Menstrual Cycle-Related Symptom Variability as a Prognostic Indicator in Lymphangioleiomyomatosis - ABSTRACT Lymphangioleiomyomatosis (LAM) is a progressive, female-predominant, cystic lung neoplasm caused by mutations in the tuberous sclerosis complex genes leading to constitutive activation of the mechanistic target of rapamycin (mTOR) pathway. In the Multicenter International LAM Efficacy of Sirolimus trial, mTOR inhibition with sirolimus was shown to stabilize lung function decline and improve quality of life in LAM patients. However, treatment with sirolimus is suppressive rather than remission inducing, does not benefit all LAM patients, and durable disease control in LAM requires long-term drug exposure. These limitations of sirolimus treatment highlight the critical need to explore novel therapies in LAM. Hormonal influences, especially estrogen, are believed to play a pathogenic role in LAM as suggested by the following observations: symptomatic LAM is restricted almost exclusively to females, LAM is exacerbated by exogenous estrogen use and pregnancy, and lung function in premenopausal women with LAM declines faster than that of postmenopausal women. Although the empirical use of hormonal agents in LAM was common in the past, the current LAM Guidelines recommend against their routine use, pending the outcome of well-done controlled trials. We submit that the key missing component in prior studies of the efficacy of hormonal agents in LAM has been the identification of the subset of patients with LAM who are most likely to benefit. We conducted a survey-based study of ~300 LAM patients and gathered information about patient demographics, clinical history including the presence of menstrual cycle associated respiratory symptom variation (MCRV), and current treatment for LAM. The key findings from this study were: 1) MCRV was reported by almost one-third of the patients with LAM, 2) treatment with sirolimus did not impact MCRV, 3) LAM patients with MCRV were less likely to report symptom improvement with sirolimus compared to patients without MCRV, and 4) patients with MCRV were more likely to report improvement after treatment with hormonal agents compared to patients without MCRV. We postulate that self-reported MCRV is associated with measurable cyclical spirometric changes, faster disease progression and suboptimal response to sirolimus in patients with LAM. In order to test our hypothesis, we will pursue the following specific aim: Determine the impact of MCRV on the rate of disease progression in patients with LAM. Successful completion of our project will enhance our understanding of the impact of hormonal changes during the menstrual cycle on lung function in LAM patients, provide the natural history of disease progression as well as response to sirolimus treatment in LAM patients with and without MCRV, and establish MCRV as a novel prognostic and predictive marker in LAM. This project is highly significant as it will establish MCRV as a unique measure that can identify the subpopulation of LAM patients who might benefit from hormonal treatment, and provide information that is both necessary and sufficient to conduct pivotal trials of hormonal agents in LAM.
