As the most common type of lung adenocarcinoma, which is the non-small cell lung cancer (NSCLC) subtype, there is considerable variability in histopathology and molecular makeup that influences the prognosis of the patient and their treatment options. This research correlates the targeted therapy responses along with histopathological variants and assesses them with respect to biochemical parameters lactate dehydrogenase (LDH), carcinoembryonic antigen (CEA), cytokeratin 19 fragment (CYFRA 21-1), neuron specific enolase (NSE) and circulating tumor DNA (ctDNA) as markers for disease progression and treatment response. A controlled clinical trial was carried out with participants suffering from various subtype adenocarcinomas (lepidic, acinar, papillary, micropapillary and solid variants). Patients received targeted therapy after molecular profiling for EGFR, ALK, KRAS, MET, HER2, and BRAF mutations. The primary outcomes comprised “progression-free survival (PFS), overall survival (OS) and biochemical marker response.” The results captured significant difference among CEA and CYFRA 21-1 concentrations with the burden of the tumor (p<0.001), whereas LDH elevation correlated with dismal prognosis and low PFS (p=0.003). Further, the change in nanogram of circulating tumor DNA decreased at the end of treatment and it was observed that it had a positive therapeutic response (p=0.005) endorsing it as a biomarker for noninvasive approach.The focus of these findings is on the integration of the classification of lung adenocarcinoma with the histopathology and biomarker to improve the approaches of precision medicine.