Breast cancer is a very heterogeneous disease compared to other malignant tumors which is commonly shows heterogeneity even within the same lesion. Since disease progression and treatment response both depend on molecular characteristics, classifying breast cancers and determining their features are crucial for predicting disease prognosis (14). Although the molecular subtypes of breast cancers should be based on gene expression profiling, they can be clinically classified simply based on the ER, PR, HER2/neu gene, and Ki67 index. Among these, the Ki67 index—which is a known marker of cell proliferation—is actively studied for its clinical value as a prognostic factor for treatment (15). High Ki67 expression is a well-known negative prognostic factor since it is strongly associated with a high recurrence rate, high metastatic rate, and low survival rate (16, 17).
The BRCA1/2 gene has the strongest relationship with hereditary breast cancer, accounting for approximately 5–10% of breast cancers. The actual BRCA gene is a tumor suppressor gene which acts to prevent the development of cancer by repairing damaged DNA. However, due to the PV/LPV of BRCA gene cannot suppress the occurrence of cancer, these variants commonly appear in patients with characteristics such as age under 40 years old, bilateral breast cancer, familial history of breast or ovarian cancer, and male breast cancer. Among all 44 autosomes, the PV/LPV of BRCA gene appear on the long arm of chromosome 17 for BRCA1 and the long arm of chromosome 13 for BRCA2 (18, 19).
Hereditary breast cancer has recently been reported to have different clinical features and prognosis compared to sporadic breast cancers; thus, management for these cases could be quite different. For BRCA-positive breast cancer, anti-cancer drugs using a platinum agent reportedly show good responses (20). Although the mechanism of the BRCA gene is not well-known, it reportedly affects the repair of DNA double strands by controlling the cell cycle checkpoint and being involved in chromosome division. Moreover, the BRCA gene can cause differences in sensitivity to anti-cancer agents (21, 22). Poly adenosine diphosphate-ribose polymerase (PARP) inhibitors have recently gathered attention as therapeutic agents for BRCA-positive breast cancer, because homologous recombination cannot be done adequately in these patients (23, 24). Similarly, studying the features of hereditary breast cancer can help to identify factors which can be used as future therapeutic targets, eventually improving patient prognosis.
The BRCA gene status can be mainly classified into three types as wild type, VUS and PV/LPV. Among them, some PV/LPV can actually influence the development of breast or ovarian cancer, with their respective risks for development being 7–10 times and 30 times higher than in the general population (25–27). In contrast, wild type BRCA variants do not influence breast and/or ovarian cancer and they have similar occurrence rates within the general population. The VUS can be benign or PV/LPV eventually, even if it has not been confirmed. Therefore, this group is ambiguous in its clinical and pathologic characteristics and this could be a limitation in research of BRCA genes. However, the possibility that these VUS turn out to be PV/LPV in the future cannot be ruled out; thus, it is crucial to study these variants.
Among the several clinical and pathologic factors assessed in this study, we found that the Ki67 index showed significantly higher rates of expression for BRCA-positive breast cancer. And the incidence of TNBC was significantly higher in PV/LPV group of BRCA gene, as well-known (28). For these reasons, the neoadjuvant chemotherapy and adjuvant chemotherapy was also significantly more commonly performed to the patients with BRCA-positive breast cancer compared to the other groups. The Ki67 index—a important prognostic factor of breast cancer—is expressed by the MKI16 gene and is usually involved with cell proliferation. Since it is expressed in all proliferating cells (except in quiescence), it is known to be highly associated with tumor cell proliferation (29). And, also, a high Ki67 index expression in breast cancer is reportedly associated with a worse prognosis regardless of lymph node metastasis (30, 31). We could predict a higher Ki67 index expression in BRCA-positive breast cancer because this is known to have a worse prognosis than general breast cancer. In fact, in our study, a significantly high Ki67 index expression was seen in the PV/LPV group. In contrast, although the VUS group had no differences with the PV/LPV group regarding prognosis, it is still important to be cautious of breast cancers with VUS, because these could potentially be reclassified into PV/LPV.
There are some limitations in our study. There was a relatively small number of subjects because this was a single-center study limited to Korean patients with breast cancer. Additionally, the wild type group was also larger than the other groups, and had a different follow-up period between three groups. This can decrease the reliability of our study. Nevertheless, regardless of oncological outcomes, comparative analysis of the clinicopathological factors of breast cancer based on BRCA gene status is still clinically relevant.