Abstract P2-10-19: Are the mitotic factors Mitotic Activity Index (MAI) and Phosphohistone 3 (PPH3) stronger prognostic proliferation factors than Ki67 in node-negative breast cancer?
Authors: Klintman M , Strand C , Gudlaugsson E , Janssen E , Skaland I , Malmström P , Baak J , Fernö M 
Published: August 2014

Background: The prognostic value of proliferation in node-negative breast cancer, either in the form of Ki67 or as the main common denominator in different gene expression profiles, has become clearer over the last years. The St Gallen guidelines recommend the use of Ki67 to distinguish between the luminal A and luminal B-like subtypes. Also, data have shown that Ki67 can separate patients with histological grade 2 into two groups with significant difference in prognosis. However, there is no consensus on the methodology for Ki67, and genetic profiling is still expensive. Previous studies have shown a strong prognostic value of the mitosis- and late G2-specific proliferation factors Phosphohistone H3 (PPH3) and mitotic activity index (MAI) in node-negative breast cancer. The present study was set up to study the value of these two factors compared to Ki67, alone and combined.

Material and methods: In 221 consecutive premenopausal node-negative breast cancer patients, of whom 87% had received no adjuvant medical treatment, PPH3 was assessed on tissue microarray (TMA), and MAI on whole sections. TMA-data on Ki67 was already available. Cut-offs for MAI, PPH3, and Ki67 were predefined. Cox proportional hazards regression was used to model the impact of the prognostic factors on distant disease-free survival (DDFS). The follow-up was restricted to the first 5 years after diagnosis, a time period during which 34 patients developed distant recurrences.

Results: In univariate analysis the strongest prognostic proliferation factor for DDFS was MAI (HR 5.1 95%CI 2.4–11, p &lt; 0.0001), followed by PPH3 (HR 3.7 95%CI 1.8–7.5, p &lt; 0.0001), and Ki67 (HR 2.7 95%CI 1.3–5.4, p = 0.005). ER, PR, HER2, histological grade, and age were also significant prognostic factors. When adding PPH3 to MAI, the prognostic value of MAI was strengthened (HR 6.3 95%CI 2.6–15, p &lt; 0.0001). This corresponded to a 5-year DDFS of 95% for the 57% of the patients who were low risk (95%CI 88–98%), and 71% (95%CI 60–80%) for the 43% high risk patients. Ki67 did however not add any prognostic value to MAI. When stratifying for ER status and histological grade, MAI was a significant prognostic factor in the ER+ patients (HR 15 95%CI 5.1–41, p &lt; 0.0001), as well as in patients with histological grade 2 (HR 11 95%CI 3.2–38, p &lt; 0.0001). In multivariate analysis including HER2, age, and ER, and one proliferation factor at a time, MAI was the only proliferation factor that added independent prognostic value (HR 3.6 95%CI 1.1–11, p = 0.028).

Discussion: The present study on node-negative breast cancer patients confirms the strong prognostic value of the proliferation factors MAI and PPH3, in all patients, and more specifically in ER+ patients, and patients with histological grade 2. The study also suggests that by combining two proliferation factors, MAI and PPH3, an even stronger prognostic value is found. Ki67 however, did not add any prognostic value to MAI. Taken together, MAI and PPH3, alone and in combination may be helpful for prognostic considerations and for selection of adjuvant medical treatment.

Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-10-19.