Clinical Correlates of 'BRCAness' in Triple-Negative Breast Cancer of Patients Receiving Adjuvant Chemotherapy

A. M. M. Oonk; C. van Rijn; M. M. Smits; L. Mulder; N. Laddach; S. P. Savola; J. Wesseling; S. Rodenhuis; A. L. T. Imholz; E. H. Lips

Disclosures

Ann Oncol. 2012;23(9):2301-2305. 

In This Article

Abstract and Introduction

Abstract

Background We have previously reported an array comparative genomic hybridization profile that identifies triple-negative breast cancers (TNBC), with BRCA1 dysfunction and a high sensitivity to intensified dose bifunctional alkylating agents. To determine the effect of conventional-dose chemotherapy in patients with this so-called BRCA1-like profile, clinical characteristics and survival were studied in a large group of TNBC patients.
Patients and methods DNA was isolated and BRCA1-like status was assessed in 101 patients with early-stage TNBC receiving adjuvant cyclophosphamide-based chemotherapy. Clinical characteristics and survival were compared between BRCA1-like and non-BRCA1-like groups.
Results Sixty-six tumors (65%) had a BRCA1-like profile. Patients with BRCA1-like tumors tended to be younger and had more often node-negative disease (P = 0.06 and P = 0.03, respectively). Five-year recurrence-free survival was 80% for the BRCA1-like group and 75% for the non-BRCA1-like group (P = 0.35). T stage was the only variable significantly associated with survival.
Conclusions BRCA1-like tumors share clinical features, like young age at diagnosis and similar nodal status, with breast cancers in BRCA1 mutation carriers. Their prognosis is similar to that of non-BRCA1-like tumors when conventional-dose chemotherapy is administered. TNBCs that are classified as BRCA1-like may contain a defect in homologous recombination and could, in theory, benefit from the addition of poly ADP ribose polymerase inhibitors.

Introduction

The triple-negative breast cancer (TNBC) subtype occurs in ~15% of cases and is associated with rapid growth, early metastasis and a worse prognosis than other breast cancer subtypes.[1] Since targeted treatment options, such as endocrine agents or HER2-directed therapy are unavailable, chemotherapy remains the mainstay of systemic treatment.

In a recent study of our institute, it was shown that TNBC frequently shows an array comparative genomic hybridization (aCGH) genomic profile that is also present in breast cancers of BRCA1 mutation carriers.[2] We have hypothesized that this profile is indicative of defects in the BRCA pathway, resulting in features that are often called 'BRCAness'. As the BRCA1 protein plays a crucial role in the DNA repair pathway of homologous recombination, it is assumed that tumors with BRCA1 dysfunction are homologous recombination deficient (HRD). In vitro and preclinical studies have shown that tumors with aberrations in the BRCA1 gene, resulting in HRD, are extremely sensitive to DNA double-strand break (DSB) inducing chemotherapy.[3–5] We have recently shown that tumors with an aCGH profile suggestive of BRCAness are extremely sensitive to high-dose platinum-based chemotherapy but have similar sensitivity to conventionally dosed chemotherapy or may even do worse than other triple-negative tumors with conventional therapy.[2]

To further investigate the clinical consequences of our assay for BRCAness, we studied a consecutive series of patients who presented for adjuvant chemotherapy of early TNBC in a community hospital. We sought to determine the proportion of TNBCs with BRCA1-like features and to identify possible correlations with clinical course and survival.

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