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Prospective Multicenter Validation of the Independent Prognostic Value of the Mitotic Activity Index in Lymph Node–Negative Breast Cancer Patients Younger Than 55 Years

From the Departments of Pathology and Epidemiology and Biostatistics, and Medical Oncology, Vrije Universiteit Medical Center, Amsterdam; University Medical Center Nijmegen, Nijmegen, the Netherlands; Departments of Pathology, Stavanger University Hospital, Stavanger; the Gade Institute, University of Bergen, Norway; and University Hospital, Antwerpen, Belgium

Address reprint requests J.P.A. Baak, MD, Department of Pathology, Stavanger University Hospital, Box 8100, 4068 Stavanger, Norway; e-mail: baja{at}sir.no

PURPOSE: To validate the independent strong prognostic value of mitotic activity index (MAI) in lymph node (LN) –negative invasive breast cancer patients younger than 55 years in a nationwide multicenter prospective study.

PATIENTS AND METHODS: Analysis of routinely assessed MAI and other prognosticators in 516 patients (median follow-up, 118 months; range, 8 to 185 months), without systemic adjuvant therapy or previous malignancies.

RESULTS: Distant metastases occurred in 127 patients (24.6%); 90 (17.4%) died as a result of metastases. MAI (< 10, 10) showed strong association with recurrence (hazard ratio [HR], 3.12; 95% CI, 2.17 to 4.50; P .0001) and mortality (HR, 4.42; 95% CI, 2.79 to 7.01; P < .0001). The absolute difference in 10-year Kaplan-Meier estimates of time to distant recurrence as well as survival was 22% between MAI less than 10 versus 10. This effect was independent of age, estrogen receptor (ER) status, and tumor diameter (which were significant prognosticators). In multivariate analysis with regard to patient age, tumor diameter, grade, ER status, and the St Gallen criterion, MAI proved to be an independent and the strongest prognosticator. Tubular formation (TF) and nuclear atypia (NA), as constituents of (expert revised) grade, had no (for TF) or limited (for NA, P = .048) additional prognostic value to the MAI. In the group with MAI less than 10, MAI less than 3 versus more than 3 had additional value but the classical threshold of 0 to 5 v 6 to 10 did not. With this additional subdivision of MAI as less than 3, 3 to 9, and more than 9, NA lost its additive prognostic value.

CONCLUSION: The MAI is the strongest, most widely available, easily assessable, inexpensive, well-reproducible prognosticator and is well suited to routinely differentiate between high- and low-risk LN-negative breast cancer patients younger than 55 years.

Supported by grant No. 28-1398 of the National Health and Research Council of The Netherlands, Zorg Onderzoek Nederland Medische Wetenschappen (ZonMw), and grant Nos. 95-112 and 98-136 of the Stichting Bevordering Diagnostiche Morfometrie (SBDM).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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