Anemia and Local Recurrence of Breast Cancer
Abstract & Commentary
By William B. Ershler, MD, Editor
Synopsis: For premenopausal ER+ breast cancer patients receiving CMF chemotherapy in an adjuvant setting, the presence of anemia during treatment was found to be a significant risk factor for the development of local recurrence.
Source: Dubsky P, et al, for the Austrian Breast and Colorectal Cancer Study Group. Anemia is a significant prognostic factor in local relapse-free survival of premenopausal primary breast cancer patients receiving adjuvant cyclophosphamide/methotrexate/5-fluorouracil chemotherapy. Clin Cancer Res. 2008;14:2082-2087.
Anemia occurs frequently in patients receiving chemotherapy. Its presence has been shown to correlate with symptoms of fatigue and other measures of reduced quality of life,1 and also to less favorable clinical outcomes.2 The occurrence of anemia in premenopausal, early stage breast cancer patients is less common and, when it does occur, can frequently be related to pre-existing iron deficiency, blood loss during surgery or to cytotoxic chemotherapy. The current study from Dubsky and colleagues was designed 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.
For this, data from the Austrian Breast and Colorectal Cancer Study Group Trial 5 were examined. In this trial, conducted between 1990 and 1999, premenopausal women with estrogen receptor positive breast cancer were randomized between cytoxan, methotrexate, 5 fluorouracil (CMF) chemotherapy or endocrine treatment, and overall the trial demonstrated the endocrine approach to be superior.3 For the purpose of this analysis, only those randomized to CMF (n=424) were included. Of these, 270 (63.7%) had breast conserving surgery followed by local radiotherapy and 154 (36.3%) had modified radical mastectomy. Twenty-seven in the latter group also received local radiotherapy. For the entire group of 424, the influence of anemia (hemoglobin <12 g/dL) on LRFS, RFS, and OS was evaluated in this retrospective analysis.
Of the 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 experienced local relapse compared with19.6% of anemic patients (P = 0.0006). Although mastectomy was associated with anemia (26% vs 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 each showed 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 non anemic patients. The overall relapse rate and overall survival were equal among anemic and non anemic patients.
Commentary
Thus, patients who developed anemia during the CMF regimen had significantly worse LRFS. Although an explanation for this is not clearly established, it is recalled that experimentally, anemia leads to a higher degree of hypoxia in tumor compared to normal tissues.4 Low levels of tissue oxygen tension (pO2) may lead to the up-regulation of hypoxia-inducible factor 1a (HIFa) and this has been shown, under experimental conditions to promote tumor growth and induce resistance to radiation and chemotherapy in a variety of different tumor types, including breast cancer.5, 6
Thus, both clinical and experimental data predict a negative effect of anemia on the host response to neoplastic growth and treatment response. Accordingly, a number of prospective randomized trials (for review, see 7, 8) were undertaken to establish a link between the treatment of anemia using erythropoiesis-stimulating agents and the improvement of cancer patient outcome. However, for reasons yet to be fully understood, the results have demonstrated not only no improvement, but in fact raised concerns regarding increased risks, such as thromboemboli and enhanced tumor growth.
In summary, the current report indicates once again, the biological importance of anemia, particularly as it relates to important clinical outcomes, such as local breast cancer recurrence. Nonetheless, standard approaches, such as with erythropoiesis-stimulating agents are not sufficient to overcome this effect and additional more precise strategies need to be developed.
References
1. Groopman JE, Itri LM. J Nat Can Inst. 1999;91(19):1616-1634.
2. Caro JJ, et al. Cancer. 2001;91(12):2214-2221.
3. Jakesz R, et al. J Clin Oncol. 2002;20(24):4621-2627.
4. Vaupel P, et al. Can Res. 2003;63(22):7634-767.
5. Helczynska K, et al. Can Res. 2003;63(7):1441-1444.
6. Vaupel P, Mayer A. Transfus Clin Biol. 2005;12(1):5-10.
7. Bohlius J, et al. J Nat Can Inst. 2006;98(10):708-714.
8. Khuri FR. NEJM. 2007;356(24):2445-2448.
For premenopausal ER+ breast cancer patients receiving CMF chemotherapy in an adjuvant setting, the presence of anemia during treatment was found to be a significant risk factor for the development of local recurrence.You have reached your article limit for the month. Subscribe now to access this article plus other member-only content.
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