Ki-67 as a prognostic marker according to breast cancer subtype and a predictor of recurrence time in primary breast cancer

Abstract

The choice of adjuvant systemic therapy is based on targeted therapy in line with the St. Gallen Consensus meeting. In addition to the traditional parameters, the panel recommended the use of proliferation markers and multigene assays. The purpose of the present study was to evaluate the clinical significance of proliferative activity using the Ki-67 index as a prognostic marker and as a predictor of recurrence time in breast cancer patients. The Ki-67 index was measured in 3,652 cases with primary breast cancer from 1987 to 2009. Out of these patients, 2,638 cases were evaluated simultaneously for estrogen receptor, progesterone receptor and HER2 from 1997, and these were analyzed as a prognostic factor according to their subtypes. The Ki-67 index exhibited a wide range of 1-99%, with a median of 20%, and cases were divided into 2 or 3 index groups; <20% and ≥20% (and ≥50%). The median Ki-67 index of tumors with luminal A was 17%, and that of luminal B type tumors was 29%. The Ki-67 index of HER2 tumors was 40% and that of triple negative tumors was 50%. A higher Ki-67 index significantly correlated with a higher grade of malignancy. Patients with a higher Ki-67 index had significantly lower disease-free survival (DFS) and overall survival rates. Moreover, there was a significant difference in the recurrence time. Multivariate analysis revealed that the Ki-67 index was a significant factor for DFS, irrespective of nodal status, and that Ki-67 was a significant marker only in luminal A type tumors. Furthermore, luminal A type cases with high Ki-67 had a similar DFS as the luminal B type cases. A higher Ki-67 index (≥20%) significantly correlated with other biological markers, poorer prognosis and early recurrence, particularly in luminal A type tumors. It is important to take the Ki-67 index into consideration in the treatment and follow-up of breast cancer patients.

Figure 1.

Distribution of the Ki-67 index and histological types in 3,652 primary breast cancer patients. Many patients had a Ki-67 index of 10–19% in all of the groups, and the median value was 20%. Therefore, Ki-67 values were divided into 2 or 3 groups; <20% and ≥20% (and ≥50%). One-third of each of the groups was divided according to the St. Gallen Consensus meeting, which recommended a cut-off value of 15 or 30%. Regarding the histological types and Ki-67 index, tumors with DCIS, lobular carcinoma and mucinous carcinoma had lower values on the Ki-67 index; the median values were 13, 14 and 17%, respectively. Most of the cases had invasive ductal carcinomas with a median Ki-67 index of 22% (see also Table II).

Figure 2.

Disease-free survival (DFS) and overall survival (OS) after operation according to Ki-67 index. Relationship between the Ki-67 index and prognosis (A, DFS and B, OS). Patients with a higher Ki-67 index had significantly lower DFS and OS rates than those with a higher index. Moreover, patients with Ki-67 ≥20% had similar DFS as those with ≥50% 10 years after the operation.

Figure 3.

Disease-free interval and the Ki-67 index in recurrent breast cancer. The disease-free interval times for recurrent cases were inversely associated with the Ki-67 index using Pearson correlation coefficient (P<0.0001). Moreover, most of the patients with a Ki-67 index of ≥50% had recurrence within 2 years after the operation. On the other hand, ∼10% of the patients with a Ki-67 index of <20% had recurrences during a 10-year period. There was a significant difference in the recurrence time after the operation among the Ki-67 index groups (see also Table VI).

Figure 4.

DFS according to the breast cancer subtypes. (A) Patients with luminal A type tumors had a more favorable DFS than patients in the other subtype groups (P<0.0001) (see also Table VIII). There were no significant differences among the luminal B, HER2 and TN types. There was no difference in DFS between luminal A types with a Ki-67 >20% and the luminal B type tumors (B).