The first reported case of trastuzumab induced interstitial lung disease associated with anti-neutrophil cytoplasmic antibody vasculitis – A case report and a prospective cohort study on the usefulness of neutrophil derived biomarkers in monitoring vasculitis disease activity during follow-up

Targeted therapies against human epidermal growth factor receptor 2 (HER2) are associated with increased interstitial lung disease (ILD). Trastuzumab, lapatinib, pertuzumab, and trastuzumab emtansine have markedly extended HER2 breast cancer survival but current knowledge on how these HER2-targeted agents induce interstitial lung disease is still poorly defined due to limited cases in the literature. Physicians mostly managed this complication by dose interruption, dose de-escalation, or discontinuation with success. In 2019, the FDA had granted accelerated approval on trastuzumab deruxtecan (T-Dxd) in HER2 breast cancer in the late line setting. Severe ILD incidence rate was over ten percent and led to fatal outcomes in 2.2% of patients in the T-Dxd trial. Searching for biomarkers to detect ILD incidence before it becomes clinically fulminant or for treatment response monitoring is of high clinical value. A Case of life-threatening trastuzumab-induced ILD was encountered in our facility. The ILD was confirmed to be antineutrophil cytoplasmic antibody (ANCA) pulmonary capillaritis. The biomarker of neutrophil extracellular traps (NETs), serum MPO-DNA complex, showed a good correlation with the clinical severity. Soon after B cell depleting agent rituximab usage, the serum MPO-DNA outperformed ANCA autoantibody and maintained its correlation with clinical severity. In addition to the trastuzumab-induced ILD case, a prospective cohort in our facility also confirmed the usefulness of MPO-DNA in monitoring vasculitis activity. We postulated that upfront testing with biomarkers of vasculitis during HER2 targeted treatment with high ILD incidence may be beneficial in the future. Interaction Between Anti-HER2 Antibody and ANCA-Associated Vasculitis and Neutrophil In lung tissues, only bronchial epithelial cells express human epidermal growth factor 2 (HER2) protein in the cell surfaces. Once trastuzumab binds to the HER2 protein, trastuzumab acts as a stimulus to activate neutrophils to express autoantigen, including leukocyte proteinase 3 (PR3) and myeloperoxidase (MPO). The neutrophils could also directly release PR3 and MPO with cell-free DNA and histone through exocytosis to form a neutrophil extracellular trap (NETs). NETs containing PR3 and MPO could further trigger autoreactive B cells to produce ANCA antibodies, resulting in more neutrophil activation and alveolar-capillary endothelial as well as alveolar epithelial damage, although alveolar epithelial ce