Predicting
relapse in estrogen receptor (ER) positive breast cancer (luminal)
subgroups treated with adjuvant tamoxifen.
Loi S,
Desmedt C, Haibe-Kains B, Lallemand F, Gillett C, Tutt A, Ryder K,
Ellis P, Harris A, Smeds J, Bergh J, Cardoso F, Piccart MJ, Sotiriou
C
Background:
ER-positive breast cancers (BC) exhibit considerable clinical
heterogeneity. Microarray profiling has lead to the notion of distinct
molecular subgroups within ER-positive BC; these are often described as
luminal subtypes (Sorlie, Sotiriou et al). The luminal subtypes seem to
be directly associated with proliferative genes, with the luminal A
group correlated with low grade, and the B and C groups with high
grade. We sought to further define these subtypes and identify genes
associated with BC recurrence within the subgroups of ER-positive
BC.
Material and Methods:
We determined gene expression profiles from 168 tamoxifen-only treated
ER positive early stage BC samples (training set) using Affymetrix U133
2.0 Plus Genechips. Median follow-up was 7.3 yrs. We divided these
tumors into 2 groups according to their degree of proliferation. These
groups, which had distinct clinical outcomes (HR:4.1, 95%CI:2.0-8.5,
p<0.001), were named low and high grade ER-positive subtypes and
are molecularly consistent with the previously described luminal
subtypes of Sorlie and Sotiriou et al. Genes associated with distant
relapse within the subtypes were identified using Cox proportional
hazards model. The independent validation set consisted of 86
ER-positive tamoxifen-only treated BC from a different institution.
Results: For
the low grade subgroup we identified 330 genes that were significantly
associated with distant relapse. Here, many genes were related to
immune function. In the high grade subgroup 195 genes were identified,
including many that were HER-2 and ER-related. The probability of
selecting these genes by chance was estimated to be p=0.01 and 0.04
after 1000 random permutations respectively. There were only 7 genes in
common. In the independent validation set, these genes could identify
distinct prognostic groups within the low (n=44) and high grade
subtypes (n=42): low grade: HR: 3.9 (95%CI: 0.9-19.2), p=0.06; high
grade HR: 2.7 (95%CI:1.1-7.1), p= 0.04. We are currently validating
this concept in a further 100 tumor samples.
Discussion:
ER-positive BC can be divided into low grade or high grade subtypes.
Furthermore, different groups of genes can identify women at high risk
of relapse on adjuvant tamoxifen within these ER-positive subgroups for
whom other therapies could be targeted. Further investigation into the
biology of these diverse gene sets could substantially aid treatment
tailoring for BC patients.