Ki67 and breast cancer mortality in women with invasive breast cancer

Abstract

Background: The percentage of cells staining positive for Ki67 is sometimes used for decision-making in patients with early invasive breast cancer (IBC). However, there is uncertainty regarding the most appropriate Ki67 cut points and the influence of interlaboratory measurement variability. We examined the relationship between breast cancer mortality and Ki67 both before and after accounting for interlaboratory variability and 8 patient and tumor characteristics.

Methods: A multicenter cohort study of women with early IBC diagnosed during 2009-2016 in more than 20 NHS hospitals in England and followed until December 31, 2020.

Results: Ki67 was strongly prognostic of breast cancer mortality in 8212 women with estrogen receptor (ER)-positive, human epidermal growth factor receptor 2 (HER2)-negative early IBC (Ptrend < .001). This relationship remained strong after adjustment for patient and tumor characteristics (Ptrend < .001). Standardization for interlaboratory variability did little to alter these results. For women with Ki67 scores of 0%-5%, 6%-10%, 11%-19%, and 20%-29% the corresponding 8-year adjusted cumulative breast cancer mortality risks were 3.3% (95% confidence interval [CI] = 2.8% to 4.0%), 3.7% (95% CI = 3.0% to 4.4%), 3.4% (95% CI = 2.8% to 4.1%), and 3.4% (95% CI = 2.8% to 4.1%), whereas for women with Ki67 scores of 30%-39% and 40%-100%, these risks were higher, at 5.1% (95% CI = 4.3% to 6.2%) and 7.7% (95% CI = 6.6% to 9.1) (Ptrend < .001). Similar results were obtained when the adjusted analysis was repeated with omission of pathological information about tumor size and nodal involvement, which would not be available preoperatively for patients being considered for neoadjuvant therapy.

Conclusion: Our findings confirm the prognostic value of Ki67 scores of 30% or more in women with ER-positive, HER2-negative early IBC, irrespective of interlaboratory variability. These results also suggest that Ki67 may be useful to aid decision-making in the neoadjuvant setting.

Figure 1.

Distribution of Ki67 score percentages in 8212 women with ER-positive and HER2-negative breast cancer. ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2.

Figure 2.

Breast cancer mortality rate ratios in women with ER-positive and HER2-negative breast cancer by percentage Ki67 score. A) Ki67 categorized in 6 groups. B) Ki67 grouped according to the IKWG recommendations. C) Ki67 grouped according to the PREDICT decision aid. Adjustment in the middle row is for all variables shown in Table 1 (except chemotherapy) using the categories shown in Table 1. Adjustment in the bottom row is similar but also omits tumor size and number of positive nodes. Breast cancer mortality rate ratios by other variables shown in Table 1 are in Supplementary Figures 6 and 7 (available online). Analyses of all-cause mortality are in Supplementary Figure 8 (available online). ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; IKWG = International Ki67 in Breast Cancer Working Group.

Figure 3.

Cumulative breast cancer mortality risks in women with ER-positive and HER2-negative breast cancer by time since diagnosis and percentage Ki67 score. A) Ki67 categorized in 6 groups. B) Ki67 grouped according to the IKWG recommendations. C) Ki67 grouped according to the PREDICT decision aid. Top row based on crude rates, middle row based on rates adjusted for all other variables shown in Table 1 (except chemotherapy), bottom row based on rates adjusted for all other variables in Table 1 except chemotherapy, tumor size, and number of positive nodes. Shaded areas in B) and C) show 95% confidence intervals. Plotted values and numbers of women at risk are in Supplementary Tables 3, (i)-(iii) (available online). Analyses of all-cause mortality are in Supplementary Figure 9 (available online). ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; IKWG = International Ki67 in Breast Cancer Working Group.

Figure 4.

Breast cancer mortality rate ratios in women with ER-positive and HER2-negative breast cancer by percentage Ki67 score categorized in 6 groups: A) for women with and B) for women without a record of receiving chemotherapy treatment. Adjustment in middle row is for all other variables shown in Table 1 using the categories shown in Table 1 (except chemotherapy). Adjustment in bottom row is for all other variables shown in Table 1 except chemotherapy, tumor size and number of positive nodes. ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2.

Figure 5.

Box and whisker plots of Ki67 scores from 25 different pathology laboratories for 8212 women with ER-positive and HER2-negative breast cancer: A) raw scores, B) log-transformed scores and C) standardized Ki67 scores. The boxes include all values from the 25th to 75th centile (ie, the IQR), the vertical internal lines are the medians (laboratories are ordered by value of median in A)). This IQR determines the length of the whiskers. The whiskers extend 1.5 times the IQR above and below the 75th and 25th centile respectively. Dots represent outlier values that are outside the range of the whiskers. The number of samples that the laboratory recorded in the study is in the right-hand column. See section D of Supplementary Methods (available online) for further details on the standardization method. ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; IQR = interquartile range.

Figure 6.

Breast cancer mortality rate ratios in women with ER-positive and HER2-negative breast cancer by percentage Ki67 score with standardization for pathology laboratory. A) Standardized Ki67 categorized in 6 groups, B) standardized Ki67 grouped according IKWG recommendations, C) standardized Ki67 grouped according to PREDICT decision aid. In middle row adjustment in middle panels is for all variables shown in Table 1 (except chemotherapy) using the categories shown in Table 1. In bottom row adjustment is for all variables except chemotherapy, tumor size and number of positive nodes. Breast cancer mortality rate ratios by other variables shown in Table 1 are in Supplementary Figures 10 and 11 (available online). ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2; IKWG = International Ki67 in Breast Cancer Working Group.

Figure 7.

Breast cancer mortality rate ratios by Ki67 score classified into 6 groups avoiding the use of preferred digits as cut points in women with ER-positive and HER2-negative breast cancer: A) without standardization and B) with standardization for pathology laboratory. Adjustment in middle panels is for all variables shown in Table 1 using the categories shown in Table 1. Adjustment in bottom panel is for all variables except tumor size and number of positive nodes. ER = estrogen receptor; HER2 = human epidermal growth factor receptor 2.