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Breast Cancer

Changes and Predictive and Prognostic Value of the Mitotic Index, Ki-67, Cyclin D1, and Cyclo-oxygenase-2 in 710 Operable Breast Cancer Patients Treated with Neoadjuvant Chemotherapy

^aCentre Jean Perrin and INSERM, Clermont Ferrand Cedex, France; ^bUniversité d'Auvergne, Faculté de Médecine, Clermont-Ferrand, France; ^cCentre d'Investigation Clinique, Clermont-Ferrand Cedex, France

Key Words. Breast cancer • Mitotic index • Ki-67 • Cyclin D1 • Cyclo-oxygenase-2

Correspondence: Catherine Abrial, Ph.D., Centre Jean Perrin, Bureau de Recherche Clinique, 58, rue Montalembert, BP 392, 63011 Clermont-Ferrand Cedex 1, France. Telephone: 33-4-73-27-80-05; Fax: 33-4-73-27-80-29; e-mail: Catherine.Abrial{at}cjp.fr

Received March 25, 2008; accepted for publication November 25, 2008; first published online in THE ONCOLOGIST Express on December 17, 2008.

Disclosure: The content of this article has been reviewed by independent peer reviewers to ensure that it is balanced, objective, and free from commercial bias. No financial relationships relevant to the content of this article have been disclosed by the authors, planners, independent peer reviewers, or staff managers.

The current study expands upon previous work using a database of 710 patients treated with neoadjuvant chemotherapy. First, we studied phenotypic characteristics of tumors before and after chemotherapy using the following factors: the mitotic index of the Scarff–Bloom–Richardson grade, Ki-67, cyclin D1, and cyclo-oxygenase-2. Second, the predictive value of these factors on response was assessed. Third, we measured the prognostic impact of these markers post-therapy in comparison with clinical and pathological responses according to the Chevallier and Sataloff classifications.

Patients were treated using different neoadjuvant chemotherapy combinations, mainly in successive prospective phase II trials. They received a median number of six cycles (range, 1–9). After neoadjuvant chemotherapy, patients underwent surgery and radiotherapy. In cases of important residual disease, some received additional courses of chemotherapy. In addition, menopausal patients with hormone receptor–positive tumors received tamoxifen for 5 years.

According to our analysis, we found significant variations before and after neoadjuvant chemotherapy only for cyclin D1 and the mitotic index. Concerning the predictive value of biomarkers for response, Ki-67 and the mitotic index were predictive on univariate analysis, both for objective clinical and pathological complete responses. Because these two factors were correlated, no multivariate analyses were conducted. We then assessed the prognostic impact of the biopathological factors. When the factors were measured before chemotherapy, all were prognostic. When evaluated after chemotherapy, the mitotic index, objective clinical response, and pathological complete response were prognostic. Because these factors were correlated, no multivariate model was done.

The main clinical fact is that there were significant correlations between clinical and pathological responses and variations in the biological factors studied.