Non-Small Cell Lung Cancer (NSCLC) Genomic Testing and Tissue Stewardship

Authored by Eric Kowalchyk, published on 2026-10-12 18:40:45.0

The algorithm is strongly aligned with contemporary NSCLC practice by stratifying testing by stage, conserving tissue, favoring broad DNA plus RNA profiling, and treating negative plasma results as non-exclusionary. It appropriately incorporates perioperative EGFR, ALK, and PD-L1 assessment, EGFR-directed consolidation after stage III chemoradiation, and comprehensive profiling in advanced disease. The quality-control and cause-directed retesting pathways are particularly strong.

  1. Confirm NSCLC, Histology, Stage, Resectability, and Treatment Urgency
    Accurate histologic classification, staging, resectability assessment, and multidisciplinary treatment planning are foundational recommendations in NSCLC guidelines.
    • Which Stage and Treatment Setting Applies?
      • Define Required Perioperative Biomarkers: EGFR, ALK, and PD-L1 (at a minimum)
        EGFR and ALK results now determine established adjuvant targeted therapies, while PD-L1 informs perioperative immunotherapy selection. Requirements still depend on stage, tumor size, nodal status, and jurisdiction.
        • Secure Adequate Tissue; Preserve It With Minimum Diagnostic IHC
          Guidelines support limited diagnostic immunohistochemistry and coordinated specimen allocation to preserve small samples for molecular and PD-L1 testing.
          • Which Molecularly Suitable Specimen Is Available?
            • Can Treatment Safely Await Complete Molecular Results?
              • Prefer Comprehensive Tissue DNA + RNA NGS and Essential IHC
                Broad panel testing reduces tissue consumption and sequential testing, while RNA analysis improves detection of fusions and splice alterations that may be missed by DNA-only assays.
                • Classify Treatment-Defining Drivers, Emerging Biomarkers, Co-Mutations, and Mutation, Fusion, Copy-Number, or Protein Expression
                  Current guidelines distinguish alterations with approved matched therapies from emerging, prognostic, resistance-associated, or nonactionable findings and link each alteration to the required assay type.
                  • Treatment-Defining Oncogenic Driver Identified?
                    • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                    • Is the Negative Result Reliable Given Testing Quality and Clinical Suspicion?
                      Reliability of a negative result depends on specimen tumor content, assay coverage, analyte type, quality-control metrics, and plasma shedding. Negative results with technical limitations or high clinical discordance warrant further evaluation.
                      • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                      • Complete Missing Biomarkers Without Redundant Sequential Testing
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Obtain Tissue or Better Specimen After Uninformative Plasma or Tissue Testing
                        Low-volume disease, organ-confined disease, low/undetectable ctDNA fraction, or otherwise low expected tumor shedding → plasma negative has reduced rule-out value.
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Add RNA or Orthogonal Testing for Fusion, Splicing, Copy-Number, or Coverage Gaps
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Review Pathology and QC When Results Conflict With Clinical Suspicion
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
              • Continue Tissue and Plasma NGS in Parallel; Use Driver-Compatible Interim Therapy
                • Classify Treatment-Defining Drivers, Emerging Biomarkers, Co-Mutations, and Mutation, Fusion, Copy-Number, or Protein Expression
                  Current guidelines distinguish alterations with approved matched therapies from emerging, prognostic, resistance-associated, or nonactionable findings and link each alteration to the required assay type.
                  • Treatment-Defining Oncogenic Driver Identified?
                    • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                    • Is the Negative Result Reliable Given Testing Quality and Clinical Suspicion?
                      Reliability of a negative result depends on specimen tumor content, assay coverage, analyte type, quality-control metrics, and plasma shedding. Negative results with technical limitations or high clinical discordance warrant further evaluation.
                      • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                      • Complete Missing Biomarkers Without Redundant Sequential Testing
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Obtain Tissue or Better Specimen After Uninformative Plasma or Tissue Testing
                        Low-volume disease, organ-confined disease, low/undetectable ctDNA fraction, or otherwise low expected tumor shedding → plasma negative has reduced rule-out value.
