BRCA1 Promoter Hypermethylation is Associated with Good Prognosis and Chemosensitivity in Triple-Negative Breast Cancer.

William Jacot,Evelyne Lopez-Crapez,Séverine Guiu,Raphael Saffroy,Pierre-Jean Lamy,Antoinette Lemoine,Florence Boissière-Michot,Charles Theillet,Caroline Mollevi,Elodie Chartron,Alexandre Ho-Pun-Cheung,Joelle Simony-Lafontaine

doi:10.3390/cancers12040828

Abstract

The aberrant hypermethylation of BRCA1 promoter CpG islands induces the decreased expression of BRCA1 (Breast Cancer 1) protein. It can be detected in sporadic breast cancer without BRCA1 pathogenic variants, particularly in triple-negative breast cancers (TNBC). We investigated BRCA1 hypermethylation status (by methylation-specific polymerase chain reaction (MS-PCR) and MassARRAY® assays), and BRCA1 protein expression using immunohistochemistry (IHC), and their clinicopathological significance in 248 chemotherapy-naïve TNBC samples. Fifty-five tumors (22%) exhibited BRCA1 promoter hypermethylation, with a high concordance rate between MS-PCR and MassARRAY® results. Promoter hypermethylation was associated with reduced IHC BRCA1 protein expression (p = 0.005), and expression of Programmed death-ligand 1 protein (PD-L1) by tumor and immune cells (p = 0.03 and 0.011, respectively). A trend was found between promoter hypermethylation and basal marker staining (p = 0.058), and between BRCA1 expression and a basal-like phenotype. In multivariate analysis, relapse-free survival was significantly associated with N stage, adjuvant chemotherapy, and histological subtype. Overall survival was significantly associated with T and N stage, histology, and adjuvant chemotherapy. In addition, patients with tumors harboring BRCA1 promoter hypermethylation derived the most benefit from adjuvant chemotherapy. In conclusion, BRCA1 promoter hypermethylation is associated with TNBC sensitivity to adjuvant chemotherapy, basal-like features and PD-L1 expression. BRCA1 IHC expression is not a good surrogate marker for promoter hypermethylation and is not independently associated with prognosis. Association between promoter hypermethylation and sensitivity to Poly(ADP-ribose) polymerase PARP inhibitors needs to be evaluated in a specific series of patients.

Highlights

Triple-negative breast cancers (TNBCs) represent 15% of all breast cancers (BCs) and are defined by the absence of estrogen receptors (ERs), progesterone receptors (PRs), and Growth Factor Receptor-2 (HER2)overexpression/amplification [1,2]
We showed that BRCA1 protein expression, assessed by IHC, correlated with promoter hypermethylation status, and that both were associated with prognosis and CT efficacy
BRCA1 promoter hypermethylation appeared to be the most robust biomarker able to identify a particular subgroup of TNBCs without BRCA1 pathogenic variants, that were associated with a better prognosis and sensitivity to adjuvant CT

Summary

Introduction

Triple-negative breast cancers (TNBCs) represent 15% of all breast cancers (BCs) and are defined by the absence of estrogen receptors (ERs), progesterone receptors (PRs), and Growth Factor Receptor-2 (HER2)overexpression/amplification [1,2]. Triple-negative breast cancers (TNBCs) represent 15% of all breast cancers (BCs) and are defined by the absence of estrogen receptors (ERs), progesterone receptors (PRs), and Growth Factor Receptor-2 (HER2). 70% of basal-like BCs have a triple-negative phenotype (defined by immunohistochemistry [IHC]) and, using the PAM50 classifier, 80% of TNBCs can be classified as basal-like tumors [6]. An expanded surrogate immunopanel of markers (ER, PR, HER2, EGFR, and cytokeratin [CK] 5/6) provides a more specific IHC definition of basal-like BC [7]. ‘BRCAness’ is defined by the phenotypic similarities that some sporadic cancers share with those occurring in either BRCA1- or BRCA2-mutation carriers [11]. These tumors share a common deficiency in DNA repair

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