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

Marie Klintman,Einar Gudlaugsson,Per Malmström,Cecilia Ahlin,Emiel A M Janssen,Jan P A Baak,Sanda Beglerbegovic,Ivar Skaland,Dorthe Grabau,Kristina Lövgren,Marie-Louise Fjällskog,Pär-Ola Bendahl,Carina Strand,Mårten Fernö

doi:10.1371/journal.pone.0081902

Abstract

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.

Highlights

To avoid overtreatment of low-risk early breast cancer patients, and at the same time justify dose-intensive treatments for high-risk patients, better tools are needed when estimating risk and deciding on adjuvant medical treatment
High mitotic activity index (MAI), Phosphohistone H3 (PPH3), cyclin B1, Ki67, and cyclin A were significantly associated with younger age, larger tumour size, estrogen receptor-positive (ER)-negativity, Human epidermal growth factor receptor 2 (HER2)-positivity, and high grade
Distant disease-free survival at 10 years The analyses presented below are based on all the 222 patients in the study or on subsets based on ER-status or histological grade

Summary

Introduction

To avoid overtreatment of low-risk early breast cancer patients, and at the same time justify dose-intensive treatments for high-risk patients, better tools are needed when estimating risk and deciding on adjuvant medical treatment. Studies on genetic profiles, where the main common denominator is proliferation genes [1], have identified groups with prognostic differences within estrogen receptor (ER) positive disease [2,3,4,5], and patients with histological grade 2 [6,7]. These profiles are to some extent recommended for clinical use [8]. High levels of the S-phase specific cyclin A, is associated with a worse outcome in breast cancer [34,35,36]

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