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Anemia Is a Significant Prognostic Factor in Local Relapse-Free Survival of Premenopausal Primary Breast Cancer Patients Receiving Adjuvant Cyclophosphamide/Methotrexate/5-Fluorouracil Chemotherapy

Authors' Affiliations: Departments of ¹ Surgery and ² Gynecology, ³ Medical Department, and ⁴ Department of Radiotherapy, Medical University Vienna; ⁵ Department of Gynecology and Obstetrics, Lainz Hospital; ⁶ Department of Surgery, Hanusch Medical Center, Vienna, Austria; ⁷ Third Medical Department with Hematology and Oncology, Private Medical University Hospital, Salzburg, Austria; ⁸ Medical Department, Graz University, Graz, Austria; ⁹ Department of Surgery, Wiener Neustadt Hospital, Wiener Neustadt, Austria; and ¹⁰ Department of Internal Medicine 3, AKH-Linz, Linz, Austria

Requests for reprints: Peter Dubsky, Department of Surgery, Medical University Vienna, AKH-Wien, Währingerstr. 18-20, Vienna A-1090, Austria. Phone: 43-1-40400/5621; Fax: 43-1-40400/6918; E-mail: peter.dubsky{at}meduniwien.ac.at.

Purpose: To determine the effects of anemia on local relapse-free, relapse-free, and overall survival (LRFS, RFS, and OS, respectively) in premenopausal, primary breast cancer patients receiving adjuvant polychemotherapy, and to determine which conventional prognostic factors affected these outcomes.

Experimental Design: Four hundred twenty-four premenopausal patients with early-stage primary breast cancer and hormone receptor–expressing tumors were treated with i.v. cyclophosphamide/methotrexate/5-fluorouracil (CMF) polychemotherapy as part of an adjuvant phase III trial (Austrian Breast and Colorectal Cancer Study Group Trial 5). The influence of anemia (hemoglobin <12 g/dL) on LRFS, RFS, and OS was evaluated in a retrospective analysis.

Results: Of 424 patients, 77 (18.2%) developed anemia on CMF chemotherapy. After a median follow-up time of 5 years, 8.9% of nonanemic patients had local relapse compared with 19.6% of anemic patients (P = 0.0006). Although mastectomy was associated with anemia (26% versus 13.7% in breast conserving surgery; P = 0.002), multivariate analysis did not show mastectomy per se to be a significant risk factor for LRFS. Age, lymph node status, and hemoglobin had an independent significant influence on LRFS (P < 0.005). Anemic patients had a relative risk of 2.96 (95% confidence interval, 1.41-6.23) for developing local relapse in comparison with nonanemic patients.

Conclusion: Premenopausal breast cancer patients who developed anemia during the CMF regimen had significantly worse LRFS. In Austrian Breast and Colorectal Cancer Study Group Trial 5, anemia may have contributed to an almost doubled incidence of local recurrence in the chemotherapy arm. Molecular targets associated with tumor hypoxia and distinct from erythropoiesis should receive further attention in experimental and clinical settings.