Abstract
The use of erythropoiesis stimulating agents (ESAs) to treat anemia in breast cancer patients who are treated with chemotherapy is a matter of ongoing debate. Several recent randomized trials challenged conventional wisdom, which holds that ESAs are contraindicated for breast cancer patients undergoing curative treatment. We aimed to perform the first large national population-based study to analyze the association between ESA use and breast cancer patient outcomes. Cytotoxic chemotherapy-treated invasive breast cancer patients were identified from the Surveillance, Epidemiology, and End Results (SEER)-Medicare database. Non-ESA users were sequentially 1:1 matched to 2,000 randomly sampled ESA users on demographics (age, diagnosis year, race, marital status, and socioeconomic status), tumor presentation (stage, grade, and status of hormone receptors), and treatments (surgery, radiation, and sub-types of chemotherapy) using a minimum distant strategy. Breast cancer-specific survival of ESA and matched non-ESA users was compared using Fine and Gray competing risk model. Compared to ESA users, non-ESA users exhibited dramatically different baseline characteristics such as less advanced tumor, and fewer co-morbidities. Non-ESA users had a significantly more favorable breast cancer-specific survival (subdistribution hazard ratio [sHR] = 0.75, p < 0.0001). This survival disparity was progressively diminished in the sequential matching of demographics (sHR = 0.74, p = 0.0004), presentation (sHR = 0.86, p = 0.06), and treatment (sHR = 0.89, p = 0.17) variables. Stratified analyses identified subgroups of patients whose breast cancer-specific survival were not different between ESA and non-ESA users. In the SEER-Medicare database, ESA usage does not seem to be associated with unfavorable breast cancer-specific survival in breast cancer patients receiving cytotoxic chemotherapy. The ESA-breast cancer prognosis association is complex and requires more intensive investigations.
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References
Aapro M, Jelkmann W, Constantinescu S, Leyland-Jones B (2012) Effects of erythropoietin receptors and erythropoiesis-stimulating agents on disease progression in cancer. Br J Cancer 106:1249–1258
Aapro M, Leonard RC, Barnadas A, Marangolo M, Untch M, Malamos N, Mayordomo J, Reichert D, Pedrini JL, Ukarma L (2008) Effect of once-weekly epoetin beta on survival in patients with metastatic breast cancer receiving anthracycline-and/or taxane-based chemotherapy: results of the breast cancer—anemia and the value of erythropoietin (BRAVE) study. J Clin Oncol 26:592–598
Aapro M, Österborg A, Gascón P, Ludwig H, Beguin Y (2012) Prevalence and management of cancer-related anaemia, iron deficiency and the specific role of iv iron. Ann Oncol 23:1954–1962
Benjamini Y, Yekutieli D (2001) The control of the false discovery rate in multiple testing under dependency. Ann Stat 1165–1188
Bennett CL, Henke M, Lai SY (2008) Erythropoiesis-stimulating agents in the treatment of cancer-associated anemia—Reply. JAMA 300:2855–2857
Bennett CL, Lai SY, Henke M, Barnato SE, Armitage JO, Sartor O (2010) Association between pharmaceutical support and basic science research on erythropoiesis-stimulating agents. Arch Intern Med 170:1490–1498
Bennett CL, Silver SM, Djulbegovic B, Samaras AT, Blau CA, Gleason KJ, Barnato SE, Elverman KM, Courtney DM, McKoy JM (2008) Venous thromboembolism and mortality associated with recombinant erythropoietin and darbepoetin administration for the treatment of cancer-associated anemia. JAMA 299:914–924
