Ki-67 index value and progesterone receptor status can predict prognosis and suitable treatment in node-negative breast cancer patients with estrogen receptor-positive and HER2-negative tumors

Abstract

Gene profiling has identified at least 4 breast cancer subtypes, including Luminal A, Luminal B, HER2-enriched and basal-like, and immunohistochemistry is used as a guide to determine these subtypes. In the present study, patients with ER-positive, HER2-negative and negative nodes were classified into 4 groups according to the PgR and the Ki-67 status and were retrospectively examined. The analysis was based on the clinicopathological findings, and includes the recurrence score (RS) and disease-free survival (DFS) rates. Patients with invasive breast cancer (n=1866) were classified as LA (high PgR/low Ki-67), LB-1 (high PgR/high Ki-67), LB-2 (low PgR/high Ki-67), and LB-3 (low PgR/low Ki-67). In addition, 41 of the cases underwent a 21-gene expression assay. The data revealed that T1 tumors were more prevalent in the LA group and rare in the LB-2 group. Furthermore, nuclear grade 3 and p53 overexpression was revealed to be significantly correlated with LB-2. In terms of prognosis, LA had a significantly more favorable DFS; however, no differences were observed in the LB-3 group. LB-2 had a significantly worse DFS in all cases, and in the cases administered with endocrine therapy alone. Chemotherapy in combination with endocrine therapy was administered to cases with a higher risk of recurrence. In the LB-2 group, there was no difference in the DFS rates between the cases with endocrine therapy and chemo-endocrine therapy. These findings suggest that chemotherapy could improve the DFS in the LB-2 group. In addition, the majority of cases with LA, LB-3 and LB-1 had a RS of ≤25 and the majority of the LB-2 cases had a RS of >25. The patients with LA and LB-3 had a favorable DFS even in the group that received endocrine therapy alone. LB-2 was significantly correlated with a higher degree of malignancy and benefited from chemotherapy. These data suggest that the PgR and the Ki-67 status are effective in predicting prognosis, and for deciding on the most effective treatment strategy in patients with breast cancer.

Keywords: Ki-67; breast cancer subtype; chemotherapy; early-stage breast cancer; endocrine therapy; estrogen receptor-positive; gene expression assays; progesterone receptor.

Figure 1.

Biological classification using Ki-67 and PgR expressions in ER-positive and HER2-negative breast cancer (n=1866). The cases were classified as follows; LA (high PgR/low Ki-67; 850 cases), LB-1 (high PgR/high Ki-67; 553 cases), LB-2 (low PgR/high Ki-67; 226 cases), and LB-3 (low PgR/low Ki-67; (237 cases). ER, estrogen receptor; HER2, human epidermal growth factor receptor 2.

Figure 2.

The representative subclassified cases of ER-positive and HER2-negative breast cancer in accordance with the PgR and the Ki-67 status. (A) LB-2 (low PgR/high Ki-67), (B) LB-1 (high PgR/high Ki-67), (C) LB-3 (low PgR/low Ki-67) and (D) LA (high PgR/low Ki-67). All magnifications ×200. ER, estrogen receptor; HER2, human epidermal growth factor receptor 2.

Figure 3.

DFS according to PgR/Ki-67 status in the node-negative cases. There were significant differences in DFS between the LA group (5-year DFS, 98%; 10-year DFS, 95.9%), the LB-2 group (5 years, 89.9%; 10 years, 83.6%; P<0.0001) and the LB-1 (5 years, 94.9%; 10 years, 89.5%; P<0.0001), but there was no difference with the LB-3 group (5 years, 98.6%; 10 years, 94.7%; P=0.88). DFS, disease-free survival; LB-1, high PgR/high Ki-67; LB-2, low PgR/high Ki-67; LB-3, low PgR/low Ki-67.

Figure 4.

DFS according to PgR/Ki-67 status in the node-negative cases with endocrine therapy alone. In the cases with endocrine therapy alone (Fig. 3), LA showed a similar DFS with LB-3 (P=0.25). LB-2 had a significantly worse DFS in all the cases and in the cases with endocrine therapy alone. DFS, disease-free survival; LB-1, high PgR/high Ki-67; LB-2, low PgR/high Ki-67; LB-3, low PgR/low Ki-67.

Figure 5.

RS using a 21-gene expression assay and biological classification using Ki-67 and PgR expressions in ER-positive and HER2-negative breast cancer. There were 29 cases with RS ≤25 and 12 cases with RS >25. Moreover, most of the cases with LA (2/2), LB-3 (2/2) and LB-1 (23/27) had a RS of ≤25, and most of the LB-2 (8/10) cases had a RS of >25. There was a significant difference in RS between LB-1 and LB-2 (*P=0.00017). ER, estrogen receptor; RS, recurrence score; HER2, human epidermal growth factor receptor 2; LB-1, high PgR/high Ki-67; LB-2, low PgR/high Ki-67; LB-3, low PgR/low Ki-67.