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Add RNA or Orthogonal Testing for Fusion, Splicing, Copy-Number, or Coverage Gaps
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Review Pathology and QC When Results Conflict With Clinical Suspicion
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
            • Rebiopsy, Then Prefer Comprehensive DNA + RNA NGS and Essential IHC
              • Classify Treatment-Defining Drivers, Emerging Biomarkers, Co-Mutations, and Mutation, Fusion, Copy-Number, or Protein Expression
                Current guidelines distinguish alterations with approved matched therapies from emerging, prognostic, resistance-associated, or nonactionable findings and link each alteration to the required assay type.
                • Treatment-Defining Oncogenic Driver Identified?
                  • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                  • Is the Negative Result Reliable Given Testing Quality and Clinical Suspicion?
                    Reliability of a negative result depends on specimen tumor content, assay coverage, analyte type, quality-control metrics, and plasma shedding. Negative results with technical limitations or high clinical discordance warrant further evaluation.
                    • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                    • Complete Missing Biomarkers Without Redundant Sequential Testing
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Obtain Tissue or Better Specimen After Uninformative Plasma or Tissue Testing
                      Low-volume disease, organ-confined disease, low/undetectable ctDNA fraction, or otherwise low expected tumor shedding → plasma negative has reduced rule-out value.
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Add RNA or Orthogonal Testing for Fusion, Splicing, Copy-Number, or Coverage Gaps
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Review Pathology and QC When Results Conflict With Clinical Suspicion
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
            • Order Plasma ctDNA NGS; Do Not Exclude a Driver From a Negative Result Alone
              Plasma ctDNA is useful when tissue is unavailable or results are urgently needed, but sensitivity depends on tumor shedding. A negative plasma result therefore requires tissue testing when feasible.
              • Classify Treatment-Defining Drivers, Emerging Biomarkers, Co-Mutations, and Mutation, Fusion, Copy-Number, or Protein Expression
                Current guidelines distinguish alterations with approved matched therapies from emerging, prognostic, resistance-associated, or nonactionable findings and link each alteration to the required assay type.
                • Treatment-Defining Oncogenic Driver Identified?
                  • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                  • Is the Negative Result Reliable Given Testing Quality and Clinical Suspicion?
                    Reliability of a negative result depends on specimen tumor content, assay coverage, analyte type, quality-control metrics, and plasma shedding. Negative results with technical limitations or high clinical discordance warrant further evaluation.
                    • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                    • Complete Missing Biomarkers Without Redundant Sequential Testing
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Obtain Tissue or Better Specimen After Uninformative Plasma or Tissue Testing
                      Low-volume disease, organ-confined disease, low/undetectable ctDNA fraction, or otherwise low expected tumor shedding → plasma negative has reduced rule-out value.
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Add RNA or Orthogonal Testing for Fusion, Splicing, Copy-Number, or Coverage Gaps
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Review Pathology and QC When Results Conflict With Clinical Suspicion
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
      • Define and Complete Required Stage III Biomarker Testing Before Definitive Chemoradiation
        EGFR status should be known because it can determine post-chemoradiation consolidation therapy. PD-L1 remains clinically informative, but US durvalumab eligibility is not restricted by PD-L1 expression; ALK currently lacks an established analogous consolidation strategy.
        • Secure Adequate Tissue; Preserve It With Minimum Diagnostic IHC
          Guidelines support limited diagnostic immunohistochemistry and coordinated specimen allocation to preserve small samples for molecular and PD-L1 testing.
          • Which Molecularly Suitable Specimen Is Available?
            • Can Treatment Safely Await Complete Molecular Results?
              • Prefer Comprehensive Tissue DNA + RNA NGS and Essential IHC
                Broad panel testing reduces tissue consumption and sequential testing, while RNA analysis improves detection of fusions and splice alterations that may be missed by DNA-only assays.
                • Classify Treatment-Defining Drivers, Emerging Biomarkers, Co-Mutations, and Mutation, Fusion, Copy-Number, or Protein Expression
                  Current guidelines distinguish alterations with approved matched therapies from emerging, prognostic, resistance-associated, or nonactionable findings and link each alteration to the required assay type.
