Abstract
BackgroundProliferation and tumor differentiation captured by the genomic grade index (GGI) are important prognostic indicators in breast cancer (BC) especially for the estrogen receptor positive (ER+) disease. The aims of this study were to convert this microarray index to a qRT-PCR assay (PCR-GGI), which could be realized on formalin fixed paraffin embedded samples (FFPE), and to assess its prognostic performance and predictive value of clinical benefit in early and advanced ER+ BC patients treated with tamoxifen.MethodsThe accuracy and concordance of the PCR-GGI with the GGI was assessed using BC patients for which frozen and FFPE tissues as well as microarray data were available (n = 19). The evaluation of the prognostic value of the PCR-GGI was assessed on FFPE material using a consecutive series of 212 systemically treated early BC patients. The predictive performance for tamoxifen benefit was assessed using two ER+ BC populations treated either with adjuvant tamoxifen only (n = 77+139) or first-line tamoxifen for advanced disease (n = 270).ResultsThe PCR-GGI is based on the expression of 8 genes (4 representative of the GGI and 4 reference genes). A significant correlation was observed between the microarray-derived GGI and the qRT-PCR assay using frozen (ρ = 0.95, p < 10E-06) and FFPE material (ρ = 0.89, p < 10E-06). The prognostic performance of the PCR-GGI was confirmed on FFPE samples (HRunivar. = 1.89; [95CI:1.01-3.54], p = 0.05). The PCR-GGI further identified two subgroups of patients with statistically different time to distant metastasis free survival (DMFS) across the two cohorts of ER+ BC patients treated with adjuvant tamoxifen. Additionally, the PCR-GGI was associated with response to tamoxifen in the advanced setting (HRunivar. = 1.98; [95CI:1.51-2.59], p = 6.9E-07).ConclusionPCR-GGI recapitulates in an accurate and reproducible manner the performances of the GGI using frozen and FFPE samples.
Highlights
Proliferation and tumor differentiation captured by the genomic grade index (GGI) are important prognostic indicators in breast cancer (BC) especially for the estrogen receptor positive (ER+) disease
Development of the reduced genomic qRT-PCR grade index (PCR-GGI) The first step in the development of the PCR-GGI was to identify a minimum number of genes that could recapitulate the performance of the original GGI
Prognostic performance of the PCR-GGI To evaluate the prognostic performance of the PCR-GGI, we considered an independent population of 212 primary BC fixed paraffin embedded samples (FFPE) samples originated from patients consecutively diagnosed at the Jules Bordet Institute between 1995 and
Summary
Proliferation and tumor differentiation captured by the genomic grade index (GGI) are important prognostic indicators in breast cancer (BC) especially for the estrogen receptor positive (ER+) disease. Several groups have evaluated the potential of gene expression profiles to improve BC prognostication. This has resulted in the identification of several gene signatures, most of them outperforming current clinico-pathological parameters in predicting clinical outcome (reviewed in [1]). The hypothesis beyond the development of this index was to improve BC grading and its prognostic value This index includes 97 genes that are consistently differentially expressed between low and high histological grade breast tumors. One of the major findings of that study was that GGI could assign intermediate histological grade tumors into two distinct subgroups whose gene expression profiles and clinical outcome was similar to the ones of low and high histological grade tumors respectively. GGI could identify two clinically relevant ER+ subtypes with very distinct clinical outcomes in both systemically untreated and tamoxifen only treated BC patients [3]
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