ABSTRACT
Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy over the last decade. Pembrolizumab, a humanized monoclonal IgG4 antibody, binds to the programmed death 1 (PD-1) receptor, blocking its interaction with programmed death-ligand 1 (PD-L1) and thereby increasing the anti-tumor activity of the host immune system. These drugs are associated with immune-mediated side effects that can be life threatening, and myocarditis is among the most serious events. We present a 48-year-old woman with a history of progressive thymoma who developed complete atrioventricular block associated with fulminant myocarditis and myasthenia gravis 2 weeks after starting treatment with pembrolizumab. She had also presented a couple of days before to the emergency department due to dyspnea that was related to pleural effusion. Electrocardiogram (ECG) and echocardiogram were unremarkable, but she had very mildly increased troponin levels that were attributed to acute respiratory compromise, so she was discharged after successful thoracentesis. Despite aggressive treatment combination of high-dose corticosteroids, immunosuppressive agents and anti-thymocyte globulin, the disease rapidly progressed to the fatal outcome. This report remarks on the importance of rapid consideration of ICI-induced myocarditis even if cardiac biomarkers are slightly elevated, as a mild presentation can go unnoticed and progress to a severe case. Therefore, a high index of suspicion is warranted in these patients and cardiac imaging techniques such as magnetic resonance could have a role diagnosing incipient cardiac inflammation.
ABSTRACT
Tyrosine kinase inhibitors (TKIs) of the anaplastic lymphoma kinase gene (ALK) have significantly improved the quality of life and survival of non-small cell lung cancer (NSCLC) patients whose tumors harbor an ALK translocation. However, most of these patients relapse within 2 to 3 years as the tumor acquires resistance mutations. Unlike beaming and digital PCR (dPCR), which only allow a few mutations to be analyzed, next-generation sequencing (NGS) approaches enable the simultaneous screening of multiple genetic alterations even when the frequencies of the variants are very low. We present the case of a 52-year-old man who was diagnosed with an ALK-positive NSCLC and was treated with crizotinib and, subsequently, ceritinib. The analysis of serial liquid biopsies by NGS detected two asynchronous mutations arising in the ALK locus during disease progression, namely p.Gly1269Ala (c.3806G>C) and p.Gly1202Arg (c.3604G>A), that conferred resistance to crizotinib and ceritinib, respectively. The resistance mutations were detected independently at different times, and could be imputed to different metastatic lesions, thereby highlighting the importance of heterogeneity in advance disease. Plasma levels of ALK resistance mutations correlated well with tumor responses assessed by CT scans and bone scintigraphy, demonstrating that non-invasive tumor molecular profiling by NGS allows the efficient dynamic monitoring of ALK-positive NSCLC patients, and outperforms dPCR and beaming because more somatic mutations can be tracked over the course of the treatment. In conclusion, this case report illustrates the usefulness NGS to guide therapeutic decisions in ALK-positive NSCLC patients based tumor molecular profile upon disease progression.
