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Journal of Clinical Oncology, Vol 25, No 11 (April 10), 2007: pp. 1438-1440 © 2007 American Society of Clinical Oncology. DOI: 10.1200/JCO.2006.10.0651
Trastuzumab-Associated Peripheral Vascular ToxicityBritish Columbia Cancer Agency, Fraser Valley Centre, Surrey, British Columbia, Canada
Surrey Memorial Hospital, Surrey, British Columbia, Canada
British Columbia Cancer Agency, Fraser Valley Centre, Surrey, British Columbia, Canada
British Columbia Cancer Agency, Vancouver Cancer Centre, Vancouver, British Columbia, Canada A 51-year-old East Indian woman underwent a right-sided modified radical mastectomy and axillary lymph node dissection for a 7-cm breast tumor which was pathologically a grade 3 ductal carcinoma with 12 of 14 positive axillary lymph nodes. The tumor was estrogen receptor- and progesterone receptor-negative, and overexpressed human epidermal growth factor receptor 2 (HER2/neu 3+ positive on immunohistochemistry [IHC]). She received six cycles of adjuvant cyclophosphamide, epirubicin, and fluorouracil-based chemotherapy. Left hand veins were used to deliver the entire course of chemotherapy without appreciable local vascular or dermatologic toxicity. Six weeks after completing chemotherapy she received her first cycle of adjuvant trastuzumab, 8 mg/kg via a left hand vein. She presented 3 days later with painless prominence of the veins in her left arm and hand (Figs 1 and 2). The veins were thickened and rope-like on palpation but there was no tenderness, edema, or skin changes. She was afebrile, had no other symptoms, and her complete clinical examination was otherwise unremarkable. Blood work revealed normal results for standard clinical chemistry as well as prothrombin time, partial thromboplastin time, and international normalized ratio, D-dimer, carcinoembryonic antigen, CA-15-3, CA-125, antinuclear antibody, extractable nuclear antigens, anticardiolipin antibody, prothrombin G mutation genotype, factor V Leiden genotype, rheumatoid factor, and erythrocyte sedimentation rate. The deep and superficial veins of the left arm and axilla were patent on ultrasonography. Contrast was administered via the left cephalic vein for computed tomography imaging of the chest and abdomen. There was no evidence of thrombus in the subclavian or brachiocephalic veins or proximal pulmonary arteries. The liver and lungs were free from metastasis. The computed tomography scan suggested a small lytic lesion in the T4 vertebral body, but a bone scan was normal. Twenty days after the trastuzumab injection, the patient underwent a surgical biopsy of a left arm vein. Pathologic examination of formalin-fixed tissue showed that the vein was dilated and had a thickened wall. There was considerable loss of smooth muscle fibers in the media and replacement with abundant Alcian blue-positive ground substance and myofibroblasts (Fig 3; arrow). The intima was mildly eccentrically thickened. Peripheral to the vein there was a very sparse mononuclear inflammatory infiltrate with some fat degeneration. No thrombus was present. The surrounding subcutaneous tissue contained smaller, histologically normal veins. The findings suggested venous wall injury in an early phase of resolution. Of note, HER2 staining of the dilated vein was negative by IHC.
