Breast cancer has become a multi-faceted disease with different histopathological and biological features. These biological features are responsible for the distinct behavior often observed in the different kinds of breast cancer and therefore require appropriate therapeutic strategies. Gene profiling has identified 4 breast cancer subtypes [Luminal A, Luminal B, human epidermal growth factor receptor 2 (HER2)-enriched and basal-like] and immunohistochemistry (IHC) is used to determine these breast cancer subtypes. In a previous study, Luminal A was defined as estrogen receptor (ER)- and PgR-positive, HER2-negative, Ki-67 ‘low’ and recurrence risk ‘low’ based on the multi-gene-expression assay (1). A high Ki-67 value (≥20%) and a low PgR value (<20%) are used to separate ‘Luminal A-like’ and ‘Luminal B-like (HER2-negative)’ breast cancers. Previous studies (2,3) found that a higher Ki-67 index value at the hotspot significantly correlated with recurrence and that the optimal cut-off value for Luminal/HER2-negative breast cancer was 20% (4). Moreover, it was reported (5,6) that the proposed IHC-based definition of luminal A tumors is a PgR >20% in hormone receptor (HR)-positive/HER2-negative tumors.

The most common subtype among breast cancer is Luminal A type tumors. In the Carolina Breast Cancer Study (7), luminal type tumors represented 64.3% of all patients and 54.3% of the cases were luminal A tumors. The luminal subtypes generally have a good prognosis but luminal B type tumors tend to have a significantly more unfavorable prognosis than the luminal A subtype (8). Moreover, luminal tumors often respond to endocrine therapy but rarely to conventional chemotherapy (9).

Oncotype DX, also known as the 21-gene assay, evaluates 16 cancer-related genes and 5 normal comparator reference genes and was designed to target ER-positive tumors (10). The purpose of using Oncotype results is to calculate the recurrence score (RS). The higher the RS (scale on a range of 1–100) the worse the prognosis but tumors with a higher RS have a higher probability of responding to chemotherapy (11). Barcenas et al (12) evaluated the recurrence-free and overall survival rates of patients with an RS of 11–25 after receiving chemotherapy. They found similar results in patients (RS of 11–25) with or without chemotherapy in HR-positive, HER2-negative, lymph node-negative breast cancer.

In this study, patients with ER-positive, HER2-negative and negative node were classified into 4 groups according to the PgR and the Ki-67 status (cutoff points, 20%) and retrospectively examined. The analysis was based on the clinicopathological findings and include the RS and disease-free survival (DFS) rates.

The purpose of this study was to investigate the clinical efficacy of a biological classification using the PgR and the Ki-67 status (cutoff points: 20%) so that it could be used as an effective prognostic and predictive classification for determining a suitable postoperative treatment for primary breast cancer with luminal/HER2-negative and negative nodes. Moreover, the above mentioned classification was also compared with the RS derived from the Oncotype DX assay. In this study, it was found that only the LB-2 cases (low PgR/high Ki-67) benefited from chemotherapy.

Luminal A type tumors tend to have a better prognosis, a higher survival rate and a lower recurrence rate among all the breast cancer subtypes and luminal B type tumors tend to have a more unfavorable prognosis (14–17). In this study, all of the Luminal type tumors (1,866 cases) were categorized into the following 4 groups; LA and three LB groups. Luminal A occupied the majority and correlated with a smaller tumor, lower nuclear grade and lower p53 overexpression. On the other hand, nuclear grade 3, larger tumor and p53 overexpression significantly correlated with LB-2. In addition, LB-3 correlated with postmenopausal status, smaller tumor and a lower nuclear grade. These findings indicate that there are biological differences among LB tumors.

In terms of prognosis after initial surgery, significant differences in DFS were observed between the LA group, the LB-2 group and the LB-1 group, but there was no difference in the LB-3 group. In the cases with endocrine therapy alone, LA showed a similar DFS as LB-3. LB-2 had a significantly worse DFS in all of the cases and in the cases with endocrine therapy alone. These findings suggest that the tumors with low Ki-67 values (LA and LB-3) had a favorable DFS irrespective of the PgR status. However, the tumors with a high Ki-67 value but a low PgR expression (LB-2) tended to have a worse DFS rate.

Oncotype DX was originally used in ER-positive tumors and is supported by the ASCO (18) and the NCCN Guidelines (19). The RS result predicts the possibility of obtaining a beneficial effect from chemotherapy and a higher score increases the potential benefit of chemotherapy (20,21). In this study, RS correlated with the biological classification. RS was lower in the LA, LB-1 and LB-3 groups but higher in the LB-2 group. These data suggest that the LB-2 group has a poorer survival rate but benefits from chemotherapy. There was no difference in DFS between the cases with endocrine therapy alone and the cases treated with chemo-endocrine therapy. On the other hand, the LA, LB-1 and LB-3 groups showed a favorable survival rate in the cases treated with endocrine therapy alone. The cases with a high Ki-67 value and low PgR benefited from chemotherapy and this was also predicted in the RS data.

A multivariate analysis revealed that the Ki-67 index was a significant factor for DFS and that the Ki-67 index value was a significant prognostic factor only in luminal type tumors (3,22). Moreover, according to the data from a large cohort clinical study (23), the Ki-67 index value is frequently evaluated in routine clinical work. The Ki-67 expression is an independent prognostic factor for DFS and OS in addition to common histopathological variables and the Ki-67 index independently raises the possibility of predicting the treatment response and prognosis in a group of breast cancer patients who underwent neoadjuvant treatment (24). The Ki-67 index was also found to be an independent predictive factor for pCR (OR 3.5; 95% CI, 1.4, 10.1). The mean Ki-67 value in patients with pCR was 50.6±23.4%, and the average Ki-67 value in non-pCR patients was 26.7±22.9%. In a previous study it was found (25) that ER-positive and PgR-negative/HER2-negative tumors were associated with poorer survival than cases with ER-positive and PgR-positive tumors and had a comparatively poorer survival rate to that of the triple negative breast cancers. Moreover, Prat et al (5) found that the IHC expression of PgR increases the prognostic value within the current IHC-based luminal A definition by improving the identification of favorable breast cancers and the percentage of PgR-positive cells. Moreover, they found that the optimal PgR expression cutoff point to predict outcome was 20%. However, the ER-positive cell rates did not correlate with DFS even after matching for the standard clinicopathologic parameters. A retrospective analysis of three adjuvant clinical trials found that low ER and low PgR expression, and potentially low PgR expression within ER-positive patients were efficacious factors for determining the validity of adding chemotherapy to endocrine therapy (26). These data indicate that the Ki-67 index value and PgR status are important predictors for prognosis and chemotherapy.

In conclusion, the biology, prognosis and suitable treatment for Luminal tumors were evaluated based on the PgR and Ki-67 index value. The patients with a Ki-67 value <20% (LA and LB-3) had a favorable DFS even in the endocrine therapy alone group, whereas those with a Ki-67 value ≥20% (LB-1 and LB-2) had a poorer DFS. Moreover, LB-2 (PgR<20% and Ki-67≥20%) significantly correlated with a higher degree of malignancy but benefited from chemotherapy. The LA and LB-3 cases with low Ki-67 values were considered to be a part of the Luminal A group. These findings suggest that the PgR and Ki-67 status are useful in predicting prognosis and determining the most effective treatment strategy for patients with ER-positive and HER2-negative breast cancer.