Elsevier

The Breast

Volume 45, June 2019, Pages 15-21
The Breast

Review
Homologous recombination deficiency in triple negative breast cancer

https://doi.org/10.1016/j.breast.2019.02.007Get rights and content

Highlights

  • Data from The Cancer Genome Atlas identified germline BRCA1/2 deleterious mutations in 10–20% of TNBC while somatic mutation in 3–5% of them.

  • Alterations in the HR system, typical of BRCA mutant tumors, can be also identified in tumors not carrying this mutation, defined as BRCAness.

  • Combination of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transition (LST) define the HRD score.

  • An HRD score ≥42 or the presence of BRCA1/2 mutations were correlated with objective response to cisplatin.

  • HRD has a potential role as a biomarker to predict response to DNA damaging drugs, PARP inhibitors, anthracyclines and/or cyclophosphamide.

Abstract

Triple negative breast cancer (TNBC) represents a heterogeneous subtype of breast cancer characterized by an unfavorable prognosis due to its aggressive biology. The median overall survival (OS) for patients with metastatic TNBC is around 9–12 months with conventional cytotoxic agents. Considering this suboptimal outcome, which is induced despite of medical treatment, new therapeutic strategies would be urgently needed. The ultimate goal of precision medicine is to identify specific molecular alterations that permit considering effective targeted drug(s). Germline BRCA mutations occur in 10–20% of TNBC patients while somatic mutations occur in 3–5% of them. Alterations in the homologous recombination (HR) system are typical of BRCA mutant tumors, but can also be identified in tumors that do not carry this mutation, defining a subgroup of patients referred to as BRCAness. In this review, we focus on the role of homologous recombination deficiency (HRD) as both predictive and prognostic factor in different settings of TNBC patients treated with DNA damaging drugs and poly ADP ribose polymerase (PARP) inhibitors.

Introduction

TNBC is an aggressive tumor accounting for 15% of breast cancers and conventionally defined by the absence of estrogen (ER), progesterone (PR) and human epidermal growth factor 2 (HER2) receptors. TNBC includes a heterogeneous group of tumors, typically occurring in very young patients and which metastasizes commonly by hematogenous spread, having lung and brain as major first sites of metastasis. It usually shows a peak of recurrence during the first three years, with the majority of deaths occurring within the first 5 years [1,2]. Data from The Cancer Genome Atlas (TCGA) and smaller prospective registries identified germline BRCA1/2 deleterious mutations in 10–20% of TNBC patients while somatic mutation in 3–5% of them [3,4].

Tumors with BRCA1/2 mutations typically carry a deficient HR system, cardinal for DNA repair from an insult [5]. DNA is exposed to continuous damage, causing a range of lesions varying from single-strand break (SSB), double-strand break (DSB), bulky adducts, base mismatches, insertions, deletions and base alkylation. The type of lesion present on DNA defines the repair mechanism of choice. In presence of DSB, the HR system removes the DSB and uses a homologous DNA template to repair it [6]. This mechanism acts in phase S and G2 of the cell cycle and requires the involvement of proteins encoded by the BRCA1, BRCA2, RAD51 and PALB2 genes. Mutations in one of these key components of DNA repair system are responsible for limited DNA repair capacity [[7], [8], [9], [10], [11]]. Tumors harboring mutations in one of these genes, for example, result more sensible to platinum agents or PARP inhibitors, since these compounds cause DNA inter- and intra-strand crosslinks that can not be recognized and subsequently repaired by HR system, ultimately resulting as defective [12]. Fig. 1 summarizes the key players and their roles in generating the phenotype of HR deficient tumors.

In this review, we focused on the contribution of HRD system as predictive and prognostic factor evaluated in different settings of TNBC patients.

Section snippets

BRCA1/2 mutation and homologous recombination (HR) system

Tumors defined as BRCA1/2 deficient show large regions of loss of heterozygosity (LOH), telomeric allelic imbalance (TAI), and large-scale transition (LST) [13]. These three characteristics combined together define the HRD score, which is useful to define the HR deficient status [[14], [15], [16]]. The test used for HRD determination hereon was based on single nucleotide polymorphism (SNP) analysis using two main assays: Myriad genetics and myChoice HRD [17,18]. The first test was analyzed in a

HRD in the adjuvant setting

A study conducted by Sharma et al. evaluated the prognostic role of HRD status, HRD score, and BRCA1 promoter methylation in 425 patients affected by TNBC, comprised either by high risk/node-negative or low-risk/node positive disease and treated with two equivalent dose schedules of doxorubicin and cyclophosphamide [25]. HRD status was positive in 67% of patients, from which 27% had BRCA1/2 mutations. Positive HRD status was associated with a prolonged disease free survival (DFS) (HR 0.72, 95%

HRD in the neoadjuvant setting

The phase III neoadjuvant trial BrighTNess randomized clinical stage II-III TNBC to receive a standard neoadjuvant chemotherapy with paclitaxel followed by anthracyclines and cyclophosphamides with or without carboplatin and with or without veliparib [26]. In an analysis conducted on global population independently from BRCA status, veliparib did not provide any benefit in comparison to chemotherapy. pCR, in fact, was significantly higher among patients receiving paclitaxel plus carboplatin

HRD in the metastatic and relapsed settings

The phase II BROCADE trial evaluated the combination of veliparib plus temozolomide (VT) versus veliparib plus carboplatin and paclitaxel (VCP) versus placebo plus carboplatin plus paclitaxel (PCP) in metastatic or locally recurred TNBC carrying a BRCA mutation [30]. Median PFS was 7.4 months in VT arm, 14.1 months for VCP and 12.3 months for PCP. Median OS was 19.1 months in the first treatment arm, 28.3 in the second and 25.9 in the third. All these data did not reach statistical

Discussion

Hereditary BRCA1/2 mutations are found in 5.3% of all breast cancer and it increases to 10–20% in the TNBC subgroup. Somatic mutations were also reported in 3–5% of TNBC [3,4]. BRCA1/2 and PALB2, among many other genes involved in the mechanism of DNA repair, are critical players in the HR repairs of DSB and are associated with TNBC phenotype [43]. Tumors harboring mutation(s) in one of these genes result more sensible to platinum agents or PARP inhibitors since these compounds cause DNA inter

Conflicts of interest

We wish confirm that there are no known conflicts of interest associated with this publication and there has been no significant financial support for this work that could have influenced its outcome. We confirm that the manuscript has been read and approved by all named authors and that there are no other persons who satisfied the criteria for authorship but are not listed. We further confirm that the order of authors listed in the manuscript has been approved by all of us.

We confirm that we

Funding source

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Acknowledgements

The authors would like to thank Camila Da Silveira Achutti Duso for help in generating the schematic figure.

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