CORRESPONDENCE Is There Still a Role for Hormonal Blockade in Lymphangioleiomyomatosis? To the Editor: We read with interest the article by Li and colleagues, which demonstrated that Faslodex (fulvestrant) promotes blockade of the dissemination of lymphangioleiomyomatosis (LAM) cells through antagonism on estradiol receptors in mice (1). This study reinforces our belief that hormonal blockade has a potential role in the treatment of patients with LAM, which could be explained by its preferential occurrence in women of reproductive age and the presence of hormonal receptors in LAM cells. Although previous studies that have evaluated antihormonal therapy in LAM produced controversial results, including one from our group, randomized trials that could lead to robust conclusions have not been performed (2–4). An important finding of this study was that Faslodex has blocked expression and activity of matrix metalloproteinase (MMP)-2, which is involved in lung metastasis and in cystic destruction of the lungs in LAM. We suggest that the association of doxycycline, an effective MMP inhibitor with a safety profile, to Faslodex may enhance the blockade of MMP activity, which could contribute to the reduction of cystic formation (1, 5). Randomized trials are necessary to establish the role of hormonal blockade on the progression of LAM because estradiol is an important pathway involved in its pathophysiology, and also there is currently no definitive treatment for this disease. There is also a favorable perspective with Faslodex because its mechanism of action is different from other hormonal treatments, which is to promote the direct blockade of the estrogen receptors. More recently, the results of the MILES trial showed that sirolimus, an inhibitor of the mammalian target of rapamycin and a promising drug for LAM, stabilized lung function and improved functional performance and quality of life only during the treatment period (6). As different pathways are involved in the proliferation of LAM cells, it would be important to test a combination of therapies that could increase the durability of the clinical and functional responses that are observed in a proportion of patients that use these drugs in isolated regimens. In the near future, we hope to participate in clinical trials evaluating the impact of the association of treatment modalities, such as hormonal blockade, doxycycline, and sirolimus, acting on different pathways involved in the pathogenesis of LAM in a similar way to the therapeutic strategy used in malignant tumors (1–6). n Author disclosures are available with the text of this letter at www.atsjournals.org. Bruno G. Baldi, M.D. Carlos R. R. Carvalho, Ph.D. University of São Paulo Medical School São Paulo, Brazil

References 1. Li C, Zhou X, Sun Y, Zhang E, Mancini JD, Parkhitko A, Morrison TA, Silverman EK, Henske EP, Yu JJ. Faslodex inhibits estradiol-induced extracellular matrix dynamics and lung metastasis in a model of lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 2013;49:135–142. 2. Baldi BG, Medeiros Junior P, Pimenta SP, Lopes RI, Kairalla RA, Carvalho CR. Evolution of pulmonary function after treatment with

Correspondence

goserelin in patients with lymphangioleiomyomatosis. J Bras Pneumol 2011;37:375–379. 3. Harari S, Cassandro R, Chiodini I, Taveira-DaSilva AM, Moss J. Effect of a gonadotrophin-releasing hormone analogue on lung function in lymphangioleiomyomatosis. Chest 2008;133:448–454. 4. Johnson SR, Tattersfield AE. Decline in lung function in lymphangioleiomyomatosis: relation to menopause and progesterone treatment. Am J Respir Crit Care Med 1999;160:628–633. 5. Pimenta SP, Baldi BG, Kairalla RA, Carvalho CR. Doxycycline use in patients with lymphangioleiomyomatosis: biomarkers and pulmonary function response. J Bras Pneumol 2013;39:5–15. 6. McCormack FX, Inoue Y, Moss J, Singer LG, Strange C, Nakata K, Barker AF, Chapman JT, Brantly ML, Stocks JM, et al; National Institutes of Health Rare Lung Diseases Consortium; MILES Trial Group. Efficacy and safety of sirolimus in lymphangioleiomyomatosis. N Engl J Med 2011;364:1595–1606.

Copyright © 2014 by the American Thoracic Society

Reply: Hormonally Targeted Therapy for Women with Lymphangioleiomyomatosis From the Authors: Baldi and Carvalho raise a critical question—“Is there still a role for hormonal blockade in lymphangioleiomyomatosis?”—concerning our article (1). We agree that randomized trials are urgently needed to establish the role of hormonal blockade on the progression of lymphangioleiomyomatosis (LAM), and we also agree that Faslodex has a favorable mechanism of action for LAM therapy. The reasons that LAM primarily affects women are not well understood, representing a fundamental knowledge gap. In a preclinical model of LAM, we found that estradiol promotes the survival and metastasis of TSC2-deficient cells and increases the levels of circulating TSC2-deficient cells (2). We have also found that both estradiol and tamoxifen stimulate the growth of LAM patient–derived cells and activate both genomic and nongenomic signaling pathways (3). Collectively, these and other studies set the stage for clinical trials that will define the appropriate role of hormonally targeted therapy for women with LAM. n Author disclosures are available with the text of this letter at www.atsjournals.org. Jane Yu, Ph.D. Brigham and Women’s Hospital Boston, Masachusetts

References 1. Li C, Zhou X, Sun Y, Zhang E, Mancini JD, Parkhitko A, Morrison TA, Silverman EK, Henske EP, Yu JJ. Faslodex inhibits estradiol-induced extracellular matrix dynamics and lung metastasis in a model of lymphangioleiomyomatosis. Am J Respir Cell Mol Biol 2013;49:135–142. 2. Yu JJ, Robb VA, Morrison TA, Ariazi EA, Karbowniczek M, Astrinidis A, Wang C, Hernandez-Cuebas L, Seeholzer LF, Nicolas E, et al. Estrogen promotes the survival and pulmonary metastasis of tuberinnull cells. Proc Natl Acad Sci USA 2009;106:2635–2640. 3. Yu J, Astrinidis A, Howard S, Henske EP. Estradiol and tamoxifen stimulate LAM-associated angiomyolipoma cell growth and activate both genomic and nongenomic signaling pathways. Am J Physiol Lung Cell Mol Physiol 2004;286:L694–L700.

Copyright © 2014 by the American Thoracic Society

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