Ki67, chemotherapy response, and prognosis in breast cancer patients receiving neoadjuvant treatment

Abstract

Background: The pathological complete response (pCR) after neoadjuvant chemotherapy is a surrogate marker for a favorable prognosis in breast cancer patients. Factors capable of predicting a pCR, such as the proliferation marker Ki67, may therefore help improve our understanding of the drug response and its effect on the prognosis. This study investigated the predictive and prognostic value of Ki67 in patients with invasive breast cancer receiving neoadjuvant treatment for breast cancer.

Methods: Ki67 was stained routinely from core biopsies in 552 patients directly after the fixation and embedding process. HER2/neu, estrogen and progesterone receptors, and grading were also assessed before treatment. These data were used to construct univariate and multivariate models for predicting pCR and prognosis. The tumors were also classified by molecular phenotype to identify subgroups in which predicting pCR and prognosis with Ki67 might be feasible.

Results: Using a cut-off value of > 13% positively stained cancer cells, Ki67 was found to be an independent predictor for pCR (OR 3.5; 95% CI, 1.4, 10.1) and for overall survival (HR 8.1; 95% CI, 3.3 to 20.4) and distant disease-free survival (HR 3.2; 95% CI, 1.8 to 5.9). The mean Ki67 value was 50.6 ± 23.4% in patients with pCR. Patients without a pCR had an average of 26.7 ± 22.9% positively stained cancer cells.

Conclusions: Ki67 has predictive and prognostic value and is a feasible marker for clinical practice. It independently improved the prediction of treatment response and prognosis in a group of breast cancer patients receiving neoadjuvant treatment. As mean Ki67 values in patients with a pCR were very high, cut-off values in a high range above which the prognosis may be better than in patients with lower Ki67 values may be hypothesized. Larger studies will be needed in order to investigate these findings further.

Figure 1

Patient selection.

Figure 2

Cut-off calculations for predicting a pathological complete response (pCR) in the group of triple-negative patients. The continuous line represents the -lg of the P value for each respective cut-off point relative to the percentage of Ki67-positive stained tumor cells. The dashed line represents the proportion of patients with a pCR in the group of patients with the higher Ki67 values for each cut-off. The gray background indicates the area for which cut-offs with a significance level of 0.05 is reached. For the maximum of each -lg (P value), the sample size and pCR rates are provided in the figure.

Figure 3

Cut-off calculations for predicting a pathological complete response (pCR) in the group of ER/PR-positive and HER2-negative patients. The continuous line represents the -lg of the P value for each respective cut-off point relative to the percentage of Ki67-positive stained tumor cells. The dashed line represents the proportion of patients with a pCR in the group of patients with the higher Ki67 values for each cut-off. The gray background indicates the area for which cut-offs with a significance level of 0.05 is reached. For the maximum of each -lg (P value), the sample size and pCR rates are provided in the figure.

Figure 4

Cut-off calculations for predicting a pathological complete response (pCR) in the group of HER2-positive patients. The continuous line represents the -lg of the P value for each respective cut-off point relative to the percentage of Ki67-positive stained tumor cells. The dashed line represents the proportion of patients with a pCR in the group of patients with the higher Ki67 values for each cut-off. The gray background indicates the area for which cut-offs with a significance level of 0.05 is reached. For the maximum of each -lg (P value), the sample size and pCR rates are provided in the figure.

Figure 5

Kaplan-Meier curves with 5 year survival rate estimates (OS) and respective 95% confidence intervals (CI) for overall survival according to pathological complete responses (pCRs). ER, estrogen receptor; HER2, HER2/neu receptor; PR, progesterone receptor.

Figure 6

Kaplan-Meier curves with 5 year survival rate estimates (OS) and respective 95% confidence intervals (CI) for distant disease-free survival according to pathological complete responses (pCRs). ER, estrogen receptor; HER2, HER2/neu receptor; PR, progesterone receptor.

Figure 7

Kaplan-Meier curves with 5 year survival rate estimates (OS) and respective 95% confidence intervals (CI) for local recurrence-free survival according to pathological complete responses (pCRs). ER, estrogen receptor; HER2, HER2/neu receptor; PR, progesterone receptor.

Figure 8

Box plots for Ki67 as a continuous variable (0-100% positive staining of assessed cells) in the different groups relative to estrogen receptor status (ER), progesterone receptor status (PR), HER2/neu receptor status, and pathological complete remission (pCR).