Bennett CL, Spiegel DM, Macdougall IC, Norris L, Qureshi ZP, Sartor O, Lai SY, Tallman MS, Raisch DW, Smith SW (2012) A review of safety, efficacy, and utilization of erythropoietin, darbepoetin, and peginesatide for patients with cancer or chronic kidney disease: a report from the Southern Network on Adverse Reactions (SONAR). In: Seminars in thrombosis and hemostasis. Thieme Medical Publishers, New York, p 783–796
Bohlius J, Schmidlin K, Brillant C, Schwarzer G, Trelle S, Seidenfeld J, Zwahlen M, Clarke M, Weingart O, Kluge S (2009) Recombinant human erythropoiesis-stimulating agents and mortality in patients with cancer: a meta-analysis of randomised trials. Lancet 373:1532–1542
Bohlius J, Wilson J, Seidenfeld J, Piper M, Schwarzer G, Sandercock J, Trelle S, Weingart O, Bayliss S, Djulbegovic B (2006) Recombinant human erythropoietins and cancer patients: updated meta-analysis of 57 studies including 9353 patients. J Natl Cancer Inst 98:708–714
Dahabreh IJ, Linardou H, Siannis F, Fountzilas G, Murray S (2008) Trastuzumab in the adjuvant treatment of early-stage breast cancer: a systematic review and meta-analysis of randomized controlled trials. Oncologist 13:620–630
Dignam JJ, Zhang Q, Kocherginsky M (2012) The use and interpretation of competing risks regression models. Clin Cancer Res 18:2301–2308
Dunne JR, Malone D, Tracy JK, Gannon C, Napolitano LM (2002) Perioperative anemia: an independent risk factor for infection, mortality, and resource utilization in surgery. J Surg Res 102:237–244
Fine JP, Gray RJ (1999) A proportional hazards model for the subdistribution of a competing risk. J Am Stat Assoc 94:496–509
Glaser CM, Millesi W, Kornek GV, Lang S, Schull B, Watzinger F, Selzer E, Lavey RS (2001) Impact of hemoglobin level and use of recombinant erythropoietin on efficacy of preoperative chemoradiation therapy for squamous cell carcinoma of the oral cavity and oropharynx. Int J Radiat Oncol Biol Phys 50:705–715
Glaspy J, Crawford J, Vansteenkiste J, Henry D, Rao S, Bowers P, Berlin JA, Tomita D, Bridges K, Ludwig H (2010) Erythropoiesis-stimulating agents in oncology: a study-level meta-analysis of survival and other safety outcomes. Br J Cancer 102:301–315
Grant MD, Piper M, Bohlius J, Tonia T, Robert N, Vats V, Bonnell C, Ziegler KM, Aronson N (2013) Epoetin and darbepoetin for managing anemia in patients undergoing cancer treatment
Henke M, Laszig R, Rübe C, Schäfer U, Haase K-D, Schilcher B, Mose S, Beer KT, Burger U, Dougherty C (2003) Erythropoietin to treat head and neck cancer patients with anaemia undergoing radiotherapy: randomised, double-blind, placebo-controlled trial. Lancet 362:1255–1260
Hershman DL, Buono DL, Malin J, McBride R, Tsai WY, Neugut AI (2009) Patterns of use and risks associated with erythropoiesis-stimulating agents among Medicare patients with cancer. J Natl Cancer Inst 101:1633–1641
Hershman DL, Neugut AI, Shim JJ, Glied S, Tsai W-Y, Wright JD (2014) Erythropoiesis-stimulating agent use after changes in medicare reimbursement policies. J Oncol Pract 2013:001255
Howlader N, Ries LA, Mariotto AB, Reichman ME, Ruhl J, Cronin KA (2010) Improved estimates of cancer-specific survival rates from population-based data. J Natl Cancer Inst 102:1584–1598
Kaplan EL, Meier P (1958) Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481
Kutikov A, Egleston BL, Wong YN, Uzzo RG (2010) Evaluating overall survival and competing risks of death in patients with localized renal cell carcinoma using a comprehensive nomogram. J Clin Oncol 28:311–317
