Abstract
BackgroundThe purpose of the work reported here is to test reliable molecular profiles using routinely processed formalin-fixed paraffin-embedded (FFPE) tissues from participants of the clinical trial BIG 1-98 with a median follow-up of 60 months.MethodsRNA from fresh frozen (FF) and FFPE tumor samples of 82 patients were used for quality control, and independent FFPE tissues of 342 postmenopausal participants of BIG 1-98 with ER-positive cancer were analyzed by measuring prospectively selected genes and computing scores representing the functions of the estrogen receptor (eight genes, ER_8), the progesterone receptor (five genes, PGR_5), Her2 (two genes, HER2_2), and proliferation (ten genes, PRO_10) by quantitative reverse transcription PCR (qRT-PCR) on TaqMan Low Density Arrays. Molecular scores were computed for each category and ER_8, PGR_5, HER2_2, and PRO_10 scores were combined into a RISK_25 score.ResultsPearson correlation coefficients between FF- and FFPE-derived scores were at least 0.94 and high concordance was observed between molecular scores and immunohistochemical data. The HER2_2, PGR_5, PRO_10 and RISK_25 scores were significant predictors of disease free-survival (DFS) in univariate Cox proportional hazard regression. PRO_10 and RISK_25 scores predicted DFS in patients with histological grade II breast cancer and in lymph node positive disease. The PRO_10 and PGR_5 scores were independent predictors of DFS in multivariate Cox regression models incorporating clinical risk indicators; PRO_10 outperformed Ki-67 labeling index in multivariate Cox proportional hazard analyses.ConclusionsScores representing the endocrine responsiveness and proliferation status of breast cancers were developed from gene expression analyses based on RNA derived from FFPE tissues. The validation of the molecular scores with tumor samples of participants of the BIG 1-98 trial demonstrates that such scores can serve as independent prognostic factors to estimate disease free survival (DFS) in postmenopausal patients with estrogen receptor positive breast cancer.Trial RegistrationCurrent Controlled Trials: NCT00004205
Highlights
The purpose of the work reported here is to test reliable molecular profiles using routinely processed formalin-fixed paraffin-embedded (FFPE) tissues from participants of the clinical trial BIG 1-98 with a median followup of 60 months
Reliable expression profiling from FFPE tumor tissue Gene expression was measured from 34 genes using TaqMan Low Density Arrays (TLDAs) with RNA isolated from FF and FFPE material of 82 breast cancers
We provide evidence independent of Genomic HealthTM that a RISK score based on similar biological processes as the recurrence score (RS), but with other genes selected through a different procedure, can predict disease free survival (DFS) [29,41,42]
Summary
The purpose of the work reported here is to test reliable molecular profiles using routinely processed formalin-fixed paraffin-embedded (FFPE) tissues from participants of the clinical trial BIG 1-98 with a median followup of 60 months. DNA-chip based expression analyses have confirmed the heterogeneity of breast cancer and allowed the development of clinically relevant gene “signatures” or “profiles” [10,11,12,13,14,15,16,17,18,19,20] Such profiles are being implemented widely in routine patient care even though many signatures were developed and validated on heterogeneous patient cohorts with respect to stage of disease and therapy. Most profiling studies are based on fresh-frozen (FF) or RNAlater conserved tissue Such material must be collected and processed separately after surgery, complicating the implementation of molecular analyses into the clinical workflow. FFPE tissues collected in the framework of clinical trials could be a valuable resource for future research
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