Immunohistochemical assessment of Ki67 with antibodies SP6 and MIB1 in primary breast cancer: a comparison of prognostic value and reproducibility.

To compare the antibodies, SP6 and MIB1, for assessment of Ki67 in primary breast cancer, regarding prognostic value and reproducibility

The Prognostic Value of Mitotic Activity Index (MAI), Phosphohistone H3 (PPH3), Cyclin B1, Cyclin A, and Ki67, Alone and in Combinations, in Node-Negative Premenopausal Breast Cancer

Proliferation, either as the main common denominator in genetic profiles, or in the form of single factors such as Ki67, is recommended for clinical use especially in estrogen receptor-positive (ER) patients. However, due to high costs of genetic profiles and lack of reproducibility for Ki67, studies on other proliferation factors are warranted. The aim of the present study was to evaluate the prognostic value of the proliferation factors mitotic activity index (MAI), phosphohistone H3 (PPH3), cyclin B1, cyclin A and Ki67, alone and in combinations. In 222 consecutive premenopausal node-negative breast cancer patients (87% without adjuvant medical treatment), MAI was assessed on whole tissue sections (predefined cut-off >= 10 mitoses), and PPH3, cyclin B1, cyclin A, and Ki67 on tissue microarray (predefined cut-offs 7th decile). In univariable analysis (high versus low) the strongest prognostic proliferation factor for 10-year distant disease-free survival was MAI (Hazard Ratio (HR)=3.3, 95% Confidence Interval (CI): 1.8-6.1), followed by PPH3, cyclin A, Ki67, and cyclin B1. A combination variable, with patients with MAI and/or cyclin A high defined as high-risk, had even stronger prognostic value (HR=4.2, 95% CI: 2.2-7). When stratifying for ER-status, MAI was a significant prognostic factor in ER-positive patients only (HR=7.0, 95% CI: 3.1-16). Stratified for histological grade, MAI added prognostic value in grade 2 (HR=7.2, 95% CI: 3.1-38) and grade 1 patients. In multivariable analysis including HER2, age, adjuvant medical treatment, ER, and one proliferation factor at a time, only MAI (HR=2.7, 95% CI: 1.1-6.7), and cyclin A (HR=2.7, 95% CI: 1.2-6.0) remained independently prognostic. In conclusion this study confirms the strong prognostic value of all proliferation factors, especially MAI and cyclin A, in all patients, and more specifically in ER-positive patients, and patients with histological grade 2 and 1. Additionally, by combining two proliferation factors, an even stronger prognostic value may be found

10-year distant disease-free survival of premenopausal women with lymph-node negative breast cancer according to (a) MAI-status (b) PPH3-status, (c) cyclin B1-status, (d) cyclin A-status, and (e) Ki67-status.

<p>10-year distant disease-free survival of premenopausal women with lymph-node negative breast cancer according to (a) MAI-status (b) PPH3-status, (c) cyclin B1-status, (d) cyclin A-status, and (e) Ki67-status.</p

10-year distant disease-free survival of 195 premenopausal women with lymph-node negative breast cancer according to MAI-status in (a) histological grade 1 (b) histological grade 2 (c) histological grade 3.

<p>10-year distant disease-free survival of 195 premenopausal women with lymph-node negative breast cancer according to MAI-status in (a) histological grade 1 (b) histological grade 2 (c) histological grade 3.</p

10-year distant disease-free survival of 195 premenopausal women with lymph-node negative breast cancer according to MAI-status in (a) ER-positive patients (b) ER-negative patients.

<p>10-year distant disease-free survival of 195 premenopausal women with lymph-node negative breast cancer according to MAI-status in (a) ER-positive patients (b) ER-negative patients.</p

10-year distant disease-free survival of 195 premenopausal women with lymph-node negative breast cancer with data available on MAI, with MAI combined with (a) PPH3 (b) cyclin B1 (c) cyclin A, and (d) Ki67 with patients stratified into four groups, with either 0, 1, or 2 factors positive.

<p>As can be seen in all figures, patients with at least one of the two proliferations factors positive have a significantly higher risk of recurrence than patients negative for both factors, and no significant differences in recurrence rates compared to patients with both factors positive. </p