                  • Treatment-Defining Oncogenic Driver Identified?
                    • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                    • Is the Negative Result Reliable Given Testing Quality and Clinical Suspicion?
                      Reliability of a negative result depends on specimen tumor content, assay coverage, analyte type, quality-control metrics, and plasma shedding. Negative results with technical limitations or high clinical discordance warrant further evaluation.
                      • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                      • Complete Missing Biomarkers Without Redundant Sequential Testing
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Obtain Tissue or Better Specimen After Uninformative Plasma or Tissue Testing
                        Low-volume disease, organ-confined disease, low/undetectable ctDNA fraction, or otherwise low expected tumor shedding → plasma negative has reduced rule-out value.
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Add RNA or Orthogonal Testing for Fusion, Splicing, Copy-Number, or Coverage Gaps
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Review Pathology and QC When Results Conflict With Clinical Suspicion
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
              • Continue Tissue and Plasma NGS in Parallel; Use Driver-Compatible Interim Therapy
                • Classify Treatment-Defining Drivers, Emerging Biomarkers, Co-Mutations, and Mutation, Fusion, Copy-Number, or Protein Expression
                  Current guidelines distinguish alterations with approved matched therapies from emerging, prognostic, resistance-associated, or nonactionable findings and link each alteration to the required assay type.
                  • Treatment-Defining Oncogenic Driver Identified?
                    • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                    • Is the Negative Result Reliable Given Testing Quality and Clinical Suspicion?
                      Reliability of a negative result depends on specimen tumor content, assay coverage, analyte type, quality-control metrics, and plasma shedding. Negative results with technical limitations or high clinical discordance warrant further evaluation.
                      • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                      • Complete Missing Biomarkers Without Redundant Sequential Testing
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Obtain Tissue or Better Specimen After Uninformative Plasma or Tissue Testing
                        Low-volume disease, organ-confined disease, low/undetectable ctDNA fraction, or otherwise low expected tumor shedding → plasma negative has reduced rule-out value.
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Add RNA or Orthogonal Testing for Fusion, Splicing, Copy-Number, or Coverage Gaps
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Review Pathology and QC When Results Conflict With Clinical Suspicion
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
            • Rebiopsy, Then Prefer Comprehensive DNA + RNA NGS and Essential IHC
              • Classify Treatment-Defining Drivers, Emerging Biomarkers, Co-Mutations, and Mutation, Fusion, Copy-Number, or Protein Expression
                Current guidelines distinguish alterations with approved matched therapies from emerging, prognostic, resistance-associated, or nonactionable findings and link each alteration to the required assay type.
                • Treatment-Defining Oncogenic Driver Identified?
                  • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                  • Is the Negative Result Reliable Given Testing Quality and Clinical Suspicion?
                    Reliability of a negative result depends on specimen tumor content, assay coverage, analyte type, quality-control metrics, and plasma shedding. Negative results with technical limitations or high clinical discordance warrant further evaluation.
                    • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                    • Complete Missing Biomarkers Without Redundant Sequential Testing
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Obtain Tissue or Better Specimen After Uninformative Plasma or Tissue Testing
                      Low-volume disease, organ-confined disease, low/undetectable ctDNA fraction, or otherwise low expected tumor shedding → plasma negative has reduced rule-out value.
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Add RNA or Orthogonal Testing for Fusion, Splicing, Copy-Number, or Coverage Gaps
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Review Pathology and QC When Results Conflict With Clinical Suspicion
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
            • Order Plasma ctDNA NGS; Do Not Exclude a Driver From a Negative Result Alone
              Plasma ctDNA is useful when tissue is unavailable or results are urgently needed, but sensitivity depends on tumor shedding. A negative plasma result therefore requires tissue testing when feasible.
              • Classify Treatment-Defining Drivers, Emerging Biomarkers, Co-Mutations, and Mutation, Fusion, Copy-Number, or Protein Expression
                Current guidelines distinguish alterations with approved matched therapies from emerging, prognostic, resistance-associated, or nonactionable findings and link each alteration to the required assay type.
