What is the role of a comprehensive genomic panel in guiding targeted therapy decisions for a patient with cancer, particularly in cases of non-small cell lung cancer, breast cancer, and colorectal cancer?

Comprehensive Genomic Panel in Oncology

Comprehensive genomic profiling using next-generation sequencing (NGS) panels should be performed for all patients with advanced non-small cell lung cancer (NSCLC), and is strongly recommended for breast and colorectal cancer to identify actionable mutations that guide targeted therapy selection and improve survival outcomes.

Role in Non-Small Cell Lung Cancer

For advanced non-squamous NSCLC, comprehensive NGS testing is mandatory and should include both DNA and RNA-based sequencing to capture all therapeutically relevant alterations. 1

Essential DNA Targets

• EGFR mutations (complete exons 18-21 sequencing), KRAS G12C, BRAF V600E, HER2 exon 20 insertions, and MET alterations (both exon 14 skipping and amplifications) must be included as FDA-approved targeted therapies exist for these alterations 1
• TP53 comutations should be assessed as they predict lower efficacy of EGFR, ALK, and ROS1 tyrosine kinase inhibitors 1
• DNA-based NGS should cover PIK3CA and include copy number analysis capabilities 1

Essential RNA Targets

• RNA-based NGS is strongly preferred over DNA-based methods for fusion detection and must include ALK, ROS1, RET, NTRK1-3, and NRG1 fusions 1
• This approach prevents missing rare but highly actionable alterations (≤1% frequency) like RET and NTRK fusions, for which effective targeted therapies are available 2

Critical Implementation Points

• Avoid sequential single-gene testing as it depletes scarce tissue material and delays treatment decisions 1
• Turnaround time must allow results before first-line therapy initiation 1
• Panel sensitivity must be ≥1% variant allele frequency with validated bioinformatics pipelines 1
• At disease progression on targeted therapy, repeat molecular testing (re-biopsy or cell-free DNA) is essential to identify resistance mechanisms 1

Patient Selection in NSCLC

• All patients with advanced non-squamous NSCLC require comprehensive NGS testing 1
• Squamous cell carcinoma patients should NOT routinely undergo testing except in specific circumstances: age <50 years, never smokers, or former light smokers 1

Role in Breast Cancer

For breast cancer, germline multigene panel testing should include at minimum BRCA1, BRCA2, PALB2, TP53, CDH1, PTEN, and STK11 as these genes have high relative risk and are highly actionable. 2

Strongly Recommended Genes

• BRCA1 and BRCA2 are critical for PARP inhibitor eligibility and surgical decision-making 2
• PALB2, TP53, CDH1, PTEN, and STK11 represent high-penetrance genes with established management implications 2

Less Strongly Recommended Genes

• ATM, BARD1, CHEK2, RAD51C, and RAD51D have moderate relative risk but may impact therapy selection 2
• NF1 should be considered given increased breast cancer risk before age 50 in neurofibromatosis patients 2

Integration with Somatic Testing

• Patients meeting germline testing criteria should receive germline testing regardless of tumor testing results, as approximately 8-10% of germline pathogenic variants are missed on tumor testing 2
• When tumor testing identifies pathogenic variants in cancer susceptibility genes, germline confirmation testing must be offered 2

Role in Colorectal Cancer

For colorectal cancer, comprehensive germline panel testing should include Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM) and polyposis-associated genes (APC, MUTYH, NTHL1, POLD1, POLE, BMPR1A, SMAD4, STK11, TP53) as these directly impact surveillance, surgical planning, and immunotherapy eligibility. 2

Strongly Recommended Genes

• Lynch syndrome genes (MLH1, MSH2, MSH6, PMS2, EPCAM) are critical for identifying microsatellite instability-high tumors eligible for immune checkpoint inhibitors 2
• APC for familial adenomatous polyposis and MUTYH, NTHL1 for polyposis syndromes 2
• POLD1, POLE for polymerase proofreading-associated polyposis 2

Syndrome-Associated Genes

• BMPR1A and SMAD4 for juvenile polyposis syndrome 2
• STK11 for Peutz-Jeghers syndrome 2
• TP53 for Li-Fraumeni syndrome 2

Less Strongly Recommended Genes

• AXIN2, CHEK2, MBD4, GREM1, MSH3, PTEN, and RNF43 have moderate risk associations 2

Clinical Benefits Across Cancer Types

Real-world evidence demonstrates that comprehensive genomic profiling significantly improves actionable biomarker detection (32% vs 14% with small panels), increases matched therapy utilization, and extends overall survival. 3

Survival Impact

• In NSCLC patients receiving matched therapy after CGP, median overall survival was 34 months versus 14 months for unmatched therapy 3
• CGP testing itself was associated with reduced mortality risk (HR 0.80) independent of matched therapy receipt 3
• Actionable biomarker detection was associated with reduced mortality (HR 0.84) 3

Therapeutic Actionability

• 73.6% of chemotherapy-naïve patients with advanced gastrointestinal cancers had actionable alterations detected by CGP 4
• 62.9% had druggable genomic alterations, with colorectal cancer showing 80% detection rate 4
• Molecular tumor board recommendations for therapy were possible in 23.4% of patients 4

Practical Advantages

• CGP uses less specimen and shortens turnaround time when multiple biomarkers need testing compared to sequential single-gene approaches 5
• Median turnaround time of 19 days is achievable in real-world settings 4
• 83% of advanced cancer patients harbor potentially actionable genetic alterations when comprehensive testing is performed 6

Critical Implementation Considerations

Panel Selection Principles

• The minimal panel should include at least the more strongly recommended genes based on personal and family cancer history 2
• Broader panels may be ordered when potential benefits can be clearly identified, but clinicians must ensure potential harms are mitigated 2
• Given the prevalence and actionability of BRCA1/2 and Lynch syndrome genes, including these in any cancer patient's germline panel is reasonable 2

Family History Integration

• All patients should have family history taken and recorded including first-degree and second-degree biological relatives, cancer types, ages at diagnosis, and any prior germline testing results 2
• Family history is crucial for gene selection, result interpretation, and cascade testing in relatives 2
• Incomplete family history should not prevent testing, but the information gathering process itself is valuable 2

Avoiding Common Pitfalls

• Do not rely on tumor testing alone for germline assessment as 8-10% of germline variants are missed 2
• Larger panels increase risk of variants of uncertain significance (VUS) and potential misinterpretation leading to unnecessary interventions 2
• Ensure genetic expertise is available for result interpretation, especially as panel size increases 2
• When ordering broader panels, clearly identify potential benefits and have systems to mitigate harms from incidental findings 2

Timing Considerations

• For treatment decision-making requiring rapid results, a smaller panel may be tested initially with subsequent expansion 2
• CGP before first-line treatment increases likelihood of receiving matched therapy (OR 3.2) 3
• Results must be available to inform first-line therapy selection whenever possible 1

Distinction from Multi-Cancer Early Detection

Comprehensive genomic profiling for treatment guidance differs fundamentally from multi-cancer early detection tests, which are NOT currently recommended by ASCO or ESMO for routine use in asymptomatic populations. 7