Distribution of Ki-67 values within HER2 & ER/PgR expression variants of ductal breast cancers as a potential link between IHC features and breast cancer biology

Abstract

Background: Unexpected differences in Ki-67 values among HER2 & ER/PgR defined subgroups were found. This study aims to detect possible subdivisions beyond the conventional breast cancer types.

Methods: One thousand one hundred eighty consecutive patients with invasive ductal breast carcinoma were included and distributed in 16 subgroups (four HER2 phenotypes (0+, 1+, 2+ and 3+) times four ER/PgR phenotypes). Complex distributions of Ki-67 values were tested by expectation maximization (EM) clustering.

Results: Pooled Ki67 values of all patients showed the presence of three EM clusters (defined as LMA-low mitotic activity, IMA-intermediate mitotic activity and HMA-high mitotic activity) with expected mean Ki-67 values of 1.17%, 40.45% and 77.79%, respectively. Only ER-PgR- tumors significantly dispersed in three clusters (29.75% tumors in LMA, 46.95% in IMA and 23.30% in the HMA cluster), while almost no detected HMA tumors were of ER + PgR+ or ER + PgR- phenotypes. Among 799 ER + PgR+ patients distribution in clusters was HER2 dependent (p = 0.000243), due to increased number of IMA HER2 3+ tumors on the expense of LMA HER2 3+ tumors (52 IMA out of 162 HER2 3+ patients versus113 IMA out of 637 HER2 < 3+ patients). This was not found among ER + PgR- patients (p = 0.186968). Among ER-PgR- patients, HER2 overexpression also increased number of IMA tumor, but by reducing the number of HMA tumors (p < 0.000001). Here, difference between HER2 absent (0+) and HER2 3+ patients was evident (10 HMA out of 125 HER2 3+ patients versus 42 HMA out of 103 HER2 0+ patients).

Conclusions: Results suggest that distributions of breast cancers in three clusters of mitotic activity depend on different mechanisms for ER + PgR+ and ER negative tumors. Although HER2 overexpression increases number of IMA tumors in both settings, in the former it is done by reducing number of LMA tumors, while in the latter it reduces the number of HMA tumors. Mitotic activity of ER + PgR- tumors seems unrelated to the HER2 status, possibly as an indicator that ER dysfunctionality in cancers that lack PgR expression. Among ER negative tumors, the absence of HER2 (0+) might be as important as the HER2 overexpression.

Keywords: Breast cancer; Cancer phenotypes; Immunohistochemistry; Ki-67.

Fig. 1

Histograms of Ki-67 values in groups of breast cancer patients accordingly to their immunohistochemical cancer phenotype

Fig. 2

Cluster distribution within nine subgroups of breast cancer patients (shown as histograms in Fig. 1) accordingly to their ER/PgR status and HER2 expression. The first stage of EM clustering detected two clusters of patients in each subgroups (marked here as clusters 1&2). In all subgroups one cluster was of intermediate Ki-67 value (labeled IMA in Table 2), while the other showed either low (LMA in Table 2) or high values (HMA in Table 2)

Fig. 3

Histogram of three EM clusters in the pooled data of 1169 breast cancer patients (LMA - low mitotic activity; IMA - intermediate mitotic activity; HMA - high mitotic activity). These are the results of the second stage of EM clustering (details in Table 3)

Fig. 4

Pie charts of HER2 expression in three EM clusters of pooled breast cancer patients accordingly to their ER/PgR phenotype (LMA - low mitotic activity; IMA - intermediate mitotic activity; HMA - high mitotic activity). These are the results of the second stage of EM clustering (details in Table 4)