                • Treatment-Defining Oncogenic Driver Identified?
                  • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                  • Is the Negative Result Reliable Given Testing Quality and Clinical Suspicion?
                    Reliability of a negative result depends on specimen tumor content, assay coverage, analyte type, quality-control metrics, and plasma shedding. Negative results with technical limitations or high clinical discordance warrant further evaluation.
                    • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                    • Complete Missing Biomarkers Without Redundant Sequential Testing
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Obtain Tissue or Better Specimen After Uninformative Plasma or Tissue Testing
                      Low-volume disease, organ-confined disease, low/undetectable ctDNA fraction, or otherwise low expected tumor shedding → plasma negative has reduced rule-out value.
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Add RNA or Orthogonal Testing for Fusion, Splicing, Copy-Number, or Coverage Gaps
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Review Pathology and QC When Results Conflict With Clinical Suspicion
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
      • Define Required Advanced-Disease Genomic and Biomarker Testing
        Broad genomic profiling and PD-L1 testing are standard before first-line treatment of advanced nonsquamous NSCLC and selected squamous cancers because numerous alterations have approved matched therapies.
        • Secure Adequate Tissue; Preserve It With Minimum Diagnostic IHC
          Guidelines support limited diagnostic immunohistochemistry and coordinated specimen allocation to preserve small samples for molecular and PD-L1 testing.
          • Which Molecularly Suitable Specimen Is Available?
            • Can Treatment Safely Await Complete Molecular Results?
              • Prefer Comprehensive Tissue DNA + RNA NGS and Essential IHC
                Broad panel testing reduces tissue consumption and sequential testing, while RNA analysis improves detection of fusions and splice alterations that may be missed by DNA-only assays.
                • Classify Treatment-Defining Drivers, Emerging Biomarkers, Co-Mutations, and Mutation, Fusion, Copy-Number, or Protein Expression
                  Current guidelines distinguish alterations with approved matched therapies from emerging, prognostic, resistance-associated, or nonactionable findings and link each alteration to the required assay type.
                  • Treatment-Defining Oncogenic Driver Identified?
                    • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                    • Is the Negative Result Reliable Given Testing Quality and Clinical Suspicion?
                      Reliability of a negative result depends on specimen tumor content, assay coverage, analyte type, quality-control metrics, and plasma shedding. Negative results with technical limitations or high clinical discordance warrant further evaluation.
                      • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                      • Complete Missing Biomarkers Without Redundant Sequential Testing
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Obtain Tissue or Better Specimen After Uninformative Plasma or Tissue Testing
                        Low-volume disease, organ-confined disease, low/undetectable ctDNA fraction, or otherwise low expected tumor shedding → plasma negative has reduced rule-out value.
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Add RNA or Orthogonal Testing for Fusion, Splicing, Copy-Number, or Coverage Gaps
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Review Pathology and QC When Results Conflict With Clinical Suspicion
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
              • Continue Tissue and Plasma NGS in Parallel; Use Driver-Compatible Interim Therapy
                • Classify Treatment-Defining Drivers, Emerging Biomarkers, Co-Mutations, and Mutation, Fusion, Copy-Number, or Protein Expression
                  Current guidelines distinguish alterations with approved matched therapies from emerging, prognostic, resistance-associated, or nonactionable findings and link each alteration to the required assay type.
                  • Treatment-Defining Oncogenic Driver Identified?
                    • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                    • Is the Negative Result Reliable Given Testing Quality and Clinical Suspicion?
                      Reliability of a negative result depends on specimen tumor content, assay coverage, analyte type, quality-control metrics, and plasma shedding. Negative results with technical limitations or high clinical discordance warrant further evaluation.
                      • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                      • Complete Missing Biomarkers Without Redundant Sequential Testing
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Obtain Tissue or Better Specimen After Uninformative Plasma or Tissue Testing
                        Low-volume disease, organ-confined disease, low/undetectable ctDNA fraction, or otherwise low expected tumor shedding → plasma negative has reduced rule-out value.
