Transforming genomic grade index (GGI) into a user-friendly qRT-PCR tool which will assist clinicians and patients in optimizing treatment of early breast cancer (BC).
Durbecq V, Toussaint J, Haibe-Kains B, Desmedt C, Rouas G, Larsimont D, Buyse M, Bontempi G, Piccart M and Sotiriou C
Background: We
have recently shown that proliferation captured by the genomic grade
index (GGI) is the most important prognostic factor in BC, far beyond
estrogen receptor (ER) status and may encompass a significant portion
of the predictive power of many previously published prognostic
signatures. Furthermore, we have demonstrated that GGI can identify two
clinically distinct ER-positive molecular subtypes in a simple and
highly reproducible manner across multiple datasets. The aims of this
study were to convert and validate by qRT-PCR assay the prognostic
value of the GGI using frozen (FS) and paraffin-embedded tumor samples
(FFPE) from early BC patients.
Methods: We first developed a
qRT-PCR assay based on 8 selected GGI genes involved in different
phases of the cell cycle and 4 reference genes. We then tested its
accuracy and concordance with the original microarray derived GGI using
a BC population from which FS, FFPE tissues and microarray data were
available (N=30). Finally, we assessed its prognostic value on an
independent ER-positive tamoxifen only treated BC population (N=82).
Results: A statistically
significant correlation was observed between GGI generated by
microarray and qRT-PCR assay using FS material (r=0.91; p<0.0001) as
well as between GGI using qRT-PCR derived from FS and FFPE tumor
samples (r=0.86; p<0.0001). A high GGI levels assessed by qRT-PCR
(GGRI) was associated with a higher risk of recurrence in the
ER-positive tamoxifen only treated patients [HR= 7.021 (95% CI:
1.245-4.321), p=0.008] in accordance with our previous microarray
results. Interestingly, in a multivariate analysis, GGRI remained
significant (HR=4.22 (95% CI: 1.031-3.710), p=0.04) together with age
(<50y) and tumor size (>2cm).
Conclusions: In this study, we
report a qRT-PCR assay based on a limited number of genes, which
recapitulates in an accurate and reproducible manner the prognostic
power of the microarray derived GGI using both FS and FFPE tumor
samples. Further validation of its prognostic value is currently
ongoing on two independent populations totaling over 500 BC patients.