Mitotic Activity Index Identifies Both Over- and Undertreated Lymph Node Negative Breast Cancer Patients < 55 Year According to the Norwegian Treatment Guidelines.

Abstract Background: It is a challenge to avoid under- and overtreatment of breast cancer patients in the adjuvant setting. Patients who have not received adjuvant systemic treatment and with a known outcome demonstrate the natural course of the disease after surgery. Such patients may be re-evaluated in specific guidelines like the Norwegian Breast Cancer Group (NBCG) based on the St. Gallen criteria. NBCG classify the patients in a low-risk group which should not receive systemic treatment, and a high-risk group which should be offered such therapy. New factors may be evaluated in these two strata, possibly discriminating groups of under- or overtreated patients. The aim of this study was to explore if the previous established marker of proliferation, the mitotic activity index (MAI), could give any additional information.Patients and methods: The study comprised 516 lymph node negative patients < 55 years from the Dutch prospective Multicenter Morphometric Mammary Carcinoma Project (MMMCP; 1987-1989)1. No adjuvant systemic treatment was given after surgery to these patients. The guidelines from NBCG-2005 were used to classify the patients in “NBCG low-risk” group (n=100) defined as pT1/Grade 1, all ages and pT1a-b/Grade 2-3, >35 years, all hormone receptor positive. The rest of the patients (n=416) was grouped as “NBCG high-risk”. Breast Cancer Specific Survival (BCSS) was estimated by the Kaplan-Meier method. MAI was analyzed after a standardized protocol in the invasive front of the tumor. The previous established thresholds of MAI with low (<3), intermediate (3-9) and high (≥10) proliferation were used in the calculations.Results: In the “NBCG low-risk” group 10 % of the patients had MAI ≥10. These had a 14-years BCSS of 50 % (HR=15.47, 95 % CI=3.61-66.30) and may be regarded as undertreated patients. Patients with MAI <3 and 3-9 had a BCSS of 95 % and 83 % respectively. In the “NBCG high-risk”group 24 % of the patients with MAI<3 had a 14-years BCSS of 92 % indicating overtreatment. Furthermore, patients with MAI 3-9 and ≥10 had a BCSS of 74 % and 63 % (p-trend <0.0001).Discussion: MAI represents the “converging mitotic drive” from all cellular signal pathways in the peripheral growing zone of the tumor, where also micro-environmental factors are known to influence proliferation of cancer cells. This may explain why MAI gives original information strong enough to identify subgroups breast cancer patients who would not get optimal adjuvant treatment. A disadvantage of this study is that the HER-2 status in this MMMCP material is not known. National prospective studies are needed to verify our results.1 Baak, JPA et al: Pathol Res Pract 185:664-70,1989. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3182.