Alterations in EGFR, FGFR1/3, IGFR, PIK3CA or RAS genes are found in 60% of HPV-negative HNSCC and drive direct or cross-talk activation of the phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) and mitogen activated protein kinase kinase/extracellular related signal kinases 1 and 2 (MEK/ERK1/2) pathways [4]. The gene discussed is PIK3CA; the disease is head and neck squamous cell carcinoma.