Leyland-Jones B (2003) Breast cancer trial with erythropoietin terminated unexpectedly. Lancet Oncol 4:459–460
Leyland-Jones B (2013) Erythropoiesis stimulating agents: a personal journey. J Natl Cancer Inst 105:999–1001
Leyland-Jones B, Semiglazov V, Pawlicki M, Pienkowski T, Tjulandin S, Manikhas G, Makhson A, Roth A, Dodwell D, Baselga J, Biakhov M, Valuckas K, Voznyi E, Liu X, Vercammen E (2005) Maintaining normal hemoglobin levels with epoetin alfa in mainly nonanemic patients with metastatic breast cancer receiving first-line chemotherapy: a survival study. J Clin Oncol 23:5960–5972
Liang K, Esteva FJ, Albarracin C, Stemke-Hale K, Lu Y, Bianchini G, Yang CY, Li Y, Li X, Chen CT (2010) Recombinant human erythropoietin antagonizes trastuzumab treatment of breast cancer cells via Jak2-mediated Src activation and PTEN inactivation. Cancer Cell 18:423–435
Lin M, Lucas HC Jr, Shmueli G (2013) Research Commentary-Too Big to Fail: large samples and the p-value problem. Inf Syst Res 24:906–917
Littlewood TJ, Bajetta E, Nortier JW, Vercammen E, Rapoport B (2001) Effects of epoetin alfa on hematologic parameters and quality of life in cancer patients receiving nonplatinum chemotherapy: results of a randomized, double-blind, placebo-controlled trial. J Clin Oncol 19:2865–2874
Ludwig H, Pohl G, Osterborg A (2004) Anemia in multiple myeloma. Clin Adv Hematol Oncol: H&O 2:233
Ludwig H, Van Belle S, Barrett-Lee P, Birgegård G, Bokemeyer C, Gascón P, Kosmidis P, Krzakowski M, Nortier J, Olmi P (2004) The European Cancer Anaemia Survey (ECAS): a large, multinational, prospective survey defining the prevalence, incidence, and treatment of anaemia in cancer patients. Eur J Cancer 40:2293–2306
McClellan WM, Flanders WD, Langston RD, Jurkovitz C, Presley R (2002) Anemia and renal insufficiency are independent risk factors for death among patients with congestive heart failure admitted to community hospitals: a population-based study. J Am Soc Nephrol 13:1928–1936
Moebus V, Jackisch C, Schneeweiss A, Huober J, Lueck HJ, du Bois A, Thomssen C, Kurbacher C, Kuhn W, Nitz U, Runnebaum IB, Hinke A, Kreienberg R, Untch M (2013) Adding epoetin alfa to intense dose-dense adjuvant chemotherapy for breast cancer: randomized clinical trial. J Natl Cancer Inst 105:1018–1026
Noll C (2012) Prosthesis infection−preoperative anemia = risk factor. Z Orthop Unfall 150:563
Pirker R, Ramlau RA, Schuette W, Zatloukal P, Ferreira I, Lillie T, Vansteenkiste JF (2008) Safety and efficacy of darbepoetin alfa in previously untreated extensive-stage small-cell lung cancer treated with platinum plus etoposide. J Clin Oncol 26:2342–2349
Rodgers GM, 3rd, Becker PS, Bennett CL, Cella D, Chanan-Khan A, Chesney C, Cleeland C, Coccia PF, Djulbegovic B, Garst JL, Gilreath JA, Kraut EH, Lin WC, Matulonis U, Millenson M, Reinke D, Rosenthal J, Sabbatini P, Schwartz RN, Stein RS, Vij R, National Comprehensive Cancer N (2008) Cancer- and chemotherapy-induced anemia. J Natl Compr Cancer Netw 6:536–564
Rodgers GM, Becker PS, Blinder M, Cella D, Chanan-Khan A, Cleeland C, Coccia PF, Djulbegovic B, Gilreath JA, Kraut EH (2012) Cancer-and chemotherapy-induced anemia. J Natl Compr Cancer Netw 10:628–653
Rosenbaum PR, Ross RN, Silber JH (2007) Minimum distance matched sampling with fine balance in an observational study of treatment for ovarian cancer. J Am Stat Assoc 102:75–83
