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A New Gene Expression Signature for Triple Negative Breast Cancer Using Frozen Fresh Tissue before Neoadjuvant Chemotherapy.

ABSTRACT: Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer tumors. Comparisons between TNBC and non-triple negative breast cancer (nTNBC) may help to differentiate key components involved in TNBC neoplasms. The purpose of the study was to analyze the expression profile of TNBC versus nTNBC tumors in a homogeneous population from northeastern Mexico. A prospective study of 50 patients was conducted (25 TNBC and 25 nTNBC). Clinic parameters were equally distributed for TNBC and nTNBC: age at diagnosis (51 vs 47 years, p=0.1), glucose levels (107 mg/dl vs 104 mg/dl, p=0.64), and body mass index (28 vs 29, p=0.14), respectively. Core biopsies were collected for histopathological diagnosis and gene expression analyses. Total RNA was isolated and expression profiling was performed. 40 genes showed differential expression pattern in TNBC tumors. Among these, 9 over-expressed genes (PRKX/PRKY, UGT8, HMGA1, LPIN1, HAPLN3, and ANKRD11), and one under-expressed (ANX9) gene are involved in general metabolism. Based on this biochemical peculiarity, and the over-expression of BCL11A and FOXC1 (involved in tumor growth and metastasis, respectively) we validated by qPCR the expression profile of 7 genes out of the signature. In this report, a new gene signature for TNBC is proposed. To our knowledge, this is the first TNBC signature which describes genes involved in general metabolism. The findings may be pertinent for Mexican patients and require to be evaluated in further ethnic groups and populations.

SUBMITTER: Santuario-Facio SK

PROVIDER: S-EPMC5469719 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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A New Gene Expression Signature for Triple Negative Breast Cancer Using Frozen Fresh Tissue before Neoadjuvant Chemotherapy.

Santuario-Facio Sandra Karina SK Cardona-Huerta Servando S Perez-Paramo Yadira Xitlalli YX Trevino Victor V Hernandez-Cabrera Francisco F Rojas-Martinez Augusto A Uscanga-Perales Grecia G Martinez-Rodriguez Jorge Luis JL Martinez-Jacobo Lizeth L Padilla-Rivas Gerardo G Muñoz-Maldonado Gerardo G Gonzalez-Guerrero Juan Francisco JF Valero-Gomez Javier J Vazquez-Guerrero Ana Lorena AL Martinez-Rodriguez Herminia Guadalupe HG Barboza-Quintana Alvaro A Barboza-Quintana Oralia O Garza-Guajardo Raquel R Ortiz-Lopez Rocio R

Molecular medicine (Cambridge, Mass.) 20170504

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer tumors. Comparisons between TNBC and non-triple negative breast cancer (nTNBC) may help to differentiate key components involved in TNBC neoplasms. The purpose of the study was to analyze the expression profile of TNBC versus nTNBC tumors in a homogeneous population from northeastern Mexico. A prospective study of 50 patients was conducted (25 TNBC and 25 nTNBC). Clinic parameters were equally distributed for TNBC and ...[more]

PMID: 28474731

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Project description:BackgroundWhile the efficacy of neoadjuvant chemotherapy (NACT) in treating triple-negative breast cancer (TNBC) is generally accepted, not all patients derive benefit from this preoperative treatment. Presently, there are no validated biomarkers to predict the NACT response, and previous attempts to develop predictive classifiers based on gene expression data have not demonstrated clinical utility. However, predictive models incorporating biological constraints have shown increased robustness and improved performance compared to agnostic classifiers.MethodsWe used the preoperative transcriptomic profiles from 298 patients with TNBC to train and test a rank-based classifier, k-top scoring pairs, to predict whether the patient will have pathological complete response (pCR) or residual disease (RD) following NACT. To reduce overfitting and enhance the signature's interpretability, we constrained the training process to genes involved in the Notch signaling pathway. Subsequently, we evaluated the signature performance on two independent cohorts with 75 and 71 patients. Finally, we assessed the prognostic value of the signature by examining its association with relapse-free survival (RFS) using Kaplan‒Meier (KM) survival estimates and a multivariate Cox proportional hazards model.ResultsThe final signature consists of five gene pairs, whose relative ordering can be predictive of the NACT response. The signature has a robust performance at predicting pCR in TNBC patients with an area under the ROC curve (AUC) of 0.76 and 0.85 in the first and second testing cohorts, respectively, outperforming other gene signatures developed for the same purpose. Additionally, the signature was significantly associated with RFS in an independent TNBC patient cohort even after adjusting for T stage, patient age at the time of diagnosis, type of breast surgery, and menopausal status.ConclusionWe introduce a robust gene signature to predict pathological complete response (pCR) in patients with TNBC. This signature applies easily interpretable, rank-based decision rules to genes regulated by the Notch signaling pathway, a known determinant in breast cancer chemoresistance. The robust predictive and prognostic performance of the signature make it a strong candidate for clinical implementation, aiding in the stratification of TNBC patients undergoing NACT.

Project description:BackgroundTriple negative breast cancer (TNBC) is a heterogeneous disease that lacks unifying molecular alterations that can guide therapy decisions. We previously identified distinct molecular subtypes of TNBC (TNBCtype) using gene expression data generated on a microarray platform using frozen tumor specimens. Tumors and cell lines representing the identified subtypes have distinct enrichment in biologically relevant transcripts with differing sensitivity to standard chemotherapies and targeted agents. Since our initial discoveries, RNA-sequencing (RNA-seq) has evolved as a sensitive and quantitative tool to measure transcript abundance.MethodsTo demonstrate that TNBC subtypes were similar between platforms, we compared gene expression from matched specimens profiled by both microarray and RNA-seq from The Cancer Genome Atlas (TCGA). In the clinical care of patients with TNBC, tumor specimens collected for diagnostic purposes are processed by formalin fixation and paraffin-embedding (FFPE). Thus, for TNBCtype to eventually have broad and practical clinical utility we performed RNA-seq gene expression and molecular classification comparison between fresh-frozen (FF) and FFPE tumor specimens.ResultsAnalysis of TCGA showed consistent subtype calls between 91% of evaluable samples demonstrating conservation of TNBC subtypes across microarray and RNA-seq platforms. We compared RNA-seq performed on 21-paired FF and FFPE TNBC specimens and evaluated genome alignment, transcript coverage, differential transcript enrichment and concordance of TNBC molecular subtype calls. We demonstrate that subtype accuracy between matched FF and FFPE samples increases with sequencing depth and correlation strength to an individual TNBC subtype.ConclusionsTNBC subtypes were reliably identified from FFPE samples, with highest accuracy if the samples were less than 4 years old and reproducible subtyping increased with sequencing depth. To reproducibly subtype tumors using gene expression, it is critical to select genes that do not vary due to platform type, tissue processing or RNA isolation method. The majority of differentially expressed transcripts between matched FF and FFPE samples could be attributed to transcripts selected for by RNA enrichment method. While differentially expressed transcripts did not impact TNBC subtyping, they will provide guidance on determining which transcripts to avoid when implementing a gene set size reduction strategy.Trial registrationNCT00930930 07/01/2009.

Dataset Information

A New Gene Expression Signature for Triple Negative Breast Cancer Using Frozen Fresh Tissue before Neoadjuvant Chemotherapy.

Publications

A New Gene Expression Signature for Triple Negative Breast Cancer Using Frozen Fresh Tissue before Neoadjuvant Chemotherapy.

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