Indium-111-labeled trastuzumab scintigraphy in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer.

PURPOSE The cardiac and antineoplastic effects of trastuzumab may be related to specific uptake of trastuzumab in myocardium and tumor tissue, respectively. We evaluated whether indium-111 (111In)-labeled trastuzumab scintigraphy can predict cardiotoxicity and identify tumor lesions. In addition, we evaluated whether plasma markers for cardiac dysfunction can be used to predict cardiotoxicity. PATIENTS AND METHODS Patients with human epidermal growth factor receptor 2 (HER2) -positive metastatic breast cancer underwent gamma camera imaging from 15 minutes to 7 days after injection of 150 MBq 111In-diethylenetriamine penta-acetic acid anhydride (DTPA) -trastuzumab, after loading-dose trastuzumab, and after once-a-week trastuzumab doses for 11 weeks, and concomitant paclitaxel once every 3 weeks. Cardiac assessments were performed before treatment, and after four and six cycles. Plasma N-terminal probrain natriuretic peptide (NT-proBNP) and serum troponin I were measured with immunoassay. RESULTS Fifteen of the 17 patients were available for cardiac and tumor uptake analysis. On the first scan, myocardial 111In-DTPA-trastuzumab uptake was observed in one patient with pre-existing cardiac arrhythmias, who did not develop heart failure during treatment. Severe cardiotoxicity occurred in three patients, without initial myocardial uptake, whereas one showed weak myocardial uptake after four cycles. The detection rate of single tumor lesions was 45%. New tumor lesions were discovered in 13 of 15 patients. Pretreatment plasma NT-proBNP levels were higher in patients with than without heart failure (mean, 534 [standard deviation, 236] v 105 [standard deviation, 79] ng/L; P = .009). CONCLUSION Radiolabeled trastuzumab scintigraphy was not valuable in predicting trastuzumab-related cardiotoxicity in metastatic breast cancer patients, but can identify HER2-positive tumors. Measurement of plasma NT-proBNP is promising regarding prediction of trastuzumab-related cardiotoxicity.

[1]  Greg Yothers,et al.  Assessment of cardiac dysfunction in a randomized trial comparing doxorubicin and cyclophosphamide followed by paclitaxel, with or without trastuzumab as adjuvant therapy in node-positive, human epidermal growth factor receptor 2-overexpressing breast cancer: NSABP B-31. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[2]  M. Dowsett,et al.  Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. , 2005, The New England journal of medicine.

[3]  Greg Yothers,et al.  Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. , 2005, The New England journal of medicine.

[4]  David Grimes,et al.  Randomized phase II trial of the efficacy and safety of trastuzumab combined with docetaxel in patients with human epidermal growth factor receptor 2-positive metastatic breast cancer administered as first-line treatment: the M77001 study group. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[5]  G. Hess,et al.  N-terminal pro-brain natriuretic peptide (NT-proBNP) in healthy blood donors and in patients from general practitioners with and without a diagnosis of cardiac disease. , 2005, Clinical laboratory.

[6]  J. Bart,et al.  Preclinical characterisation of 111In‐DTPA‐trastuzumab , 2004, British journal of pharmacology.

[7]  P. Regitnig,et al.  Change of HER‐2/neu status in a subset of distant metastases from breast carcinomas , 2004, The Journal of pathology.

[8]  Tanja Fehm,et al.  HER-2 gene amplification can be acquired as breast cancer progresses. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[9]  W. Lichtenegger,et al.  Analysis of HER2 and HER4 in Human Myocardium to Clarify the Cardiotoxicity of Trastuzumab (Herceptin™) , 2003, Breast Cancer Research and Treatment.

[10]  S. Takekoshi,et al.  Heterogeneous gene alterations in primary breast cancer contribute to discordance between primary and asynchronous metastatic/recurrent sites: HER2 gene amplification and p53 mutation. , 2003, International journal of oncology.

[11]  J. Bartlett,et al.  The clinical evaluation of HER‐2 status: which test to use? , 2003, The Journal of pathology.

[12]  Carmen Birchmeier,et al.  Conditional mutation of the ErbB2 (HER2) receptor in cardiomyocytes leads to dilated cardiomyopathy , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[13]  Susumu Minamisawa,et al.  ErbB2 is essential in the prevention of dilated cardiomyopathy , 2002, Nature Medicine.

[14]  D. Sawyer,et al.  Modulation of Anthracycline-Induced Myofibrillar Disarray in Rat Ventricular Myocytes by Neuregulin-1&bgr; and Anti-erbB2: Potential Mechanism for Trastuzumab-Induced Cardiotoxicity , 2002, Circulation.

[15]  B. Wörmann,et al.  Trastuzumab and breast cancer. , 2001, The New England journal of medicine.

[16]  H. Moch,et al.  Patterns of her-2/neu amplification and overexpression in primary and metastatic breast cancer. , 2001, Journal of the National Cancer Institute.

[17]  M. P. van den Berg,et al.  Prospective evaluation of early cardiac damage induced by epirubicin-containing adjuvant chemotherapy and locoregional radiotherapy in breast cancer patients. , 2001, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[18]  T. Fleming,et al.  Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. , 2001, The New England journal of medicine.

[19]  M. van Glabbeke,et al.  New guidelines to evaluate the response to treatment in solid tumors , 2000, Journal of the National Cancer Institute.

[20]  Kuo-Fen Lee,et al.  Requirement for neuregulin receptor erbB2 in neural and cardiac development , 1995, Nature.

[21]  R. Simon,et al.  Optimal two-stage designs for phase II clinical trials. , 1989, Controlled clinical trials.

[22]  W. McGuire,et al.  Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. , 1987, Science.