Sarnak MJ, Tighiouart H, Manjunath G, MacLeod B, Griffith J, Salem D, Levey AS (2002) Anemia as a risk factor for cardiovascular disease in The Atherosclerosis Risk in Communities (ARIC) study. J Am Coll Cardiol 40:27–33
Scrijvers D, Roila FO (2009) Erythropoiesis-stimulating agents in cancer patients: ESMO recommendations for use. Ann Oncol 20:iv159–iv161
Seidenfeld J, Piper M, Flamm C, Hasselblad V, Armitage JO, Bennett CL, Gordon MS, Lichtin AE, Wade JL, Woolf S (2001) Epoetin treatment of anemia associated with cancer therapy: a systematic review and meta-analysis of controlled clinical trials. J Natl Cancer Inst 93:1204–1214
Silber JH, Rosenbaum PR, Clark AS, Giantonio BJ, Ross RN, Teng Y, Wang M, Niknam BA, Ludwig JM, Wang W, Even-Shoshan O, Fox KR (2013) Characteristics associated with differences in survival among black and white women with breast cancer. JAMA 310:389–397
Tas F, Eralp Y, Basaran M, Sakar B, Alici S, Argon A, Bulutlar G, Camlica H, Aydiner A, Topuz E (2002) Anemia in oncology practice: relation to diseases and their therapies. Am J Clin Oncol 25:371–379
Tonelli M, Hemmelgarn B, Reiman T, Manns B, Reaume MN, Lloyd A, Wiebe N, Klarenbach S (2009) Benefits and harms of erythropoiesis-stimulating agents for anemia related to cancer: a meta-analysis. Can Med Assoc J 180:E62–E71
Unger EF, Thompson AM, Blank MJ, Temple R (2010) Erythropoiesis-stimulating agents–time for a reevaluation. N Engl J Med 362:189–192
Vansteenkiste J, Hedenus M, Gascon P, Bokemeyer C, Ludwig H, Vermorken J, Hamilton L, Bridges K, Pujol B (2009) Darbepoetin alfa for treating chemotherapy-induced anemia in patients with a baseline hemoglobin level <10 g/dL versus > or = 10 g/dL: an exploratory analysis from a randomized, double-blind, active-controlled trial. BMC Cancer 9:311
Vincent JL, Baron J-F, Reinhart K, Gattinoni L, Thijs L, Webb A, Meier-Hellmann A, Nollet G, Peres-Bota D (2002) Anemia and blood transfusion in critically ill patients. JAMA 288:1499–1507
Vlagopoulos PT, Tighiouart H, Weiner DE, Griffith J, Pettitt D, Salem DN, Levey AS, Sarnak MJ (2005) Anemia as a risk factor for cardiovascular disease and all-cause mortality in diabetes: the impact of chronic kidney disease. J Am Soc Nephrol 16:3403–3410
Wright JR, Ung YC, Julian JA, Pritchard KI, Whelan TJ, Smith C, Szechtman B, Roa W, Mulroy L, Rudinskas L, Gagnon B, Okawara GS, Levine MN (2007) Randomized, double-blind, placebo-controlled trial of erythropoietin in non-small-cell lung cancer with disease-related anemia. J Clin Oncol 25:1027–1032
Yang D, Small DS, Silber JH, Rosenbaum PR (2012) Optimal matching with minimal deviation from fine balance in a study of obesity and surgical outcomes. Biometrics 68:628–636
Zhang C, Duan X, Xu L, Ye J, Zhao J, Liu Y (2012) Erythropoietin receptor expression and its relationship with trastuzumab response and resistance in HER2-positive breast cancer cells. Breast Cancer Res Treat 136:739–748
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The work was supported by grants from Pennsylvania Department of Health, Thomas Jefferson University, and a Research Scholar Grant 123741-RSG-13-003-01-CCE from the American Cancer Society.
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Lai, Y., Palazzo, J.P., Cristofanilli, M. et al. Erythropoiesis stimulating agents and clinical outcomes of invasive breast cancer patients receiving cytotoxic chemotherapy. Breast Cancer Res Treat 148, 175–185 (2014). https://doi.org/10.1007/s10549-014-3152-y
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DOI: https://doi.org/10.1007/s10549-014-3152-y