Discovery of a Novel Mutation in NSCLC Patient
A recent medical case has shed light on a rare genetic mutation potentially responsible for drug resistance in advanced (non–small cell lung cancer) NSCLC treatment. According to a case report published in Oncotarget, clinicians at the Vanderbilt-Ingram Cancer Center identified a previously unreported genetic alteration known as RUFY1-RET fusion in a patient undergoing for NSCLC treatment. The study, led by Jenny L. Wu and Wade T. Iams documented the first case of RET fusion contributing to resistance against lorlatinib, a targeted therapy.
The patient, a 42-year-old non-smoker diagnosed with stage IV CD74-ROS1 fusion NSCLC, initially responded to standard treatment protocols. A chest CT scan at the time of diagnosis revealed a lung mass, pleural effusion, and mediastinal lymphadenopathy. Genetic analysis through RNA next-generation sequencing (RNA NGS) identified multiple mutations, including ROS1 fusion, a targetable genetic alteration linked to lung cancer development.
Treatment Journey and Emergence of Drug Resistance
The patient’s initial treatment included a combination of chemotherapy agents carboplatin, pemetrexed, pembrolizumab, and novel immunotherapy from a clinical trial. This approach led to a partial response lasting 10 months. However, as the disease progressed, further treatments were administered, including docetaxel with ramucirumab and, later, gemcitabine, which provided temporary disease control for four months.
Upon disease progression, additional genetic testing revealed a persistent CD74-ROS1 rearrangement. The patient was then placed on entrectinib for 10 months, followed by lorlatinib as per National Comprehensive Cancer Network (NCCN) guidelines. Although initial treatment with lorlatinib showed effectiveness, the cancer began to progress again after six months. To address this, clinicians added vinorelbine to the regimen and conducted another round of genetic testing on newly obtained biopsy samples. The results confirmed the presence of the RUFY1-RET fusion, a mutation previously undocumented concerning lorlatinib resistance.
Clinical Insights and Future Implications
Following the discovery of the RET alteration, the patient’s treatment was adjusted to include a reduced dose of lorlatinib combined with pralsetinib, a targeted therapy for RET-driven cancers. This modified approach initially showed promise, with no severe adverse effects. Unfortunately, after four months, the patient succumbed to respiratory failure caused by disease progression.
The case underscores the significance of advanced genetic testing, particularly RNA NGS, in detecting mutations that may influence treatment outcomes. Researchers highlighted RNA NGS’s ability to identify both the original ROS1 fusion and the subsequent RUFY1-RET mutation, suggesting that such alterations may serve as escape mechanisms for drug resistance.
Clinicians concluded that this case adds to the growing body of evidence on bypass signaling as a mechanism of resistance to lorlatinib. The findings suggest that RET activation could be a novel pathway for drug resistance, emphasizing the need for continued research on combination therapies to counteract such genetic adaptations. The study contributes valuable insights into the evolving landscape of precision medicine in NSCLC treatment, highlighting the potential for more effective, personalized therapeutic approaches in the future.
