Gene Expression Profiling in Breast Cancer: Understanding the Molecular Basis of Histologic Grade To Improve Prognosis
Sotiriou
C, Wirapati P, Loi S, Harris A, Bergh J, Smeds J, Farmer P, Praz V,
Haibe-Kains B, Lallemand F, Buyse M, Piccart M and Delorenzi M
Background:
Histologic grade in breast cancer provides clinically important
prognostic information. However, 30%-60% of tumors are classified as
histologic grade 2. This grade is associated with an intermediate
risk of recurrence and is thus not informative for clinical decision
making. We examined whether histologic grade was associated with gene
expression profi les of breast cancers and whether such profi les could
be used to improve histologic grading.
Methods: We analyzed microarray
data from 189 invasive breast carcinomas and from three published gene
expression datasets from breast carcinomas. We identified
differentially expressed genes in a training set of 64 estrogen
receptor (ER)-positive tumor samples by comparing expression profiles
between histologic grade 3 tumors and histologic grade 1 tumors and
used the expression of these genes to define the gene expression grade
index. Data from 597 independent tumors were used to evaluate the
association between relapse-free survival and the gene expression grade
index in a Kaplan-Meier analysis. All statistical tests were
two-sided.
Results: We identified 97
genes in our training set that were associated with histologic grade;
most of these genes were involved in cell cycle regulation and
proliferation. In validation datasets, the gene expression grade index
was strongly associated with histologic grade 1 and 3 status; however,
among histologic grade 2 tumors, the index spanned the values for
histologic grade 1-3 tumors. Among patients with histologic
grade 2 tumors, a high gene expression grade index was associated with
a higher risk of recurrence than a low gene expression grade index
(hazard ratio = 3.61, 95% confidence interval = 2.25 to
5.78; P<.001, log-rank test).
Conclusions: Gene expression
grade index appeared to reclassify patients with histologic grade 2
tumors into two groups with high versus low risks of recurrence. This
approach may improve the accuracy of tumor grading and thus its
prognostic value.