Introduction
Breast cancer (BC) heterogeneity is associated with diverse causal factors, such as heredity, environmental exposure, hormonal impregnation and infectious agents. Among these factors, viruses are regularly implicated in the pathogenesis of cancer, although the results of different studies have been inconsistent (1). In particular, the Epstein Barr virus (EBV) is clearly associated with nasopharyngeal cancer, but a causal relationship with BC was also demonstrated in the mid-1990s (2). The reported incidence of EBV-positive BC varies according to the technique used and the targeted viral genomic regions (1). We previously demonstrated the presence of EBV in ≤ 30% of BC specimens (3, 4). Of note, EBV-related BC were found to be associated with more aggressive patterns (4).
A previous study published by Perou et al using genomic profiling has made a major contribution to the understanding of BC heterogeneity (5). A new classification is currently available, based on 5 expression signatures revealing distinct patterns. The BC subtypes clearly reflect groups with different outcomes and response to chemotherapy (6). Using clinicopathological factors, such as hormone receptors (HRs), human epidermal growth receptor 2 (HER2) and grade or Ki67, this intrinsic BC classification may be determined in routine practice (7).
Several questions regarding the significance of EBV in BC remain challenging and the association with oncogenesis remains obscure. An adverse outcome for EBV-positive BC was previously suggested (8, 9). The purpose of our study was to evaluate the prognosis of EBV-positive BC. In addition, we incorporated the BC subtype classification in order to refine the evaluation of the prognosis.
Discussion
Several converging studies have demonstrated the presence of EBV in BC. However, despite evidence on the presence of EBV in BC specimens, an oncogenic role for EBV has yet to be established and the significance of EBV-positive BC has not been fully elucidated.
Virus-related BC has a poor prognosis, particularly when multiple viruses are detected in breast specimens (8). We previously demonstrated that EBV-positive BC exhibits more aggressive characteristics (3, 4). Other authors corroborated our findings (2, 8); however, the effect on survival has not been extensively investigated. The subgroup analyses as a function of the BC phenotype confirmed that the EBV status exerted no effect on survival outcome (DFS or OS). Of note, in EBV-positive tumours, DFS was of borderline significance, with an adverse prognostic outcome for lumB and HER2 tumours. LumB and HER2 tumours were previously demonstrated to carry a poor prognosis (6).
There were certain limitations to our study. Our series was small, information was lacking on the adjuvant therapies administered and the treatments received were heterogeneous. In particular, the unavailability of trastuzumab therapy when the patients were treated may have significantly affected the prognosis of HER2 tumours.
In response to published comments by Khan G et al (10) on our previous study (4) and in order to understand the discrepancies regarding the detection of viral genomic DNA in BC, it is important to take into consideration the viral genomic load and the amount of DNA in the samples tested. Similarly, in tests for gene mutations in somatic samples, we cannot consider the limits of the detection method without taking into account the total amount of DNA tested. In this study, we demonstrated that the presence of EBV did not exert an adverse effect on the prognosis, or on OS and DFS. This finding is quite surprising, given the greater representation of high-grade and HER2 tumours, but significance was not demonstrated when survival estimates were stratified according to the EBV status (P=0.08 for EBV-negative and 0.06 for EBV-positive tumours), although the values were of borderline significance. It is noteworthy that TN, HER2 and lumB tumours were more frequent among EBV-positive BC cases (P=0.02). The implication of EBV in BC requires further investigation, which may be facilitated by the improvement of droplet digital PCR. The sensitivity of this technology is well suited to address these questions and, above all, the presence or absence of viral genome in tumours of epithelial origin.
The presence of EBV in BC is frequently reported and has been associated with more aggressive forms. However, the prognostic significance of EBV presence remains unclear. Future studies are required to identify the association of EBV presence and activity at the DNA level, as it has not been clearly determined whether EBV acts as an oncogene in BC.