Abstract
Purpose
Triple negative breast cancers (TNBC) frequently have high epidermal growth factor receptor (EGFR) expression and are sensitive to DNA-damaging agents. Improved therapies are needed for this aggressive malignancy.
Patients and methods
We performed a phase I trial of bendamustine and erlotinib, an EGFR tyrosine kinase inhibitor, in patients with metastatic TNBC, ECOG performance status ≤2, and ≤1 prior chemotherapy for metastatic disease. Each 28-day cycle included intravenous bendamustine on days 1, 2 and oral erlotinib on days 5–21 with dose escalation according to a 3 + 3 phase I study design. Dose-limiting toxicity (DLT) was determined by toxicities related to study therapy observed during cycle 1.
Results
Eleven patients were treated, 5 on dose level 1 and 6 on dose level 2. One patient had DLT on dose level 2. However, cumulative toxicities were observed, including grade 3/4 lymphopenia in 91 % (95 % CI 0.59–0.998) with progressively decreased CD4 counts and grade ≥3 infections in 36 % (95 % CI 0.11–0.69) of patients.
Conclusions
Combination therapy with bendamustine and erlotinib causes excessive toxicity with severe, prolonged lymphopenia, depressed CD4 counts, and opportunistic infections and should not be pursued further. Future trials of bendamustine combinations in TNBC patients should account for potential cumulative lymphocyte toxicity necessitating patient monitoring during and after treatment.
Similar content being viewed by others
References
Cheang MC, Voduc D, Bajdik C et al (2008) Basal-like breast cancer defined by five biomarkers has superior prognostic value than triple-negative phenotype. Clin Cancer Res 14:1368–1376
Haffty BG, Yang Q, Reiss M et al (2006) Locoregional relapse and distant metastasis in conservatively managed triple negative early-stage breast cancer. J Clin Oncol 24:5652–5657
Reis-Filho JS, Tutt AN (2008) Triple negative tumours: a critical review. Histopathology 52:108–118
Rakha EA, El-Sayed ME, Green AR et al (2007) Prognostic markers in triple-negative breast cancer. Cancer 109:25–32
Hoffken K, Merkle K, Schonfelder M et al (1998) Bendamustine as salvage treatment in patients with advanced progressive breast cancer: a phase II study. J Cancer Res Clin Oncol 124:627–632
Reichmann U, Bokemeyer C, Wallwiener D et al (2007) Salvage chemotherapy for metastatic breast cancer: results of a phase II study with bendamustine. Ann Oncol 18:1981–1984
von Minckwitz G, Chernozemsky I, Sirakova L et al (2005) Bendamustine prolongs progression-free survival in metastatic breast cancer (MBC): a phase III prospective, randomized, multicenter trial of bendamustine hydrochloride, methotrexate and 5-fluorouracil (BMF) versus cyclophosphamide, methotrexate and 5-fluorouracil (CMF) as first-line treatment of MBC. Anticancer Drugs 16:871–877
Zulkowski K, Kath R, Semrau R et al (2002) Regression of brain metastases from breast carcinoma after chemotherapy with bendamustine. J Cancer Res Clin Oncol 128:111–113
Leoni LM, Bailey B, Reifert J et al (2008) Bendamustine (Treanda) displays a distinct pattern of cytotoxicity and unique mechanistic features compared with other alkylating agents. Clin Cancer Res 14:309–317
Cleator S, Heller W, Coombes RC (2007) Triple-negative breast cancer: therapeutic options. Lancet Oncol 8:235–244
Nielsen TO, Hsu FD, Jensen K et al (2004) Immunohistochemical and clinical characterization of the basal-like subtype of invasive breast carcinoma. Clin Cancer Res 10:5367–5374
Reis-Filho JS, Milanezi F, Steele D et al (2006) Metaplastic breast carcinomas are basal-like tumours. Histopathology 49:10–21
Reis-Filho JS, Milanezi F, Carvalho S et al (2005) Metaplastic breast carcinomas exhibit EGFR, but not HER2, gene amplification and overexpression: immunohistochemical and chromogenic in situ hybridization analysis. Breast Cancer Res 7:R1028–R1035
