Gene expression analysis to detect disseminated tumor cells in the bone marrow of triple-negative breast cancer patients predicts metastatic relapse

Purpose Disseminated tumor cells (DTCs) in the BM of breast cancer patients predict early disease relapse, but the molecular heterogeneity of these cells is less well characterized. Expression of a 46-gene panel was used to detect DTCs and classify patient BM samples to determine whether a composite...

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Bibliographic Details
Published in:Breast cancer research and treatment 2019-11, Vol.178 (2), p.317-325
Main Authors: Siddappa, Chidananda M., Pillai, Sreeraj G., Snider, Jackie, Alldredge, Patsy, Trinkaus, Kathyrn, Watson, Mark A., Aft, Rebecca
Format: Article
Language:English
Subjects:
Adjuvant treatment
Analysis
Biomarkers, Tumor
Bone marrow
Bone Marrow - metabolism
Bone Marrow - pathology
Breast cancer
Cancer
Cancer research
Development and progression
Diseases
ErbB-2 protein
Ethylenediaminetetraacetic acid
Female
Gene expression
Gene Expression Regulation, Neoplastic
Genes
Genetic research
Health aspects
Humans
Kaplan-Meier Estimate
Medical research
Medicine
Medicine & Public Health
Medicine, Experimental
Metastases
Metastasis
Neoplasm Grading
Neoplasm Metastasis
Neoplasm Staging
Neoplastic Cells, Circulating
Oncology
Patients
Preclinical Study
Prognosis
Relapse
Therapeutic applications
Transcription
Transcriptome
Triple Negative Breast Neoplasms - genetics
Triple Negative Breast Neoplasms - mortality
Triple Negative Breast Neoplasms - pathology
Tumor Burden
Tumor cells
Women
Zoledronic acid
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Summary:Purpose Disseminated tumor cells (DTCs) in the BM of breast cancer patients predict early disease relapse, but the molecular heterogeneity of these cells is less well characterized. Expression of a 46-gene panel was used to detect DTCs and classify patient BM samples to determine whether a composite set of biomarkers could better predict metastatic relapse. Methods Using a high-throughput qRT-PCR assay platform, BM specimens collected from 70 breast cancer patients prior to neoadjuvant therapy were analyzed for the expression of 46 gene transcripts. Gene expression was scored positive (detectable) relative to a reference pool of 16 healthy female control BM specimens. To validate findings from a subset of 28 triple-negative breast cancer (TNBC) patients in the initial 70 patient cohort, an independent set of pre-therapeutic BM specimens from 16 TNBC patients was analyzed. Results Expression of each of the 46 gene transcripts was highly variable between patients. Individual gene expression was detected in 0–84% of BM specimens analyzed and all but two patient BM specimens expressed at least one transcript. Among a subset of 28 patients with TNBC, positivity of one or more of eight transcripts correlated with time to distant relapse ( p  = 0.03). In an independent set of 16 triple-negative patient BM samples, detection of five of these same eight gene transcripts also correlated with time to distant relapse ( p  = 0.03) with a positive predictive value of 89%. Conclusions We identified a set of gene transcripts whose detection in the BM of TNBC patients, prior to any treatment intervention, predicts time to first distant relapse, thus identifying a TNBC patient population which requires additional treatment intervention. Because these genes are presumably expressed in populations of DTCs and many encode proteins that are known therapeutic targets (e.g., ERBB2), these results also suggest a potential approach for targeted DTC therapy to mitigate distant metastases in TNBC.
ISSN:0167-6806
1573-7217
DOI:10.1007/s10549-019-05405-7