Abstract
BackgroundPathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40% approximately. To provide further insight into the prediction of pCR, we evaluated the role of an epigenetic methylation-based signature.MethodsEpigenetic assessment of DNA extracted from biopsy archived samples previous to NAC from TNBC patients was performed. Patients included were categorized according to previous response to NAC in responder (pCR or residual cancer burden, RCB = 0) or non-responder (non-pCR or RCB > 0) patients. A methyloma study was performed in a discovery cohort by the Infinium HumanMethylation450 BeadChip (450K array) from Illumina. The epigenetic silencing of those methylated genes in the discovery cohort were validated by bisulfite pyrosequencing (PyroMark Q96 System version 2.0.6, Qiagen) and qRT-PCR in an independent cohort of TN patients and in TN cell lines.ResultsTwenty-four and 30 patients were included in the discovery and validation cohorts, respectively. In the discovery cohort, nine genes were differentially methylated: six presented higher methylation in non-responder patients (LOC641519, LEF1, HOXA5, EVC2, TLX3, CDKL2) and three greater methylation in responder patients (FERD3L, CHL1, and TRIP10). After validation, a two-gene (FER3L and TRIP10) epigenetic score predicted RCB = 0 with an area under the ROC curve (AUC) = 0.905 (95% CI = 0.805–1.000). Patients with a positive epigenetic two-gene score showed 78.6% RCB = 0 versus only 10.7% RCB = 0 if signature were negative.ConclusionsThese results suggest that pCR in TNBC could be accurately predicted with an epigenetic signature of FERD3L and TRIP10 genes. Further prospective validation of these findings is warranted.
Highlights
Pathological complete response after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40% approximately
A 70-gene panel combined with Deoxyribonucleic acid (DNA) deficient biomarkers have shown a 75% Pathological complete response (pCR) in a subset of TNBC patients treated with carboplatin and veliparib in a recent publication of this cohort [15]
All patients were treated with NAC based on a taxane and/or anthracycline regimen and all of them were considered TNBC according to immunohistochemistry for Estrogen receptors (ER), Progesterone receptor (PR), and Erb-b2 receptor tyrosine kinase 2 (HER2)
Summary
Pathological complete response (pCR) after neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) varies between 30 and 40% approximately. 33-gene panel and has been validated in 1129 patients across five independent data sets [13] All these predictive panels have shown to do better in ER positive breast cancer than in ER negative. A 70-gene panel combined with DNA deficient biomarkers have shown a 75% pCR in a subset of TNBC patients treated with carboplatin and veliparib in a recent publication of this cohort [15]. All these panels have been designed based on arrays of gene-expression techniques. Epigenetic modifications of certain genes can lead to silence or activation of different genes [16, 17]
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