Graham DL, Hillman DW, Hobday TJ et al (2005) N0234: Phase II study of erlotinib (OSI-774) plus gemcitabine as first-or-second line therapy for metastatic breast cancer (MBC). J Clin Oncol 23, Abstract #644
Kaur H, Silverman P, Singh D et al (2006) Toxicity and outcome data in a phase II study of weekly docetaxel in combination with erlotinib in recurrent and/or metastatic breast cancer (MBC). J Clin Oncol 24, Abstract#10623
Thome S, Hobday T, Hillman D et al (2007) Translational correlates, including outcome for patients with ER-/PR-/HER2- (triple neg (Tneg)) disease from N0234, a phase II trial of gemcitabine and erlotinib for patients with previously treated metastatic breast cancer (MBC). J Clin Oncol 25, Abstract #1071
Twelves C, Trigo JM, Jones R et al (2008) Erlotinib in combination with capecitabine and docetaxel in patients with metastatic breast cancer: a dose-escalation study. Eur J Cancer 44:419–426
Solit DB, She Y, Lobo J et al (2005) Pulsatile administration of the epidermal growth factor receptor inhibitor gefitinib is significantly more effective than continuous dosing for sensitizing tumors to paclitaxel. Clin Cancer Res 11:1983–1989
Mahaffey CM, Davies AM, Lara PN Jr et al (2007) Schedule-dependent apoptosis in K-ras mutant non-small-cell lung cancer cell lines treated with docetaxel and erlotinib: rationale for pharmacodynamic separation. Clin Lung Cancer 8:548–553
Gumerlock PH, Pryde BJ, Kimura T et al (2003) Enhanced cytotoxicity of docetaxel OSI-774 combination in non-small cell lung carcinoma (NSCLC). Proc Am Soc Clin Oncol 22, Abstract #2661
Herbst RS, Prager D, Hermann R et al (2005) TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol 23:5892–5899
Knauf WU, Lissichkov T, Aldaoud A et al (2009) Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia. J Clin Oncol 27:4378–4384
Eisenhauer EA, Therasse P, Bogaerts J et al (2009) New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer 45:228–247
Kahl BS, Bartlett NL, Leonard JP et al (2010) Bendamustine is effective therapy in patients with rituximab-refractory, indolent B-cell non-Hodgkin lymphoma: results from a Multicenter Study. Cancer 116:106–114
Kath R, Blumenstengel K, Fricke HJ et al (2001) Bendamustine monotherapy in advanced and refractory chronic lymphocytic leukemia. J Cancer Res Clin Oncol 127:48–54
Schoffski P, Seeland G, Engel H et al (2000) Weekly administration of bendamustine: a phase I study in patients with advanced progressive solid tumours. Ann Oncol 11:729–734
Klippstein A, Schneider CP, Sayer HG et al (2003) Pneumocystis carinii pneumonia as a complication of bendamustine monotherapy in a patient with advanced progressive breast cancer. J Cancer Res Clin Oncol 129:316–319
Shepherd FA, Rodrigues Pereira J, Ciuleanu T et al (2005) Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med 353:123–132
Gatzemeier U, Pluzanska A, Szczesna A et al (2007) Phase III study of erlotinib in combination with cisplatin and gemcitabine in advanced non-small-cell lung cancer: the Tarceva Lung Cancer Investigation Trial. J Clin Oncol 25:1545–1552
Acknowledgments
This study was approved and funded by the National Comprehensive Cancer Network (NCCN) from general research support provided by Cephalon, Inc. Study supply of bendamustine was supplied by Cephalon, Inc. Study supply of erlotinib was provided by Genentech/OSI Pharmaceuticals.
Conflict of interest
The authors declare that they have no conflict of interest.
Ethical standards
The clinical trial described in this manuscript complies with the current laws of the country in which it was performed (USA).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Layman, R.M., Ruppert, A.S., Lynn, M. et al. Severe and prolonged lymphopenia observed in patients treated with bendamustine and erlotinib for metastatic triple negative breast cancer. Cancer Chemother Pharmacol 71, 1183–1190 (2013). https://doi.org/10.1007/s00280-013-2112-2
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00280-013-2112-2