Comprehensive molecular testing (PD-L1, EGFR, ALK) is no longer reserved for advanced disease. It is now critical for all patients with stage 1B or higher resectable NSCLC *before* starting any treatment to guide neoadjuvant and adjuvant therapy decisions.

While liquid biopsies are a valuable, less invasive tool, a negative result is inconclusive for ruling out actionable mutations in NSCLC. It may simply mean the tumor isn't shedding enough DNA. Therefore, a negative liquid biopsy should never be the final word; it must be followed by a tissue biopsy to ensure patients don't miss out on targeted therapies.

Standard Next-Generation Sequencing (NGS) reports often just state "MET amplification" without a specific copy number. To make informed treatment decisions with MET inhibitors, clinicians must proactively contact the testing company's molecular pathology department to obtain this crucial, unlisted data point.

Genetic tests like DecisionDX for squamous cell carcinoma are evolving from simply predicting recurrence risk to actively informing treatment choices. Ongoing studies are exploring whether these tests can determine a patient's potential benefit from adjuvant radiation therapy, representing a critical step toward personalized medicine.

Unlike novel challenges from bispecifics, upcoming SCLC therapies like antibody-drug conjugates (ADCs) and radiopharmaceuticals will benefit from existing familiarity. Community practices are already comfortable with these drug classes from their use in breast cancer (ADCs) and prostate cancer (radioligands), which should streamline their integration.

Unlike rare biomarkers that necessitate a 'test-and-wait' approach, IB6 is expressed in over 80-90% of NSCLC tumors. This ubiquity could make pre-screening unnecessary for drugs like Sigvotatug Vedotin, allowing clinicians to initiate targeted therapy much faster and for a broader patient population.

Clinicians ordering "NGS for lung" often misunderstand that Next-Generation Sequencing alone does not cover all actionable biomarkers, such as PD-L1 or HER2. This requires pathologists to interpret the clinician's intent and order a more comprehensive and appropriate test panel.

For post-progression biopsies, which are often small and contain necrotic tissue, institutions may prioritize DNA-based NGS panels. This strategy is based on the rationale that most resistance mechanisms are genetic mutations detectable by DNA sequencing, reserving RNA panels primarily for identifying less common fusion events.

The success of perioperative osimertinib means oncologists cannot choose the optimal strategy (targeted therapy vs. chemoimmunotherapy) for resectable lung cancer without first knowing the patient's EGFR, ALK, and PD-L1 status. This elevates biomarker profiling from a metastatic-setting tool to a critical first step in early-stage disease.