Abstract Introduction Lung adenocarcinoma in young, non-smoking individuals presents a diagnostic and therapeutic challenge, often driven by uncommon genomic alterations. Identifying actionable mutations through molecular profiling has become essential in guiding personalized treatment. We present a case of a 40-year-old Burmese non-smoker male with a rare presentation of lung adenocarcinoma harboring a rare ERBB2 mutation. The detection of this rare mutation enabled the use of trastuzumab-deruxtecan, underscoring the evolving role of targeted therapy in improving outcomes for patients with advanced NSCLC. Case A 40-year-old Burmese male, lifelong non-smoker, presented with a persistent cough for three months, accompanied by two self-limited episodes of hemoptysis. He denied dyspnea, chest pain, or systemic symptoms. Physical examination and routine laboratory investigations were unremarkable. Chest CT revealed diffuse pulmonary micronodules with a mass-like consolidation in the left lower lobe. Differential diagnosis included infectious, inflammatory, and malignant etiologies. Sputum AFB and relevant serum serologies were negative. Bronchoscopy with endobronchial ultrasound-guided biopsy of intrathoracic lymph node confirmed adenocarcinoma of pulmonary origin. MRI brain showed no intracranial metastases, while PET-CT demonstrated a hypermetabolic left lower lobe mass with diffuse pulmonary, mediastinal, hepatic, and osseous metastases, consistent with Stage IV metastatic lung adenocarcinoma. Given his demographic and clinical profile, molecular profiling was pursued which revealed an activating insertion mutation in ERBB2 exon 20, sensitive to trastuzumab-deruxtecan targeted immunotherapy. Discussion This case underscores the growing importance of genomic profiling in NSCLC, particularly in non-smokers and populations of Asian descent, where driver mutations are more prevalent. Traditionally associated with smoking, advances in genomic profiling have shown an increasing subset of NSCLC associated with various driver mutations such as EGFR, ALK, ROS1, and ERBB2 which activate oncogenic signaling pathways and are actionable targets for targeted therapies. ERBB2 gene mutation is rare and accounts for 1-2% of cases. Of these, the most common ERBB2 activating mutations includes the in-frame exon 20 insertions. Trastuzumab-deruxtecan was FDA approved for the treatment of ERBB2-mutant NSCLC in 2022 and has demonstrated significant clinical benefits, offering improved outcomes over conventional chemotherapy. Conclusion This case highlights the critical role of comprehensive genomic profiling in non-small cell lung cancer, particularly among non-smokers. Detection of molecular mutation by doing genomic profiling enables targeted therapy and hence improving outcomes in lung cancer. This abstract is funded by: NONE
Gupta et al. (Fri,) studied this question.