An improved understanding of factors impacting disease pathogenesis alongside the identification of possible mechanisms of primary or acquired resistance to systemic therapy, either molecular (i.e., BRAF, MET, HER2) [32,33] or histologic (small-cell transformation, present in 3–10% of EGFRm+ and squamous cell carcinoma transformation, present in up to 15% of patients treated with targeted therapy) [34,35], would help guide treatment and disease management, which optimize patient outcome and quality of life. The gene discussed is ERBB2; the disease is squamous cell carcinoma.