Everolimus-induced Severe Pulmonary Toxicity with Diffuse Alveolar Hemorrhage

To the Editor: We report a case of severe diffuse alveolar hemorrhage (DAH) attributed to treatment of breast cancer with everolimus. Lung injury resolved after the drug was discontinued. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, is approved for use as an immunosuppressant agent and an anti-neoplastic drug (1). The U.S. Food and Drug Administration (FDA) approved indications include treatment of postmenopausal women with advanced hormone-receptor positive, HER2-negative breast cancer (2, 3). Commonly reported adverse effects of everolimus include stomatitis (40%), rash (25%), and fatigue (20%) (1). Potentially life-threatening complications of everolimus and other mTOR inhibitors include pulmonary toxicity. A recently published meta-analysis reported incidence rates of 10.4% and 2.4% for everolimus-induced all-grade and high-grade pulmonary toxicity, respectively (4) The pathogenesis of the pulmonary toxicity remains unclear. A recent in vivo study suggested that mTOR inhibitors can interact with the STAT1 gene, causing amplification of cellular apoptosis and augmenting lung injury (5). Although diffuse alveolar hemorrhage (DAH) is a well-recognized manifestation of sirolimus-induced pulmonary toxicity, this complication has been reported only rarely for everolimus. Our patient, a 65-year-old woman with a history of stage 4 breast cancer (ER-positive/HER2-negative) was initiated on treatment with everolimus and anastrozole for a relapse of breast cancer. Four months later, she presented with a 2-week history of progressive shortness of breath and dry cough. These symptoms