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Add RNA or Orthogonal Testing for Fusion, Splicing, Copy-Number, or Coverage Gaps
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                      • Review Pathology and QC When Results Conflict With Clinical Suspicion
                        • Reclassify Cause-Directed Additional Testing Results
                          • Treatment-Defining Oncogenic Driver Now Identified?
                            • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                            • Could an Actionable Driver Still Reasonably Have Been Missed?
                              • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                              • Continue Cause-Directed Molecular Investigation Before Final Handoff
                              • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
            • Rebiopsy, Then Prefer Comprehensive DNA + RNA NGS and Essential IHC
              • Classify Treatment-Defining Drivers, Emerging Biomarkers, Co-Mutations, and Mutation, Fusion, Copy-Number, or Protein Expression
                Current guidelines distinguish alterations with approved matched therapies from emerging, prognostic, resistance-associated, or nonactionable findings and link each alteration to the required assay type.
                • Treatment-Defining Oncogenic Driver Identified?
                  • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                  • Is the Negative Result Reliable Given Testing Quality and Clinical Suspicion?
                    Reliability of a negative result depends on specimen tumor content, assay coverage, analyte type, quality-control metrics, and plasma shedding. Negative results with technical limitations or high clinical discordance warrant further evaluation.
                    • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                    • Complete Missing Biomarkers Without Redundant Sequential Testing
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Obtain Tissue or Better Specimen After Uninformative Plasma or Tissue Testing
                      Low-volume disease, organ-confined disease, low/undetectable ctDNA fraction, or otherwise low expected tumor shedding → plasma negative has reduced rule-out value.
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Add RNA or Orthogonal Testing for Fusion, Splicing, Copy-Number, or Coverage Gaps
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Review Pathology and QC When Results Conflict With Clinical Suspicion
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
            • Order Plasma ctDNA NGS; Do Not Exclude a Driver From a Negative Result Alone
              Plasma ctDNA is useful when tissue is unavailable or results are urgently needed, but sensitivity depends on tumor shedding. A negative plasma result therefore requires tissue testing when feasible.
              • Classify Treatment-Defining Drivers, Emerging Biomarkers, Co-Mutations, and Mutation, Fusion, Copy-Number, or Protein Expression
                Current guidelines distinguish alterations with approved matched therapies from emerging, prognostic, resistance-associated, or nonactionable findings and link each alteration to the required assay type.
                • Treatment-Defining Oncogenic Driver Identified?
                  • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                  • Is the Negative Result Reliable Given Testing Quality and Clinical Suspicion?
                    Reliability of a negative result depends on specimen tumor content, assay coverage, analyte type, quality-control metrics, and plasma shedding. Negative results with technical limitations or high clinical discordance warrant further evaluation.
                    • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                    • Complete Missing Biomarkers Without Redundant Sequential Testing
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Obtain Tissue or Better Specimen After Uninformative Plasma or Tissue Testing
                      Low-volume disease, organ-confined disease, low/undetectable ctDNA fraction, or otherwise low expected tumor shedding → plasma negative has reduced rule-out value.
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Add RNA or Orthogonal Testing for Fusion, Splicing, Copy-Number, or Coverage Gaps
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
                    • Review Pathology and QC When Results Conflict With Clinical Suspicion
                      • Reclassify Cause-Directed Additional Testing Results
                        • Treatment-Defining Oncogenic Driver Now Identified?
                          • Handoff to Genomic-Specific NSCLC Treatment Algorithm
                          • Could an Actionable Driver Still Reasonably Have Been Missed?
                            • Handoff to Stage-Appropriate Non-Genomic NSCLC Treatment Algorithm
                            • Continue Cause-Directed Molecular Investigation Before Final Handoff
                            • Document Testing Limits; Enter Treatment Pathway While Molecular Testing Continues
tosprivacyReal-World Association Between Up-Front Next-Generation Sequencing and Overall Survival in Advanced Non–Small Cell Lung Cancer in the United StatesNon‐Small Cell Lung Cancer, Version 4.2026, NCCN Clinical Practice Guidelines in Oncology