letters to the editor
Tamoxifen contraindicated in women with hereditary angioedema? We report a first case of hereditary angioedema (HAE) exacerbated by tamoxifen. A 69-year-old woman with hereditary angioedema (HAE) type I received tamoxifen for breast cancer. Aged 40, she was diagnosed with HAE type 1, based on a patient history of mesenteric crises, family history and decreased levels of C1 inhibitor (C1-INH): 0.09 g/l (normal range 0.15–0.35). Under danazol treatment (200 mg · thrice per week), only occasional crises required tranexamic acid prescription. When 65 years old, she was diagnosed with a hormone-dependent invasive breast carcinoma (T1NO). Treatment consisted of tumorectomy and radiotherapy. An aromatase inhibitor (AI) (anastrozole) was only acutely administered because of intolerance. Recurrence of breast cancer occurred 4 years later and was treated by mastectomy, axillary curage and tamoxifen. Use of tamoxifen rapidly increased the severity and frequency of episodes of angioedema, despite usual treatment (Figure 1). Her C1-INH level fell to 0.068 g/l. On substitution of tamoxifen by the AI (letrozole), symptoms improved, and HAE has been stable for 5 months. ª The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email:
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letters to the editor
Annals of Oncology 20: 1281–1286, 2009
letters to the editor
Annals of Oncology
C. Rousset-Jablonski*, J.-C. Thalabard & A. Gompel Universite´ Paris Descartes, Assistance Publique Hoˆpitaux de Paris, Department of Gynecological Endocrinology, CREAK (Centre de Re´fe´rence associe´ des Angioede´mes a´ Kinines), Hoˆpital Hoˆtel Dieu, Paris, France (*E-mail:
[email protected])
references
Figure 1. Swelling of the left hand during an hereditary angioedema crisis.
The prevalence of the classical forms of HAE is 1/50 000 [1]. In HAE type I (up to 85% of patients), C1-INH protein level is decreased due to a mutation in the C1-Inh gene. In HAE type II, mutation leads to a nonfunctional protein. HAE is characterized by the occurrence of recurrent, selflimited and unpredictable episodes of subcutaneous and submucosal swellings in any part of the skin, the respiratory and gastrointestinal tracts. Type I and II are especially sensitive to estrogen administration. An additional type of HAE, named HAE type III or estrogen-dependent HAE, clinically indistinguishable from the HAE types I and II, with no alterations in the levels or the activity of C1-INH has been reported more recently [2]. C1-INH is a serine protease that blocks classical complement pathways. It is also a major inhibitor of kallikrein and of coagulation factors XI and XII (F12). Suppression of contact system activation via inactivation of plasma kallikrein and F12a, which prevents excessive generation of bradykinin, modulates vascular permeability [1]. The onset or worsening of the attacks in HAE has been related in a majority of patients with high-estrogen conditions (puberty, menstrual cycles and pregnancy) [3]. Over 60% of HAE types I and III patients have more frequent attacks on estrogen-containing contraception [3]. Several mechanisms have been reported by which estrogens can induce episodes of angioedema [4]. Estrogens lower C1-INH levels and modulate F12 gene transcription through estrogen responsive element sequences on the promoter. Estrogens also modulate the kallikrein/kinine cascade, induce bradykinin type II receptor expression and potentialize bradykinin action [4]. These observations led to the recommendation via a consensus of experts that estrogens should be avoided where possible in patients with HAE type I and II [5]. Since tamoxifen displays partial agonist/antagonist properties, we propose that it mimics estrogen action in HAE. This observation has some direct implications for breast cancer hormone therapy in the women with HAE. Clinicians should not administer tamoxifen to women known to have HAE and AI should be the preferred form of treatment.
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1. Agostoni A, Aygoren-Pursun E, Binkley KE et al. Hereditary and acquired angioedema: problems and progress: proceedings of the third C1 esterase inhibitor deficiency workshop and beyond. J Allergy Clin Immunol 2004; 114: S51–S131. 2. Bork K. Hereditary angioedema with normal C1 inhibitor activity including hereditary angioedema with coagulation factor XII gene mutations. Immunol Allergy Clin North Am 2006; 26: 709–724. 3. Bork K, Fischer B, Dewald G. Recurrent episodes of skin angioedema and severe attacks of abdominal pain induced by oral contraceptives or hormone replacement therapy. Am J Med 2003; 114: 294–298. 4. Gompel A. Genomic effects of estradiol in Angioedema. Implications for contraception and hormonal menopause treatment. Rev Fr Allergol Immunol Clin 2008; 48: 448–451. 5. Bowen T, Cicardi M, Farkas H et al. Canadian 2003 International Consensus Algorithm for the diagnosis, therapy, and management of hereditary angioedema. J Allergy Clin Immunol 2004; 114: 629–637.
doi:10.1093/annonc/mdp295 Published online 29 May 2009
Volume 20 | No. 7 | July 2009
