Non-Small Cell Lung Cancer
NSCLC accounts for ~85% of all lung cancers. It is the most genetically complex solid tumor with the largest number of actionable driver mutations. Comprehensive molecular profiling is recommended for all advanced/metastatic NSCLC and for select resectable cases where adjuvant targeted therapy may be indicated.
Select Subtype — 3 subtypes with recommendations
Adenocarcinoma
→The most common NSCLC histology (~40–50% of cases). Arises predominantly in peripheral lung. Has the highest prevalence of targetable driver mutations: EGFR mutations (10–35%), ALK fusions (3–7%), ROS1 fusions (1–2%), KRAS G12C (~13%), BRAF V600E (~2–4%), MET exon 14 (~3–4%), RET fusions (~1–2%), NTRK fusions (<1%), HER2 alterations (~2–4%). NCCN recommends broad molecular profiling for all adenocarcinoma regardless of stage.
Squamous Cell Carcinoma
→Second most common NSCLC (~25–30%). Arises centrally in proximal airways. Historically lower targetable driver mutation prevalence than adenocarcinoma, but NCCN now recommends comprehensive molecular profiling for advanced squamous NSCLC. KRAS G12C, BRAF V600E, FGFR1 amplification, and NTRK fusions occur at lower but clinically relevant frequencies. PD-L1 expression is common and drives immunotherapy selection.
NSCLC, Not Otherwise Specified (NOS)
→NSCLC where histologic subtype cannot be determined or is unknown — often due to small biopsy specimens or cytology only. Molecular profiling is essential both for subtype determination and biomarker-guided therapy selection. Management follows adenocarcinoma guidelines unless squamous differentiation is confirmed.