indices associated with different biological stages of disease characterized by the expression of hormone receptors, HER2 amplification, p53 mutation, angiogenesis, tumor invasion and proliferation. Multivariable analyses were used to characterize the dependency patterns between these indices and their impact on survival.

Results: Estrogen receptor (ER) and HER2 indices were the most prominent discriminators dichotomizing tumor samples into two main subsets in agreement with the previously proposed BC subtypes. Tumor proliferation, assessed by our previously reported gene expression index (GGI), was the most strongly associated with prognosis (HR 2.29, CI 1.88-2.78, p<0.0001). Almost all ER- and HER2+ tumors were associated with high GGI scores. In contrast, ER+ and HER2- tumors showed a whole range of GGI values. Within the high proliferation subset, ER- and HER2+ indices did not have any prognostic value. Similar results were found with relation to p53 mutation index. Nodal status and tumor size, which essentially measure the duration of disease, retained prognostic value in addition to proliferation.

Conclusions: Proliferation captured by the GGI appears to be a key biological factor, downstream of ER, HER2 and p53. Although understanding the upstream factors is important for advancing biological knowledge and therapeutic interventions, GGI seems to be the most important factor predicting clinical outcome in BC and deserves consideration as stratification factor in clinical trials.