Trastuzumab (Herceptin; Genenetech, South San Francisco, CA) is a humanized monoclonal antibody that binds the extracellular domain of HER2.1,2 Trastuzumab was approved for treatment of metastatic breast cancer in 1998, and more recently became a standard adjuvant treatment in HER2-overexpressing breast cancer.3,4 The most significant adverse effects of trastuzumab are cardiac. Adjuvant trials report a 1.67% to 3.3% absolute increase in the risk of congestive heart failure. Trastuzumab-related cardiac dysfunction has been termed type II chemotherapy-related cardiac dysfunction and is reversible in a significant proportion of patients.5,6 It is differentiated from anthracycline-related cardiotoxicity as it is not dose related and is not associated with ultrastructural abnormalities.7 The peripheral vascular toxicity observed in our patient was not associated with clinically overt myocardial damage. The prechemotherapy ejection fraction on a nuclear multigated ventriculogram was 65%, and the postchemotherapy, pretrastuzumab ejection fraction was unchanged. The ejection fractions 5, 11, and 36 weeks after the trastuzumab injection were 58%, 58%, and 60% with normal left ventricular wall motion and contractility. At no time did the patient develop cardiac symptoms or peripheral edema. To our knowledge, there are no other reports in the literature describing similar acute venous toxicity from trastuzumab. Vasculitis and angialgia were reported in a series of patients treated with trastuzumab and vinorelbine for metastatic, HER2-positive breast cancer8; however, phlebitis is a recognized adverse effect of vinorelbine. The temporal relation between the administration of trastuzumab and the clinical presentation suggests a causal role for trastuzumab in this case. The clinical findings slowly improved over the last 12 months. The mechanism of action of trastuzumab is incompletely understood. A recent report suggests that trastuzumab may contribute to apoptosis through inhibition of phosphatidylinositol 3 kinase/Akt pathways.9 Antibody-dependent cellular toxicity and alteration in vessel development may also play important roles.10 Whether these mechanisms contributed to the considerable loss of smooth muscle fibers in the media of the veins in this patient is not known. Cardiac function was preserved suggesting the mechanism underlying this vascular adverse effect may be unrelated to trastuzumab-related type II cardiac dysfunction. Trastuzumab was permanently discontinued in this patient as the peripheral vascular toxicity was associated with significant pathologic changes. The consequences of re-treatment through a central venous catheter are unknown. If similar pathologic changes occurred in central vein or myocardium the effects could have been severe and potentially lethal. Trastuzumab is now widely used in the treatment of breast cancer in the metastatic and adjuvant setting. As a result, our understanding of both common and rare adverse effects will evolve with increased use as randomized clinical trials are not designed to detect rare events.11 A case of trastuzumab-associated lung injury was recently reported.12 Vigilance in the documentation and reporting of trastuzumab-related adverse effects will better define the toxicity profile of this drug in unselected patients and may provide insight into the pathophysiological mechanisms underlying its effects. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment: N/A Leadership: N/A Consultant: Brian Norris, Roche; Karen A. Gelmon, Roche Stock: N/A Honoraria: Brian Norris, Roche; Karen A. Gelmon, Roche Research Funds: Karen A. Gelmon, Roche Testimony: N/A Other: N/A
REFERENCES
1. Slamon DJ, Clark GM, Wong SG, et al: Human breast cancer: Correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 235:177-182, 1987 2. Slamon DJ, Godolphin W, Jones LA, et al: Studies of the HER-2/neu proto-oncogene in human breast and ovarian cancer. Science 244:707-712, 1989 3. Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al: Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 353:1659-1672, 2005 4. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:1673-1684, 2005 5. Ewer MS, Vooletich MT, Durand JB, et al: Reversibility of trastuzumab-related cardiotoxicity: New insights based on clinical course and response to medical treatment. J Clin Oncol 23:7820-7826, 2005 6. Tan-Chiu E, Yothers G, Romond E, 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. J Clin Oncol 23:7811-7819, 2005 7. Ewer MS, Lippman SM: Type II chemotherapy-related cardiac dysfunction: Time to recognize a new entity. J Clin Oncol 23:2900-2902, 2005 8. Suzuki Y, Tokuda Y, Saito Y, et al: Combination of trastuzumab and vinorelbine in metastatic breast cancer. Jpn J Clin Oncol 33:514-517, 2003 9. Mohsin SK, Weiss HL, Gutierrez MC, et al: Neoadjuvant trastuzumab induces apoptosis in primary breast cancers. J Clin Oncol 23:2460-2468, 2005 10. Menard S, Pupa SM, Campiglio M, et al: Biologic and therapeutic role of HER2 in cancer. Oncogene 22:6570-6578, 2003[CrossRef][Medline] 11. Erban J, Lau J: On the toxicity of chemotherapy for breast cancer–the need for vigilance. J Natl Cancer Inst 98:1096-1097, 2006 12. Vahid B, Mehrotra A: Trastuzumab (Herceptin)-associated lung injury. Respirology 11:655-658, 2006[CrossRef][Medline]
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Copyright © 2007 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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