Letrozole for Lymphangioleiomyomatosis

The hypothesis in this study is that estrogen suppression by an aromatase inhibitor in postmenopausal women with lymphangioleiomyomatosis (LAM) will prevent or delay progression of lung disease and result in a decrease in the rate of decline in FEV1

Lymphangioleiomyomatosis, or LAM, is an uncommon, progressive, cystic lung disease that predominantly affects young women. Pulmonary parenchymal changes consistent with LAM are found in about one third of women with tuberous sclerosis complex (TSC), an autosomal dominant tumor suppressor syndrome. LAM also occurs in a sporadic form that is not associated with germline mutations in TSC genes. Recent evidence that recurrent LAM after lung transplantation results from seeding of the graft from a remote source and suggests a metastatic mechanism for the disease.

Since LAM occurs almost exclusively in women, and is exacerbated by pregnancy, menses and hormonal therapies suggest that estrogen suppression might be expected to prevent or delay progression of disease.

In postmenopausal women, estrogens are mainly derived from the action of the aromatase enzyme, which converts adrenal androgens (primarily androstenedione and testosterone) to estrone and estradiol. The suppression of estrogen biosynthesis in peripheral tissues can therefore be achieved by specifically inhibiting the aromatase enzyme. Letrozole is a nonsteroidal aromatase inhibitor (inhibitor of estrogen synthesis) that has been shown to be effective in other neoplasms that affect women, such as breast cancer.

Eligibility Criteria:
Inclusion Criteria:

* Definite diagnosis of based on compatible chest CT and at least one of the following:

  1. biopsy or cytology consistent with LAM, or
  2. tuberous sclerosis, renal angiomyolipoma, cystic abdominal lymphangiomas, or chylous effusion in the chest or abdomen, or
  3. serum VEGF-D ≥ 800 pg/uL.
* post bronchodilator FEV1 ≤80% predicted or DLCO ≤70% predicted or RV≥120% predicted
* female and postmenopausal status as defined by one of the following:

  1. prior bilateral oophorectomy or bilateral ovarian irradiation, or
  2. age greater than 55 years, and no menstrual period for 12 months or longer.
  3. age 18-55 years and estradiol level in the postmenopausal range in the absence of current use of progestational agents.

     * If still premenopausal, may enter if rendered medically postmenopausal on clinical grounds with the use of gonadotropin releasing hormone (e.g. leuprolide), as long as serum estradiol, FSH, and LH are in the postmenopausal range
* Patients with osteopenia or osteoporosis must be receiving appropriate treatment for their osteoporosis or osteopenia at entry into this study.

Exclusion Criteria:

* Known allergy to letrozole
* Inability to comply with pulmonary function tests or follow up visits.
* Treatment with investigational agents within 30 days
* Hormonal therapy (e.g. estrogen, progestin, LHRH agonists or antagonists, estrogen receptor blockers, estrogen receptor down regulators, aromatase inhibitors) within 30 days month of registration
* Medical or psychiatric conditions that would interfere with the ability to provide informed consent.
* abnormal hematologic and hepatic function as defined by the following at the time of randomization.:
* Neutrophils \< 1500/mm3 and platelets \< 100,000/mm3
* Bilirubin \< 1.25 X upper limit of normal
* SGPT (ALT) or SGOT (AST) \>2.5 X upper limit of normal